WO2019011323A1 - 内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 - Google Patents
内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 Download PDFInfo
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- WO2019011323A1 WO2019011323A1 PCT/CN2018/095614 CN2018095614W WO2019011323A1 WO 2019011323 A1 WO2019011323 A1 WO 2019011323A1 CN 2018095614 W CN2018095614 W CN 2018095614W WO 2019011323 A1 WO2019011323 A1 WO 2019011323A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- 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
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
Definitions
- the present invention belongs to the field of medicine, and in particular, the present invention relates to an endocyclic thioxamamide-arylamide compound and its use as a medicament for the treatment of hepatitis B.
- Hepatitis B virus is an enveloped, partially double-stranded DNA (dsDNA), hepatovirus DNA family (Hepadnaviridae) virus. Its genome contains four overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode three envelope proteins), and the X gene.
- the partially double-stranded DNA genome is transformed into a covalently closed circular DNA (cccDNA) in the host cell nucleus (open loop DNA, rcDNA) and the viral mRNA is transcribed.
- the pre-genomic RNA which is also encoded by the core protein and Pol, is used as a template for reverse transcription, which regenerates this portion of the dsDNA genome (rcDNA) in the nucleocapsid.
- HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected about 2 billion people worldwide, and about 350 million of them have developed chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a high increased risk of development of cirrhosis and liver cancer.
- the spread of hepatitis B virus is derived from exposure to infectious blood or body fluids, while viral DNA is detected in the saliva, tears, and urine of chronic carriers with high-priced DNA in serum.
- heteroaryldihydropyrimidines have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78) .
- a sulfamoyl-arylamide involving anti-HBV activity is also disclosed in WO 2013/006394 (published on Jan. 10, 2013) and WO 2013/096744 (published on June 27, 2013).
- HBV inhibitor having advantages such as high potency, lower toxicity, and the like.
- a compound of the formula L or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
- n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- a substituted or unsubstituted five- or six-membered ring wherein the five- or six-membered ring optionally contains one or more heteroatoms selected from the group consisting of: O, S, N or P;
- Substituted means that the hydrogen atom on the group is substituted by one or more substituents selected from the group consisting of C1-C3 alkyl (especially methyl), C3-C4 cycloalkyl, cyano, or halogen;
- X is -CR a R b -;
- Y is a substituted or unsubstituted C1-C7 alkylene group, or a substituted or unsubstituted C2-C7 alkenylene group, wherein the substituent is selected from the group consisting of a C1-C4 alkyl group and a hydroxyl group;
- Z is selected from the group consisting of O, S, N or P, or Z is a C-C single bond (ie Z is none);
- W is NRc or none
- R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkane a substituted or unsubstituted C1-C4 alkoxy group; wherein said substituent means that the hydrogen atom on the group is substituted by one or more substituents selected from the group consisting of halogen, C1-C4 alkyl (eg difluoromethyl, difluoroethyl, monofluoromethyl, trifluoromethyl, trifluoromethoxy);
- substituted means substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C6 alkyl, halo. C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, a group selected from the group consisting of a carboxyl group, unsubstituted or substituted with one or more substituents selected from the group consisting of C6-C10 aryl, halogenated C6-C10 aryl, having 1-3 selected from N a 5-10 membered heteroaryl group of a hetero atom of S and O, a halogenated 5-10 membered heteroaryl group having 1 to 3 hetero atoms selected from N, S and O; said substituents selected from the group consisting of halogen
- said Y is selected from the group consisting of C1-C4 alkylene groups, or substituted or unsubstituted C2-C4 alkenylene groups.
- the Ra and Rb are each independently a substituted or unsubstituted C 1 -C 8 alkyl group, a substituted or unsubstituted C 1 -C 8 alkoxy group; wherein the substitution The group is selected from the group consisting of halogen, hydroxyl, and cyano.
- the compound has a structure selected from the group consisting of L-1, L-2, L-3, and L-4:
- n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10;
- the A ring, the B ring, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined in the first aspect of the invention.
- the Ra and Rb are each independently a substituted or unsubstituted C 1 -C 8 alkyl group, a substituted or unsubstituted C 1 -C 8 alkoxy group; wherein the substitution The group is selected from the group consisting of halogen, hydroxyl, and cyano.
- the compound of formula I has the structure shown in formula II below:
- X 2 is -NR-
- R is H or a C1-C4 alkyl group.
- the X 2 is -NCH 3 -.
- the compound of formula I has the structure:
- the compound of formula I has the structure of formula IV-1 or formula IV-2:
- n 1
- Ra is selected from the group consisting of substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C1-C6 alkoxy Base-alkyl group;
- Rb is H.
- the Ra is selected from the group consisting of a substituted or unsubstituted C 1 -C 8 alkyl group; wherein the substituent refers to one or more hydrogen atoms on the group selected from the group consisting of Substituent substituents of the group: C1-C4 alkoxy, hydroxy, unsubstituted or C6-C10 aryl substituted by one or more substituents selected from the group consisting of halogen, C1-C6 alkoxy.
- the B ring is a benzene ring or a pyridine ring.
- the A ring is a pyrrole ring.
- said R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, halogen, and cyano.
- said R 5 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl.
- the R 6 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl.
- the compound is a compound 10a1-60y2 as described in Table 1, wherein Peak 1 and Peak 2 refer to the peak order of the enantiomers in reverse phase HPLC, and Peak 1 is The enantiomer of the first peak, Peak2 is the enantiomer of the post-peak.
- HPLC is reversed phase HPLC, wherein peak 1 refers to a compound of higher polarity and peak 2 refers to a compound of less polarity.
- a second aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof a preparation method, the method comprising the steps of:
- R is a leaving group, and the remaining groups are as defined in the first aspect of the invention.
- the compound of formula L is a compound of formula VII-1, and the method comprises the steps of:
- the compound of formula L is a compound of formula II-2, and the method comprises the steps of:
- each group is as defined above.
- the compound of formula L is a compound of formula VII-3, and the method comprises the steps of:
- each group is as defined above.
- the compound of formula L is a compound of formula II-4, and the method comprises the steps of:
- each group is as defined above.
- a fourth aspect of the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof , hydrate or solvate; (2) a pharmaceutically acceptable carrier.
- the invention provides a hepatitis B virus inhibitor, characterized in that the inhibitor comprises the compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, Or a pharmaceutically acceptable salt, hydrate or solvate thereof.
- a method of preventing and/or treating hepatitis B comprising the step of administering a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, to a patient in need thereof A construct, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the fourth aspect of the invention.
- a method for inhibiting replication of hepatitis B virus comprising the steps of: the compound of the first aspect of the invention, or a stereoisomer or tautomer thereof; Or a pharmaceutically acceptable salt, hydrate or solvate thereof, in contact with hepatitis B virus, thereby inhibiting hepatitis B virus replication.
- the inventors have conducted extensive and intensive research and found a novel class of compounds having excellent therapeutic effects on hepatitis B. On this basis, the inventors completed the present invention.
- alkyl as used herein includes a straight or branched alkyl group.
- C 1 -C 8 alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.
- alkenyl as used herein, includes a straight or branched alkenyl group.
- C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.
- alkynyl includes a straight or branched alkynyl group.
