CN114262348A - Cyclic nucleoside phosphate ester compound and application thereof - Google Patents
Cyclic nucleoside phosphate ester compound and application thereof Download PDFInfo
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Abstract
The invention provides a cyclic nucleoside phosphate compound shown as a formula I and pharmaceutically acceptable salts thereof;
z is a connecting bond or CHR1(ii) a When W is a bond OR C (O), R is CH (R') C (Y) OR2(ii) a When W is CHC (Y) OR2When R is H; y is O or S; each Z1、Z2、Z3、Z4Independently N, CRa，RaIs H, halogen, CN, ORb、N(Rb)2Or CO2RbOr R on two adjacent carbon atomsaForm a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-3 hetero atoms selected from N, O and S with the carbon atom to which it is attached. The tenofovir cyclic phosphoramidate prodrug shown in formula I provided by the invention is very stable in plasma and is not detected in the plasma at allThe metabolite namely tenofovir is detected, and has excellent anti-hepatitis virus effect.
Description
Technical Field
The invention relates to the technical field of synthesis of antiviral compounds, and particularly relates to a cyclic nucleoside phosphate ester compound and application thereof.
Background
Hepatitis B Virus (HBV) is a pathogen causing hepatitis B (hepatitis B for short), belongs to the hepadnaviridae, contains two genera of orthopathodnaviridae and avian hepadnaviridae, and causes human body infection, namely, the orthopathodnaviridae. Hepatitis b is a potentially life-threatening liver infection caused by the hepatitis b virus. Hepatitis B has become a major global health problem, and according to the report of the world health organization, the number of hepatitis B infections has reached 2.57 hundred million in 2015 worldwide, and hepatitis B patients have high risk of dying from cirrhosis and liver cancer. Hepatitis b virus DNA (deoxyribonucleic acid) is the core material of hepatitis b virus and the basis for viral replication. Nucleosides inhibit the activity of viral polymerases by binding directly competitively to natural deoxyribose substrates, and can also be incorporated into DNA to stop DNA strand synthesis. Therefore, nucleoside compounds are the main drugs for treating hepatitis B, and mainly comprise cidofovir, adefovir, lamivudine, tenofovir (tenofovir) and the like. Tenofovir is a novel nucleotide reverse transcriptase inhibitor, can effectively resist various viruses and is used for treating virus infectious diseases. Because tenofovir is a phosphonic acid group of a dication ion under physiological pH conditions, tenofovir is not easily absorbed through cell membranes, bioavailability is low, and dose-dependent nephrotoxicity also exists, thereby limiting its therapeutic effects. Therefore, Tenofovir must be esterified and salified to prepare phosphonate prodrug for clinical use, for example, Tenofovir disoproxil fumarate (Tenofovir disoproxil fumarate) is the first generation of orally effective Tenofovir prodrug developed by Gilids scientific Inc. (Gilead Science), and is used for treating AIDS and hepatitis B.
Because tenofovir disoproxil fumarate is highly sensitive to hydrolysis reaction mediated by serum enzyme, the concentration of a medicament at an action part cannot be effectively increased, two equivalents of formaldehyde with potential toxicity is released in a metabolic process, and side effects such as lactic acidosis, severe hepatomegaly, lipodystrophy and the like are also found in a clinical treatment process. Therefore, in order to improve the stability and bioavailability of a tenofovir prodrug in plasma and reduce the concentration of a metabolite, namely tenofovir in plasma, so as to reduce the toxicity of the medicament, research and development of a new generation of tenofovir prodrug are always research hotspots of various companies, and some results are obtained at present, for example, a patent of girlidd application (patent document No. WO0208241) discloses that a tenofovir phosphoramidate prodrug synthesized by natural amino acid (monosubstitution) (such as GS-7340) has obtained approval of FDA for treating hepatitis b, and is a novel tenofovir targeted prodrug, namely fumarate of virid (vimid, tenofovir fumarate/TDF, 300mg), and clinical experiments show that the medicament effect of the tenofovir prodrug is similar to the hepatitis b virus resistance effect of virread (Viread, tenofovir fumarate/TDF, 300mg), but compared with virread, virtide can improve the kidney and bone laboratory safety parameters, and the dosage is only one tenth of the latter.
