CN106800573A - A kind of phosphonate-nucleotide ester monohydrate and preparation method thereof and in application pharmaceutically - Google Patents

A kind of phosphonate-nucleotide ester monohydrate and preparation method thereof and in application pharmaceutically Download PDF

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CN106800573A
CN106800573A CN201610973798.7A CN201610973798A CN106800573A CN 106800573 A CN106800573 A CN 106800573A CN 201610973798 A CN201610973798 A CN 201610973798A CN 106800573 A CN106800573 A CN 106800573A
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compound
monohydrate
disease
methyl
water
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CN106800573B (en
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魏用刚
邱关鹏
雷柏林
祝国智
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • 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

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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This present invention relates to a kind of monohydrate its preparation method of compound (I), composition and prepare for treat disease of viral infection medicine on application.

Description

A kind of phosphonate-nucleotide ester monohydrate and preparation method thereof and in application pharmaceutically
Technical field
The present invention relates to a kind of phosphonate-nucleotide ester monohydrate and preparation method thereof and in application pharmaceutically, specifically Say, monohydrate its preparation method, composition the present invention relates to a kind of compound (I) and preparing for treating viral infection Application on the medicine of property disease.
Background technology
Hepatitis B is one of global disease, and it is caused by hepatitis B.There is 1/3rd population in the world at certain Hepatitis B is infected in the degree of kind, including 300,000,000 5 thousand ten thousand chronic carriers.In some Asia and African country, hepatitis B is Through becoming epidemic disease, especially in China.Hepatitis B can cause acute and chronic infection, acute infection generally along with Liver inflammation, vomiting, jaundice, extremely it is individual it is other can also cause death, and chronic infection is possible to induce cirrhosis and liver cancer.At present Although by vaccine prevention hepatitis B virus infection, but still chronic hepatitis B disease can be treated without effective method.
Tenofovir (tenofovir), chemical name is [(1R) -2- (adenine -9- bases) -1- methyl-ethoxy Base] methyl acid phosphate (PMPA) is a kind of nucleotide reverse transcriptase inhibitor, with Anti-HBV activity and HIV；But because it contains Phosphate group, with larger polarity, membranes penetration ability, in vivo the shortcomings of poor bioavailability.In order to overcome This shortcoming, can be made into phosphonate ester or phosphonic amide prodrug forms.Medicine by the research and development listing of lucky Leadd B.V in 2002 Viread (tenofovir disoproxil fumarate) is a kind of prodrug mode of PMPA, is prepared into the prodrug forms of phosphonate ester significantly Improve bioavilability.Viread played an important role in terms of HIV and HBV is treated.Meanwhile, the said firm another The prodrug tenofoviralafenamide (TAF) of PMPA and answering that emtricitabine/cobicistat/elvitegravir is constituted Side (trade name Genvoya) is ratified by FDA, for treating HIV.Tenofoviralafenamide individually takes, Clinical 3 phase is currently under for treating HBV infection.
The invention provides a kind of hydrate of new PMPA prodrugs, can be used to treat disease of viral infection, wherein disease Malicious infectious diseases includes the infectious diseases that HBV and inhibition of HIV cause.
The content of the invention
The present invention provides a kind of monohydrate of compound (I)：
A kind of preferred scheme of the present invention, monohydrate of compound (I), compound is true by single crystal diffraction structural analysis Surely monoclinic system is belonged to, space group is P21, cell parameter is α=γ=90 ° and β=95.086 (5) °, crystallographic axis is than a/b=0.8391, b/c=0.4076 and c/a= 2.9237, Z=2,
The present invention provides a kind of method of the monohydrate of prepare compound (I), and the method is that compound (I) is dissolved in into second In the mixed solvent of nitrile and water, at a suitable temperature, solvent volatilization can prepare the monohydrate of compound (I).
Preferred scheme of the present invention, a kind of method of the monohydrate of prepare compound (I), the method is by compound (I) It is dissolved in the mixed solvent of acetonitrile and water, at a suitable temperature, solvent volatilization can prepare a hydration of compound (I) Thing, preferably 10~30 DEG C of the suitable temperature.
Preferred scheme of the present invention, a kind of method of the monohydrate of prepare compound (I), the method is by compound (I) It is dissolved in the mixed solvent of acetonitrile and water, at a suitable temperature, solvent volatilization can prepare a hydration of compound (I) The volume ratio of thing, acetonitrile and water is 10:1 to 2:1, preferably 10:1 to 1:1, more preferably 5:1 to 1:1, further preferred 4:1, fit Preferably 10~30 DEG C of suitable temperature.