- C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
- C 3 -C 10 cycloalkyl means a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.
- C 1 -C 8 alkylamino refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamine and the like.
- C 1 -C 8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.
- the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" means having from 3 to 10 atoms and wherein 1-3 of the atoms are A saturated or partially saturated cyclic group selected from the group consisting of heteroatoms of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
- C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.
- the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from A cyclic aromatic group of the following group of heteroatoms of N, S and O. It may be a single ring or a fused ring.
- Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
- the groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl
- halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo” means substituted with an atom selected from the group consisting of F, Cl, Br, and I.
- the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond.
- a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.
- tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
- proton tautomers ie, proton shifts
- proton transfer such as 1H-carbazole and 2H-carbazole.
- Valence tautomers include interconversion through some bonding electron recombination.
- solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
- hydrate refers to a complex formed by the coordination of a compound of the invention with water.
- a compound of the invention refers to a compound of formula L, and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula L:
- pharmaceutically acceptable salt refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
- Pharmaceutically acceptable salts include inorganic and organic salts.
- a preferred class of salts are the salts of the compounds of the invention with acids.
- Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
- mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
- Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
- the A ring, the B ring, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently a group corresponding to each compound in Table 1.
- the pharmaceutical composition wherein the compound is the main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) hepatitis B virus infection or for preventing and/or treating (stabilizing, alleviating or curing) a hepatitis B virus-related disease ( For example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer).
- hepatitis B progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer.
- compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier.
- safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound.
- pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
- magnesium stearate magnesium stearate
- calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
- the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
- the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
- inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
- compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
- the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
- suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
- compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
- Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
- other pharmaceutically acceptable compounds e.g., anti-HBV agents.
- the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
- one or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound e.g, an anti-HBV agent
- a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
- the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
- specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
- the compound of the present invention has a novel structure and an excellent anti-hepatitis B virus infection effect.
- the existing inner ring sulfoxide amide-aryl amide compound is modified into an inner ring thioxamamide-aryl amide compound, so that it can better interfere with the assembly process of the capsid protein. Thereby, the activity or expression amount of HBV is suppressed.
- the compound of the present invention is very low in toxicity to normal cells, and thus can be applied to a subject in a large dose range.
- the compound of the present invention has good drug-forming properties, and the compound of the present invention has better solubility than the existing compounds, and exhibits good bioavailability in vivo experiments, and bioavailability of some compounds.
- the compounds of the present invention are readily formed into pharmaceutically acceptable salts, thereby facilitating further formulation.
- a compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of a hepatitis B virus-related disease (for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis) And necrosis, terminal liver disease, ethyl liver cancer).
- a hepatitis B virus-related disease for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis
- necrosis terminal liver disease, ethyl liver cancer
- reaction system was cooled to 0 °, sodium hydride (180 mg) was added to DMF, and then stirred for 10 min.
- TBDPSCl 2.7 g
- 7 1.1 g
- DMF solution were added dropwise to the reaction system at 0 °C, room temperature. Reaction 1.5h.
- the reaction liquid was added to a mixed solution of 1N HCl and saturated ammonium chloride, ethyl acetate (3*50 mL), dried over anhydrous sodium sulfate, and the organic phase was dried. 497).
- Example 72 The following 20, 40 series of compounds were synthesized according to the synthesis method of Example 72 or Example 74:
- Example 167 According to the synthesis method of Example 167, the following 50 series of compounds were synthesized:
- Example 186 According to the synthesis method of Example 186, the following 60 series of compounds were synthesized:
- Example 74 and Example 167 According to the synthetic procedure of Example 74 and Example 167, the compound of the following list can be obtained by substituting a pyrazole compound for the azole compound.
- [C150Bo] (A280- x 1300M -1 ) / 60,900M -1 ;
- Fluorescent labeling efficiency /[C150Bo]
- [C150Bo] represents the concentration of a fluorescently labeled protein
- A504 represents an absorbance value of a wavelength of 504 nM
- A280 represents an absorption value of a wavelength of 280 nM
- M -1 represents the reciprocal of the molar concentration.
- the mother liquor of the compound was diluted to 6 mM with DMSO, diluted to 600 ⁇ M with 50 mM HEPES, and then further diluted 8 times with 10% DMSO/50 mM HEPES.
- C150Bo was diluted to 2 ⁇ M with 50 mM HEPES. 37.5 ⁇ L of C150Bo and 2.5 ⁇ L of each concentration of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes. 10 ⁇ l of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM.
- Control wells were assembled with 0% protein, 10 ⁇ L of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.
- Control wells were assembled with 100% protein and 10 ⁇ L of 5 M NaCl/50 mM HEPES was added with a final concentration of 1 M NaCl.
- the final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 ⁇ M, and the final concentration of C150Bo was 1.5 ⁇ M. Incubate for 1 hour at room temperature. The fluorescence signal (excitation light 485 nm; emission light 535 nm) was measured.
- % protein assembly [1- (sample fluorescence value - 1M NaCl fluorescence value) / (0M NaCl fluorescence value - 1M NaCl fluorescence value)] ⁇ 100.
- the IC 50 value is calculated by the prism software and the equation is as follows:
- X represents the logarithm of the concentration
- Y represents the effect value
- Y is fitted from the bottom to the top with an S-shape
- Top indicates that Top represents the top of the curve
- HillSlope represents the absolute value of the maximum slope of the curve.
- HepG2.2.15 cells (4 x 10 4 cells/well) were plated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.
- the supernatant in the culture well was collected for extracting HBV DNA from the supernatant, and qPCR was used to detect the HBV DNA content in the supernatant of HepG2.2.15.
- the culture medium and the Cell-titer Glo reagent were added to the culture well, and the chemiluminescence value of each well was detected by a microplate reader.
- the activity calculation formula is as follows:
- X represents the logarithm of the concentration
- Y represents the effect value
- Y is fitted from the bottom to the top with an S-shape
- HillSlope represents the absolute value of the maximum slope of the curve.
- test compounds The cytotoxicity of the test compounds was tested using HepG2 cells, and these cells were incubated for 4 days in the presence of the test compound. Cell rejuvenation was assessed using the resazurin assay.
- the compound of the present invention has good anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and has low cytotoxicity.
- +++ means IC 50 ⁇ 1 ⁇ M
- +++ means EC 50 0.1 ⁇ 100nM
- the compounds of the present application have excellent anti-HBV activity.
- mice Eighteen male C57 mice (9 intravenously administered, 9 orally administered) were randomly divided into body weights, and the test compounds were administered at 2 mg/kg (intravenous) and 50 mg/kg (administered orally). Three mice were taken at each time point in each group for a total of 8 time points (5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours).
- the oral bioavailability F is calculated as AUC po /Dose po /AUC iv /Dose iv .