Vemlidy was approved in China in 2018 at 11 months for the treatment of chronic Hepatitis B (HBV) in adults and adolescents (over 12 years old, at least 35kg body weight). It is worth mentioning that Vemlidy is the first new oral regimen approved for the treatment of hepatitis b in the chinese market for a decade. However, GS-7340 is degraded in plasma to a certain extent, and 1-2% of tenofovir metabolites can be detected in plasma, so that toxic and side effects such as tenofovir disoproxil are inevitably generated, and the safety of the drug use is problematic. Therefore, the further research and development of the tenofovir prodrug with high curative effect and low toxicity has important significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention starts from the design concept of further improving the stability of the tenofovir prodrug in blood plasma, and synthesizes a series of tenofovir cyclic phosphoramidate prodrugs by utilizing phenylglycine derivatives, the prodrugs are very stable in blood plasma on one hand, and a metabolite namely tenofovir is not detected in the blood plasma at all, and on the other hand, compared with GS-7340, the concentration of the tenofovir which is an active metabolite in Peripheral Blood Mononuclear Cells (PBMCs) is obviously increased, thereby providing a novel anti-hepatitis B oral drug with high curative effect and low toxic and side effects.
The invention relates to a cyclic nucleoside phosphate compound shown in formula I and pharmaceutically acceptable salts thereof;
z is a connecting bond or CHR1；
When W is a bond OR C (O), R is CH (R') C (Y) OR2(ii) a When W is CHC (Y) OR2When R is H; y is O or S; r' is H, D or C which is unsubstituted or substituted by 1-5 halogens1-6Alkyl or C3-8A cycloalkyl group;
each Z1、Z2、Z3、Z4Independently N, CRa，RaIs H, halogen, CN, ORb、N(Rb)2Or CO2RbOr R on two adjacent carbon atomsaForm a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-3 hetero atoms selected from N, O and S with the carbon atom to which it is attached; each RbIndependently H, C1-6Alkyl radical, C3-8Cycloalkyl radical, C1-6Acyl or C1-6A sulfonamide group; or two RbCan form a 4-8 membered ring with the nitrogen atom to which it is attached;
R1is hydrogen, oxo (═ O) or C unsubstituted or substituted by 1 to 5 halogens1-6Alkyl radical, C3-8Cycloalkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
R2is unsubstituted or substituted by 1 to 5 halogen or C1-6Alkoxy-substituted C1-6Alkyl or C3-8A cycloalkyl group.
In the formula I, the compound has the following structure,
in a preferred embodiment of the invention, R' is H, D or C unsubstituted or substituted with 1-3 halogens1-4Alkyl or C3-7A cycloalkyl group; preferably H, D or C unsubstituted or substituted by 1-2 halogens1-3Alkyl or C3-6A cycloalkyl group.
In a preferred embodiment of the invention, each Z1、Z2、Z3、Z4Independently N, CRa，RaIs H, halogen, CN, ORb、N(Rb)2Or CO2RbOr R on two adjacent carbon atomsaForm a 4-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring containing 1-3 hetero atoms selected from N, O and S with the carbon atom to which it is attached; each RbIndependently H, C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Acyl or C1-4A sulfonamide group; or two RbCan form a 4-7 membered ring with the nitrogen atom to which it is attached; preferably, each Z1、Z2、Z3、Z4Independently N, CRa， RaIs H, halogen, CN, ORb、N(Rb)2Or CO2RbOr R on two adjacent carbon atomsaForm a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring containing 1-2 hetero atoms selected from N, O and S with the carbon atom to which it is attached; each RbIndependently H, C1-3Alkyl radical, C3-6Cycloalkyl radical, C1-3Acyl or C1-3A sulfonamide group; or two RbMay form a 4-6 membered ring with the nitrogen atom to which it is attached.
