WO2017124896A1 - 一种核苷类似物的磷酰胺酯前药及其应用 - Google Patents

一种核苷类似物的磷酰胺酯前药及其应用 Download PDF

Info

Publication number
WO2017124896A1
WO2017124896A1 PCT/CN2016/112299 CN2016112299W WO2017124896A1 WO 2017124896 A1 WO2017124896 A1 WO 2017124896A1 CN 2016112299 W CN2016112299 W CN 2016112299W WO 2017124896 A1 WO2017124896 A1 WO 2017124896A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
pharmaceutically acceptable
formula
pyridyl
Prior art date
Application number
PCT/CN2016/112299
Other languages
English (en)
French (fr)
Inventor
易仕旭
何永耀
肖宁
潘旭松
罗杰
惠帅
Original Assignee
四川海思科制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川海思科制药有限公司 filed Critical 四川海思科制药有限公司
Priority to CN201680042114.XA priority Critical patent/CN107849075A/zh
Publication of WO2017124896A1 publication Critical patent/WO2017124896A1/zh

Links

Classifications

    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention relates to the field of pharmacy and organic chemistry, and in particular to a phosphate prodrug of a nucleoside analog and a preparation method thereof, and a preparation for preventing and/or treating a viral infection, in particular hepatitis B virus (HBV) and/or Or use in drugs that are infected with human immunodeficiency virus (HIV).
  • a viral infection in particular hepatitis B virus (HBV) and/or Or use in drugs that are infected with human immunodeficiency virus (HIV).
  • Nucleosides are structural units of nucleic acids that are involved in the retention, replication and transcription of genetic information in biosynthesis.
  • the antiviral nucleoside analog drug its mechanism of action is basically through the synthesis of raw materials such as pyrimidine, purine and its nucleotides required for DNA synthesis or DNA synthesis of the virus, thereby inhibiting the survival and replication of viral cells.
  • Nucleoside analog drugs have similar metabolic pathways, are recognized by cell membrane transfer factors and transported into cells, and then phosphorylated by kinases into triphosphorylated actives. The monophosphorylation in this process is rate-limiting, some contain phosphoric acid. The nucleoside analog drug of the group can skip the step of monophosphorylation, thereby increasing the therapeutic index of the drug.
  • the phosphate group is a double negative ion, which is difficult to penetrate the cell membrane, and the oral bioavailability is not high, so that the concentration of the drug reaching the therapeutic target is very low, and the therapeutic effect is not satisfactory.
  • the phosphoric acid group can be esterified to form a prodrug form of the phosphodiester to increase the fat solubility of the phosphate group-containing nucleoside analog drug, thereby improving the membrane permeability and improving the bioavailability of the drug. degree.
  • the nucleoside analog prodrugs developed by this method have been successfully marketed or entered into phase III clinical trials, such as the marketed adefovir dipivoxil (a compound of formula I) and tenofovir disoproxil. (tenofovir disoproxil, a compound of formula II), currently in phase III clinical besifovir (compound of formula III) and the like.
  • the compound of the above formula III has strong antiviral activity and the effect is comparable to that of entecavir. It is not easy to be resistant and has a significant effect on patients who are resistant to lamivudine, so prisprevir is expected to be a new generation of antiviral (especially anti-HBV and / or HIV) drugs.
  • the drug in addition to the inherent deficiency of the phosphodiester prodrug, the drug also has the side effect of consuming the L-carnitine in the body. Therefore, it is necessary to develop a new prodrug of besifovir in order to further enhance its antiviral activity and reduce its side effects while maintaining its advantages of being resistant to drugs.
  • prodrug candidate compound appears to be simple, the identification of appropriate physicochemical and pharmacokinetic properties, in vivo transformation and safety is a complex multidisciplinary task due to the complexity of the interaction between the human and the drug, but in practice Prodrugs obtained through “reasonable design” are often far from the expected results, and even “prodrugs” with physicochemical properties or biological activity are worse than the parent drug. Unpredictability in the development process will be greatly increased if new prodrugs are developed that not only improve the physical properties of the drug or the pharmacokinetic properties of the drug, but also enhance the efficacy or reduce side effects.
  • this new prodrug of besifovir overcomes the shortcomings of phosphodiester in besifovir and also eliminates the side effects of eslavelvir consumption of L-carnitine, while further enhancing its antiviral activity.
  • Another object of the present invention is to provide a process for the preparation of the novel nucleoside analog.
  • a further object of the present invention is to provide the use of the novel nucleoside analogs for the preparation of a medicament for the prevention and/or treatment of viral infections.
  • the present invention provides a compound of the formula IV or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutically acceptable cocrystal, a hydrate or a solvate thereof,
  • R 1 is hydrogen, C 1-6 alkyl, or substituted or unsubstituted C 6-10 aryl, 6 to 10 membered heteroaryl or benzyl;
  • R 2 , R 3 are each a C 1-6 alkyl group, or R 2 , R 3 form a C 3-7 cycloalkyl group with the attached carbon atom;
  • R 4 is a substituted or unsubstituted C 6-10 aryl group or a 6 to 10 membered heteroaryl group.
  • C 1-6 alkyl refers to a linear or branched saturated aliphatic hydrocarbon group of 1 to 6 carbon atoms, selected from the group consisting of methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-amyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, 4 -methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1 - dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-hexyl, isohexyl, etc
  • C 6-10 aryl group refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic group having a conjugated ⁇ -electron system selected from the group consisting of phenyl, 1 -naphthyl, 2-naphthyl and the like.
  • the "6- to 10-membered heteroaryl” refers to a heterocyclic or heterocyclic ring having a conjugated ⁇ -electron system containing a heteroatom of oxygen, sulfur or nitrogen in a ring of 6 to 10 members.
  • a fused polycyclic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidine-4 -yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-3-yl, decyl, isodecyl, oxazolyl, pyridazinyl, fluorenyl, quinazolyl, quinolinyl , isoquinolyl, porphyrinyl, pyridazinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, thieno[2,3-b]furanyl, furo[3,2-b]- Pyranyl, pyrido[2,3-d]oxazinyl, pyrazolo[4,3-d]
  • the "substituent" of the aryl, heteroaryl or benzyl group is selected from an alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, etc.), alkenyl (such as vinyl, propenyl, etc.), alkynyl (such as ethynyl, propynyl, etc.), hydroxyl, alkoxy (such as methoxy, ethoxy, N-propoxy, isopropoxy, tert-butoxy, etc.), acyloxy (eg formyloxy, acetoxy, propionyloxy, butyryloxy, isopropyl) Carbonyloxy, t-butylcarbonyloxy, etc.), mercapto, alkylthio (such as methylthio, ethylthio
  • C 3-7 cycloalkyl refers to a saturated cyclic aliphatic hydrocarbon-containing group of 3 to 7 carbon atoms, selected from the group consisting of cyclopropyl, cyclobutyl, and ring.
  • the “isomer” includes optical isomers, tautomers, cis and trans isomers, conformational isomers, meso compounds, and the like, or mixtures thereof, having an enantiomeric or diastereomeric relationship.
  • the phosphorus atom of the compound of Formula I is chiral, its configuration is selected from the group consisting of S, R or a mixture of S and R.
  • the compound of Formula IV is selected from the group consisting of the following structures, or isomers, pharmaceutically acceptable salts, pharmaceutically acceptable co-crystals, hydrates or solvates of these compounds:
  • the compound of Formula IV is selected from the group consisting of the following structures, or isomers, pharmaceutically acceptable salts, pharmaceutically acceptable co-crystals, hydrates or solvates of these compounds:
  • the compound of Formula IV is selected from the group consisting of the following structures, or isomers, pharmaceutically acceptable salts, pharmaceutically acceptable co-crystals, hydrates or solvates of these compounds:
  • salt is well known to those skilled in the art and refers to a compound formed by the action of an ionic bond between a cation and an anion.
  • Co-Crystals refers to a multi-component crystal having a fixed stoichiometric ratio in which the components are at the molecular level, by hydrogen bonding or other non-covalent bonds, nonionic The roles of the keys combine to coexist.
  • drug eutectic it generally comprises a pharmaceutically active ingredient and another or a plurality of co-crystal formers.
  • solvate When a single pure eutectic former is present in a liquid state at room temperature, the eutectic is also referred to as a "solvate” wherein the solvent is referred to as "hydrate” when it is water.
  • the "eutectic” also includes multi-component crystals having a fixed stoichiometric ratio in which a portion of the pharmaceutically active ingredient and the other components are partially hydrogen-bonded or otherwise non-covalently bonded, and the other portion is passed. The ionic bond or a force between the hydrogen bond and the ionic bond is combined.
  • the “salt” or “eutectic” also includes the form of a salt or a eutectic solvate, hydrate, and the like.
  • a salt or a eutectic is prepared, slurried or crystallized in a solvent, it is possible for the solvent to enter a salt or a eutectic crystal to form a solvate; when the solvent is water, it is possible to form a hydrate.
  • the "pharmaceutically acceptable salt” or “pharmaceutically acceptable co-crystal” includes: a compound of the invention and a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, a salt or eutectic formed by sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid, nitric acid, or the like, or a compound of the present invention and a pharmaceutically acceptable organic acid such as maleic acid, malic acid, fumaric acid, succinic acid, tartaric acid, lemon a salt or eutectic formed by acid, acetic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid or the like.
  • a pharmaceutically acceptable inorganic acid such as hydrochloric acid, a salt or eutectic formed by sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid, nitric acid
  • the present invention provides a process for the preparation of a compound of formula IV, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutically acceptable co-crystal, a hydrate or a solvate thereof, the process comprising:
  • R 4 has the same definition as above;
  • R 1 , R 2 , R 3 , and R 4 are as defined above;
  • the compound of the formula IV can be chiralized, made into a salt, made into a eutectic, made into a hydrate or made into a solvate, if necessary.
  • the compound represented by the formula V can be produced according to the method disclosed in CN1487949A or the like; the compound represented by the formula VI is generally commercially available, and the corresponding chlorinated product or brominated product can also be used. Conversion to a hydroxylate is carried out by methods conventional in the art.
  • the reaction In the production method step (1), the reaction generally needs to be carried out in the presence of a condensing agent.
  • the condensing agent of the step (1) comprises N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropane) Carbonated diimine such as carbodiimide (EDCI).
  • DCC N,N-dicyclohexylcarbodiimide
  • EDCI 1-ethyl-3-(3-dimethylaminopropane) Carbonated diimine
  • the carbodiimide condensing agent is generally used in combination with a reagent such as triethylamine, dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBT).
  • the molar ratio of the condensing agent of the step (1) to the compound of the formula V is generally from 0.8:1 to 2:1.
  • the molar ratio of the compound represented by the formula V to the compound of the formula VI is generally 1:1 to 1:3.
  • the solvent of the reaction is generally an aprotic solvent such as N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl Ketosulfone and the like.
  • the compound of the formula VIII is generally commercially available or according to Arch. Pharm. (Weinheim) 314, 44-51 (1980), Bioorganic & Medicinal Chemistry 16 (17), 8054-6602 (2008), WO2006123145, WO2011089396, WO2009158393, WO ⁇ 2007020193, WO2014033617 and the like.
  • the reaction is generally carried out in the presence of a condensing agent.
  • the condensing agent of the step (2) comprises thionyl chloride (SOCl 2 ), phosphorus oxychloride (POCl 3 ), hexafluorophosphate N-[(dimethylamino)- 1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethylamine N-oxide (HATU), hexafluorophosphate N-[(1H -benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethylamine N-oxide (HBTU), benzotriazol-1-yl-N-oxygen hexafluorophosphate Phenyl-tris(pyrrolidinyl)phosphonium (PyBOP), of which sulfoxide (SOCl 2 ) or phosphorus oxychloride (POCl 3 ) is preferred.
  • SOCl 2 thionyl chloride
  • POCl 3 phospho
  • the molar ratio of the condensing agent of the step (2) to the compound of the formula VII is generally from 1:1 to 5:1.
  • the molar ratio of the compound represented by the formula VII to the compound of the formula VIII is generally from 1:1 to 1:5.
  • the solvent of the reaction is generally an aprotic solvent such as acetonitrile, dichloromethane, chloroform, tetrahydrofuran or the like.
