WO2014026582A1 - Composé diester de ténofovir, procédé de préparation et utilisation de celui-ci, et composition pharmaceutique comprenant celui-ci - Google Patents

Composé diester de ténofovir, procédé de préparation et utilisation de celui-ci, et composition pharmaceutique comprenant celui-ci Download PDF

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WO2014026582A1
WO2014026582A1 PCT/CN2013/081304 CN2013081304W WO2014026582A1 WO 2014026582 A1 WO2014026582 A1 WO 2014026582A1 CN 2013081304 W CN2013081304 W CN 2013081304W WO 2014026582 A1 WO2014026582 A1 WO 2014026582A1
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och
compound
salt
tautomer
group
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PCT/CN2013/081304
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English (en)
Chinese (zh)
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游国战
刘洪海
杨松峰
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洛阳聚慧投资股份有限公司
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Priority claimed from CN201310134491.4A external-priority patent/CN103242366B/zh
Priority claimed from CN201310134492.9A external-priority patent/CN103232490B/zh
Priority claimed from CN201310134160.0A external-priority patent/CN103224530B/zh
Application filed by 洛阳聚慧投资股份有限公司 filed Critical 洛阳聚慧投资股份有限公司
Publication of WO2014026582A1 publication Critical patent/WO2014026582A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • 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 Table
    • 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
    • C07F9/65616—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 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a tenofovir diester compound, a process for the preparation thereof, use thereof, and a pharmaceutical composition comprising the same.
  • the acyclic nucleoside compounds adefovir and tenofovir have obvious advantages in preventing viral resistance, and they are resistant to cyclic nucleosides.
  • the virus strain is effective, the incidence of drug resistance is low, and the toxicity is relatively small.
  • the polarity is strong, and the biofilm permeability is poor, resulting in low bioavailability, making it impossible to be used as a drug in clinical applications.
  • TDF diester prodrug tenofovir diisopropionyl Oxymethyl ester fumarate
  • WO 2012/041015 A1 discloses the following: "Chinese patent (CN1810816A) introduces a fat-soluble oxiranyl ethyl long chain on a hydroxyl group of a phosphate group in the tenofovir molecule to give a hydroxyl group of a phosphate group in the molecular structure. A long chain oxirane/propyl monoester derivative of adefovir and tenofovir obtained by esterification and still in a free state.
  • the compound is introduced not only after the introduction of long chain oxirane/propyl group
  • the pharmacokinetic properties of the compound are improved, and another free hydroxyl group in the phosphate group can still be phosphorylated, participate in the virus replication process, and exert an antiviral effect, thereby retaining the antiviral activity of tenofovir.
  • the introduction of the chain not only improves the pharmacokinetic properties of the compound but also retains the antiviral activity.”
  • the compounds have completed preclinical tests, respectively, which not only proves that the compounds in the above patents are highly active and It is also resistant to drug resistance, and it is also found to be very toxic, and does not inhibit the enzymes that metabolize these drugs in the liver.
  • the above compounds are all prodrugs of tenofovir, and the main purpose of modifying tenofovir is to improve its fat solubility, improve membrane permeability, and thereby improve the bioavailability of the human body.
  • one hydroxyl group of a phosphate group is esterified while the other is still in a free state, so it is still a highly polar compound. The availability of materials still needs to be further improved.
  • Another object of the invention is to provide a process for the preparation of said compounds.
  • Another object of the invention is to provide the use of said compounds.
  • Another object of the invention is to provide a pharmaceutical composition comprising the compound.
  • the present invention provides a tenofovir diester compound represented by the formula (I), a salt thereof or a tautomer thereof,
  • R a and R b are independently selected from R 2 or R 3 , and R a and R b are not simultaneously R 2 ;
  • R c is selected from hydrogen or C 1 C 5 fluorenyl;
  • the Ri is -OCH 2 (CH 2 ) m CH 2 OCH 2 (CH 2 ) n CH 3 , wherein m is an integer of 0 to 4, and n is an integer of 10 20 ;
  • the R 3 is a residue obtained by removing an amine from an amino group of any natural or pharmaceutically acceptable amino acid, wherein the carboxyl group in the amino acid is esterified with a thiol group or an aryl group.
  • amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, phenylalanine, valine, tryptophan, serine, tyrosine, cysteine, Methionine, aspartic acid, glutamic acid, threonine, lysine, arginine or histidine.
  • the structure is represented by the general formula ( ⁇ ),
  • R 5 is independently selected from a C1 to C12 fluorenyl group, a C3 to C12 cycloalkane group, a C2 to C12 alkenyl group, a C2 to C12 alkynyl group, a C6 to C12 aryl group or a C6 to C12 aryl group. ⁇ .