In a preferred embodiment of the invention, R1Is hydrogen, oxo (═ O) or C unsubstituted or substituted by 1 to 3 halogens1-4Alkyl radical, C3-7Cycloalkyl radical, C2-5Alkenyl or C2-5An alkynyl group; preferably hydrogen, oxo (═ O) or C unsubstituted or substituted by 1 to 2 halogens1-3Alkyl radical, C3-6Cycloalkyl radical, C2-4Alkenyl or C2-4An alkynyl group;
R2is unsubstituted or substituted by 1 to 3 halogen or C1-4Alkoxy-substituted C1-4Alkyl or C3-7A cycloalkyl group; preferably unsubstituted or substituted by 1 to 2 halogen or C1-3Alkoxy-substituted C1-3Alkyl or C3-6A cycloalkyl group.
The invention also aims to provide the application of the cyclic nucleoside phosphate ester compound in preparing the medicine for treating hepatitis virus. In particular, the hepatitis virus is hepatitis B virus.
The synthetic process of the cyclic nucleoside phosphate compound of the invention is as follows:
the tenofovir cyclic phosphoramidate prodrug shown in the formula I is very stable in plasma, a metabolite namely tenofovir is not detected in the plasma at all, and the tenofovir cyclic phosphoramidate prodrug has an excellent anti-hepatitis virus effect.
Detailed Description
Example 1
The method comprises the following steps: synthesis of intermediate D1
2g (12mmol) of 2-hydroxyphenylglycine was dissolved in 40mL of isopropanol, and 2eq of thionyl chloride (2.8g,239mmol) was added dropwise thereto and the mixture was refluxed overnight. Mother liquor is dried by spinning, 1mol/L diluted hydrochloric acid and methyl tert-butyl ether are added for extraction for 2 times, the pH of a water phase is adjusted to be alkaline by saturated sodium bicarbonate, the extraction is carried out for 3 times by ethyl acetate, an ethyl acetate layer is washed by brine, dried by anhydrous sodium sulfate and concentrated to obtain 1.1g of crude product, and the crude product is purified by column chromatography to obtain an intermediate D1.
1H NMR(400MHz,CDCl3):δ7.21(td,J＝7.2Hz,J＝1.2Hz,1H),7.07(dd,J＝ 7.2Hz,J＝1.2Hz,1H),6.87(dd,J＝8.0Hz,J＝0.8Hz,1H)，6.82(td,J＝7.6Hz,J＝ 1.2Hz,1H),5.07～5.13(m,1H),4.80(s,1H),1.28(d,J＝6.4Hz,3H),1.19(d,J＝6.4Hz, 3H)。
Step two: synthesis of Compound C1
To a suspension of tenofovir (l g,3.5mmol) in anhydrous acetonitrile (2.5mL) at 70 ℃ was added dropwise thionyl chloride (1.67g,14mmol) and the mixture was allowed to react at 70 ℃ for 1.5 h until the mixture was totally clear, the solvent and excess thionyl chloride were evaporated under reduced pressure to give a yellow solid, cooled to room temperature, dichloromethane (10mL) was added, a solution of intermediate D1(732mg,3.5mmol) in dichloromethane (10mL) and N, N-Diisopropylethylamine (DIEA) (2mL) was added, stirred at room temperature overnight, filtered and dried to give the title compound C1 as a white powder.
1HNMR(400MHz,CDCl3):δ8.31(m,1H),8.09(m,1H),7.32-7.41(m,2H), 7.21-7.14(m,1H),7.07(m,1H),6.10(m,1H),5.80(b,2H),5.15-4.99(m,1H), 4.46(m,2H),3.93(m,2H),3.79(m,2H),1.34-1.26(m,3H),1.28-1.19(m,6H)。 LC/MS(ESI)：m/z 461.1[M+H]+。
Example 2
The method comprises the following steps: intermediate D2 was synthesized according to the same procedure as in example 1, except that isopropanol was replaced with isobutanol.
Step two: synthesis of Compound C2
Compound C2 was obtained in the same manner as in example 1 (yield: 52%).