The present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition contains any of the above-described institute for the treatment of effective dose The monohydrate of the compound (I) stated, and pharmaceutically acceptable carrier or excipient.
The monohydrate or its composition that the present invention provides the compound (I) described in a kind of any of the above-described are preparing use Application on the medicine for the treatment of disease of viral infection, the infection that described disease of viral infection preferred HBV and HIV causes Property disease.
Unless there are opposite statement, the term for using in the specification and in the claims has following implications.
Involved elemental carbon, hydrogen, oxygen, sulphur, nitrogen or halogen include theirs in group of the present invention and compound In isotope situation, and group of the present invention and compound involved elemental carbon, hydrogen, oxygen, sulphur or nitrogen optionally further by One or more their corresponding isotopes are substituted, and the isotope of wherein carbon includes12C、13C and14C, the isotope of hydrogen includes Protium (H), deuterium (D is called heavy hydrogen), tritium (T is called superheavy hydrogen), the isotope of oxygen includes16O、17O and18O, the isotope bag of sulphur Include32S、33S、34S and36S, the isotope of nitrogen includes14N and15N, the isotope of fluorine19F, the isotope of chlorine includes35Cl and37Cl, bromine Isotope include79Br and81Br。
" pharmaceutical composition " represent compound or its physiology/pharmaceutically acceptable salt described in one or more text with The mixture of other constituents, wherein other components include physiology/pharmaceutically acceptable carrier and excipient.
" carrier " refers to organism to produce obvious stimulation and will not eliminating the bioactivity of given compound With the carrier or diluent of characteristic.
" excipient " refers to being added in pharmaceutical composition further relying on the inert substance of compound administration.Assign The example of shape agent include but is not limited to calcium carbonate, calcium phosphate, various sugared and different types of starch, cellulose derivative (including Microcrystalline cellulose), gelatin, vegetable oil, polyethylene glycols, diluent, granulating agent, lubricant, adhesive, disintegrant etc..
Brief description of the drawings
Fig. 1 is the monohydrate single crystal diffraction spectrogram of compound (I).
Specific embodiment
Implementation process of the invention and the beneficial effect for producing are described in detail below by way of specific embodiment, it is intended to which help is read Reader more fully understands essence of the invention and feature, not as to this case can practical range restriction.
The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10-6 (ppm) unit is given.The measure of NMR is to use (Bruker Avance III 400 and BrukerAvance 300) nuclear magnetic resonance spectrometer, Measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethyl Silane (TMS).
The measure of MS uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
The measure of HPLC uses Agilent 1260DAD high pressure liquid chromatographs (100 × 4.6mm of Zorbax SB-C18).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes The specification that silica gel plate is used is 0.15mm~0.20mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~ 0.5mm。
It is carrier that column chromatography generally uses the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.
The initiation material that oneself knows of the invention can use or synthesize according to methods known in the art, or it is commercially available in The company such as safe smooth science and technology, silent pacify resistance to Jilin Chemical, Shanghai moral, the imperial chemical industry of Chengdu section, splendid remote chemistry science and technology, lark prestige science and technology.
Blanket of nitrogen refers to that reaction bulb connects a nitrogen balloon for about 1L volumes.
Nitrogen atmosphere refers to that reaction bulb connects a hydrogen balloon for about 1L volumes.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.
Embodiment 1
(2S) -2- [[[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl-phenoxv-phosphoryl] ammonia Base] the thio isopropyl ester monohydrate of propionic acid (compound 1, optical voidness Rp-1)
S-isopropyl
(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy- phosphoryl]amino ]propanethioatehydrate
The first step：(S) the thio isopropyl ester of -2- (tert-butoxycarbonyl) alanine (1B)
(S)-S-isopropyl 2-((tert-butoxycarbonyl)amino)propanethioate
N- tert-butoxycarbonyls-ALANINE (1A) (5g, 26.4mmol) is dissolved in tetrahydrofuran (40mL), is added N, N'- carbonyl dimidazoles (CDI) (4.7g, 29.1mmol), are stirred at room temperature 2 hours.Add thio isopropanol (6.2g, 79.3mmol), room temperature reaction is overnight.The sodium hydroxide solution (30mL) of 4mol/L is added, is extracted with dichloromethane (50mL × 4) Take, merge organic layer, anhydrous sodium sulfate drying, concentration, residue silica gel column separating purification (petroleum ether：Ethyl acetate (v/v) =1:0~9:1) title compound (S) the thio isopropyl ester of -2- (tert-butoxycarbonyl) alanine (1B), light yellow liquid, are obtained (4g, yield 61%).