  • R4 and R 5 are independently selected from a sulfhydryl group of CI ⁇ C12, a cyclic fluorenyl group of C3 C12 or C6 ⁇ An aromatic group of C12.
  • the R4 is selected from a methyl group, an ethyl group or a benzyl group.
  • the m is an integer of 0 to 2; more preferably 0 or 1.
  • n is an integer of 12 18; more preferably 14, 15 or 16.
  • the present invention provides a compound represented by any one of the following structures, a salt thereof or a tautomer thereof:
  • the compound represented by the formula (I) has an asymmetric center and has an S configuration or configuration
  • the technical solution of the present invention includes all possible stereoisomers and a mixture of two or more isomers.
  • the technical solution of the present invention also includes a cis isomer, a trans isomer or a mixture of these isomers. Among them, a single isomer can be isolated according to a conventional method or synthesized by stereoselective synthesis.
  • the salt means a physiologically acceptable salt, that is, an organic salt and an inorganic salt of the compound of the present invention.
  • Physiologically acceptable salts are well known in the art to those skilled in the art.
  • Physiologically acceptable salts include, but are not limited to, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and the like, and organic Acid salts such as fumarate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or by other methods described in the literature, such as ion exchange The salt obtained.
  • the preparation method of the present invention is as follows: a compound represented by the general formula (1-1) is used as a starting material, and a condensation reaction is carried out to obtain a monoester compound (1-2), and then a condensation reaction is carried out to obtain a general formula.
  • the respective esterification processes are preferably: when the esterification substituent is Ri, the reactant is Alcohol HOCH 2 (CH 2 )mCH 2 OCH 2 (CH 2 ) nCH 3 (m, n is as defined above), using N-methylpyrrolidone as solvent, in the presence of triethylamine, hydrazine, hydrazine '-Dicyclohexylcarbodiimide is a complexing agent for dehydration condensation reaction.
  • the reaction temperature during the reaction is 70 ° C - 110 ° C, and the reaction time is 7-15 hours.
  • the reactant is isopropyl chloromethyl carbonate
  • the condensation reaction is carried out in the presence of triethylamine using N-methylpyrrolidone as a solvent, and the reaction temperature during the reaction is 45 ° C. -75 °C, reaction time is 12-18 hours.
  • the reactant is an amino acid ester hydrochloride
  • N-methylpyrrolidone is used as a solvent
  • triethylamine is a dehydrating agent
  • 2,2'-dithiodipyridine or triphenylphosphine is used as a solvent.
  • the mixture is subjected to a condensation reaction in which the reaction temperature is 45 V -85 V and the reaction time is 8-26 hours.
  • the present invention provides the use of a compound according to any one of the above aspects, a salt thereof or a tautomer thereof for the preparation of a medicament for preventing or treating a tumor or a viral disease.
  • the viral disease is a disease caused by HIV and/or a hepadnavirus.
  • hepadnavirus is hepatitis B virus.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to any one of the above aspects, a salt thereof or a tautomer thereof, and a pharmaceutically acceptable carrier.
  • compositions provided herein can be prepared according to methods known in the art to produce any dosage form suitable for human or animal use.
  • the active ingredient is usually present in the pharmaceutical composition in an amount of from 0.1 to 95% by weight, or may be adjusted accordingly by those skilled in the art depending on the application.
  • the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, a powder, a granule, a suspension, an emulsion or an injection.
  • the compound of the formula (I), a salt thereof or a tautomer thereof can be prepared according to known methods with pharmaceutically acceptable suitable pharmaceutical carrier materials such as fillers, fragrances, Flavoring agents, colorants, wetting agents,
  • suitable pharmaceutical carrier materials such as fillers, fragrances, Flavoring agents, colorants, wetting agents,
  • the excipient, the disintegrating agent or the surfactant is mixed by a known method, and is prepared into a liquid dosage form such as a solid dosage form or a suspension agent such as a tablet or the like.
  • the pharmaceutical composition of the present invention can be prepared into a general preparation, a sustained release preparation, a controlled release preparation or a delivery system for various preparations and the like.
  • the pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of enhancing the therapeutic effect for the purpose of administration.
  • the tenofovir diester compound provided by the invention, the salt thereof or the tautomer thereof has novel structure, simple synthesis, reduced polarity of the compound, and better fat solubility than the existing tenofovir diester compound.