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Abstract
一种内环硫脒酰胺-芳基酰胺类化合物和包含上述化合物的药物组合物及其化合物或药物组合物治疗乙型肝炎的用途。具体地,其为一种可作HBV复制抑制剂,其具有化学式(L)所示结构的化合物或其立体异构体或互变异构体,或其药学上可接受的盐,水合物或溶剂化物。
Description
本发明属于医药领域,具体地,本发明涉及一种内环硫脒酰胺-芳基酰胺类化合物和其作为药物用于治疗乙型肝炎的用途。
乙型肝炎病毒(HBV)是一种有包膜的、部分双链DNA(dsDNA)的、嗜肝病毒DNA家族(肝病毒科(Hepadnaviridae))的病毒。它的基因组包含4个重叠阅读框:前核/核基因,聚合酶基因,UM和S基因(它们编码三个包膜蛋白质),以及X基因。在感染前时,该部分双链DNA基因组在宿主细胞核中(开环DNA,rcDNA)转变为共价闭合环状DNA(cccDNA)并且该病毒mRNA进行转录。一旦被壳体化,该前基因组RNA(pgRNA)(其还为核心蛋白和Pol编码)作为模板用于逆转录,这种逆转录在核衣壳中再生该部分dsDNA基因组(rcDNA)。
HBV在亚洲和非洲的部分地区造成了流行病,并且它在中国是地方性的。HBV已经在全球感染了大约20亿人,其中大约3.5亿人发展成了慢性传染病。该病毒造成了乙型肝炎疾病并且慢性传染病与肝硬化和肝癌的发展的高增加风险相关联。
乙型肝炎病毒的传播来源于暴露于传染性的血液或体液,同时在血清中具有高效价DNA的慢性携带者的唾液、泪液以及尿液中检测到了病毒DNA。
虽然目前存在一种有效的并且具有良好耐受性的疫苗,但是直接治疗的选择目前还限于干扰素以及以下的抗病毒药;替诺福韦、拉米夫定、阿德福韦、恩替卡韦以及替比夫定。
此外,杂芳基二氢嘧啶(HAPs)在组织培养以及动物模型中被鉴别作为一类HBV抑制剂(韦伯(Weber)等人,《抗病毒研究》(Antiviral Res.)54:69-78)。
WO 2013/006394(公开于2013年1月10日)和WO 2013/096744(公开于2013年6月27日)还公开了涉及抗HBV活性的氨磺酰基-芳基酰胺。
然而,在这些直接的HBV抗病毒药中会遇到的是毒性、致突变性、缺乏选择性、疗效差、生物利用度差以及合成困难等问题。
因此,为了克服以上缺陷,需要开发具有如效价高、毒性更低等优点的HBV抑制剂。
发明内容
本发明的目的是提供一类可用作HBV抑制剂的结构新颖的化合物。
本发明第一方面,提供了一种如式L所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物,
其中,n为1、2、3、4、5、6、7、8、9、或10;
为取代或未取代的五元或六元环,其中,所述的五元或六元环任选地含有一个或多个选自下组的杂原子:O、S、N或P;所述的取代指基团上的氢原子被一个或多个选自下组的取代基取代:C1-C3烷基(尤其是甲基)、C3-C4环烷基、氰基,或卤素;
X为-CR
aR
b-;
Y为取代或未取代的C1-C7亚烷基,或取代或未取代的C2-C7亚烯基,其中,所述的取代基选自下组:C1-C4的烷基、羟基;
Z选自下组:O、S、N或P,或Z为C-C单键(即Z为无);
W为NRc或无;
R
1,R
2,R
3和R
4各自独立的地选自下组:H、卤素、氰基、取代或未取代的C3-C4的环烷基,取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基;其中,所述的取代指基团上的氢原子被一个或多个选自下组的取代基取代:卤素、C1-C4的烷基(如二氟甲基、二氟乙基、单氟甲基、三氟甲基、三氟甲氧基);
R
5、R
6各自独立地选自下组:H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C
1-C
8烷基、取代或未取代的C
1-C
8烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
1-C
8烷胺基、取代或未取代的C
1-C
8烷氧基、取代或未取代的C
3-C
10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C
6-C
10芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
R
a、R
b各自独立地为H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C
1-C
8烷基、取代或未取代的C
1-C
8烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
1-C
8烷胺基、取代或未取代的C
1-C
8烷氧基、取代或未取代的C1-C6烷氧基-烷基、取代或未取代的C
3-C
10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C
6-C
10芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
Rc为H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C
1-C
8烷基、取代或未取代的C
1-C
8烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取 代或未取代的C
1-C
8烷胺基、取代或未取代的C
1-C
8烷氧基、取代或未取代的C
3-C
10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C
6-C
10芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个选自下组的取代基取代的选自下组的基团:C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基;所述的取代基选自下组:卤素、C1-C6烷氧基。
在另一优选例中,所述的Y选自下组:C1-C4亚烷基,或取代或未取代的C2-C4亚烯基。
在另一优选例中,所述的Ra、Rb各自独立地为取代或未取代的C
1-C
8烷基、取代或未取代的C
1-C
8烷氧基;其中,所述的取代基选自下组:卤素、羟基、氰基。
在另一优选例中,所述化合物具有选自下式L-1、L-2、L-3、L-4所示的结构:
各式中,n为1、2、3、4、5、6、7、8、9、10;
A环、B环、X、R
1、R
2、R
3、R
4、R
5、R
6的定义如本发明第一方面所述。
在另一优选例中,所述的Ra、Rb各自独立地为取代或未取代的C
1-C
8烷基、取代或未取代的C
1-C
8烷氧基;其中,所述的取代基选自下组:卤素、羟基、氰基。
在另一优选例中,所述的式I化合物具有如下式II所示的结构:
其中X
1为-CR=或-N=,X
2为-NR-;且所述的R为H或C1-C4的烷基。
在另一优选例中,所述的X
2为-NCH
3-。
在另一优选例中,所述的式I化合物具有以下结构:
在另一优选例中,所述的式I化合物具有如下式IV-1或式IV-2所示的结构:
在另一优选例中,所述的n为1。
在另一优选例中,Ra选自下组:取代或未取代的C
1-C
8烷基、取代或未取代的C
1-C
8烷氧基、取代或未取代的C1-C6烷氧基-烷基;
Rb为H。
在另一优选例中,所述的Ra选自下组:取代或未取代的C
1-C
8烷基;其中,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:C1-C4烷氧基、羟基、未 取代或被一个或多个选自下组的取代基取代的C6-C10芳基:卤素、C1-C6烷氧基。
在另一优选例中,所述的B环为苯环或吡啶环。
在另一优选例中,所述的A环为吡咯环。
在另一优选例中,所述的R
1,R
2,R
3和R
4各自独立地选自下组:H、卤素、氰基。
在另一优选例中,所述的R
5选自下组:H、取代或未取代的C
1-C
8烷基、取代或未取代的C
3-C
10环烷基。
在另一优选例中,所述的R
6选自下组:H、取代或未取代的C
1-C
8烷基、取代或未取代的C