1H NMR(400MHz,CDCl3)δ3.61(m,1H),2.37–2.16(m,1H),1.46(s,9H),1.36(d, 3H),1.30(d,6H)。
Second step：(S) the thio isopropyl ester trifluoroacetate (1C) of -2- alanines
(S)-S-isopropyl 2-aminopropanethioate triflouroacetate
The thio isopropyl ester of (S) -2- (tert-butoxycarbonyl) alanine (1B) (4g, 16.2mmol) is dissolved in dichloromethane In (10mL), trifluoroacetic acid (10mL) is added, be stirred at room temperature 4 hours.It is concentrated under reduced pressure into dry crude product (S) -2- alanine sulphur For isopropyl ester trifluoroacetate (1C) (4g), next step is directly used in.
3rd step：[[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phenoxy group hypophosphorous acid (1E)
[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid
Nitrogen protection is lower by [[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phosphoric acid (i.e. PMPA) (1D) (5g, 17.4mmol) is added in three-necked bottle, adds acetonitrile (40mL), triethylamine (3.5g, 34.8mmol), 4- dimethylaminos After pyridine (i.e. DMAP) (2.1g, 17.4mmol) and triphenyl phosphite (8.1g, 26.1mmol) are added, 80 DEG C of interior temperature is heated to Reaction two days.By reaction solution removing acetonitrile concentrated under reduced pressure, to ethyl acetate (10mL) and water (15mL) is added in residue, divide Liquid, aqueous layer with ethyl acetate (10mL × 2) extraction, combining water layer, water layer concentrated hydrochloric acid adjusts pH to 3, is stirred at room temperature 10 minutes, PH to 2 is adjusted with concentrated hydrochloric acid, frozen water stands overnight after being cooled to 10 DEG C of stirrings two hours, filters, and filter cake washs with water (10mL), Collect filter cake, drying title compound [[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phenoxy group Phosphoric acid (1E), (3.5g, yield 56%).
1H NMR(400MHz,DMSO)δ8.16(s,1H),8.14(s,1H),7.55(s,2H),7.32–7.25(m,2H), 7.09(m,3H),4.30(dd,1H),4.19(dd,1H),3.97(m,1H),3.87–3.69(m,2H),1.05(d,3H)。
31P NMR(400MHz,DMSO)δ16.66。
4th step：[[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphoryl chloride phosphorus oxychloride (1F)
9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine
By [[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phenoxy group hypophosphorous acid (1E) (2g, 5.5mmol) it is suspended in acetonitrile (20mL), adds thionyl chloride (2.6g, 22.0mmol) to be heated to the 85 DEG C of reactions 4 of interior temperature small When, reaction solution is concentrated under reduced pressure, obtain crude product and be directly used in next step.
5th step：(2S) -2- [[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphinylidyne The thio isopropyl ester of alanine (1G) (optical voidness Rp-1)
S-isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy] methyl-phenoxy-phosphoryl]amino]propanethioate
The thio isopropyl ester trifluoroacetate (1C) of (S) -2- alanines (4g, 16.2mmol) are dissolved in dry dichloromethane In alkane (20mL), under nitrogen protection, dry ice-ethanol is cooled to -50 DEG C, triethylamine (5mL, 35.8mmol) is added dropwise and stirs 10 points Clock, dropwise addition [[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphoryl chloride phosphorus oxychloride (1F) (2.1g, Dichloromethane (20mL) suspension 5.5mmol), after the completion of, warm naturally to room temperature reaction 1 hour.Added in reaction solution Water (20mL), point liquid, organic layer water (10mL) washed once, anhydrous sodium sulfate drying, be concentrated under reduced pressure, and dissolve the residue in second In acetoacetic ester (50mL), to 2, point liquid, aqueous layer with ethyl acetate (20mL) extracts the ice bath lower salt acid for adjusting pH with 4mol/L of cooling Take, layer of fetching water, add dichloromethane (50mL), dropwise addition saturated sodium bicarbonate aqueous solution regulation pH to 8 under ice bath cooling, point liquid, Water layer is extracted with dichloromethane (20mL), merges organic layer, saturated sodium-chloride (10mL) washing, anhydrous sodium sulfate drying, decompression Concentration, obtains (2S) -2- [[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphinylidyne alanine Two kinds of non-enantiomer mixtures (300mg, yield 11%) of thio isopropyl ester (1G), the mixture is split using HPLC Obtain 1G (optical voidness Rp-1)), compound 1G is the peak 1 after HPLC splits.