  • the membrane permeability of the drug can be improved to improve bioavailability; in addition, the compound provided by the present invention also exhibits a strong antiviral effect, especially for HIV and hepadnavirus, the activity is superior to the existing one.
  • the tenofovir diester compound which does not show obvious toxicity and has high safety, is suitable for the prevention and treatment of AIDS and hepatitis, and has a very broad application prospect.
  • FIG. 1 is a high performance liquid chromatogram of the inventive compounds COP12-114 and CMX157 described in Experimental Example 1;
  • FIG. 2 is a high performance liquid chromatogram of the inventive compounds COP130-114 and CMX157 described in Experimental Example 1;
  • Fig. 4 is a high performance liquid chromatogram of the inventive compounds COP233 and TDF described in Experimental Example 1.
  • the abscissa is time and the unit is minute.
  • 1,3-propanediol (9.13 g, 0.12 mol), potassium t-butoxide (6.8 g, 0.06 mol) and tert-amyl alcohol (50 ml) were added in this order, and slowly added dropwise under reflux.
  • NM 400 MHz, CDC1 3 ) ⁇ (ppm ): 0.88 (3H, t, CH 3 ), 1.06-1.49 (30H, m, 15 CH 2 ), 1.53- 1.654(2H, m, CH 2 ), 1.90 -2.10(1H, br, OH), 3.47(2H, t, OCH 2 ), 3.53 (2H, t, OCH 2 ), 3.73 (2H, t, OCH 2 ).
  • L410 was synthesized in the same manner as in the synthesis of L114 to give 6-dodecyloxy-1-hexanol (L410).
  • NM 400 MHz, CDC1 3 ) ⁇ (ppm ): 0.88 (3 ⁇ , t, CH 3 ), 1.14-1.34 (18H, m, 9 x CH 2 ), 1.35-1.42 (4H, m, 2 CH 2 ) , 1.48-1.64 (6H, m, 3 x CH 2 ), 1.93-2.01 (1H, br, OH), 3.28-3.48 (4H, m, 2 OCH 2 ), 3.62 (2H, t, OCH 2 ).
  • L220 was synthesized in the same manner as in the synthesis of L114 to give 4-teledecyloxy-1-butanol (L220).
  • Example 1 Preparation of C0P12-114 In a 50 ml round bottom flask, (R)-9-[2-(phosphomethoxy)propyl]adenine (tenofovir, PMPA) (1.3 g, 4.5 mmol), triethylamine (7 ml) were added in sequence.
  • PMPA tenofovir
  • COP02 (1.23 g, 3.04 mmol)
  • L016 (1.11 g, 6.08 mmol) was mixed and dissolved in 10 ml of N-methylpyrrolidone, heated to 75 ° C and stirred for 15 minutes, then added dropwise.
  • Example 4 Preparation of C0P12-220 In a 50 ml round bottom flask, COP02 (1.23 g, 3.04 mmol) and L220 (2.42 g, 6.08 mmol) were mixed and dissolved in 10 ml of N-methylpyrrolidone, heated to 90 ° C and stirred for 20 minutes, then added dropwise.
  • tenofovir (PMPA) ( 1.18 g, 4.13 mmol), L-alanine ethyl ester hydrochloride (2.6 g, 17 mmol), 2,2'-dithiodipyridine were added in sequence.
  • COP031 (9.7 g, 25 mmol) and L114 (15 g, 50 mmol) were added and dissolved in 65 ml of N-methylpyrrolidone. After heating to 85 ° C for 30 minutes, slowly add dropwise. 22 ml of triethylamine, and then the temperature was raised to 10 CTC, and dicyclohexylcarbodiimide (DCC) llg (dissolved in 16 ml of N-methylpyrrolidone) was added dropwise.
  • DCC dicyclohexylcarbodiimide
  • NM 400 MHz, CDC1 3 ), ⁇ (ppm ): 0.88 (3H, t, CH 3 ), 1.16-1.36 (36H, m, 15 x CH 2 and 2 x CH 3 ), 1.37 (3H, t, CH 3 ), 1.47-1.62(2H, m, CH 2 ), 3.35-3.68(6H, m, 3 x OCH 2 ), 3.76-4.20(8H, m, OCH 2 P, NCH 2 , COOCH 2 , OCH and NH), 4.28-4.45(lH, m, NCH), 6.15(2H, s, NH 2 ), 7.94-8.04 (lH, d, H on the anthracene ring), 8.28-8.37 (1 ⁇ , d, anthracene ring H).