3-C
10环烷基。
在另一优选例中,所述的化合物为如表1中所述的化合物10a1-60y2,其中,Peak 1和Peak 2指对映异构体在反相HPLC中的出峰顺序,Peak 1为先出峰的对映异构体,Peak2为后出峰的对映异构体。
在另一优选例中,上表中,HPLC为反相HPLC,其中peak1指极性较大的化合物,peak2指极性较小的化合物。
本发明的第二方面,提供了一种如本发明第一方面所述的化合物、或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物的制备方法,所述方法包括步骤:
其中,所述的R为离去基团,其余各基团的定义如本发明第一方面中所述。
在另一优选例中,所示式L化合物为式VII-1所示的化合物,所述的方法包括步骤:
其中,Rg选自下组:H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C
1-C
8烷基、取代或未取代的C
1-C
8烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
1-C
8烷胺基、取代或未取代的C
1-C
8烷氧基、取代或未取代的C
3-C
10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C
6-C
10芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
各个基团的定义如上文中所述。
在另一优选例中,所示式L化合物为式II-2所示的化合物,所述方法包括步骤:
各式中,各个基团的定义如上文中所述。
在另一优选例中,所示式L化合物为式VII-3所示的化合物,所述方法包括步骤:
各式中,各个基团的定义如上文中所述。
在另一优选例中,所示式L化合物为式II-4所示的化合物,所述方法包括步骤:
各式中,各个基团的定义如上文中所述。
本发明的第三方面,提供了选自下组的化合物:
各式中,R
g选自下组:H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C
1-C
8烷基、取代或未取代的C
1-C
8烷基、取代或未取代的C
2-C
6烯基、取代或未取代的C
2-C
6炔基、取代或未取代的C
1-C
8烷胺基、取代或未取代的C
1-C
8烷氧基、取代或未取代的C
3-C
10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C
6-C
10芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
各个基团的定义如本发明第一方面所述。
本发明的第四方面,提供了一种药物组合物,包含(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物;(2)药学上可接受的载体。
本发明的第五方面,提供了一种如本发明第一方面所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物或如本发明第四方面所述的药物组合物的用途,用于制备预防和/或治疗乙型肝炎病毒感染的药物。
本发明的第六方面,提供了一种乙型肝炎病毒抑制剂,其特征在于,所述抑制剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
本发明的第七方面,提供了一种预防和/或治疗乙型肝炎的方法,包括步骤:向所需患者施用本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或本发明第四方面所述的药物组合物。
本发明的第八方面,提供了一种抑制乙型肝炎病毒复制的方法,其特征在于,包括步骤:将本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物,与乙型肝炎病毒接触,从而抑制乙型肝炎病毒复制。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明人经过广泛而深入的研究,发现了一类对乙型肝炎具有优异的治疗效果的新型化合物。在此基础上,发明人完成了本发明。
定义
如本文所用,术语“烷基”包括直链或支链的烷基。例如C
1-C
8烷基表示具有1-8个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C
2-C
6烯基指具有2-6个碳原子的直链或支链的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C
2-C
6炔基是指具有2-6个碳原子的直链或支链的炔基,例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“C
3-C
10环烷基”指具有3-10个碳原子的环烷基。其可以是单环,例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环或螺环形式。
如本文所用,术语“C
1-C
8烷胺基”是指被C
1-C
8烷基所取代的胺基,可以是单取代或双取代的;例如,甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。
如本文所用,术语“C
1-C
8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基;例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环,也可以是双环形式,例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用,术语“C
6-C
10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C
1-C
6烷基-胺基、C
1-C
6烷基、C
2-C
6烯基、C
2-C
6炔基、C
1-C
6烷氧基、卤代C
1-C
6烷基、卤代C
2-C
6烯基、卤代C
2-C
6炔基、 卤代C
1-C
6烷氧基、烯丙基、苄基、C
6-C
12芳基、C
1-C
6烷氧基-C
1-C
6烷基、C
1-C
6烷氧基-羰基、苯氧羰基、C
2-C
6炔基-羰基、C
2-C
6烯基-羰基、C
3-C
6环烷基-羰基、C
1-C
6烷基-磺酰基等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用,术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用,术语“水合物”是指本发明化合物与水进行配位形成的配合物。
活性成分
如本文所用,“本发明化合物”指式L所示的化合物,并且还包括及式L化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物:
如本文所用,“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
在另一优选例中,所述的A环、B环、R
1、R
2、R
3、R
4、R
5、R
6各自独立地为表1中各个化合物所对应的基团。
优选的本发明化合物如表1所示:
表1
药物组合物和施用方法
由于本发明化合物具有优异的乙型肝炎病毒(HBV)的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)乙型肝炎病毒感染或用于预防和/或治疗(稳定、减轻或治愈)乙型肝炎病毒相关疾病(例如,乙型肝炎、进展性肝纤维化、导致肝硬化的炎症和坏死、末期肝病、乙基肝癌)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放 可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物(例如抗-HBV剂)联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的化合物(例如抗-HBV剂)。该其他药学上可接受的化合物(例如抗-HBV剂)中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗HBV感染或HBV相关疾病。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