  • the chiral resolution can be carried out by a conventional method in the art, such as chiral column separation, chiral acid selective salt formation or eutectic separation, by chiral separation.
  • the compound shown by IV can be converted into the compound of the formula IV1 or the compound of the formula IV2.
  • the compound of the formula V, the compound of the formula VI, the compound of the formula VII and the compound of the formula VIII can be converted from the corresponding salt, eutectic, hydrate or solvate in the preparation method. This can be carried out before the reaction, or in the reaction or after-treatment, and these conversion methods can be carried out by a conventional method in the art.
  • the step (1), the step (2) and the step (3), the separation and purification of the product can be carried out according to a conventional method in the art, for example, according to the reaction system, using a concentrated reaction solution, pH adjustment, extraction, The resulting product is isolated or purified by one or more of the methods of crystallization, column chromatography, and the like.
  • the present invention provides a therapeutically effective amount of a compound of the formula IV or an isomer thereof
  • the invention provides a therapeutically effective amount of a compound selected from the group consisting of Formulas a to Formula 1, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutically acceptable co-crystal, a hydrate or a solvent And pharmaceutical compositions or preparations of pharmaceutical excipients.
  • the present invention provides a therapeutically effective amount of a compound selected from the group consisting of Formulas a1 to Formula I or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutically acceptable cocrystal, a hydrate or a solvent. And a pharmaceutical composition or formulation of a pharmaceutical excipient.
  • the invention provides a therapeutically effective amount of a compound selected from the group consisting of Formulas a2 to Formula I or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutically acceptable co-crystal, a hydrate or a solvent And pharmaceutical compositions or preparations of pharmaceutical excipients.
  • compositions or preparations can be administered orally or parenterally.
  • tablets, capsules, pills, granules, solutions, syrups, suspensions, powders, sustained release preparations or controlled release preparations can be prepared by conventional formulation techniques.
  • it When it is not administered orally, it can be made into a transdermal preparation, an injection, an infusion solution or a suppository by a conventional formulation technique.
  • a therapeutically effective amount of a compound of Formula IV, or a compound selected from Formulas a to Formula 1, or a compound selected from Formulas a1 to Formulal, or a compound selected from Formulas a2 to Formulal Or an isomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable co-crystal, a hydrate or a solvate thereof, optionally in combination with another therapeutically effective amount of the active ingredient, with one or more drugs Mix or contact with the excipients and then make them into the desired dosage form.
  • the above pharmaceutical composition or preparation is preferably an oral dosage form including a tablet, a capsule, a pill, a granule, a solution, a syrup, a dry suspension, a suspension, a powder, a sustained release preparation or a controlled release preparation.
  • solid oral preparations such as tablets, capsules, granules, dry suspensions, and sustained release preparations or controlled release preparations are preferred, and tablets and capsules are more preferred.
  • the preferred pharmaceutical compositions or formulations of the present invention can be prepared according to any of the conventional methods employed in the preparation of solid oral formulations.
  • any form of coating can be carried out according to need, such as tablets can be made into any release form (such as immediate release, enteric and controlled release, etc.); capsules can be used It can be prepared by wet granulation capsule preparation, etc., and the capsule contents can be prepared into any release form (such as immediate release preparation, enteric preparation and controlled release preparation, etc.).
  • the present invention provides a compound of Formula IV, or a compound selected from Formulas a to Formula 1, or a compound selected from Formulas a1 to Formulal, or selected from Formulas a2 to Formulal2.
  • the particle size distribution of the compounds shown, or their isomers, pharmaceutically acceptable salts, pharmaceutically acceptable co-crystals, hydrates or solvates, is controlled to be 95% less than 200 ⁇ m, preferably small It is preferably 180 ⁇ m, more preferably less than 150 ⁇ m, still more preferably less than 100 ⁇ m.
  • Pharmaceutical excipients conventional in the art in oral dosage forms include fillers, disintegrants, binders, dispersants, lubricants or retention aids, as well as various types of coating materials and the like.
  • the filler generally comprises pregelatinized starch, starch, lactose, dextrin, calcium hydrogen phosphate, calcium carbonate, mannitol, microcrystalline cellulose, sorbitol, glucose, etc., which may be used singly or in combination, and preferably It is pre-gelatinized one or more of starch, lactose, microcrystalline cellulose and mannitol.
  • the disintegrant generally comprises croscarmellose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and the like. They may be used singly or in combination, and preferably one or more of croscarmellose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, microcrystalline cellulose, and low-substituted hydroxypropylcellulose.
  • the binder generally comprises microcrystalline cellulose, pre-treated starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch syrup, gum arabic, polyethylene glycol 4000, polyvinyl alcohol Alginate, water, various concentrations of ethanol solution, which may be used singly or in combination, preferably one of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone and starch slurry or A variety.
  • the lubricant generally comprises magnesium stearate, stearic acid, calcium stearate, sodium stearate, sodium stearate, palmitic acid, differential silica gel, stearamide, talc, solids.
  • sweeteners such as aspartame, stevioside, etc.
  • coloring agents such as various medicinal or food colors such as tartrazine and iron oxide
  • Stabilizers such as calcium carbonate, calcium bicarbonate, sodium bicarbonate, sodium carbonate, calcium phosphate, calcium hydrogen phosphate, glycine, etc.
  • surfactants such as Tween 80, sodium lauryl sulfate, etc.
  • coating materials eg Opadry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resin copolymers, etc.
  • the present invention provides a composition or formulation wherein the active ingredient is selected from a therapeutically effective amount of a compound of Formula IV, or a compound selected from Formulas a to Formula 1, or selected from A1 to a compound represented by Formula 1 or a compound selected from the group consisting of Formulas a2 to 12, or an isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable cocrystal, a hydrate or a solvate.
  • the composition or formulation is preferably an oral preparation, more preferably a tablet and a capsule; in a unit composition or formulation, they are usually present in an amount of from 1 mg to 200 mg, preferably from 5 mg to 100 mg.
  • the present invention provides a compound of the formula IV or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutically acceptable co-crystal, a hydrate or a solvate thereof for the preparation of a medicament for preventing and/or treating a viral infection.
  • the present invention provides a compound of the formula IV or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutically acceptable cocrystal, hydrated Use of a substance or solvate for the manufacture of a medicament for the prevention and/or treatment of hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
  • HBV hepatitis B virus
  • HAV human immunodeficiency virus
  • the present invention provides a compound of Formula IV, or a compound selected from Formulas a to Formula 1, or a compound selected from Formulas a1 to Formulal, or selected from Formulas a2 to Formulal
  • the compounds shown, or their isomers, pharmaceutically acceptable salts, pharmaceutically acceptable co-crystals, hydrates or solvates, are prepared for the prevention and/or treatment of hepatitis B virus (HBV) and/or human immunodeficiency virus Application in drugs for (HIV) infection.
  • HBV hepatitis B virus
  • HCV human immunodeficiency virus
  • the compound of the formula IV provided by the present invention is, for example, selected from the compounds represented by the formulae a to the formula 1, or selected from the compounds represented by the formulas a1 to l1, or selected from the formulas a2 to l12.
  • HBV hepatitis B virus
  • HIV infection has higher activity and better safety than prior art (such as besfovir).
  • Example 1 The compound a obtained in Example 1 was isolated by HPLC to give the compound a1 (retention time 15.5 min) and the compound a2 (retention time 16.7 min).
  • Example 3 The compound b obtained in Example 3 was isolated as in Example 2 to give Compound b1 (retention time 17.3 min) and Compound b2 (retention time 18.9 min).
  • Example 1 The preparation method of Example 1 was carried out except that p-methylphenol was used instead of phenol to obtain a compound c.
  • Example 5 The compound c obtained in Example 5 was isolated as in Example 2 to give Compound C1 (retention time: 18.4 min) and Compound C2 (retention time: 19.8 min).
  • Example 1 The preparation method of Example 1 was carried out except that 2,6-dimethylphenol was used instead of phenol to obtain a compound d.
  • Example 7 The compound d obtained in Example 7 was isolated by the method of Example 2 to give Compound d1 (retention time 20.1 min) and Compound d2 (retention time 22.4 min).
  • Example 1 The preparation method of Example 1 was carried out except that 1-naphthol was used instead of phenol to obtain compound e.
  • Example 9 The compound e obtained in Example 9 was isolated in the same manner as in Example 2 to give Compound e1 (retention time 21.2 min) and compound e2 (retention time 22.9 min).
  • Example 1 The preparation method of Example 1 was carried out except that 2-naphthol was used instead of phenol to obtain a compound f.
  • Example 11 The compound f obtained in Example 11 was separated in the same manner as in Example 2 to give Compound f1 (retention time 21.8 min) and compound f2 (retention time 22.7 min).
  • Example 1 The preparation method of Example 1 was carried out except that p-fluorophenol was used instead of phenol to obtain a compound g.
  • Example 13 The compound g obtained in Example 13 was isolated in the same manner as in Example 2 to give Compound g1 (retention time 16.4 min) and compound g2 (retention time 17.2 min).
  • Example 15 The compound h obtained in Example 15 was isolated in the same manner as in Example 2 to give Compound H1 (reservation time: 17.0 min) and compound h2 (retention time 18.3.min).
  • Example 17 The compound i obtained in Example 17 was isolated as in Example 2 to give Compound i1 (retention time 15.4 min) and Compound i2 (retention time 16.1 min).
  • Example 1 The preparation method of Example 1 was carried out except that p-methoxyphenol was used instead of phenol to obtain Compound j.
  • Example 19 The compound j obtained in Example 19 was isolated by the method of Example 2 to give Compound j1 (retention time 17.9 min) and Compound j2 (retention time 19.0 min).
  • Example 1 The preparation method of Example 1 was carried out except that ethyl hydroxybenzoate was used instead of phenol to obtain compound k.
  • Example 21 The compound k obtained in Example 21 was separated in the same manner as in Example 2 to give Compound k1 (retention time 16.8 min) and Compound K2 (retention time 18.1 min).
  • Example 1 The preparation method of Example 1 was carried out except that ⁇ -isobutyric acid benzyl ester was used instead of ⁇ -isobutyrin isopropyl ester (Compound 3) to give Compound 1.
  • Example 23 The compound 1 obtained in Example 23 was isolated in the same manner as in Example 2 to give the compound l1 (retention time 19.0 min) and the compound l2 (retention time 20.2 min).
  • Example 25 film coated tablet of compound a1 and preparation thereof
  • Chip core Compound a1 50.0 Lactose monohydrate 100.0 Microcrystalline cellulose 60.0 Croscarmellose sodium 15.0 Magnesium stearate 3.0 Film coating material: Opadi II 10.0
  • HepG 2.2.15 cells Compounds were tested for anti-HBV activity using HepG 2.2.15 cells.
  • the materials and instruments used were as follows: HepG2.2.15 cells, RPMI 1640 medium, fetal bovine serum, 96-well plates, DMSO, QIAamp 96 DNA Blood Kit, Cell-titer blue, microplate reader, Applied Biosystems 7900 real-time PCR system.
  • Each compound was dissolved in DMSO at 20 mM and stored at -20 ° C, and a 20 mM stock solution of each compound was diluted with a DMSO 3 fold gradient for a total of 9 concentrations. It was further diluted 200-fold with RPMI 1640 medium containing 2.0% FBS. The highest test final concentration of the compound was 100 ⁇ M.
  • Experimental Procedure The compounds were tested for anti-HBV activity and the EC 50 (half effective inhibitory concentration) was determined by qPCR using the QIAamp 96 DNA Blood Kit (QIAGEN 51161) instructions.
  • inhibition rate (%) (total amount of HBV in the DMSO control group - total amount of HBV in the test sample group) / total amount of HBV in the DMSO control group ⁇ 100.
  • EC 50 values were calculated using GraphPad Prism software compound.

