CN113501853B - 4-thiouracil deoxynucleoside phosphate and its antiviral medicine use - Google Patents
4-thiouracil deoxynucleoside phosphate and its antiviral medicine use Download PDFInfo
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- CN113501853B CN113501853B CN202111065792.7A CN202111065792A CN113501853B CN 113501853 B CN113501853 B CN 113501853B CN 202111065792 A CN202111065792 A CN 202111065792A CN 113501853 B CN113501853 B CN 113501853B
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- 239000003814 drug Substances 0.000 title claims abstract description 27
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- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 19
- 239000010452 phosphate Substances 0.000 title claims abstract description 19
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
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- 229960005311 telbivudine Drugs 0.000 description 3
- KUEFXPHXHHANKS-UHFFFAOYSA-N 5-nitro-1h-1,2,4-triazole Chemical compound [O-][N+](=O)C1=NC=NN1 KUEFXPHXHHANKS-UHFFFAOYSA-N 0.000 description 2
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- 206010019799 Hepatitis viral Diseases 0.000 description 2
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 239000002777 nucleoside Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- NHEULQMXMXIOJY-UHFFFAOYSA-N Cl[PH2]=O Chemical compound Cl[PH2]=O NHEULQMXMXIOJY-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
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- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to 4-thiouracil deoxynucleoside phosphate and an antiviral drug application thereof.
Background
Hepatitis B Virus (HBV) infection is a main pathogenic factor of viral hepatitis, and then cirrhosis and liver cancer are caused, and the serious hepatitis threatens life. Although China is used as a world-wide big country infected with hepatitis B, the vaccine is very successfully used, but due to the large population base, the previous infection rate and the like, the hepatitis B virus carrying rate and the hepatitis B morbidity are both at a high level. Aiming at viral hepatitis with certain indications, the antiviral treatment is adopted clinically, and the curative effect is very good. The anti-hepatitis B virus medicine mainly comprises interferon and nucleoside (acid) medicines, and the nucleoside (acid) anti-hepatitis B virus medicines are more clinically applied and have a large market ratio. Although the types of the medicines are various, after the medicines are used again, the phenomenon of medicine withdrawal and rebound exists in different degrees, so that the phenomenon of medicine withdrawal and relapse occurs in the treatment of hepatitis B, medicine resistance is generated, the medicine effect is not strong, and a new medicine needs to be searched.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The invention aims to provide 4-thiouracil deoxynucleoside phosphate, thereby overcoming the defects in the prior art and providing a new technical choice.
In order to achieve the above object, the present invention provides a 4-thiouracil deoxynucleoside phosphate ester, having a structural formula:
preferably, in the above technical scheme, the 4-thiouracil deoxynucleoside phosphate is yellow solid.
The application also claims the use of 4-thiouracil deoxynucleoside phosphate esters according to the preceding description for the preparation of a medicament for inhibiting hepatitis B virus.
Preferably, in the above technical scheme, the inhibitory rate of 4-thiouracil deoxynucleoside phosphate ester to HBV virus is not less than 29.95%.
Preferably, in the above technical scheme, the medicament is prepared into any one of the dosage forms in pharmacy, including tablets, capsules, granules, pills, oral liquid, injection, or other dosage forms suitable for preparation.
The synthesis method of the 4-thiouracil deoxynucleoside phosphate comprises the following steps:
mixing the compound A, trimethyl phosphate and sodium iodide in acetonitrile, refluxing and stirring at 90 ℃ under the protection of inert gas overnight, cooling the reaction solution to room temperature after the reaction is finished, filtering, concentrating the filtrate, and separating the crude product by column chromatography to obtain a compound B;
dissolving the compound B and lithium bromide in acetonitrile, and refluxing and stirring at 90 ℃ overnight; cooling to room temperature after the reaction is finished, separating out a product, filtering, washing a filter cake with petroleum ether, and drying the filter cake at room temperature to obtain a compound C;
dissolving the compound D and acetic anhydride in pyridine, stirring at room temperature for reaction overnight under the protection of argon, directly concentrating under reduced pressure after the reaction is finished, adding dichloromethane for dilution, washing an organic phase with saturated citric acid, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a compound E; compound E was directly subjected to the next step without purification;
dissolving the compound E in toluene, refluxing and stirring until the system is clear, adding a Lawson reagent, continuously refluxing for 2 hours, cooling the reaction liquid to room temperature, concentrating, and performing column chromatography separation to obtain a compound F;
dissolving the compound F in an ammonia methanol solution, stirring overnight at room temperature, and concentrating the reaction solution to obtain a compound G which can be directly used in the next step;
dissolving the compound G and the compound C in THF, sequentially adding 3-nitro-1, 2, 4-triazole, diisopropylethylamine and bis (2-oxo-3-oxazolidinyl) hypophosphorous chloride at 0 ℃, and stirring for 1h at room temperature; diluting the reaction solution with dichloromethane, then adding 1M citric acid for washing, separating out an organic phase, washing the organic phase with water, and then washing with saturated saline water; drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate, and separating by column chromatography to obtain 4-thiouracil deoxynucleoside phosphate Q06.