(1)本发明的化合物结构新颖且具有优异的抗乙肝病毒感染的作用。本申请中,将现有的内环亚砜酰胺-芳基酰胺类化合物改造为内环硫脒酰胺-芳基酰胺类化合物,使其能够更好地起到干扰衣壳蛋白组装过程的作用,从而抑制HBV的活性或表达量。
(2)本发明的化合物对正常细胞的毒性非常低,因而可以在较大的剂量范围内应用于治疗对象。
(3)本发明化合物具有良好的成药性,相较于现有化合物而言,本发明化合物具有更好的溶解度,且在体内实验之中表现出良好的生物利用度,部分化合物的生物利用度达到或超过70%,除此之外,相较于现有化合物,本发明的化合物极易制成药学上可接受的盐,因而有助于进一步形成制剂。
(4)本发明化合物以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗乙型肝炎病毒相关疾病(例如,乙型肝炎、进展性肝纤维化、导致肝硬化的炎症和坏死、末期肝病、乙基肝癌)。
下面结合具体实施,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。本发明实施例中所用原料或仪器,若非特别说明,均市售可得。
下面为10类化合物的合成:
实施例1:化合物10a的合成
步骤1:化合物2的合成
将化合物1(10g)溶于二氯甲烷(40mL)中,室温下将氨水(30mL)滴加入反应体系,室温,反应5h,抽滤,滤饼用水(5mL)洗涤,得2淡黄色固体5g,MS(M+1=267)。
步骤2:化合物3的合成
将底物2(5g)溶于DMF(10mL),0度下将氢化钠(1.5g)加入反应体系,搅拌15min然后将TBDPSCl加入反应体系,反应18h,将反应体系倒入冰水中,乙酸乙酯(3*30mL)萃取,有机相干燥、旋干,粗品柱层析(正庚烷:乙酸乙酯=1:4),得产物3(3g)。MS(M+1=505)。
步骤3:化合物4的合成
将PPh3Cl2的氯仿溶液(80mL)冷至0度,然后将三乙胺(7mL),搅拌10min后0度下加入化合物3,搅拌20min后,将2-异丙基-3-丙烯胺加入反应体系,室温反应18h,向反应体系中加水(20mL),乙酸乙酯(3*25mL)萃取,有机相干燥、旋干,粗品柱层析(正庚烷:乙酸乙酯=1:5),得产物4(1.9g)。MS(M+1=586)。
步骤4:化合物5的合成
将化合物4(1.8g),四三苯基膦钯(100mg),乙烯基硼酸酯(900g),碳酸铯(2.7g),溶于DMF(410mL)中,氮气保护下,100度反应15h,用水溶液淬灭反应,乙酸乙酯萃取,有机相干燥、旋干,所得粗品柱层析(正庚烷:乙酸乙酯=1:5)得化合物5(1.0g)。MS(M+1=340)。
步骤5:化合物6的合成
将化合物5(1.0g)溶于二氯甲烷(500ml)中,然后将詹氏催化剂(0.1g)加入反应体系,搅拌过夜,将反应液旋干,粗品柱柱层析(正庚烷:乙酸乙酯=1:3)得化合物6,TLC显示的下点6-1(0.22g),TLC显示的上点6-2(0.27g)MS(M+1=312)。
步骤6:化合物10a1的合成
将化合物6-1(30mg)和4-氟-3-氰基苯胺(20mg)溶于四氢呋喃(5mL)中,降温至0度,然后将NaHMDS(0.2mL)加入反应体系,室温搅拌反应16h,将水加入反应体系,乙酸乙酯(3*15mL)萃取,有机相用无水硫酸钠干燥,旋干,粗品经柱层析(正庚烷:乙酸乙酯=1:3)目标产物10a1(11mg)。
1H NMR(400MHz,DMSO-d
6)δ10.78(s,1H),7.89–7.83(m,1H),7.71(s,1H),7.44(qd,J=4.7,4.2,2.5Hz,2H),6.54(dd,J=12.4,2.7Hz,1H),5.75(dd,J=12.4,2.8Hz,1H),4.0(dq,J=7.8,2.6Hz,1H),3.74(s,3H),1.97-1.89(m,1H),0.98(dd,J=12.6,6.7Hz,6H).MS(M+1=395)。
实施例2:化合物10a2的合成
根据实施例1的步骤6,只需用化合物6-2代替化合物6-1,其他条件不变,经柱层析(正庚烷:乙酸乙酯=1:1)目标产物10a2(8mg)。
1H NMR(400MHz,DMSO-d
6)δ10.69(s,1H),7.89–7.83(m,1H),7.51(s,1H),7.44(qd,J=4.7,4.2,2.5Hz,2H),6.53(dd,J=12.4,2.7Hz,1H),5.72(dd,J=12.4,2.8Hz,1H),3.87(dq,J=7.8,2.6Hz,1H),3.72(s,3H),
1.91-1.85(m,1H),0.96(dd,J=12.6,6.7Hz,6H).MS(M+1=395)。
实施例3:化合物10b1的合成
步骤1:化合物7的合成
将2(2.5g),乙烯基硼酸酯(1.5g),碳酸钠(3.5g),醋酸钯(120mg)和Xphos(500mg)溶于DMF中,氮气保护下,将反应体系至于100度油浴下,反应6h,将水(50mL)加入反应体系,乙酸乙酯(3*60mL)萃取,无水硫酸钠干燥,旋干,柱层析得黄色固体1.2g。MS(M+1=259)。
步骤2:化合物8的合成
将反应体系降温至0度,氢化钠(180mg)加入到DMF中,然后搅拌10min,将TBDPSCl(2.7g)和7(1.1g)的DMF溶液,在0度下,滴加入反应体系中,室温反应1.5h。将反应液滴加入1NHCl和饱和氯化铵的混合溶液中,乙酸乙酯(3*50mL),无水硫酸钠干燥,有机相旋干,柱层析得白色固体800mg,MS(M+1=497)。
1H NMR(400MHz,DMSO-d
6)δ10.78(s,1H),7.62–7.59(m,1H),7.45–7.41(m,1H),7.33–7.29(m,3H),7.13(qd,J=4.7,4.2,2.5Hz,2H),6.16(dd,J=12.4,2.7Hz,1H),5.58(dd,J=12.4,2.8Hz,1H),5.09(s,1H),4.35-4.40(m,2),3.56(s,3H),1.45-1.40(m,3),1.04(s,9H).
步骤3:化合物11的合成
将PPh
3Cl
2的混合液降温至0度,然后向反应体系中滴加三乙胺(3mL)滴加完毕后,0度反应10min中,然后再想体系内一次性加入固体8(500mg),0度下搅拌20min,最后将异丙基烯丙基胺(200mg)的氯仿溶液加入反应体系,室温反应18h,将硅胶直接加入反应体系,旋干后柱层析得浅黄色油状物650mg。MS(M+1=578)
1H NMR(400MHz,DMSO-d
6)δ7.81–7.73(m,4H),7.38-7.32(m,7H),7.06–6.91(m,2H),6.01-5.89(m,1H),5.48-5.33(m,2H),4.92-4.70(m,2H),4.36-4.30(m,2H),3.79(s,1.55H),3.76(s,1.36H),3.50-3.41(m,1H),1.71-1.66(m,0.5H),1.56-1.51(m,0.5H),1.40-1.35(m,3),1.14(s,4.2H),1.12(s,4.5H),0.76-0.73(m,3H),0.68-0.64(m,3H).
步骤4:化合物12的合成
将化合物11(650mg)溶于1,2二氯乙烷中,然后zhan1B加入反应体系,然后再氮气保护下,将体系温度升至70度下搅拌24h,将硅胶直接加入反应体系,旋干后柱层析得浅黄色油状物12:TLC显示的下点12-1(0.22g),TLC显示的上点12-2(0.27g)MS(M+1=550)。
1H NMR(400MHz,DMSO-d
6)δ7.81–7.74(m,5H),7.40-7.37(m,7H),7.28-7.21(m,1H),6.01-5.89(m,1H),6.99(s,1H),5.77-5.73(m,1H),4.42-4.35(m,2H),4.15-4.11(m,1H),3.80(s,3H),1.91-1.86(m,1H),1.43-1.39(m,3),1.14(s,9H),0.87-0.78(m,6H).