Abstract

本发明提供了一种式IV所示的核苷类似物的磷酸酯前药及其制备方法，以及在制备预防和/或治疗病毒感染，特别是乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的用途。

Description

一种核苷类似物的磷酰胺酯前药及其应用 技术领域
本发明涉及药学领域和有机化学领域，具体涉及一种核苷类似物的磷酸酯前药及其制备方法，以及在制备预防和/或治疗病毒感染，特别是乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的用途。
背景技术
核苷是核酸的结构单元，在生物合成中参与了基因信息的保留、复制和转录。而抗病毒核苷类似物药物，其作用机制基本都是通过干扰病毒的DNA合成或DNA合成所需的嘧啶、嘌呤及其核苷酸等原料的合成，从而通过抑制病毒细胞的存活和复制的代谢途径，以及抑制病毒细胞合成核酸所需的酶或者以核酸为靶点而产生药效作用。
核苷类似物药物的代谢途径基本相似，被细胞膜的转移因子识别后转运到细胞内，然后被激酶磷酸化为三磷酸化活性物，该过程中的单磷酸化是限速的，一些含磷酸基团的核苷类似物药物可跳过单磷酸化这一步，从而可提高药物的治疗指数。但磷酸基团在生理pH条件下，为双负离子，很难透过细胞膜，口服生物利用度不高，从而到达治疗靶点的药物浓度非常低，疗效不理想。
根据磷酸基团的特点，可以将磷酸基团酯化形成磷酸二酯的前药形式来增加含磷酸基团的核苷类似物药物的脂溶性，进而改善其透膜性，提高药物的生物利用度。该方法开发的核苷类似物前药已有多个成功上市或进入III期临床，比如已上市的阿德福韦酯(adefovir dipivoxil，式I所示化合物)和替诺福韦二吡呋酯(tenofovir disoproxil，式II所示化合物)，目前处于III期临床倍司福韦(besifovir，式III所示化合物)等。但此类前药吸收入血后，其中的磷酸二酯基团代谢较快，容易转化为磷酸基团，限制了其进一步从血循环中到达治疗靶细胞的药物浓度；另外，这些前药在代谢过程中还产生对机体有害的甲醛。
Figure PCTCN2016112299-appb-000001
上述式III所示化合物倍司福韦(besifovir)的抗病毒活性强，效果与恩替卡韦相当且 不易耐药，且对拉米夫定耐药的患者有显著的效果，因此倍司福韦有望成为新一代的抗病毒(特别是抗HBV和/或HIV病毒)药物。但该药物除存在磷酸二酯类前药固有的不足外，还存在消耗机体内左旋肉碱的副作用。因此，有必要开发倍司福韦的新前药，以期在保持其不易耐药等优势的基础上，进一步增强其抗病毒活性，减少其副作用。
通过合理的前药设计可以改善药物理化性质或体内药代动力学性质，提高口服生物利用度，这是本领域技术人员所公知的。尽管理论上可以根据分子中的化学官能团合理设计假定的前药，但是化学修饰母药后产生的是全新的分子实体，该新化合物可能显示与母体化合物中不存在的有害物理化学或生物活性性质。虽然设想前药候选化合物看似简单，但是由于人体与药物相互作用的复杂性，鉴定具有适当的理化性质和药代动力学性质、体内转化和安全性是复杂的多学科任务，而实际上常常通过“合理设计”得到的前药，往往与预期的结果相差甚远，甚至得到理化性质或者生物活性比母药更差的“前药”。如果要开发出不仅改善药物理化性质或体内药代动力学性质，而且还能增强药效或减小副作用的新前药，那么开发过程中的不可预测性更将大大增加。
本发明在对倍司福韦新前药的研究过程中，惊喜地发现了倍司福韦的一类新型结构的芳香氧基磷酸酰胺类前药(其结构中含有一个芳香酯基和一个磷酰胺基)，倍司福韦的该新前药克服了倍司福韦中磷酸二酯的缺点，还消除了倍司福韦消耗左旋肉碱的副作用，同时进一步增强了其抗病毒活性。
发明内容
本发明一个目的在于提供一种新的核苷类似物。
本发明的另一目的在于提供该新核苷类似物的制备方法。
本发明的又一目的在于提供包含该新核苷类似物的药物组合物。
本发明的又一目的在于提供该新核苷类似物在制备预防和/或治疗病毒感染的药物中的应用。
根据本发明的目的，本发明提供了一种式IV所示化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，
Figure PCTCN2016112299-appb-000002
其中：
R1为氢、C1-6烷基，或取代或非取代的C6-10芳基、6至10元杂芳基或苄基；
R2，R3分别为C1-6烷基，或R2、R3与所连的碳原子形成C3-7环烷基；
R4为取代或非取代的C6-10芳基或6至10元杂芳基。
根据本发明一些具体实施方案，其中，所述“C1-6烷基”指1至6个碳原子的直链或支链饱和脂肪烃基团，选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、叔戊基、2-甲基丁基、3-甲基丁基、1-乙基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、正己基、异己基等，其中优选甲基、乙基、异丙基或叔丁基。
根据本发明一些具体实施方案，其中，所述“C6-10芳基”指6至10元具有共轭π电子体系的全碳单环或稠合多环基团，选自苯基、1-萘基、2-萘基等。
根据本发明一些具体实施方案，其中，所述“6至10元杂芳基”指6至10元的环中含氧、硫或氮杂原子的具有共轭π电子体系的杂单环或杂稠合多环基团，选自吡啶-2-基、吡啶-3-基、吡啶-4-基、哒嗪-3-基、哒嗪-4-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、吡嗪-2-基、吡嗪-3-基、吲哚基、异吲哚基、吲唑基、吲嗪基、嘌呤基、喹嗪基、喹啉基、异喹啉基、噌啉基、酞嗪基、萘啶基、喹唑啉基、喹喔啉基、噻吩并[2,3-b]呋喃基、呋喃并[3,2-b]-吡喃基、吡啶并[2,3-d]噁嗪基、吡唑并[4,3-d]噁唑基、咪唑并[4,5-d]噻唑基、吡嗪并[2,3-d]哒嗪基、咪唑并[2,1-b]噻唑基、咪唑并[1,2-b][1,2,4]三嗪基、苯并噻吩基、苯并噁唑基、苯并咪唑基、苯并噻唑基、苯并噁庚因基、苯并噁嗪基、苯并呋喃基、苯并***基、吡咯并[2,3-b]吡啶基、吡咯并[3,2-c]吡啶基、吡咯并[3,2-b]吡啶基、咪唑并[4,5-b]吡啶基、咪唑并[4,5-c]吡啶基、吡唑并[4,3-d]吡啶基、吡唑并[4,3-c]吡啶基、吡唑并[3,4-c]吡啶基、吡唑并[3,4-d]吡啶基、吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡咯并[1,2-b]哒嗪基、咪唑并[1,2-c]嘧啶基、吡啶并[3,2-d]嘧啶基、吡啶并[4,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[2,3-b]吡嗪基、吡啶并[3,4-b]吡嗪基、嘧啶并[5,4-d]嘧啶基、吡唑并[2,3-b]吡嗪基、嘧啶并[4,5-d]嘧啶基等，其中优选吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-2-基、嘧啶-4-基或嘧啶-5-基。
根据本发明一些具体实施方案，其中，所述芳基、杂芳基或苄基的“取代基”选自烷基(如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等)、烯基(如乙烯基、丙烯基等)、炔基(如乙炔基、丙炔基等)、羟基、烷氧基(如甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基等)、酰氧基(如甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、异丙基 羰基氧基、叔丁基羰基氧基等)、巯基、烷硫基(如甲硫基、乙硫基、正丙硫基、异丙硫基、叔丁硫基等)、氨基、烷氨基(如甲氨基、乙氨基、二甲氨基、二乙氨基、正丙氨基、异丙氨基、叔丁氨基等)、酰氨基(如甲酰氨基、乙酰氨基、丙酰氨基、丁酰氨基、异丙基羰基氨基、叔丁基羰基氨基等)、卤素(如氟、氯、溴、碘)、氰基、硝基、酰基(如甲酰基、乙酰基、羧基、甲氧羰基、乙氧羰基、异丙氧羰基、叔丁氧羰基、氨基羰基、N,N-二甲基氨基羰基等)等，其中优选甲基、乙基、羟基、甲氧基、乙氧基、乙酰氧基、氨基、二甲氨基、乙酰氨基、氟、氯、氰基、乙酰基、甲氧羰基、乙氧羰基、氨基羰基或N,N-二甲基氨基羰基。
根据本发明一些具体实施方案，其中，所述“C3-7环烷基”指3至7个碳原子的含饱和环状脂肪烃的基团，选自环丙基、环丁基、环戊基、环己基、环庚基、2-甲基环丙基、2-乙基环丙基、2-丙基环丙基、2-异丙基环丙基、2-丁基环丙基、2-异丁基环丙基、2-叔丁基环丙基、2-甲基环丁基、3-甲基环丁基、2-乙基环丁基、3-乙基环丁基、2-丙基环丁基、3-丙基环丁基、2-异丙基环丁基、3-异丙基环丁基、2-甲基环戊基、3-甲基环戊基、4-甲基环戊基、2-乙基环戊基、3-乙基环戊基、2-甲基环己基、3-甲基环己基、4-甲基环己基、2,3-二甲基环丙基、2-甲基-3-乙基环丙基、2,3-二乙基环丙基、2,3-二甲基环丁基、2-甲基-3-乙基环丁基、3-甲基-2-乙基环丁基、2,3,4-三甲基环丁基，2,3-二甲基环戊基、2,4-二甲基环戊烷基等，其中优选环丙基或环丁基。