  • PMPA C0P034 C0P134-1 14 In a 50 ml round bottom flask, tenofovir (PMPA) ( 1.18 g, 4.13 mmol), L-alanine n-butyl ester hydrochloride (3.08 g, 0.017 mol), 2 , 2'-dithiodipyridine (1.82g, 8.26mmol), triethylamine (3.44g, 4.8ml, 34mol), triphenylphosphine (2.16g, 8.24mmol) and N-methylpyrrolidone (10ml) After stirring at 80 ° C for 12 h, the solvent was evaporated, and then ethyl acetate: EtOAc: EtOAc (EtOAc: EtOAc) .
  • PMPA C0P035 C0P135-114 In a 50 ml round bottom flask, tenofovir (PMPA) ( 1.18 g, 4.13 mmol), L-alanine cyclohexyl ester hydrochloride (3.52 g, 17 mmol), 2, 2 were added in sequence. '-Dithiodipyridine (1.82 g, 8.26 mmol), triethylamine (3.44 g, 4.8 ml, 34 mol), triphenylphosphine (2.16 g, 8.24 mmol) N-methylpyrrolidone (10 ml), After the mixture was stirred at 75 ° C for 14 h, the solvent was evaporated. mjjjjjjjjj 45.1%. .
  • Example 40 Pharmaceutical Formulation Containing Compound CO12-12-114
  • the composition is as follows (tablet unit: 200 mg / tablet; capsule unit: 200 mg / tablet): Compound C0P12-114: lOOmg;
  • Lactose 65mg
  • Microcrystalline cellulose 5mg
  • Carboxymethyl starch sodium 5mg;
  • Magnesium stearate lmg.
  • Test substances include: Determination of the fat solubility of the compounds of the present invention COP12-114 and CMX157, COP130-114 and CMX157, COP 131-114 and CMX 157, COP233 and TDF.
  • the fat-soluble nature of the test substance is usually characterized by the length of time that different substances remain on the reversed-phase chromatogram under the same conditions. The higher the fat solubility of a substance, the longer the retention time of the substance on the reverse phase chromatogram.
  • the retention times of the compounds of the present invention COP12-114, COP130-114, and C0P131-114 were 2.69 minutes, 7.542 minutes, and 2.648 minutes, respectively, and the retention time of the compound C0P233 was longer than that of the TDF. 0.542 minutes. This indicates that the fat solubility of the compound of the present invention is much higher than that of CMX157 and TDF, indicating that the membrane permeability is improved.
  • HepG2.2.15 cells were cultured in a 24-well cell culture plate for 48 hours, and then the drug-containing culture solutions were added at different concentrations. The culture was continued for 9 days (changing every 3 days), and the supernatant was collected and subjected to real-time quantitative PCR detection by a fluorescent probe method. The results are shown in Table 1.
  • HBV primer HBV upstream primer: 5,-TgT CCT ggT TAT CgC Tgg-3,
  • HBV downstream primer 5,-CAA ACg ggC AAC ATA CCT T-3'
  • HBV fluorescent probe sequence 5 '(FAM)-TgT gTC TgC ggC gTT TTA TCA T-(TAMRA)3,
  • PCR pre-denaturation at 95 °C for 5 min; denaturation at 95 °C for 10 s, annealing and extension at 60 °C for 30 s, 40 cycles.
  • the compounds C0P12-114, C0P131-114, C0P132-114, C0P133-114, C0P134-114, C0P135-114, C0P230, C0P231, C0P232, C0P233, C0P235 can effectively inhibit the replication of HBV virus DNA, and the effect is better than TDF.
  • Test sample See Table 2.
  • Experimental medium Dimethyl sulfoxide (DMSO), from Sigma, USA; 1.7 Main instruments and reagents: BS124S electronic balance: Sartorius, Germany; Centrifuge: Beckman, USA; C0 2 cell incubator: ShellAB, USA; Sirius chemiluminescence detector: Berthold, Germany; Trypsin: Invitrogen, USA; Streptomycin: American Invitrogen; Fetal bovine serum: Gibco, USA; Solution for lysing and luciferase detection: Promega, USA.
  • test compound was dissolved in DMSO, added to the cell culture medium 15 minutes before infection, and the DMSO solvent was used as a blank control. Then add 0.5 ml of virus solution (diluted the virus stock to 0.1-0.5 ng p24/ml according to p24 concentration). 48 hours after infection, the supernatant was removed, 50 ⁇ M of cell lysate (Promega) was added to each well to lyse the cells, and 20 ⁇ M of cell lysate was added to 30 ⁇ L of luciferase substrate (Promega) using FB15 fluorescence detector. The relative activity of luciferase was determined by (Sirius) instrument, and the half-inhibitory concentration of the compound on wild-type HIV-1 replication was calculated using DMSO as a control. The detection data are shown in Table 2.
