CN103845345A - Hepatitis treatment medicament - Google Patents
Hepatitis treatment medicament Download PDFInfo
- Publication number
- CN103845345A CN103845345A CN201210505773.6A CN201210505773A CN103845345A CN 103845345 A CN103845345 A CN 103845345A CN 201210505773 A CN201210505773 A CN 201210505773A CN 103845345 A CN103845345 A CN 103845345A
- Authority
- CN
- China
- Prior art keywords
- acid
- formula
- hepatitis
- acceptable salt
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CCOc1ccccc1OP(CO[C@](C)C[n]1c2ncnc(N)c2nc1)(Oc1ccccc1*)=O Chemical compound CCOc1ccccc1OP(CO[C@](C)C[n]1c2ncnc(N)c2nc1)(Oc1ccccc1*)=O 0.000 description 1
Abstract
The invention aims at providing an acyclic nucleotide derivative shown as a formula I and a non-toxic pharmaceutically acceptable salt thereof, a pharmaceutical composition which contains the acyclic nucleotide derivative shown as the formula I and the non-toxic pharmaceutically acceptable salt thereof as an active ingredient and employs common pharmaceutical excipients in the pharmacy field, and application of the pharmaceutical composition to treat hepatitis and virus hepatitis B as a medicine. The formula I is shown in the specification.
Description
Technical field
The present invention relates to the acyclic nucleoside acid-like substance shown in formula I and non-toxicity pharmaceutically acceptable salt thereof the purposes as treatment hepatitis and hepatitis B medicine:
Background technology
Hepatitis is the liver damage disease take transaminase's rising as symptom, comprises the hepatic injury that chemicals causes, the hepatic injury due to metabolism disorder, and virus is as the hepatic injury due to hepatitis B virus or hepatitis c virus infection.Chronic persistent hepatitis will cause hepatic fibrosis, then be further development of even hepatocarcinoma of liver cirrhosis.The main target for the treatment of hepatitis is by using medicine to reduce transaminase, suppress the generation of inflammation, suppressing the formation and development of hepatic fibrosis.Conventional Antihepatitis medicament mainly contains silibinin, diammonium glycyrrhizinate, bifendate and bicyclol etc.; These medicines can reduce transaminase effectively, significantly improve hepatitis symptom, but viral hepatitis is not had to significant curative effect.
To hepatitis B, antiviral therapy can suppress virus replication, thereby improves by the caused hepatic injury of hepatitis B virus duplication.Conventional treating hepatitis B medicine has interferon, lamivudine, adefovir ester, tenofovir disoproxil, Entecavir etc.Interferon therapy effective percentage only has 30-50%, and side effect is larger.Lamivudine can reduce rapidly virus load, but it is quite slow to remove the process of residual virus, needs long term administration, thereby produces drug resistance, medication after 2 years drug resistance incidence rate up to 40-50%; Entecavir is current the strongest active anti-hepatic-B virus medicine, but as nucleoside analog, Entecavir and lamivudine have cross resistance, invalid to lamivudine resistance strain, and animal experiment shows that it has higher carcinogenecity.
Tenofovir pyrrole furan ester is the prodrug with the acyclic nucleotide analogue, tenofovir (PMPA) of anti-hepatitis B activity, the oral interior rear activity form tenofovir that discharges of body that enters, and performance antivirus action:
As nucleotide analog, the HBV DNA level of tenofovir pyrrole furan ester in clinically can fast reducing hepatitis B patient blood, effective to lamivudine resistance Strain, prolonged application is difficult for producing drug resistance.But tenofovir pyrrole furan ester poor chemical stability, its crude drug and preparation are more responsive to temperature humidity, are easily decomposed to form the nonabsorbable monoesters of human body; Its interior metabolism product formaldehyde has toxicity to human body; Tenofovir pyrrole furan ester is unstable at gastrointestinal tract, and hydrolysis generates highly acid tenofovir, irritant to gastrointestinal tract.