所述“异构体”包括具有对映或非对映关系的光学异构体、互变异构体、顺反异构体、构象异构体、内消旋化合物等或它们的混合物。在一实施方案中，由于所述的式I所示的化合物中磷原子具有手性，因此其构型选自S型、R型或S型与R型的混合物。
在一具体实施方案中，式IV所示化合物选自以下结构的化合物，或这些化合物的异构体、可药用盐、可药用共晶、水合物或溶剂合物：
Figure PCTCN2016112299-appb-000003
Figure PCTCN2016112299-appb-000004
在另一具体实施方案中，式IV所示化合物选自以下结构的化合物，或这些化合物的异构体、可药用盐、可药用共晶、水合物或溶剂合物：
Figure PCTCN2016112299-appb-000005
在另一具体实施方案中，式IV所示化合物选自以下结构的化合物，或这些化合物的异构体、可药用盐、可药用共晶、水合物或溶剂合物：
Figure PCTCN2016112299-appb-000006
所述“盐”的定义是本技术领域技术人员熟知的，是指由阳离子和阴离子通过离子键的作用而形成的化合物。
所述“共晶”(Co-Crystals)是指一种具有固定化学计量比的多组分晶体，在该晶体中各组分是以分子水平，通过氢键或其他非共价键、非离子键的作用结合而共存。在药物共晶中，一般包括药物活性成分和另一种或多种共晶形成体(Co-crystal former)。当单独的纯共晶形成体在室温下以液态存在时，该共晶也被称为“溶剂合物”，其中溶剂为水时被称为“水合物”。所述“共晶”还包括这样一些具有固定化学计量比的多组分晶体，在这些晶体中药物活性成分与其他组分之间，一部分通过氢键或其他非共价键作用，另一部分通过离子键或介于氢键与离子键之间的作用力而结合。
所述“盐”或“共晶”还包括盐或共晶的溶剂合物、水合物等形式。当盐或共晶在某种溶剂中制备、浆化或结晶时，该溶剂有可能进入到盐或共晶晶体中，形成溶剂合物；当该溶剂为水时，即有可能形成水合物。
确定“共晶”或“盐”的方法是本技术领域技术人员熟知的，如用单晶X-射线衍射分析等。
所述“可药用盐”或“可药用共晶”包括：本发明化合物与可药用无机酸，如盐酸、 硫酸、磷酸、亚磷酸、氢溴酸、硝酸等所成的盐或共晶，或本发明化合物与可药用有机酸，如马来酸、苹果酸、富马酸、琥珀酸、酒石酸、柠檬酸、乙酸、乳酸、甲磺酸、乙磺酸、甲苯磺酸、对甲苯磺酸等所成的盐或共晶。
根据本发明的目的，本发提供了式IV所示化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物的制备方法，该方法包括：
(1)、将式V所示化合物与式VI所示化合物在适合的条件下反应得到式VII所示化合物，
Figure PCTCN2016112299-appb-000007
其中R4的定义同上；
(2)、将式VII所示化合物与式VIII所示化合物在适合的条件下反应得到式所示IV化合物，
Figure PCTCN2016112299-appb-000008
其中R1、R2、R3、和R4的定义同上；
(3)、可选的，根据需要将式IV所示化合物进行手性拆分、制成盐、制成共晶、制成水合物或制成溶剂合物。
所述制备方法步骤(1)中，所述式V所示化合物可以按CN1487949A等中公开的方法制备；所述式VI所示化合物一般可商业化购得，也可用相应的氯代物、溴代物用本领域常规的方法转化为羟基化物。
所述制备方法步骤(1)中，所述反应一般需要在缩合剂的存在下进行。
根据本发明一些具体实施方案，其中，步骤(1)的所述缩合剂包括N,N-二环己基碳化二亚胺(DCC)、1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺(EDCI)等碳化二亚胺。碳化二亚胺类缩合剂一般需与如三乙胺、二甲氨基吡啶(DMAP)、1-羟基苯并***(HOBT)等试剂组合使用。
步骤(1)的所述缩合剂与式V所示化合物的投料摩尔比一般为0.8:1～2:1。
所述制备方法步骤(1)中，所述式V所示化合物与式VI所示化合物的投料摩尔比一般为1:1～1:3。
所述制备方法步骤(1)中，所述反应的溶剂一般为非质子溶剂，如N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜等。
所述制备方法步骤(2)中，所述式VIII所示化合物一般可商业化购得或按Arch.Pharm.(Weinheim)314,44-51(1980)，Bioorganic&Medicinal Chemistry16(17),8054-8062(2008)，WO2006123145，WO2011089396，WO2009158393，WO\2007020193，WO2014033617等相关文献制得。
所述制备方法步骤(2)中，所述反应一般需要在缩合剂的存在下进行。
根据本发明一些具体实施方案，其中，步骤(2)的所述缩合剂包括氯化亚砜(SOCl2)、三氯氧磷(POCl3)、六氟磷酸N-[(二甲氨基)-1H-1,2,3-***并[4,5-b]吡啶-1-基亚甲基]-N-甲基甲胺N-氧化物(HATU)、六氟磷酸N-[(1H-苯并***-1-基)(二甲基氨基)亚甲基]-N-甲基甲胺N-氧化物(HBTU)、六氟磷酸苯并***-1-基-N-氧基-三(吡咯烷基)鏻(PyBOP)，其中优选氯化亚砜(SOCl2)或三氯氧磷(POCl3)。
步骤(2)的所述缩合剂与式VII所示化合物的投料摩尔比一般为1:1～5:1。
所述制备方法步骤(2)中，所述式VII所示化合物与式VIII所示化合物的投料摩尔比一般为1:1～1:5。
所述制备方法步骤(2)中，所述反应的溶剂一般为非质子溶剂，如乙腈、二氯甲烷、氯仿、四氢呋喃等。
所述制备方法步骤(3)中，所述手性拆分可通过手性柱分离、手性酸选择性成盐或共晶分离等本领域内的常规方法进行，通过手性拆分，式IV所示化合物可转化为其异构体式IV1所示化合物或式IV2所示化合物。
Figure PCTCN2016112299-appb-000009
所述制备方法中所述式V所示化合物、式VI所示化合物、式VII所示化合物和式VIII所示化合物可由相应的盐、共晶、水合物或溶剂合物转化而来，该转化可在反应前进行，也可在反应或后处理中进行，这些转化方法可用本技术领域的常规方法进行。
所述制备方法步骤(1)、步骤(2)和步骤(3)中，产物的分离纯化可按本技术领域的常规方法进行，比如根据反应体系情况，采用浓缩反应液、pH调节、萃取、结晶、柱层析等方法中的一种或多种对所得产物进行分离或纯化。
根据本发明的目的，本发明提供了一种包含治疗有效量的式IV所示化合物或其异构 体、可药用盐、可药用共晶、水合物或溶剂合物，以及药用辅料的药物组合物。
在一实施方案中，本发明提供了一种包含治疗有效量的选自式a～式l所示的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，和药用辅料的药物组合物或制剂。
在另一实施方案中，本发明提供了一种包含治疗有效量的选自式a1～式l1所示的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，和药用辅料的药物组合物或制剂。
在一实施方案中，本发明提供了一种包含治疗有效量的选自式a2～式l2所示的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，和药用辅料的药物组合物或制剂。
上述药物组合物或制剂可经口或不经口给药。经口服给药时，可采用常规的制剂技术制成片剂、胶囊剂、丸剂、颗粒剂、溶液剂、糖浆剂、混悬剂、散剂、缓释制剂或控释制剂等。非经口服给药时，可采用常规的制剂技术将其制成透皮制剂、注射液、输液剂或栓剂等。
上述药物组合物的各种剂型可以按照药学领域的常规方法制备。例如将治疗有效量的式IV所示化合物、或选自式a～式l所示的化合物、或选自式a1～式l1所示的化合物、或选自式a2～式l2所示的化合物，或它们的异构体、可药用盐、可药用共晶、水合物或溶剂合物，可选地与另一种或多种治疗有效量的活性成分，与一种或多种药用辅料混合或接触，然后将其制成所需的剂型。
上述药物组合物或制剂优选口服剂型，包括片剂、胶囊剂、丸剂、颗粒剂、溶液剂、糖浆剂、干混悬剂、混悬剂、散剂、缓释制剂或控释制剂等。其中优选片剂、胶囊剂、颗粒剂、干混悬剂以及缓释制剂或控释制剂等固体口服制剂，其中更优选片剂和胶囊剂。可以按照制备固体口服制剂所采用的任何一种常规方法来制备本发明优选的药物组合物或制剂。如片剂可采用湿法制粒压片等方式制备，可根据需要进行任意形式的包衣，如片剂可以制成任意释放形式(如速释、肠溶和缓控释等)；胶囊剂可采用湿法制粒装胶囊剂等方式制备，胶囊剂内容物可以制成任意释放形式(如速释制剂、肠溶制剂和缓控释制剂等)。