步骤5:化合物13的合成
将12-1(90mg)(TLC显示的下点)和3,4-二氟苯胺(43mg)溶于THF(8mL)中,然后将体系温度降至0度,将6当量的NaHMDS加入反应体系反应体系,0度反应1h,将水(20mL)加入反应体系,乙酸乙酯(3*30mL)萃取,无水硫酸钠干燥,旋干,柱层析的黄色油状物80mg,MS(M+1=640)。
步骤6:化合物10b1的合成
将13-1(40mg)(TLC显示的下点)溶于THF(3mL)中,然后将120当量的3HF.TEA滴加入反应体系,室温下反应3天,制备板分离冷冻干燥后得白色固体10b1(4.5mg)。
1H NMR(400MHz,DMSO-d
6)δ10.90(s,1H),8.18(dd,J=5.8,2.7Hz,1H),7.99(ddd,J=9.2,4.8,2.7Hz,1H),7.78–7.70(m,2H),7.57(d,J=10.3Hz,1H),6.57(dd,J=12.4,2.7Hz,1H),5.77(dd,J=12.4,2.8Hz,1H),4.07(ddt,J=10.6,5.4,2.7Hz,1H),3.76(s,3H),1.92(tq,J=12.1,6.7,5.6Hz,1H),0.99(dd,J=12.0,6.7Hz,6H).Ms(ESI)m/z=402(M+1)
实施例4:化合物10b2的合成
根据实施例3的步骤6,只需用化合物13-2(TLC显示的上点)代替化合物13-1(TLC显示的下点),其他条件不变,经柱层析(正庚烷:乙酸乙酯=1:1)目标产物10b2(8mg)。
1H NMR(400MHz,DMSO-d
6)δ10.89(s,1H),8.20(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.2,4.8,2.7Hz,1H),7.90–7.88(m,2H),7.56(d,J=10.3Hz,1H),6.65(dd,J=12.4,2.7Hz,1H),5.91(dd,J=12.4,2.8Hz,1H),3.80(s,3H),3.69-3.63(m,1H),1.95(tq,J=12.1,6.7,5.6Hz,1H),0.99(dd,J=12.0,6.7Hz,6H).Ms(ESI)m/z=402(M+1)
根据实施例3的合成方法又合成了如下10,30类系列化合物:
下面为20类化合物的合成:
实施例72:化合物20a1的合成
步骤1
将化合物10a1(20mg)溶于甲醇(5mL),然后将钯碳(5mg)加入反应体系,氢气保护下室温反应6h,粗品经柱层析(正庚烷:乙酸乙酯=1:3)目标产物20a1(11mg)。
1H NMR(400MHz,DMSO-d
6)δ10.56(s,1H),7.88–7.83(m,1H),7.63(s,2H),7.46–7.42(m,1H), 7.21–6.96(m,1H),3.72(s,3H),3.12–3.09(m,1H),3.00(dd,J=15.0,6.7Hz,1H),2.89–2.78(m,1H),1.89-1.85(m,1H),1.69-1.50(m,1H),1.43(q,J=12.0Hz,1H),0.92(dd,J=6.8,3.5Hz,6H).MS(M+1=397)。
实施例73:化合物20a2的合成
根据实施例1的步骤6,只需用化合物10a2代替化合物10a1,其他条件不变,经柱层析(正庚烷:乙酸乙酯=1:1)目标产物20a2(8mg)。
1H NMR(400MHz,DMSO-d
6)δ10.67(s,1H),8.20–8.18(m,1H),7.97(d,J=3.7Hz,1H),7.68–7.59(m,1H),7.55(d,J=10.3Hz,1H),3.76(s,3H),3.04–2.92(m,2H),2.85(dd,J=15.0,6.7Hz,1H),1.90–1.83(m,1H),1.73(dd,J=14.3,6.7Hz,1H),1.69-1.50(m,1H),1.45(q,J=12.0Hz,1H),0.89(dd,J=6.8,3.5Hz,6H).MS(M+1=397)。
实施例74:化合物20b1的合成
步骤1
将化合物1(150mg)溶于甲醇(8mL)中,将Pd/C(30mg)加入反应体系,氮气换气三次,氢气换气三次,氢气球条件下室温(25度)反应18h,TLC检测原料反应完全,抽滤,旋干溶剂,柱层析(正庚烷:乙酸乙酯=5:1)得目标产物130mg MS(M+1=552)。
步骤2
将12-1(45mg)和3-氰基-4-氟苯胺(23mg)溶于THF(6mL)中,然后将体系温度降至0度,将8当量的NaHMDS加入反应体系反应体系,0度反应1h,将水(20mL)加入反应体系,乙酸乙酯(3*30mL)萃取,无水硫酸钠干燥,旋干,柱层析的黄色油状物18mg,MS(M+1=640)。
步骤3:化合物20b1的合成
将2(18mg)溶于THF(3mL)中,然后将50当量的3HF.TEA滴加入反应体系,室温下反应3天,制备板分离冷冻干燥后得白色固体4.0mg目标产物。
1H NMR(400MHz,DMSO-d
6)δ10.77(s,1H),8.20(dd,J=5.8,2.7Hz,1H),7.98(ddd,J=9.2,4.9,2.7Hz,1H),7.90(s,1H),7.51(t,J=9.1Hz,1H),3.77(s,3H),3.11–3.02(m,2H),2.89–2.87(m,1H),1.97-1.92(m,1H),1.78-1.73(m,1H),1.60-1.51(m,1H),0.96(dd,J=6.8,3.4Hz,6H).Ms(ESI)m/z=404(M+1)
实施例75:化合物20b2的合成
根据实施例74的步骤3,只需用化合物19b2代替化合物19b1,其他条件不变,经柱层析(正庚烷:乙酸乙酯=1:1)目标产物20b2(8mg)。
1H NMR(400MHz,DMSO-d
6)δ10.67(s,1H),8.19(dd,J=5.8,2.7Hz,1H),7.97(ddd,J=9.2,4.9,2.7Hz,1H),7.68(s,1H),7.57(t,J=9.1Hz,1H),3.76(s,3H),3.04-2.92(m,2H),2.85–2.83(m,1H),1.90-1.83(m,1H),1.74-1.69(m,1H),1.67-1.46(m,1H),0.89(dd,J=6.8,3.4Hz,6H).Ms(ESI)m/z=404(M+1)
根据实施例72或实施例74的合成方法又合成了如下20,40类系列化合物:
下面为50类化合物的合成:
实施例167:化合物50a1的合成
步骤1:化合物42的合成
将化合物41(10g)溶于二氯甲烷(40mL)中,室温下将甲胺水溶液(30mL)滴加入反应体系,室温,反应5h,抽滤,滤饼用水(5mL)洗涤,得42淡黄色固体5g,MS(M+1=281)。
步骤2:化合物43的合成
将PPh3Cl2的氯仿溶液(80mL)冷至0度,然后将三乙胺(7mL),搅拌10min后0度下加入化合物42,(5.0g)搅拌20min后,将2-异丙基-3-丙烯胺(5g)加入反应体系,室温反应18h,向反应体系中加水(20mL),乙酸乙酯(3*25mL)萃取,有机相干燥、旋干,粗品柱层析(正庚烷:乙酸乙酯=1:5),得产物43(400mg)。MS(M+1=362)。
步骤3:化合物44的合成
将化合物43(1.8g),四三苯基膦钯(100mg),乙烯基硼酸酯(900g),碳酸铯(2.7g),溶于DMF(410mL)中,氮气保护下,100度反应15h,用水溶液淬灭反应,乙酸乙酯萃取,有机相干燥、旋干,所得粗品柱层析(正庚烷:乙酸乙酯=1:5)得化合物44(0.5g)。MS(M+1=354)。
步骤4:化合物45的合成
将化合物44(1.0g)溶于二氯甲烷(500ml)中,然后将詹氏催化剂(0.1g)加入反应体系,搅拌过夜,将反应液旋干,粗品柱柱层析(正庚烷:乙酸乙酯=1:3)得化合物45。TLC显示的下点45-1(0.22g),TLC显示的上点45-2(0.27g)MS(M+1=312)。
步骤5:化合物50a1的合成
将化合物45-1(30mg)和4-氟-3-氰基苯胺(20mg)溶于四氢呋喃(5mL)中,降温至0度,然后将NaHMDS(0.2mL)加入反应体系,室温搅拌反应16h,将水加入反应体系,乙酸乙酯(3*15mL)萃取,有机相用无水硫酸钠干燥,旋干,粗品经柱层析(正庚烷:乙酸乙酯=1:3)目标产物50a1(11mg)。MS(M+1=409)。
根据实施例167的合成方法又合成了如下50类系列化合物:
下面为60类化合物的合成:
实施例186:化合物60a1的合成
步骤1
将化合物50a1(20mg)溶于甲醇(5mL),然后将钯碳(5mg)加入反应体系,氢气保护下室温反应6h,粗品经柱层析(正庚烷:乙酸乙酯=1:3)目标产物60a1(11mg)。MS(M+1=411)
根据实施例186的合成方法又合成了如下60类系列化合物:
下面为70、80和90类化合物的合成:
实施例234:化合物70a1的合成
根据实施例74和实施例167的合成步骤,用吡唑类化合物代替吡咯类化合物可以得到下面列表中的化合物。
生物学实施例--抗-HBV活性实验
实验一:体外抗乙肝病毒核衣壳组装活性试验方法
主要试剂和原料:
C150蛋白为药明康德公司表达和纯化;
蛋白荧光标记:
向96孔板每孔加入150μL 2%w/v脱脂牛奶,室温孵育2小时。吸掉脱脂牛奶,用去离子水清洗后烘干,室温保存。将C150蛋白(每管3毫克)用5ml Hitrap脱盐柱脱盐。向每管脱盐后的C150蛋白加入50mM
荧光染料20μl混合均匀,4℃避光孵育过夜。用Sephadex G-25凝胶过滤去除未与C150结合的荧光染料。计算C150的荧光标记效率,公式如下:
其中,
[C150Bo]表示荧光标记蛋白的浓度;
A504表示波长504nM的吸光值;
A280表示波长280nM的吸光值;
M
-1表示摩尔浓度的倒数。
化合物稀释:
将化合物母液用DMSO稀释到6mM,再用50mM HEPES稀释到600μM,然后用10%DMSO/50mM HEPES进一步3倍系列稀释8个浓度。
将C150Bo用50mM HEPES稀释到2μM。取37.5μL C150Bo和2.5μL各个浓度的化合物加入到96孔反应板中混匀,室温孵育15分钟。取10μl的750mM NaCl/50mM HEPES加入到反应孔中,NaCl的终浓度为150mM。
0%蛋白组装对照孔,加入10μL的50mM HEPES,NaCl的终浓度为0mM。