Once at present clinical conventional ucleosides HBV medicine, as drug withdrawals such as lamivudine, adefovir ester, tenofovir disoproxil, Entecavirs, there will be the knock-on of hepatitis B virus duplication, cause thus the serious consequence such as acute attack of hepatitis.
At present known nucleoside medicine is if lamivudine, adefovir ester, tenofovir disoproxil, Entecavir etc. are to reducing transaminase and suppressing hepatic fibrosis, and onset is slower.
Summary of the invention
In order to overcome above-mentioned deficiency, find particularly viral hepatitis treatment medicine of better hepatitis, the inventor has the oral administration biaavailability of better chemical stability and Geng Gao than tenofovir pyrrole furan ester by the target compound shown in large quantity research discoverable type I; The inventor finds more unexpectedly, although the target compound effect on hepatitics B virus in vitro activity shown in formula I is nothing like tenofovir pyrrole furan ester, in its body, the effect of anti-hepatitis virus is stronger more than 5 times than tenofovir pyrrole furan ester; The inventor is unexpected discovery also, compared with tenofovir pyrrole furan ester, and after the target compound oral administration shown in I, can fast reducing HBV DNA; The inventor is unexpected discovery also, compared with tenofovir pyrrole furan ester, after the target compound oral administration shown in I, has lasting anti-HBV effect, HBV DNA dead stroke after drug withdrawal.
Inventor further research also finds, after the target compound oral administration shown in formula I, can reduce chemicals as CCl
4, transaminase due to acetaminophen, D-Gal or isothiocyanic acid α-naphthylacetate etc. raises; Also can suppress hepatitis virus as the hepatic injury due to hepatitis B virus.
Therefore, the invention provides the acyclic nucleoside acid-like substance shown in formula I and non-toxicity pharmaceutically acceptable salt thereof the purposes as the medicine for the treatment of hepatitis.
The present invention also provides the acyclic nucleoside acid-like substance shown in formula I and non-toxicity pharmaceutically acceptable salt thereof as the purposes for the treatment of hepatitis B medicine.
Formula I compound of the present invention can itself also can the acceptable salt of its pharmacy or the form of solvate use.
The acceptable salt of pharmacy of formula I compound comprises the salt forming with pharmaceutically acceptable mineral acid or organic acid.
The example of suitable acid-addition salts comprises the salt forming with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propanoic acid, succinic acid, hydroxyacetic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid etc.Pharmaceutical salts comprises its inorganic or acylate, comprising but be not limited to: hydriodate, disulfate, hydrophosphate, butyrate, oxalates, pivalate, adipate, alginate, picrate, aspartate, gluconate, esilate, tosilate, embonate, pyruvate, glycollate, trifluoroacetate, para-aminosalicylic acid salt, pamoate and Ascorbate etc.(referring to for example S.M.Berge, et al., " Pharmaceutical Salts, " J.Pharm.Sci., 66:1-19 (1977).
The present invention provides a kind of pharmaceutical composition on the other hand, and the acyclic nucleoside acid-like substance shown in its contained I and non-toxicity pharmaceutically acceptable salt thereof are as pharmaceutical excipient conventional in active component and pharmaceutical field.
The present invention also provides a kind of pharmaceutical composition, wherein, comprises the acyclic nucleoside acid-like substance shown in the formula I of 1mg to 300mg and non-toxicity pharmaceutically acceptable salt thereof as pharmaceutical excipient conventional in active component and pharmaceutical field in per unit dosage.
The present invention also provides a kind of pharmaceutical composition, wherein, comprises the acyclic nucleoside acid-like substance shown in the formula I of 10mg to 100mg and non-toxicity pharmaceutically acceptable salt thereof as pharmaceutical excipient conventional in active component and pharmaceutical field in per unit dosage.