在一实施方案中，本发明提供的式IV所示化合物、或选自式a～式l所示的化合物、或选自式a1～式l1所示的化合物、或选自式a2～式l2所示的化合物，或它们的异构体、可药用盐、可药用共晶、水合物或溶剂合物的粒径分布控制在95％小于200μm,优选小 于180μm，再优选小于150μm，更优选小于100μm。在口服剂型中本领域常规的药用辅料，包括填充剂、崩解剂、粘合剂、分散剂、润滑剂或助留剂以及各类型的包衣材料等。
所述填充剂一般包括预胶化淀粉、淀粉、乳糖、糊精、磷酸氢钙、碳酸钙、甘露醇、微晶纤维素、山梨醇、葡萄糖等，它们可以单独使用也可以混合使用，其中优选为预胶化淀粉、乳糖、微晶纤维素和甘露醇中的一种或多种。
所述崩解剂一般包括交联羧甲纤维素钠、羧甲基纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、淀粉、微晶纤维素、低取代羟丙基纤维素等，它们可以单独使用也可以混合使用，其中优选为交联羧甲纤维素钠、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、微晶纤维素和低取代羟丙基纤维素中的一种或多种。
所述粘合剂一般包括微晶纤维素、预交化淀粉、羟丙基甲基纤维素、羟丙基纤维素、聚维酮、淀粉浆、***胶、聚乙二醇4000、聚乙烯醇、藻酸盐、水、各种浓度的乙醇溶液，它们可以单独使用也可以混合使用，其中优选为羟丙基甲基纤维素、羟丙纤维素、聚维酮和淀粉浆中的一种或多种。
所述润滑剂一般包括硬脂酸镁、硬脂酸、硬脂酸钙、硬脂酸富马酸钠、硬脂酸富马酸钾、棕榈酸、微分硅胶、硬脂酰胺、滑石粉、固体聚乙二醇、三乙酸甘油酯等。它们可以单独使用也可以混合使用，其中优选为硬脂酸镁、硬脂酸、滑石粉、微分硅胶和三乙酸甘油酯中的一种或多种。
如果需要，还可以向上述组合物或制剂中添加其他辅料，如甜味剂(如阿司帕坦、甜菊素等)、着色剂(如柠檬黄、氧化铁等各种药用或食用色素)、稳定剂(如碳酸钙、碳酸氢钙、碳酸氢钠、碳酸钠、磷酸钙、磷酸氢钙、甘氨酸等)、表面活性剂(如吐温80、十二烷基硫酸钠等)包衣材料(如欧巴代，羟丙基甲基纤维素、羟丙基纤维素、丙烯酸树脂共聚物等。
在一具体实施方案中，本发明提供了一种组合物或制剂，其中活性成分选自治疗有效量的式IV所示化合物、或选自式a～式l所示的化合物、或选自式a1～式l1所示的化合物、或选自式a2～式l2所示的化合物，或它们的异构体、可药用盐、可药用共晶、水合物或溶剂合物。该组合物或制剂优选口服制剂，更优选片剂和胶囊剂；在单位组合物或制剂中，它们的重量含量一般为1mg至200mg，优选5mg至100mg。
根据本发明的目的，本发明提供了式IV所示化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物在制备预防和/或治疗病毒感染的药物中的应用。
具体地，本发明提供了式IV所示化合物或其异构体、可药用盐、可药用共晶、水合 物或溶剂合物在制备预防和/或治疗乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的应用。
在一实施方案中，本发明提供了式IV所示化合物、或选自式a～式l所示的化合物、或选自式a1～式l1所示的化合物、或选自式a2～式l2所示的化合物，或它们的异构体、可药用盐、可药用共晶、水合物或溶剂合物在制备预防和/或治疗乙型肝炎病毒(HBV)和/或人类免疫缺陷病毒(HIV)感染的药物中的应用。
经实验证明，本发明提供的式IV所示化合物，比如选自式a～式l所示的化合物、或选自式a1～式l1所示的化合物、或选自式a2～式l2所示的化合物，或它们的异构体、可药用盐、可药用共晶、水合物或溶剂合物等，在抗病毒感染，特别在抗乙型肝炎病毒(HBV)、人类免疫缺陷病毒(HIV)感染方面比现有技术(比如倍司福韦)具有更高的活性和更好的安全性。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
实施例1化合物a制备
步骤1
Figure PCTCN2016112299-appb-000010
将1-((2-氨基-9H-嘌呤-9-基)甲基)环丙氧基甲基磷酸(化合物V)5.0g(16.7mmol)、苯酚(化合物1)3.1g(33.4mmol)、三乙胺2.7ml与1-甲基-2-吡咯烷酮50ml混合，加热至约90℃，再加入DCC 5.5g(26.7mmol)，搅拌反应过夜。反应完毕后，冷却至室温，加入水30ml，过滤除去固体，滤液经减压浓缩，浓缩物中加水30ml，用25％的氢氧化钠水溶液调pH至约11，经硅藻土过滤，滤液用乙酸乙酯萃取，水相用浓盐酸调pH至约3，过滤，滤饼经柱层析纯化，得化合物2。
步骤2
Figure PCTCN2016112299-appb-000011
将化合物2 3.5g(9.3mmol)与乙腈10ml混合，再加入氯化亚砜1.5ml(21.0mmol)，加热至约80℃，搅拌反应，待溶液变清后减压蒸除溶剂；所得残余物冷却后加入二氯甲烷25ml溶解，冷却至约-20℃，加入α-异丁氨酸异丙酯(化合物3)2.7g(18.6mmol)溶于二氯甲烷15ml的溶液和三乙胺2.4ml，缓慢升温至室温。反应完毕后，用10％磷酸二氢钠溶液洗涤，有机层经无水硫酸钠干燥、减压浓缩，所得浓缩物经柱层析纯化，得化合物a。
1H-NMR(δ)：8.34(s,1H)，8.05(s,1H)，7.63～6.95(m,5H)，6.49(b,2H)，4.35～4.00(m,5H)，3,74(m,2H)，1.52～1.18(m,13H)，0.92(t,2H)。
MS(m/z)：503.2(MH+)。
实施例2手性化合物a1和a2的制备
Figure PCTCN2016112299-appb-000012
将实施例1所得的化合物a按以下条件进行HPLC制备分离，得化合物a1(保留时间15.5min)和化合物a2(保留时间16.7min)。
仪器：Instrument:Thar analytical SFC
色谱柱：Chiralpak AS-H,250×4.6mm
流动相：A：CO2；B:乙醇(0.05％二乙醇胺)
梯度:B 40％
流速:2.4mL/min
柱压:100bar
柱温:35℃
波长:220nm。
实施例3化合物b的制备
Figure PCTCN2016112299-appb-000013
参照实施例1的制备方法，不同点在于，用化合物4代替α-异丁氨酸异丙酯(化合物3)，得化合物b。
1H-NMR(δ)：8.32(s,1H)，8.07(s,1H)，7.62～6.93(m,5H)，6.49(b,2H)，4.35～4.04(m,5H)，3,71(m,2H)，1.51～1.19(m,9H)，0.96(m,4H)。
MS(m/z)：501.1(MH+)。
实施例4手性化合物b1和b2的制备
Figure PCTCN2016112299-appb-000014
将实施例3所得的化合物b按实施例2的方法进行分离，得化合物b1(保留时间17.3min)和化合物b2(保留时间18.9min)。
实施例5化合物c的制备
Figure PCTCN2016112299-appb-000015
参照实施例1的制备方法，不同点在于，用对甲基苯酚代替苯酚，得化合物c。
1H-NMR(δ)：8.31(s,1H)，8.21(s,1H)，7.35～6.61(m,4H)，6.21(b,2H)，4.41～4.01(m,5H)，3,83(m,2H)，1.51～1.31(m,16H)，0.96(m,2H)。
MS(m/z)：517.3(MH+)。
实施例6手性化合物c1和c2的制备
Figure PCTCN2016112299-appb-000016
将实施例5所得的化合物c按实施例2的方法进行分离，得化合物c1(保留时间18.4min)和化合物c2(保留时间19.8min)。
实施例7化合物d的制备
Figure PCTCN2016112299-appb-000017
参照实施例1的制备方法，不同点在于，用2,6-二甲基苯酚代替苯酚，得化合物d。
1H-NMR(δ)：8.42(s,1H)，8.12(s,1H)，7,83～6.32(m,3H)，6.22(b,2H)，4.31～4.01(m,5H)，3,84(m,2H)，1.54～1.41(m,19H)，0.94(m,2H)。
MS(m/z)：531.3(MH+)。
实施例8手性化合物d1和d2的制备
Figure PCTCN2016112299-appb-000018
将实施例7所得的化合物d按实施例2的方法进行分离，得化合物d1(保留时间20.1min)和化合物d2(保留时间22.4min)。
实施例9化合物e的制备
Figure PCTCN2016112299-appb-000019
参照实施例1的制备方法，不同点在于，用1-萘酚代替苯酚，得化合物e。