1HNMR(400MHz,CDCl3):δ8.31(m,1H),8.09(m,1H),7.32-7.41(m,2H), 7.21-7.14(m,1H),7.07(m,1H),6.10(m,1H),5.80(b,2H),5.15-4.99(m,1H), 4.46(m,2H),3.93(m,2H),3.79(m,2H),3.45(m,1H),1.89-1.95(m,1H),1.34-1.26(m, 3H),0.84-0.91(m,6H)。LC/MS(ESI)：m/z 475.1[M+H]+。
Example 3
The method comprises the following steps: synthesis of intermediate D3
Salicylaldehyde (1.22g,10mmol) was dissolved in 1, 2-dichloroethane (20mL), and L-alanine isopropyl ester hydrochloride (1.68g,10mmol), triethylamine (1.01g,10mmol), sodium triacetoxyborohydride (4.2g, 20mmol), and a few drops of acetic acid were added. Stirring at room temperature until the reaction was complete. Reaction mixtureDiluting with water, extracting with dichloromethane, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness, and purifying by column chromatography to obtain intermediate D3 (yield: 62%). LC/MS (ESI): m/z 238[ M + H ]]+。
Step two: synthesis of Compound C3
The same procedure for the second step of example 1 was repeated except for using intermediate D3 instead of intermediate D1 to obtain compound C3 (yield: 41%).
1HNMR(400MHz,CDCl3):δ8.30(m,1H),8.11(m,1H),7.11-7.33(m,4H), 5.84(b,2H),4.41-4.51(m,3H),3.93-4.22(m,2H),3.75-4.08(m,4H),1.58(m,3H), 1.26-1.34(m,3H),1.07-1.15(m,6H)。LC/MS(ESI)：m/z 489.1[M+H]+。
Example 4
The method comprises the following steps: intermediate D4
To salicylic acid (1.38g,10mmol) in dichloromethane (20mL) was added one drop of DMF (N, N-dimethylformamide) followed by the addition of oxalyl chloride (12mmol) dropwise at 0 deg.C, after 2 hours, concentrated to dryness under reduced pressure, then dissolved in 20mL dichloromethane.
L-alanine isopropyl ester hydrochloride (1.68g,10mmol) and triethylamine (1.01g,10mmol) were dissolved in 20mL of dichloromethane, cooled to 0 deg.C, and then the above prepared salicyloyl chloride dichloromethane solution was added dropwise. The reaction mixture was stirred overnight. Then, the reaction mixture was washed with 40mL of water and 1N hydrochloric acid, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain intermediate D4 (yield 81%).1H-NMR(400MHz,CDCl3):δ12.2(s,1H),7.40-7.48(m,2H),7.03(brs,1H),7.00(dd, J＝0.8,8.4Hz,1H),6.89(dt,J＝0.8,8.0Hz,1H),5.13(m,1H),4.72(m,1H),1.54(d, J＝7.2Hz,3H),1.34(d,J＝6.4Hz,3H),1.31(d,J＝6.4Hz,3H)。
Step two: synthesis of Compound C4
The same procedure for the second step of example 1 was repeated except for using intermediate D4 instead of intermediate D1 to obtain compound C4 (yield: 41%).1HNMR(400MHz,CDCl3):δ8.31(m,1H),8.09(m,1H),7.52-7.43(m, 2H),7.24-7.14(m,2H),5.86(b,2H),5.15-5.19(m,1H),4.73(m,1H),4.46-3.97(m,2H), 3.79(m,2H),3.41(m,1H),1.54(m,3H),1.34(m,6H),1.31(m,3H)。。LC/MS(ESI)： m/z 503.1[M+H]+。
Example 5
Synthesis of compound C5:
the same procedures used in example 1 were repeated except for using 2-amino-3- (2-hydroxyphenyl) acetic acid as a starting material in place of 2-hydroxyphenylglycine to obtain compound C5 (yield: 36%). LC/MS (ESI): m/z 475.1[ M + H ]]+。
Starting from the following starting materials, the corresponding intermediate compounds are obtained according to the methods of examples 1, 3 and 4
Table 1 synthesis of intermediate compounds
Effect example 1 in vitro antiviral experiment
a. In vitro anti-hepatitis B virus activity study HepG 2.2.15 cells were used as hepatitis B virus vectors, and the ability of compounds to inhibit DNA replication of hepatitis B virus was determined.