According to pharmaceutical composition of the present invention, it can be for example following dosage form: tablet is such as but not limited to fast-release tablet, slow releasing tablet, controlled release tablet, Film coated tablets, coated tablet, buccal tablet, Sublingual tablet, biological adhesive tablet etc.; Capsule is such as but not limited to hard capsule, soft capsule etc.; Injection is such as but not limited to water type injection aseptic or bacteriostatic agent, oleo-injection, lyophilization injectable powder, injectable microsphere etc.; The spray that spray is used etc. with, the local skin spraying of, nasal spray such as but not limited to mouthspray; Aerosol sucks with aerosol, local skin aerosol etc. such as but not limited to lung; Nasal drop is such as but not limited to solution, a nasal gel etc. for collunarium; Powder spray is such as but not limited to powder spray for oral cavity, powder spray for nasal cavity, powder spray etc. for local skin.The preparation technology of these preparations is that art technology people can prepare according to its existing knowledge or with reference to being correlated with textbook or reference book.
Target compound shown in formula I can be prepared by following synthetic route:
PMPA and o-ethoxyphenol are under DCC effect, and condensation generates target compound.
The specific embodiment
Further illustrate the present invention below by specific embodiment, still, should be understood to, these embodiment are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and operational approach are well known in the art.
Embodiment 1[[(R)-2-(6-amino-purine-9-yl)-1-methyl-ethyoxyl-] methyl] preparation of phosphonic acids two (2-ethyoxyl) phenyl ester (I)
144g (0.50mol) [[(R)-2-(6-amino-purine-9-yl)-1-methyl-ethyoxyl-] methyl] phosphonic acids, 276g (2.00mmol) o-ethoxyphenol and 390g 1-Methyl-2-Pyrrolidone are heated to 85 ℃, then add 63g triethylamine, add 309g (1.50mmol) DCC, in 100 ℃ of heated and stirred 16 hours.Cooling, elimination solid; Filtrate decompression is concentrated, with the separation of silica gel (200-300 order) post, use dichloromethane: methanol (20: 1) mixed solvent eluting, collect required component, evaporated under reduced pressure.By residue re-crystallizing in ethyl acetate, obtain I 35g, fusing point 110-112 ℃.Elementary analysis C
25h
27n
5o
6p value of calculation: C 56.92%, H 5.73%, N 13.28%, P 5.87%.Measured value: C 56.72%, H5.71%, N 13.18%, P 5.88%.
Embodiment 2[[(R)-2-(6-amino-purine-9-yl)-1-methyl-ethyoxyl-] methyl] preparation of phosphonic acids two (2-ethyoxyl) phenyl ester hydrochlorate (IHCl)
13gI is dissolved in to 50ml acetone, drips the diethyl ether solution of hydrogen chloride, to pH be 2-3, backflow 10min, cooling, separates out solid naturally, is dried, and obtains IHCl 13.3g, fusing point 178-186 ℃.Elementary analysis C
25h
27n
5o
6pHCl value of calculation: C 53.24%, H 5.54%, Cl 6.29%, N 12.42%, P 5.49%; Measured value (%): C 53.31%, H 5.58%, Cl 6.19%, N 12.41%, P 5.40%.
Embodiment 3 stability tests
According to the content of high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2000) working sample.
Chromatographic condition and system suitability: with amino bonded silica gel be filler; Take acetonitrile-0.05mol/L potassium dihydrogen phosphate aqueous solution (22: 78) as mobile phase, flow velocity 1.0ml/min, detection wavelength is 260nm.Theoretical cam curve is pressed tenofovir disoproxil and is calculated, and should be not less than 2000.