100%蛋白组装对照孔,加入10μL的5M NaCl/50mM HEPES,NaCl的终浓度为1M。
DMSO终浓度为0.5%,化合物最高终浓度为30μM,C150Bo终浓度为1.5μM。室温孵育1小时。测量荧光信号(激发光485nm;发射光535nm)。
数据分析
%蛋白组装=【1-(样品荧光值–1M NaCl荧光值)/(0M NaCl荧光值-1M NaCl荧光值)】×100.
IC
50值通过prism软件计算,方程如下:
Y=Bottom+(Top-Bottom)/(1+10
((LogIC50-X)*HillSlope));
其中,
X表示浓度的对数值,Y表示效应值,Y从底部起始以S型拟合至顶部;
Bottom表示表示曲线的底部;
Top表示Top表示曲线的顶部;
HillSlope表示:曲线的最大斜率的绝对值。
实验二:在HepG2.2.15细胞的抗乙肝病毒活性测定
主要试剂:
QIAamp 96 DNA血液试剂盒(12)(Qiagen,货号51162);
FastStart Universal Probe Master(Roche,货号04914058001);
Cell–titer Glo检测试剂(Promega,货号G7573)。
化合物稀释:体外抗HBV活性实验和细胞毒性实验所有化合物均3倍系列稀释,8个浓度。受试化合物最终起始浓度为30μM,参照化合物GLS4最终起始浓度为1μM,DMSO终浓度为0.5%。
种HepG2.2.15细胞(4×10
4细胞/孔)到96孔板,在37℃,5%CO
2培养过夜。第二天,加入含不同浓度化合物的新鲜培养液到培养孔中。第五天,吸除培养孔中旧的培养液,加入含不同浓度化合物的新鲜培养液。
第八天,收集培养孔中的上清,用于提取上清中的HBV DNA,qPCR检测HepG2.2.15上清中的HBV DNA含量。收集上清后,再向培养孔中补加培养基和Cell-titer Glo试剂,酶标仪检测各孔的化学发光值。
活性计算公式如下:
Y=Bottom+(Top-Bottom)/(1+10
((LogIC50-X)*HillSlope));
其中,
X表示浓度的对数值,Y表示效应值,Y从底部起始以S型拟合至顶部;
Bottom表示曲线的底部;
Top表示曲线的顶部;
HillSlope表示:曲线的最大斜率的绝对值。
实验三:细胞毒性测定
待测化合物的细胞毒性是使用HepG2细胞进行测试的,将这些细胞在待测化合物存在下孵育4天。使用刃天青测定来评估细胞活力。
结果表明:本发明的化合物的体外抗乙肝病毒核衣壳组装活性和抗乙肝病毒活性良好,且细胞毒性低。
实验一至实验三的活性数据见表13:
表13
表中:
+++表示IC
50<1μM;
++表示IC
50为1~100μM;
+表示IC
50为>100μM。
++++表示EC
50<0.1nM;
+++表示EC
50 0.1~100nM;
++表示EC
50为100~1000nM;
+表示EC
50为>1000nM。
由此可见,本申请的化合物具有优异的抗乙肝病毒活性。
此外。对于本发明化合物,经HPLC拆分后,可将基于手性硫原子中心(即O=S=N-R6中的S)的两种构型化合物进行有效分离。本发明人意外地发现,在两种基于手性硫原子中心的两种构型化合物中,极性较小的对映异构体的抑制HBV核衣壳蛋白的活性显著高于极性较大的对映异构体,在一些实施例中,活性差异可以达到数倍。
实验四小鼠PK实验实施例:
18只雄性C57小鼠(9只静脉给药,9只口服给药)按照体重随机分组,分别给予受试化合物2mg/kg(静脉给药)和50mg/kg(口服给药)。每组每个时间点取3只小鼠,共取8个时间点(5分钟、15分钟、30分钟、1小时、2小时、4小时、8小时、24小时)。口服生物利用度F的计算方法为AUC
po/Dose
po/AUC
iv/Dose
iv。
用本发明化合物进行给药,结果显示,各个在体内实验之中表现出良好的生物利用度,部分化合物的生物利用度达到或超过70%。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (14)
- 一种如式L所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物,其中,n为1、2、3、4、5、6、7、8、9、或10;为取代或未取代的五元或六元环,其中,所述的五元或六元环任选地含有一个或多个选自下组的杂原子:O、S、N或P;所述的取代指基团上的氢原子被一个或多个选自下组的取代基取代:C1-C3烷基(尤其是甲基)、C3-C4环烷基、氰基,或卤素;X为-CR aR b-;Y为取代或未取代的C1-C7亚烷基,或取代或未取代的C2-C7亚烯基,其中,所述的取代基选自下组:C1-C4的烷基、羟基;Z选自下组:O、S、N或P,或Z为C-C单键(即Z为无);W为NRc或无;R 1,R 2,R 3和R 4各自独立的地选自下组:H、卤素、氰基、取代或未取代的C3-C4的环烷基,取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基;其中,所述的取代指基团上的氢原子被一个或多个选自下组的取代基取代:卤素、C1-C4的烷基(如二氟甲基、二氟乙基、单氟甲基、三氟甲基、三氟甲氧基);R 5、R 6各自独立地选自下组:H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 1-C 8烷胺基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;R a、R b各自独立地为H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷基、取代或未取代的C 2-C 6烯基、取代或未取代的 C 2-C 6炔基、取代或未取代的C 1-C 8烷胺基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C1-C6烷氧基-烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;Rc为H、卤素、-CN、羟基、氨基、羧基、-(C=O)-取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 1-C 8烷胺基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个选自下组的取代基取代的选自下组的基团:C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基;所述的取代基选自下组:卤素、C1-C6烷氧基。
- 如权利要求1所述的化合物、或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物,其特征在于,所述的X 2为-NCH 3-。
- 如权利要求1所述的化合物、或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物,其特征在于,Ra选自下组:取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C1-C6烷氧基-烷基;Rb为H。
- 如权利要求1所述的化合物、或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物,其特征在于,所述的化合物为如表1中所述的化合物10a1-60y2,其中,Peak 1和Peak 2指对映异构体在反相HPLC中的出峰顺序,Peak 1为先出峰的对映异构体,Peak 2为后出峰的对映异构体。
- 一种药物组合物,其特征在于,包含(1)如权利要求1所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物;(2)药学上可接受的载体。
- 如权利要求1所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物或如权利要求11所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗乙型肝炎病毒感染的药物。
- 一种乙型肝炎病毒抑制剂,其特征在于,所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
- 一种体外抑制乙型肝炎病毒的方法,其特征在于,包括步骤:将权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物,与乙型肝炎病毒接触,从而抑制乙型肝炎病毒复制。
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Cited By (12)
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---|---|---|---|---|
US10450270B2 (en) | 2013-07-25 | 2019-10-22 | Janssen Sciences Ireland Uc | Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10457638B2 (en) | 2013-05-17 | 2019-10-29 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10676429B2 (en) | 2012-08-28 | 2020-06-09 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
WO2020143798A1 (zh) * | 2019-01-11 | 2020-07-16 | 上海长森药业有限公司 | 内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 |
US10875876B2 (en) | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10941113B2 (en) | 2013-02-28 | 2021-03-09 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