1H-NMR(δ)：8.31(s,1H)，8.11(s,1H)，7,88～6.61(m,7H)，6.22(b,2H)，4.34～4.10(m,5H)，3,74(m,2H)，1.53～1.42(m,13H)，0.93(m,2H)。
MS(m/z)：553.3(MH+)。
实施例10手性化合物e1和e2的制备
Figure PCTCN2016112299-appb-000020
将实施例9所得的化合物e按实施例2的方法进行分离，得化合物e1(保留时间21.2min)和化合物e2(保留时间22.9min)。
实施例11化合物f的制备
Figure PCTCN2016112299-appb-000021
参照实施例1的制备方法，不同点在于，用2-萘酚代替苯酚，得化合物f。
1H-NMR(δ)：8.22(s,1H)，8.14(s,1H)，7,85～6.81(m,7H)，6.21(b,2H)，4.35～4.11(m,5H)，3,72(m,2H)，1.51～1.41(m,13H)，0.93(m,2H)。
MS(m/z)：553.3(MH+)。
实施例12手性化合物f1和f2的制备
Figure PCTCN2016112299-appb-000022
将实施例11所得的化合物f按实施例2的方法进行分离，得化合物f1(保留时间21.8min)和化合物f2(保留时间22.7min)。
实施例13化合物g的制备
参照实施例1的制备方法，不同点在于，用对氟苯酚代替苯酚，得化合物g。
1H-NMR(δ)：8.21(s,1H)，8.11(s,1H)，7.65～6.91(m,4H)，6.31(b,2H)，4.43～4.02(m,5H)，3,81(m,2H)，1.54～1.33(m,13H)，0.91(m,2H)。
MS(m/z)：521.3(MH+)。
实施例14手性化合物g1和g2的制备
Figure PCTCN2016112299-appb-000024
将实施例13所得的化合物g按实施例2的方法进行分离，得化合物g1(保留时间16.4min)和化合物g2(保留时间17.2min)。
实施例15化合物h的制备
Figure PCTCN2016112299-appb-000025
参照实施例1的制备方法，不同点在于，用对氯苯酚代替苯酚，得化合物h。
1H-NMR(δ)：8.22(s,1H)，8.14(s,1H)，7.65～6.91(m,4H)，6.31(b,2H)，4.33～4.02(m,5H)，3,75(m,2H)，1.54～1.31(m,13H)，0.98(m,2H)。
MS(m/z)：537.2(MH+)。
实施例16手性化合物h1和h2的制备
Figure PCTCN2016112299-appb-000026
将实施例15所得的化合物h按实施例2的方法进行分离，得化合物h1(保留时间17.0min)和化合物h2(保留时间18.3.min)。
实施例17化合物i的制备
Figure PCTCN2016112299-appb-000027
参照实施例1的制备方法，不同点在于，用4-羟基吡啶代替苯酚，得化合物i。
1H-NMR(δ)：8.48～6.61(m,6H)，6.21(b,2H)，4.34～4.04(m,5H)，3,84(m,2H)，1.54～1.41(m,13H)，0.94(m,2H)。
MS(m/z)：504.1(MH+)。
实施例18手性化合物i1和i2的制备
Figure PCTCN2016112299-appb-000028
将实施例17所得的化合物i按实施例2的方法进行分离，得化合物i1(保留时间15.4min)和化合物i2(保留时间16.1min)。
实施例19化合物j的制备
Figure PCTCN2016112299-appb-000029
参照实施例1的制备方法，不同点在于，用对甲氧基苯酚代替苯酚，得化合物j。
1H-NMR(δ)：8.24(s,1H)，8.12(s,1H)，7.61～6.93(m,4H)，6.35(b,2H)，4.32～4.01(m,5H)，3,75(m,5H)，1.51～1.21(m,13H)，0.95(m,2H)。
MS(m/z)：533.2(MH+)。
实施例20手性化合物j1和j2的制备
Figure PCTCN2016112299-appb-000030
将实施例19所得的化合物j按实施例2的方法进行分离，得化合物j1(保留时间17.9min)和化合物j2(保留时间19.0min)。
实施例21化合物k的制备
Figure PCTCN2016112299-appb-000031
参照实施例1的制备方法，不同点在于，用对羟基苯甲酸乙酯代替苯酚，得化合物k。
1H-NMR(δ)：8.32(s,1H)，8.13(s,1H)，7.31～6.21(m,4H)，6.21(b,2H)，4.11～4.02(m,7H)，3,85(m,2H)，1.54～1.12(m,16H)，0.95(m,2H)。
MS(m/z)：575.1(MH+)。
实施例22手性化合物k1和k2的制备
Figure PCTCN2016112299-appb-000032
将实施例21所得的化合物k按实施例2的方法进行分离，得化合物k1(保留时间16.8min)和化合物k2(保留时间18.1min)。
实施例23化合物l的制备
Figure PCTCN2016112299-appb-000033
参照实施例1的制备方法，不同点在于，用α-异丁氨酸苄酯代替α-异丁氨酸异丙酯(化合物3)，得化合物l。
MS(m/z)：551.2(MH+)。
实施例24手性化合物l1和l2的制备
Figure PCTCN2016112299-appb-000034
将实施例23所得的化合物l按实施例2的方法进行分离，得化合物l1(保留时间19.0min)和化合物l2(保留时间20.2min)。
实施例25化合物a1的薄膜包衣片及其制备
组分 含量(mg/片)
片芯：  
化合物a1 50.0
一水乳糖 100.0
微晶纤维素 60.0
交联羧甲纤维素钠 15.0
硬脂酸镁 3.0
薄膜包衣材料：  
欧巴代Ⅱ 10.0
按照上表中各原辅料称量，将微晶纤维素与交联羧甲纤维素钠混合，然后加入一水乳糖混合，再加入化合物a1混合；加纯化水适量湿法制粒；干燥；整粒；外加硬脂酸镁混匀，压片；然后将包衣材料用75％乙醇配成混悬液包衣，即得。
制备例1化合物V的制备
Figure PCTCN2016112299-appb-000035
按CN1487949A中实施例5公开的方法制备。
制备例2化合物III的制备
Figure PCTCN2016112299-appb-000036
按CN1487949A中实施例6公开的方法制备。
制备例3化合物VI的制备
Figure PCTCN2016112299-appb-000037
按CN104119385A中实施例1公开的方法制备。
制备例4化合物VII的制备
Figure PCTCN2016112299-appb-000038
按CN104119385A中实施例2公开的方法制备。
测试例 抗乙型肝炎病毒活性筛选
用HepG2.2.15细胞测定化合物的抗乙肝病毒活性。使用的材料与仪器如下：HepG2.2.15细胞，RPMI 1640培养液，胎牛血清，96孔板，DMSO，QIAamp 96DNA Blood Kit，Cell-titer blue，酶标仪，Applied Biosystems 7900real-time PCR system。
用DMSO将各化合物溶解至20mM，-20℃贮存，将各化合物的20mM贮存液用DMSO 3倍梯度稀释，共9个浓度。再用含2.0％FBS的RPMI 1640培养液稀释200倍。化合物的最高测试终浓度为100μM。实验步骤参照QIAamp 96DNABlood Kit(QIAGEN 51161)说明书，qPCR法测定化合物抗乙肝病毒活性并计算EC50(半数有效抑制浓度)。分析数据和计算抑制百分比：应用如下公式计算抑制百分比：抑制率(％)＝(DMSO对照组的HBV总量-受试样品组的HBV总量)/DMSO对照组的HBV总量×100。最后使用GraphPad Prism软件计算化合物的EC50值。
Cell-titer blue法测定化合物的细胞毒性并计算CC50(致50％细胞毒性浓度)。分析数据和计算相对细胞活力：应用如下公式计算细胞活性百分比：细胞生存率(％)＝(受试样品 的荧光数值-背景荧光数值)/(DMSO对照组的荧光数值-背景荧光数值)×100。最后使用GraphPad Prism软件计算化合物的CC50值。实验结果如下：
Figure PCTCN2016112299-appb-000039
实验表明，式a1～式l1所示的化合物、式a2～式l2所示的化合物与式III所示的化合物相比，EC50值明显更低，明显具有更好的抗乙肝病毒活性，CC50均>100μM,在测试的浓度范围内没有细胞毒性。
本领域技术人员可以理解，在本说明书的教导之下，可以对本发明做出一些修改或变化。这些修改和变化也应当在本发明权利要求所限定的范围之内。