Algoscopy: get the about 25mg of testing sample, accurately weighed, put in 25ml measuring bottle, add mobile phase and dissolve and be diluted to scale, shake up, the accurate 5ml that draws, puts in 25ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, as need testing solution.Precision measures need testing solution 10 μ l, and injection liquid chromatography, records chromatogram; Separately learn from else's experience drying under reduced pressure to the corresponding reference substance of constant weight, be measured in the same method,, to obtain final product with calculated by peak area by external standard method.The results are shown in Table 1:
Table 1 stability test result
The anti-CCl of embodiment 4
4the evaluation of induced mice hepatic injury
Get the Kunming mouse of the about 18-22g of quality, random packet, every group of 10 mices.By the oral testing compound that gives various dose; After 1h, according to the dosage of 10mL/kg, subcutaneous injection 0.1%CCl
4peanut oil solution, prepare liver injury model; Subcutaneous injection normal saline is as Normal group.After modeling after 12 hours, the oral testing compound that gives various dose again.After administration 24 hours for the second time, put to death animal, leave and take serum specimen, unified with full automatic biochemical apparatus for the ALT in serum, AST level detects.Evaluation result is in table 2.
The anti-CCl of table 2
4the evaluation result of poisoning induced mice hepatic injury
The evaluation of the anti-acetaminophen induced mice of embodiment 5 hepatic injury
Get the Kunming mouse of the about 18-22g of quality, random packet, every group of 10 mices.By the oral testing compound that gives various dose; After 1h, prepare liver injury model with the acetaminophen subcutaneous injection of 100mg/kg, subcutaneous injection normal saline is as Normal group.After modeling 12h, by the oral testing compound that again gives various dose.After administration 24 hours for the second time, put to death animal, leave and take serum specimen, unified with full automatic biochemical apparatus for the ALT in serum, AST level detects.Evaluation result is in table 3.
The evaluation result of the anti-acetaminophen induced mice of table 3 hepatic injury
The evaluation of the anti-isothiocyanic acid α-naphthylacetate of embodiment 6 induced mice hepatic injury
Get the Kunming mouse of the about 18-22g of quality, random packet, every group of 10 mices.Testing sample is suspended or is dissolved in 0.5% carboxymethylcellulose sodium solution, give the testing compound of various dose by gavage; After 2h, the peanut oil solution (500mg isothiocyanic acid α-naphthylacetate is dissolved in 50ml Oleum Arachidis hypogaeae semen) that gives isothiocyanic acid α-naphthylacetate (ANIT) by the dosage gavage of 10mL/kg is prepared liver injury model, and gavage Oleum Arachidis hypogaeae semen is Normal group.After modeling 2h, by the oral testing compound that again gives various dose.After administration 16 hours for the second time, put to death animal, leave and take serum specimen, unified with full automatic biochemical apparatus for the ALT in serum.Evaluation result is in table 4.
The evaluation result of the poisoning induced mice hepatic injury of the anti-ANIT of table 4
The evaluation of the anti-D-Gal induced mice of embodiment 7 hepatic injury
Get the Kunming mouse of the about 18-22g of quality, random packet, every group of 10 mices.Testing sample is suspended or is dissolved in 0.5% carboxymethylcellulose sodium solution, give the testing compound of various dose by gavage; After 2h, give D-Gal prepare liver injury model by the dosage lumbar injection of 750mg/kg, subcutaneous injection normal saline is as Normal group.After modeling 2h, by the oral testing compound that again gives various dose.After administration 16 hours for the second time, put to death animal, leave and take serum specimen, unified with full automatic biochemical apparatus for the ALT in serum.Evaluation result is in table 5.
The evaluation result of the anti-D-Gal induced mice of table 5 hepatic injury
Embodiment 8 In Vitro Anti HBV activity and Cytotoxic evaluation
With Hep G 2.2.15 cells in vitro test method determination inhibitory action and the cytotoxicity of target compound to HBV DNA:
Experimental technique
Measure the inhibitory action of target compound to HBV DNA by quantitative real-time fluorescence PCR method: Hep G 2.2.15 cell culture, in containing in the DMEM culture fluid of 10% calf serum, is hatched in 5%CO2 incubator.Then cell is inoculated in 96 orifice plates to cell number 3x10
4, continue to cultivate, when cell density reaches 80% left and right, discard old culture fluid, add the new culture fluid containing variable concentrations medicine to be measured, 3 parallel holes are set; Changed culture fluid every 2 days.After administration the 10th day, get 100 μ l supernatants, by the method for quantitative PCR, measure the content of HBV DNA, calculate 50% inhibition concentration, be IC
50value.