Method for separating and analyzing：Instrument, Thar analytical SFC；Post, ChiralPak AS-H, 250 × 4.6mm；Stream Dynamic phase, A is CO2And B is Methanol (0.05%DEA)；Gradient, B 40%；Flow, 2.4mL/min；Back pressure, 100bar； Column temperature, 35 DEG C；Wavelength, 220nm.
Preparative separation method：Instrument, the preparative SFC of MG II；Post, ChiralPak AS-H, 250 × 30mmI.D.；Mobile phase, A is CO2And B is Methanol；Gradient, B 40%；Flow, 40mL/min；Back pressure, 100bar； 38 DEG C of column temperature；Wavelength, 220nm；Cycle, 5.5min.
Sample preparation:Two kinds of non-enantiomer mixtures (300mg) of 1G are dissolved in methyl alcohol, and sample concentration is obtained The solution of 10mg/mL, sample introduction 3mL/ obtains two optical isomer compounds per pin after separation, wherein peak 1 is compound 1G (retention time：2.21min, 106mg, white solid, ee%=100%), peak 2 is the diastereoisomer 1G ' of compound 1G (retention time：3.82min, 109mg, white solid, ee%=100%).
Compound 1G
1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.01(s,1H),7.32(t,2H),7.21–7.11(m,3H), 6.04(s,2H),4.47(dd,1H),4.21–4.13(m,1H),4.13–4.06(m,1H),4.06–3.96(m,2H),3.69 (dd,1H),3.54–3.39(m,2H),1.28–1.17(m,12H)。
31P NMR(162MHz,CDCl3)δ23.15。
LC-MS M/Z(ESI):493.1[M+1]。
The diastereoisomer 1G ' of compound 1G
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.97(s,1H),7.25–7.17(m,2H),7.13–7.05 (m,1H),7.03–6.95(m,2H),5.90(s,2H),4.34(dd,1H),4.16–4.03(m,2H),3.99–3.89(m, 2H),3.84(t,1H),3.76–3.52(m,2H),1.33–1.20(m,12H)。
31P NMR(162MHz,CDCl3)δ22.12。
LC-MS M/Z(ESI):493.1[M+1]。
6th step：(2S) -2- [[[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl-phenoxvs-phosphorus Acyl group] amino] the thio isopropyl ester monohydrate of propionic acid (compound 1, optical voidness Rp-1)
S-isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy] methyl-phenoxy-phosphoryl]amino]propanethioate hydrate
Take about 5mg (2S) -2- [[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl] phenoxy group phosphinylidyne The thio isopropyl ester of alanine (1G) (optical voidness Rp-1)) it is put in vial, it is super with acetonitrile (1.6mL) and water (0.4mL) Sound is molten clear, and aperture volatilization, obtains bulk crystals, as (2S) -2- [[[(1R) -2- (adenine -9- bases) -1- at room temperature Methyl ethoxy] methyl-phenoxv-phosphoryl] amino] propionic acid thio isopropyl ester monohydrate (compound 1, optical voidness Rp- 1)。
Embodiment 2：Compound 1 (optical voidness Rp-1) single crystal X-ray crystallography is measured (shown in Fig. 1)
1. device information and detection method parameter
2 single crystal structural datas
3. compound 1 (optical voidness Rp-1) atomic coordinates (x 104), effective homogeneity displacement parameterAnd U (eq)
U (eq) is defined as 1/3rd (U (eq) is defined as one third of orthogonalization Uij tensors track of the trace of the orthogonalizedUijtensor)
4. compound 1 (optical voidness Rp-1) hydrogen atom coordinates (x 104), effective homogeneity displacement parameterAnd U (eq)
5. compound 1 (optical voidness Rp-1) anisotropy displacement parameter
Anisotropic shift factor index takes following form:-2π2[h2a*2U11+...+2h k a*b*U12]。
Biological test example
Anti-hepatitis B virus activity is screened
With the anti-hepatitis B activity of HepG2.2.15 raji cell assay Raji compounds.The material for using is as follows with instrument： HepG2.2.15 cells, RPMI RPMI-1640s, hyclone, 96 orifice plates, DMSO, QIAamp 96DNABlood Kit, Cell-titer blue, ELIASA, Applied Biosystems 7900real-time PCR system.