The test method comprises the following steps: HepG 2.2.15 cells were seeded in 96-well plates at a cell count of 3.5X 104Culturing, placing CO2Incubate in incubator until cell density reaches 80%. Adding sample and positive control drug (GS-7340 and GS-7171 (diastereoisomer mixture of GS-7340)) at different dilutions after 24 hr, setting cell control hole, adding drug, changing culture solution containing samples with different dilutions after 72 hr, and collecting samples at 6 days after drug additionCollecting cell supernatant and HepG 2.2.15 cells, detecting HBV DNA replication degree in the cells by dot hybridization method, and calculating IC50(the results are shown in Table 2).
b. Cytotoxicity assays
The test method comprises the following steps: inoculating HepG 2.2.15 cells in a 96-well culture plate, adding samples and positive control drugs according to different dilutions, adding CellTiter-Blue (Promega, Catalog # G8081) on the 6 th day after adding the drugs, measuring the fluorescence reading by using a Flexstation 3 instrument, and calculating CC50(the results are shown in Table 2).
TABLE 2 HBV inhibition and cytotoxicity results for each compound
*SI＝CC50/IC50
Effect example 2 metabolic stability of Tenofovir prodrug in fresh human whole blood and distribution test in Peripheral Blood Mononuclear Cells (PBMCs) cells
1. Test method
The compound and fresh human whole blood were incubated at 37 ℃ and the plasma and PBMCs cells were isolated after 0.5 and 2 hours of incubation, respectively, and the concentrations of the drug protoform and the metabolite tenofovir (PAMA) in the plasma and PBMCs cells were determined and the PBMCs cells were counted by a cell counter.
2. plasma/PBMC sample processing
To L00. mu.L of plasma sample or PBMCs sample was added 20. mu.L of internal standard solution (400ng/mL SN-38 solution), 5. mu.L of methanol-water (50:50, v/v) and 200. mu.L of acetonitrile, vortexed, homogenized for L min, and centrifuged for 5min (14000 rpm). mu.L of the supernatant was mixed with 180. mu.L of the mobile phase, vortexed for L min, and L0. mu.L was taken for LC/MS/MS analysis.
TABLE 3 Metabolic stability and distribution of Tenofovir prodrugs in fresh human Whole blood in PBMCs cells
Claims (10)
1. A cyclic nucleoside phosphate compound represented by formula I, and pharmaceutically acceptable salts thereof;
z is a connecting bond or CHR1；
When W is a bond OR C (O), R is CH (R') C (Y) OR2(ii) a When W is CHC (Y) OR2When R is H; y is O or S; r' is H, D or C which is unsubstituted or substituted by 1-5 halogens1-6Alkyl or C3-8A cycloalkyl group;
each Z1、Z2、Z3、Z4Independently N, CRa，RaIs H, halogen, CN, ORb、N(Rb)2Or CO2RbOr R on two adjacent carbon atomsaForm a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-3 hetero atoms selected from N, O and S with the carbon atom to which it is attached; each RbIndependently H, C1-6Alkyl radical, C3-8Cycloalkyl radical, C1-6Acyl or C1-6A sulfonamide group; or two RbCan form a 4-8 membered ring with the nitrogen atom to which it is attached;
R1is hydrogen, oxo (═ O) or C unsubstituted or substituted by 1 to 5 halogens1-6Alkyl radical, C3-8Cycloalkyl radical, C2-6Alkenyl or C2-6An alkynyl group;
R2is unsubstituted or substituted by 1 to 5 halogen or C1-6Alkoxy-substituted C1-6Alkyl or C3-8A cycloalkyl group.
2. A cyclic nucleoside phosphate ester compound according to claim 1, wherein in the formula I,
3. a cyclic nucleoside phosphate ester compound according to claim 1,
r' is H, D or C unsubstituted or substituted by 1-3 halogens1-4Alkyl or C3-7A cycloalkyl group.
4. A cyclic nucleoside phosphate ester compound according to claim 3,
r' is H, D or C which is unsubstituted or substituted by 1-2 halogens1-3Alkyl or C3-6A cycloalkyl group.
5. A cyclic nucleoside phosphate ester compound according to claim 1,
each Z1、Z2、Z3、Z4Independently N, CRa，RaIs H, halogen, CN, ORb、N(Rb)2Or CO2RbOr R on two adjacent carbon atomsaForm a 4-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring containing 1-3 hetero atoms selected from N, O and S with the carbon atom to which it is attached; each RbIndependently H, C1-4Alkyl radical, C3-7Cycloalkyl radical, C1-4Acyl or C1-4A sulfonamide group; or two RbMay form a 4 to 7 membered ring with the nitrogen atom attached.