US10973801B2 (en) | 2018-03-14 | 2021-04-13 | Janssen Sciences Ireland Unlimited Company | Capsid assembly modulator dosing regimen |
US11078193B2 (en) | 2014-02-06 | 2021-08-03 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US11096931B2 (en) | 2019-02-22 | 2021-08-24 | Janssen Sciences Ireland Unlimited Company | Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases |
CN113423712A (zh) * | 2019-02-14 | 2021-09-21 | 阿里戈斯治疗公司 | 双环磺酰胺 |
US11129834B2 (en) | 2016-04-15 | 2021-09-28 | Novira Therapeutics, Inc. | Combinations and methods comprising a capsid assembly inhibitor |
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Families Citing this family (3)
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013006394A1 (en) | 2011-07-01 | 2013-01-10 | Institute For Hepatitis And Virus Research | Sulfamoylbenzamide derivatives as antiviral agents against hbv infection |
WO2013096744A1 (en) | 2011-12-21 | 2013-06-27 | Novira Therapeutics, Inc. | Hepatitis b antiviral agents |
CN108250121A (zh) * | 2016-12-28 | 2018-07-06 | 上海长森药业有限公司 | 磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途 |
CN108264520A (zh) * | 2017-01-03 | 2018-07-10 | 上海长森药业有限公司 | 用于治疗乙型肝炎的化合物及其用途 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9963464B2 (en) * | 2014-04-11 | 2018-05-08 | Bayer Pharma Aktiengesellschaft | Macrocyclic compounds |
US10875876B2 (en) * | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
CN109251212A (zh) * | 2017-07-14 | 2019-01-22 | 上海长森药业有限公司 | 内环硫醚酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 |
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- 2018-07-13 WO PCT/CN2018/095614 patent/WO2019011323A1/zh unknown
- 2018-07-13 US US16/630,729 patent/US11168055B2/en active Active
- 2018-07-13 JP JP2020501557A patent/JP7079527B2/ja active Active
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013006394A1 (en) | 2011-07-01 | 2013-01-10 | Institute For Hepatitis And Virus Research | Sulfamoylbenzamide derivatives as antiviral agents against hbv infection |
WO2013096744A1 (en) | 2011-12-21 | 2013-06-27 | Novira Therapeutics, Inc. | Hepatitis b antiviral agents |
CN108250121A (zh) * | 2016-12-28 | 2018-07-06 | 上海长森药业有限公司 | 磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途 |
CN108250122A (zh) * | 2016-12-28 | 2018-07-06 | 上海长森药业有限公司 | 磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途 |
CN108264520A (zh) * | 2017-01-03 | 2018-07-10 | 上海长森药业有限公司 | 用于治疗乙型肝炎的化合物及其用途 |
Non-Patent Citations (3)
Title |
---|
See also references of EP3653630A4 |
WEBER ET AL., ANTIVIRAL RES., vol. 54, pages 69 - 78 |
WEBER, O. ET AL.: "Inhibition of human hepatitis B virus(HBV) by a novel non-nucleosidie compound in a transgenic mouse model", ANTIVIRAL RESEARCH, vol. 54, no. 2, May 2002 (2002-05-01), pages 69 - 78, XP002660530, DOI: 10.1016/S0166-3542(01)00216-9 * |
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US10973801B2 (en) | 2018-03-14 | 2021-04-13 | Janssen Sciences Ireland Unlimited Company | Capsid assembly modulator dosing regimen |
WO2020143798A1 (zh) * | 2019-01-11 | 2020-07-16 | 上海长森药业有限公司 | 内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 |
CN113286798A (zh) * | 2019-01-11 | 2021-08-20 | 上海长森药业有限公司 | 内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 |
CN113286798B (zh) * | 2019-01-11 | 2022-08-02 | 上海长森药业有限公司 | 内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途 |
EP3909957A4 (en) * | 2019-01-11 | 2022-09-07 | Shanghai Longwood Biopharmaceuticals Co., Ltd. | INTERNAL CYCLIC SULFIAMIDE DINAMIDE ARYLAMIDE COMPOUND AND USE THEREOF FOR THE TREATMENT OF HEPATITIS B |
CN113423712A (zh) * | 2019-02-14 | 2021-09-21 | 阿里戈斯治疗公司 | 双环磺酰胺 |
JP2022519764A (ja) * | 2019-02-14 | 2022-03-24 | アリゴス セラピューティクス インコーポレイテッド | 二環式スルホンアミド |
US11096931B2 (en) | 2019-02-22 | 2021-08-24 | Janssen Sciences Ireland Unlimited Company | Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases |
US11491148B2 (en) | 2019-05-06 | 2022-11-08 | Janssen Sciences Ireland Unlimited Company | Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases |
Also Published As
Publication number | Publication date |
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EP3653630A1 (en) | 2020-05-20 |
US20200399216A1 (en) | 2020-12-24 |
JP7079527B2 (ja) | 2022-06-02 |
CN109843893B (zh) | 2022-04-01 |
EP3653630A4 (en) | 2021-03-24 |
CN109251212A (zh) | 2019-01-22 |
JP2020526569A (ja) | 2020-08-31 |
CN109843893A (zh) | 2019-06-04 |
US11168055B2 (en) | 2021-11-09 |
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