  • the effect of compounds on cell survival was examined by MTS assay: 293T cells in logarithmic growth phase were seeded into 96-well plates at a cell density of 8000-10000 cells/well, each well 37 ⁇ , 37 °C, 5% CO 2 incubator After 24 hours of culture, the test compound was added, and DMSO was used as a blank control (final concentration: 0.1%), and the culture was continued for 44 hours at 37 ° C in a 5% CO 2 incubator. Add 2 ( ⁇ 1 MTS/PMS mixture) to each well, and continue to culture for 4 hours at 37 ° C in a 5% CO 2 incubator. On the enzyme-linked detector, the wavelengths are 490 nm and 650 nm ( The light absorption value (OD) of each well was measured, and the cell survival rate was calculated.
  • OD light absorption value
  • C0P134-114, C0P135-114, C0P230, C0P23 C0P233 or C0P234 can effectively inhibit the replication of wild-type HIV-1, and the half effective concentrations are COP12-114 (5.9 ⁇ 0.6nM), C0P130 (4.8 ⁇ 0.9nM), C0P131-114 (1.6 ⁇ 0.6nM), C0P132-114 (2.7 ⁇ 0.2nM), C0P133-114 (4.9 ⁇ 0.6nM), C0P134-114 (4.6 ⁇ 0.2nM), C0P135-114 (7.5 ⁇ 0.4nM), C0P230 (40 ⁇ 0.2nM), C0P231 (33.4 ⁇ 8.1nM), C0P233 (4.15 ⁇ 1.35nM) or COP234 (5.0 ⁇ 0.4nM), the half effective concentration of CMX157 and positive control AZT measured in parallel under the same conditions were 8.7. At ⁇ 1.8 nM and 24.3 nM, all compounds were not cytotoxic at a final concentration of ⁇ .
  • the compound of the present invention exhibits a strong antiviral action, and has the advantages of low toxicity and good fat solubility, and is expected to be a novel drug for treating HIV infection.
  • the present invention provides a tenofovir diester compound, a salt thereof or a tautomer thereof, and a process for the preparation thereof, a use thereof, and a pharmaceutical composition comprising the same.
  • the compound provided by the invention has novel structure, simple synthesis, reduced polarity of the compound, and better fat solubility than the existing tenofovir diester compound, thereby improving the membrane permeability of the drug and improving the bioavailability;
  • the compounds provided by the present invention also exhibit strong antiviral effects, especially for HIV and hepadnaviruses, which are superior to the existing tenofovir diesters and show no significant toxicity. It has high safety and is suitable for the prevention and treatment of AIDS and hepatitis. It has a very broad application prospect.

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Abstract

La présente invention concerne un composé diester de ténofovir décrit par la formule générale (I), un sel ou un tautomère de celui-ci, ainsi qu'un procédé de préparation et l'utilisation de celui-ci et une composition pharmaceutique comprenant celui-ci. Le composé a une bonne liposolubilité, et un effet anti-VIH et un effet anti-VHB puissants.
PCT/CN2013/081304 2012-08-13 2013-08-12 Composé diester de ténofovir, procédé de préparation et utilisation de celui-ci, et composition pharmaceutique comprenant celui-ci WO2014026582A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CN2012102868791A CN102786549B (zh) 2012-08-13 2012-08-13 一组具有抑制hiv-1病毒复制活性的替诺福韦双酯化合物、制备方法及其药物用途
CN201210286879.1 2012-08-13
CN201310134491.4A CN103242366B (zh) 2012-08-13 2013-04-17 一组替诺福韦酯化合物、制备方法及其在抗病毒方面的应用
CN201310134492.9 2013-04-17
CN201310134160.0 2013-04-17
CN201310134492.9A CN103232490B (zh) 2013-01-31 2013-04-17 具有抑制hiv-1/hbv病毒复制活性的核苷类化合物、制备方法及抗病毒方面的应用
CN201310134491.4 2013-04-17
CN201310134160.0A CN103224530B (zh) 2012-08-13 2013-04-17 一组替诺福韦酯化合物、制备方法及其在抗病毒方面的应用

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CN108137630A (zh) * 2016-09-23 2018-06-08 鲁汶天主教大学 氟化无环核苷膦酸酯的前药
CN109485676A (zh) * 2017-12-21 2019-03-19 深圳市塔吉瑞生物医药有限公司 用于抗病毒的新型核苷类逆转录酶抑制剂

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