Claims (10)

  1. 一种式IV所示化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，
    Figure PCTCN2016112299-appb-100001
    其中：
    R1为氢、C1-6烷基，或取代或非取代的C6-10芳基、6至10元杂芳基或苄基；
    R2，R3分别为C1-6烷基，或R2、R3与所连的碳原子形成C3-7环烷基；
    R4为取代或非取代的C6-10芳基或6至10元杂芳基。
  2. 根据权利要求1所述的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，其特征在于，其中所述C1-6烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、叔戊基、2-甲基丁基、3-甲基丁基、1-乙基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、正己基或异己基；所述6至10元杂芳基选自吡啶-2-基、吡啶-3-基、吡啶-4-基、哒嗪-3-基、哒嗪-4-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、吡嗪-2-基、吡嗪-3-基、吲哚基、异吲哚基、吲唑基、吲嗪基、嘌呤基、喹嗪基、喹啉基、异喹啉基、噌啉基、酞嗪基、萘啶基、喹唑啉基、喹喔啉基、噻吩并[2,3-b]呋喃基、呋喃并[3,2-b]-吡喃基、吡啶并[2,3-d]噁嗪基、吡唑并[4,3-d]噁唑基、咪唑并[4,5-d]噻唑基、吡嗪并[2,3-d]哒嗪基、咪唑并[2,1-b]噻唑基、咪唑并[1,2-b][1,2,4]三嗪基、苯并噻吩基、苯并噁唑基、苯并咪唑基、苯并噻唑基、苯并噁庚因基、苯并噁嗪基、苯并呋喃基、苯并***基、吡咯并[2,3-b]吡啶基、吡咯并[3,2-c]吡啶基、吡咯并[3,2-b]吡啶基、咪唑并[4,5-b]吡啶基、咪唑并[4,5-c]吡啶基、吡唑并[4,3-d]吡啶基、吡唑并[4,3-c]吡啶基、吡唑并[3,4-c]吡啶基、吡唑并[3,4-d]吡啶基、吡唑并[3,4-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡咯并[1,2-b]哒嗪基、咪唑并[1,2-c]嘧啶基、吡啶并[3,2-d]嘧啶基、吡啶并[4,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[2,3-b]吡嗪基、吡啶并[3,4-b]吡嗪基、嘧啶并[5,4-d]嘧啶基、吡唑并[2,3-b]吡嗪基或嘧啶并[4,5-d]嘧啶基；当所述芳基、杂芳基或苄基为取代的时，所述芳基、杂芳基或苄基的取代基选自烷基、烯基、炔基、羟基、烷氧基、酰氧基、巯基、烷硫基、氨基、烷氨基、酰氨基、卤素、氰基、硝基或酰基；所述C3-7环烷基选自环丙基、环丁 基、环戊基、环己基、环庚基、2-甲基环丙基、2-乙基环丙基、2-丙基环丙基、2-异丙基环丙基、2-丁基环丙基、2-异丁基环丙基、2-叔丁基环丙基、2-甲基环丁基、3-甲基环丁基、2-乙基环丁基、3-乙基环丁基、2-丙基环丁基、3-丙基环丁基、2-异丙基环丁基、3-异丙基环丁基、2-甲基环戊基、3-甲基环戊基、4-甲基环戊基、2-乙基环戊基、3-乙基环戊基、2-甲基环己基、3-甲基环己基、4-甲基环己基、2,3-二甲基环丙基、2-甲基-3-乙基环丙基、2,3-二乙基环丙基、2,3-二甲基环丁基、2-甲基-3-乙基环丁基、3-甲基-2-乙基环丁基、2,3,4-三甲基环丁基，2,3-二甲基环戊基或2,4-二甲基环戊烷基。
  3. 根据权利要求2所述的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，其特征在于，其中所述C1-6烷基选自甲基、乙基、异丙基或叔丁基；所述C6-10芳基选自苯基、1-萘基或2-萘基；所述6至10元杂芳基选自吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-2-基、嘧啶-4-基或嘧啶-5-基；当所述芳基、杂芳基或苄基为取代的时，所述芳基、杂芳基或苄基的取代基选自甲基、乙基、羟基、甲氧基、乙氧基、乙酰氧基、氨基、二甲氨基、乙酰氨基、氟、氯、氰基、乙酰基、甲氧羰基、乙氧羰基、氨基羰基或N,N-二甲基氨基羰基；所述C3-7环烷基选自环丙基或环丁基。
  4. 根据权利要求1～3任一项所述的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，其特征在于，所述的化合物选自：
    Figure PCTCN2016112299-appb-100002
    Figure PCTCN2016112299-appb-100003
  5. 根据权利要求1～3任一项所述的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，其特征在于，所述的化合物选自：
    Figure PCTCN2016112299-appb-100004
  6. 根据权利要求1～3任一项所述的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，其特征在于，所述的化合物选自：
    Figure PCTCN2016112299-appb-100005
    Figure PCTCN2016112299-appb-100006
  7. 一种式IV所示化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物的制备方法，该方法包括：
    (1)、将式V所示化合物与式VI所示化合物在适合的条件下反应得到式VII所示化合物，
    Figure PCTCN2016112299-appb-100007
    其中R4的定义同权利要求1；
    (2)、将式VII所示化合物与式VIII所示化合物在适合的条件下反应得到式所示IV化合物，
    Figure PCTCN2016112299-appb-100008
    其中R1、R2、R3、和R4的定义同权利要求1；
    (3)、可选的，根据需要将式IV所示化合物进行手性拆分、制成盐、制成共晶、制成水合物或制成溶剂合物。
  8. 一种药物组合物，其包含治疗有效量的权利要求1～6中任一项所述的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物，以及药用辅料。
  9. 权利要求1～6中任一项所述的化合物或其异构体、可药用盐、可药用共晶、水合物或溶剂合物在制备预防和/或治疗病毒感染的药物中的应用。
  10. 根据权利要求9的应用，其特征在于，所述病毒感染选自乙型肝炎病毒感染和/或人类免疫缺陷病毒感染。
PCT/CN2016/112299 2016-01-19 2016-12-27 一种核苷类似物的磷酰胺酯前药及其应用 WO2017124896A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680042114.XA CN107849075A (zh) 2016-01-19 2016-12-27 一种核苷类似物的磷酰胺酯前药及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610036040.0 2016-01-19
CN201610036040 2016-01-19