6. A cyclic nucleoside phosphate ester compound according to claim 5,
each Z1、Z2、Z3、Z4Independently N, CRa，RaIs H, halogen, CN, ORb、N(Rb)2Or CO2RbOr R on two adjacent carbon atomsaForm a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring containing 1-2 hetero atoms selected from N, O and S with the carbon atom to which it is attached; each RbIndependently H, C1-3Alkyl radical, C3-6Cycloalkyl radical, C1-3Acyl or C1-3A sulfonamide group; or two RbMay form a 4-6 membered ring with the nitrogen atom to which it is attached.
7. A cyclic nucleoside phosphate ester compound according to claim 1,
R1is hydrogen, oxo (═ O) or C unsubstituted or substituted by 1 to 3 halogens1-4Alkyl radical, C3-7Cycloalkyl radical, C2-5Alkenyl or C2-5An alkynyl group;
R2is unsubstituted or substituted by 1 to 3 halogen or C1-4Alkoxy-substituted C1-4Alkyl or C3-7A cycloalkyl group.
8. A cyclic nucleoside phosphate ester compound according to claim 7,
R1is hydrogen, oxo (═ O) or C unsubstituted or substituted by 1 to 2 halogens1-3Alkyl radical, C3-6Cycloalkyl radical, C2-4Alkenyl or C2-4An alkynyl group;
R2is unsubstituted or substituted by 1 to 2 halogen or C1-3Alkoxy-substituted C1-3Alkyl or C3-6A cycloalkyl group.
9. Use of a cyclic nucleoside phosphate ester compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of hepatitis virus.
10. The use of claim 9, wherein the hepatitis virus is hepatitis b virus.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015261A2 (en) * | 2004-07-27 | 2006-02-09 | Gilead Sciences, Inc. | Nucleoside phosphonate conjugates as anti hiv agents |
| WO2014032481A1 (en) * | 2012-08-30 | 2014-03-06 | 上海源力生物技术有限公司 | Tenofovir prodrug and pharmaceutical uses thereof |
| WO2016184361A1 (en) * | 2015-05-15 | 2016-11-24 | 上海唐润医药科技有限公司 | Anti-hepatitis c virus nucleoside compound and use thereof |
| CN106188139A (en) * | 2015-05-29 | 2016-12-07 | 江苏天士力帝益药业有限公司 | Tenofovir list benzyl ester phosphoamide prodrug, its preparation method and application |
| WO2017162169A1 (en) * | 2016-03-25 | 2017-09-28 | 江苏天士力帝益药业有限公司 | Uridine phosphoramide prodrug, preparation method therefor, and medicinal uses thereof |
-
2020
- 2020-09-16 CN CN202010970772.3A patent/CN114262348A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015261A2 (en) * | 2004-07-27 | 2006-02-09 | Gilead Sciences, Inc. | Nucleoside phosphonate conjugates as anti hiv agents |
| WO2014032481A1 (en) * | 2012-08-30 | 2014-03-06 | 上海源力生物技术有限公司 | Tenofovir prodrug and pharmaceutical uses thereof |
| WO2016184361A1 (en) * | 2015-05-15 | 2016-11-24 | 上海唐润医药科技有限公司 | Anti-hepatitis c virus nucleoside compound and use thereof |
| CN106279322A (en) * | 2015-05-15 | 2017-01-04 | 上海唐润医药科技有限公司 | The nucleoside compound of anti-hepatitis C virus and application thereof |
| CN106188139A (en) * | 2015-05-29 | 2016-12-07 | 江苏天士力帝益药业有限公司 | Tenofovir list benzyl ester phosphoamide prodrug, its preparation method and application |
| CN107709340A (en) * | 2015-05-29 | 2018-02-16 | 江苏天士力帝益药业有限公司 | Tenofovir list benzyl ester phosphamide prodrug, its preparation method and application |
| WO2017162169A1 (en) * | 2016-03-25 | 2017-09-28 | 江苏天士力帝益药业有限公司 | Uridine phosphoramide prodrug, preparation method therefor, and medicinal uses thereof |
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