Preferably, in the above technical solution, step S1 specifically includes: mixing the compound A, trimethyl phosphate and sodium iodide in acetonitrile, adding a plurality of 4A molecular sieves into the reaction solution, refluxing and stirring at 90 ℃ under the protection of inert gas overnight, cooling the reaction solution to room temperature after the reaction is finished, filtering by using kieselguhr, washing filter residues by using ethyl acetate, concentrating the filtrate, and separating the crude product by using column chromatography to obtain the compound B.
Preferably, in the above technical solution, the developing solvent for column chromatography in step S1 is petroleum ether/ethyl acetate = 15/1-5/1.
Preferably, in the above technical scheme, the compound B is a colorless transparent oil, the compound C is a white solid, the compound E is a white solid, the compound F is a yellow oil, and the compound G is a yellow solid.
Compared with the prior art, the invention has the following beneficial effects:
the discovery of new drug molecules not only has new choice for drugs for treating hepatitis B, but also has important significance for developing more ideal drugs for treating hepatitis B.
Drawings
FIG. 1 is a nuclear magnetic spectrum of 4-thiouracil deoxynucleoside phosphate.
Detailed Description
The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
It will be appreciated by those skilled in the art that the 4-thiouracil deoxynucleoside phosphate of the present invention is a yellow solid and can be formulated into various preparation forms well known in the art, such as tablets, capsules, granules, pills, oral liquids, injections, depending on the particular mode of administration.
Example 1: synthesis of Compound B
1) Compound A (25 g, 178.48 mmol) was dissolved in acetonitrile (250 mL), the reaction mixture was replaced with argon and then protected with argon, trimethyl phosphate (107.5 g, 713.93 mmol), sodium iodide (80 g, 535.45 mmol) and 4A molecular sieve were added to the reaction mixture in this order, and after the addition, the reaction mixture was heated to 90 ℃ in an oil bath and stirred overnight. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1-5/1) to give compound B (50.7 g, colorless transparent oily substance, yield: 65%).
2) Compound A (11.2 g, 79.96 mmol) was dissolved in acetonitrile (100 mL), the reaction mixture was replaced with argon and then argon-protected, trimethyl phosphate (41.15 g, 279.86 mmol) and sodium iodide (35.96 g, 239.88 mmol) were added to the reaction solution in this order, and after completion of addition, the reaction solution was heated to 90 ℃ in an oil bath and stirred for 30 h. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1-5/1) to give compound B (23.9 g, colorless transparent oily substance, yield: 68%).
Example 2: synthesis of Compound C
1) Compound B (50.7 g, 115.11 mmol) was dissolved in acetonitrile (250 mL), lithium bromide (10 g, 115.11 mmol) was added to the reaction mixture, the reaction mixture was replaced with argon and then protected with argon, and the oil bath was warmed to 90 ℃ for 16 h. The reaction solution was naturally cooled to room temperature, a large amount of solid was precipitated, filtered, the filter cake was washed with petroleum ether, and the filter cake was dried to give Compound C (26.6 g, white solid, yield: 71.9%).
2) Compound B (23.9 g, 54.27 mmol) was dissolved in acetonitrile (150 mL), lithium bromide (4.7 g, 54.27 mmol) was added to the reaction mixture, the reaction mixture was replaced with argon and then under argon, the oil bath was warmed to 90 ℃ for 16 h. The reaction mixture was naturally cooled to room temperature, directly concentrated under reduced pressure, and the crude product was slurried with petroleum ether (300 mL) and filtered to give Compound C (14.3 g, white solid, yield: 81%).
Example 3:
1) synthesis of Compound E
Compound D (5 g, 21.91mmol) and acetic anhydride (4.92 g, 48.2 mmol) were dissolved in pyridine (50 mL), the reaction mixture was replaced with argon and the reaction was stirred at room temperature for 16h under argon. The reaction mixture was directly concentrated under reduced pressure, diluted with dichloromethane (200 mL), and the organic phase was washed with saturated citric acid (80 mLx 2), once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Compound E (7.57 g, white solid).
2) Synthesis of Compound E
Compound D (5 g, 21.91mmol) and acetic anhydride (4.92 g, 48.2 mmol) were dissolved in acetonitrile (50 mL), the reaction mixture was replaced with argon and then stirred for 10min under argon atmosphere, triethylamine (4.88 g, 48.2 mmol) was slowly added dropwise and the reaction was stirred at room temperature for 16 h. The reaction mixture was directly concentrated under reduced pressure, diluted with dichloromethane (200 mL), the organic phase was washed with water (100 mLx 2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Compound E (4.3 g, white solid).
Example 4: synthesis of Compound F
1) Compound E (7.57 g, 24.24 mmol) was dissolved in toluene (170 mL), the oil bath was warmed to 100 ℃ and stirred until the system was clear, Lawson's reagent (10.78 g, 26.67 mmol) was added and the reaction continued at 100 ℃ for 1.5 h. The reaction mixture was naturally cooled to room temperature, and directly concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 9/1-1/1) to give compound F (6.95 g, yellow oily substance, yield: 87.3%).