Publications (1)

Publication Number Publication Date
WO2017124896A1 true WO2017124896A1 (zh) 2017-07-27

Family

ID=59361465

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/112299 WO2017124896A1 (zh) 2016-01-19 2016-12-27 一种核苷类似物的磷酰胺酯前药及其应用

Country Status (2)

Country Link
CN (1) CN107849075A (zh)
WO (1) WO2017124896A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1950383A (zh) * 2003-12-30 2007-04-18 吉里德科学公司 用于治疗病毒性疾病的膦酸酯、单膦酸酰胺化物、双膦酸酰胺化物
WO2012142075A1 (en) * 2011-04-13 2012-10-18 Merck Sharp & Dohme Corp. 2'-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
CN104119385A (zh) * 2014-07-24 2014-10-29 廖国超 核苷类似物的磷酸酯前药及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1950383A (zh) * 2003-12-30 2007-04-18 吉里德科学公司 用于治疗病毒性疾病的膦酸酯、单膦酸酰胺化物、双膦酸酰胺化物
WO2012142075A1 (en) * 2011-04-13 2012-10-18 Merck Sharp & Dohme Corp. 2'-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
CN104119385A (zh) * 2014-07-24 2014-10-29 廖国超 核苷类似物的磷酸酯前药及其应用

Also Published As

Publication number Publication date
CN107849075A (zh) 2018-03-27

Similar Documents

Publication Publication Date Title
EP3558322B1 (en) Antiviral benzyl-amine phosphodiamide compounds
RU2750935C2 (ru) Положительные аллостерические модуляторы мускаринового ацетилхолинового рецептора m4
ES2384708T3 (es) Nueva forma cristalina y amorfa de un compuesto de triazolo(4,5-D)pirimidina
US11866432B2 (en) Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
TWI265031B (en) Novel pharmaceuticals
JP6323885B2 (ja) ヤヌスキナーゼ（ｊａｋ）阻害剤の硫酸水素塩およびその製造方法
ES2702194T3 (es) Compuestos de 6,7-dihidropirazolo[1,5-]pirazin-4(5H)-ona y su uso como moduladores alostéricos negativos de receptores mGlu2
WO2011078221A1 (ja) イミダゾピリダジン化合物
WO2009005693A1 (en) Novel hiv reverse transcriptase inhibitors
KR20230119022A (ko) 트라이아진 유도체를 함유하는 경구 투여하는 제제
CN105524045B (zh) 四环类间变性淋巴瘤激酶抑制剂
EP3476854B1 (en) Antiviral precursor drug nucleoside cyclophosphate compound and use thereof
TW202329973A (zh) 整合素抑制劑及其與其他藥劑併用之用途
CN113045569B (zh) 用作ret激酶抑制剂的化合物及其应用
CA3104365A1 (en) Crystal form of compound for inhibiting the activity of cdk4/6 and use thereof
TW201016698A (en) Antiviral compounds
AU2012274292B2 (en) Crystal of fused heterocyclic compound
JP4711228B2 (ja) 複素環を有する新規縮合多環式化合物及びその医薬用途
JP5781537B2 (ja) ヒスタミンｈ４受容体アンタゴニストとしてのアミノアルキルピリミジン誘導体
WO2017157137A1 (zh) 一种新型的无环核苷类似物及其药物组合物
US10189857B2 (en) Positive allosteric modulators of the muscarinic acetylcholine receptor M4
WO2017124896A1 (zh) 一种核苷类似物的磷酰胺酯前药及其应用
CN116583530A (zh) N4-羟基胞苷的酯衍生物及其用途
WO2017124895A1 (zh) 一种核苷类似物的烷氧烷基酯前药及其应用
CN113583020B (zh) 一种jak2抑制剂及应用

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: 16886155

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16886155

Country of ref document: EP

Kind code of ref document: A1