Compound 1 (optical voidness Rp-1) is dissolved to 20mM, -20 DEG C of storages, by compound 1 (optical voidness Rp-1) with DMSO 20mM storage liquid 3 times of gradient dilutions of DMSO, totally 9 concentration.Diluted with the RPMI RPMI-1640s containing 2.0%FBS again 200 times.The highest of compound tests final concentration of 100M.Experimental procedure is with reference to QIAamp 96DNA Blood Kit (QIAGEN 51161) specification, qPCR methods determine compound anti-hepatitis B activity and calculate EC50(half effective inhibition concentration).Analysis number According to calculate suppression percentage：Suppression percentage is calculated using equation below：Inhibiting rate (%)=(HBV of DMSO control groups is total The HBV total amounts of amount-test sample group)/DMSO control groups HBV total amount × 100.Finally use GraphPad Prism software meters Calculate the EC of compound50Value.
Cell-titer blue methods determine the cytotoxicity of compound and calculate CC50(causing 50% cytotoxic concentration).Point Analysis data and calculating versus cell vigor：Cytoactive percentage is calculated using equation below：Cells survival rate (%)=(tested The fluorescence values of sample-background fluorescence numerical value)/(fluorescence values of DMSO control groups-background fluorescence numerical value) × 100.Finally make The CC of compound is calculated with GraphPad Prism softwares50Value.Result is as shown in the table：
Compound number
Compound 1 (optical voidness Rp-1) 8 >100

Claims (9)

1. a kind of monohydrate of compound (I)：
2. the monohydrate of compound (I) according to claim 1, it is characterised in that the compound passes through single crystal diffraction Structural analysis determines to belong to monoclinic system, and space group is P21, cell parameter is α=γ=90 ° and β=95.086 (5) °, crystallographic axis is than a/b=0.8391, b/c= 0.4076 and c/a=2.9237, Z=2,
3. prepare claim 1 described in compound (I) monohydrate method, it is characterised in that compound (I) is dissolved in In the mixed solvent of acetonitrile and water, at a suitable temperature, solvent volatilization can prepare the monohydrate of compound (I).
4. method according to claim 3, suitable temperature is selected from 10~30 DEG C.
5. method according to claim 3, it is characterised in that the volume ratio of acetonitrile and water is 10:1 to 2:1.
6. method according to claim 5, it is characterised in that the volume ratio of acetonitrile and water is 4:1.
7. a kind of pharmaceutical composition, described pharmaceutical composition contains any one of the claim 1~2 for the treatment of effective dose Compound (I) monohydrate, and pharmaceutically acceptable carrier or excipient.
8. the pharmaceutical composition described in monohydrate or 7 described in claim 1 or 2 is being prepared for treating viral infection disease Application on the medicine of disease.
9. application according to claim 8, described disease of viral infection includes the infectious disease that HBV and HIV causes Disease.
CN201610973798.7A 2015-11-25 2016-11-07 Nucleotide phosphonate monohydrate, preparation method and medical application thereof Expired - Fee Related CN106800573B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0481214A1 (en) * 1990-09-14 1992-04-22 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
WO2002008241A2 (en) * 2000-07-21 2002-01-31 Gilead Sciences, Inc. Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same
CN103224530A (en) * 2012-08-13 2013-07-31 洛阳聚慧投资股份有限公司 Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects
CN103665043A (en) * 2012-08-30 2014-03-26 上海源力生物技术有限公司 Tenofovir prodrug and medical application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0481214A1 (en) * 1990-09-14 1992-04-22 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
WO2002008241A2 (en) * 2000-07-21 2002-01-31 Gilead Sciences, Inc. Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same
CN103224530A (en) * 2012-08-13 2013-07-31 洛阳聚慧投资股份有限公司 Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects
CN103665043A (en) * 2012-08-30 2014-03-26 上海源力生物技术有限公司 Tenofovir prodrug and medical application thereof

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