2) Compound E (7.57 g, 24.24 mmol) was dissolved in toluene (170 mL), the oil bath was warmed to 100 ℃ and stirred until the system was clear, Lawson's reagent (5.88 g, 14.54 mmol) was added and the reaction continued at 100 ℃ for 1.5 h. The reaction mixture was naturally cooled to room temperature, and directly concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 9/1-1/1) to give compound F (7.16 g, yellow oily substance, yield: 90.1%).
Example 5: synthesis of Compound G
1) Compound F (6.95 g, 21.17 mmol) was dissolved in methanolic ammonia (100 mL, 7M) and stirred at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (dichloromethane/methanol = 30/1-20/1) to give compound G (5.6G, yellow solid).
2) Compound F (6.95 g, 21.17 mmol) was dissolved in methanolic ammonia (80 mL, 7M) and stirred at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure to give a crude product, which was separated by silica gel column chromatography (dichloromethane/methanol = 30/1-20/1) to give compound G (5.8G, yellow solid).
Example 6:
1) synthesis of Compound Q06
Compound G (100 mg, 0.409 mmol), compound C (204 mg, 0.614 mmol) and triphenylphosphine (161 mg, 0.614 mmol) were dissolved in tetrahydrofuran (7 mL), purged with nitrogen three times and protected, stirred at room temperature for 10min, added diethyl azodicarboxylate, stirred at room temperature overnight, and there was no product.
2) Synthesis of Compound Q06
Compound G (1.45G, 5.94 mmol), compound C (1.97G, 5.94 mmol) were dissolved in tetrahydrofuran (50 mL), the temperature was lowered to 0 ℃ with ice water, 3-nitro-1H-1, 2, 4-triazole (1.35G, 11.87 mmol), diisopropylethylamine (3.07G, 23.75 mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (3.02G, 11.87 mmol) were added in this order, and the reaction was allowed to spontaneously warm to room temperature and stirred for 1H. The reaction mixture was diluted with ethyl acetate (500 mL), washed three times with 1M citric acid, twice with water, once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, the filtrate was concentrated, and separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1-1/1) to obtain final product Q06 (820 mg, yellow solid, yield: 25%).
1H NMR (500 MHz, DMSO-d 6) δ 12.87 – 12.60 (m, 1H), 7.53 (d, J = 7.6 Hz, 1H), 6.29 (dd, J = 7.6, 2.0 Hz, 1H), 6.10 (t, J = 6.6 Hz, 1H), 5.61 (dd, J = 13.8, 1.5 Hz, 4H), 5.49 (s, 1H), 4.35 – 4.09 (m, 3H), 4.04 – 3.86 (m, 1H), 2.25 – 2.14 (m, 2H), 1.17 (d, J = 2.4 Hz, 18H)。
Example 7:
the in vitro anti-HBV activity, the test medicine and the positive control drug telbivudine prepared by the embodiment of the invention are used as the in vitro anti-HBV virus efficacy evaluation test. The method comprises the following steps:
and (3) detecting the antiviral activity of the medicine: collecting HepG2.2.15 cell 1 bottle with good growth, digesting with pancreatin to obtain single cell suspension, counting with cell counting plate, adjusting cell density to 2 × 10 with DMEM medium containing 10% FBS serum5 one/mL, inoculated in culture plates (96 wells, 100uL per well). Placing in carbon dioxide incubator under 5% CO2Incubate at 37 ℃ until 80% contact inhibition. The supernatant was aspirated off and 10. mu. mol/L of test drug was addedThe culture solution is added with the control drug telbivudine culture solution, and a cell blank control hole is additionally arranged. 3 replicate wells were set for each concentration gradient and cell blank. Placing in a carbon dioxide incubator, culturing at 37 ℃ for 3d/6d/9d, sucking supernatant, centrifuging, and detecting the HBV-DNA content in the supernatant by a fluorescent quantitative PCR method, wherein the result is shown in Table 1.
TABLE 1
The results in the table show that the compounds in the table have good inhibition effect on HBV DNA secretion of HepG2.2.15 cells, and the inhibition rate of the compound Q06 is higher than that of a positive control medicament telbivudine, so that the compound has good application prospect.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (5)
2. the 4-thiouracil deoxynucleoside phosphate according to claim 1, characterized in that: 4-Thiouropyrimidine deoxynucleoside phosphate is a yellow solid.
3. The use of a 4-thiouracil deoxynucleoside phosphate according to claim 1 for the preparation of a medicament for inhibiting hepatitis b virus.
4. The use of 4-thiouracil deoxynucleoside phosphate for preparing a medicament for inhibiting hepatitis B virus according to claim 3, wherein the inhibitory rate of 4-thiouracil deoxynucleoside phosphate against HBV virus is not less than 29.95%.
5. The use of 4-thiouracil deoxynucleoside phosphate according to claim 3 for preparing a medicament for inhibiting hepatitis B virus, wherein the medicament is prepared into any one of pharmaceutical dosage forms, including tablets, capsules, granules, pills, oral liquid, injections, or other dosage forms suitable for preparation.
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