Measure the cytotoxicity of target compound by mtt assay: Hep G
2cell culture, in containing in the DMEM culture fluid of 10% calf serum, is hatched in 5%CO2 incubator.Then cell is inoculated in 96 orifice plates to cell number 5X10
4/ hole, continues to cultivate 3 days, adds the new culture fluid containing variable concentrations medicine, and 3 parallel holes are set; After administration the 3rd day, add MTT to 7.5mg/ml, continue to cultivate 2 hours, supernatant discarded, adds the isopropyl alcohol containing 10% tween x-100,120 μ l/ holes, then add 0.4 μ l/ hole, and measure the absorption at 540nm place with enzyme connection instrument, calculating 50% inhibition concentration, is CC
50value.
The results are shown in Table 6.
Table 6 target compound In Vitro Anti HBV activity and cytotoxicity the selection result
The evaluation of anti-hepatitis virus and antihepatitic activity in embodiment 9 bodies
By the sheldrake random packet of vertical transmission infection, the DHBV DNA detection positive, 10 every group.Gavage gives the testing compound of water and various dose respectively, once a day, and totally 30 days.Respectively before administration, venous blood collection the 14th day time after the 7th day, the 14th day, the 28th day and drug withdrawal after administration, adopt outer standard TaqMan real-time fluorescence PCR method to measure serum DHBV DNA content.The results are shown in Table 7.
Experiment finishes rear execution experiment duck, gets liver, carries out respectively light microscopic pathologic finding.According to the chronic chronic hepatitis stage and step standard shown in following table, lesion degree is marked:
Chronic hepatitis stage and step standard
Then convert by formula below, the variation number of falling ill: 0～±: 0.25; ±: 0.5; ±～+: 0.75; +: 1.0; +～++: 1.5; ++: 2.0; ++～+++: 2.5.
Pathological examination results is in table 8.
Table 7 interior resisting virus activity rating result
Table 8 duck hepatic pathology sections observation result
2 weeks toxicity tests of embodiment 10 rat repeat administration
SD rat, random packet, every group of 10 animals, male and female half and half.Gavage gives the IHCl of solvent, 300mg/kg dosage and the tenofovir pyrrole furan ester of 300mg/kg dosage respectively, and every day 1 time, this medicine 2 weeks continuously, continues to observe, and measures body weight.Put to death animal to 14 days, gather blood, measure hematology, blood parameters.The results are shown in Table 9:
Table 9 mice subacute toxicity test result
The tablet composition of embodiment 1120mg/ sheet
Selection lactose is diluent, low-substituted hydroxypropyl cellulose is disintegrating agent, microcrystalline Cellulose is as the diluent that has certain disintegration concurrently, polyvinylpyrrolidone aqueous solution is as binding agent, butylated hydroxyarisol and citric acid are antioxidant, and starch is filler, and magnesium stearate is as lubricant, carry out prescription screening by the unit dose of 20mg/ sheet IHCl, in Table 10-1.
Preparation technology: the adjuvants such as active component IHCl and microcrystalline Cellulose, lactose are crossed respectively to 100 mesh sieves, for subsequent use; By adjuvants such as the IHCl of recipe quantity and microcrystalline Cellulose, lactose, by volume the progressively increase principle of method of equivalent is fully mixed; Above-mentioned mixture is added 3% polyvinylpyrrolidone aqueous solution appropriate, limit edged is mixed, makes soft material, granulates twice through 20 mesh sieves, and wet granular is put 40 ± 5 ℃, and moisture≤3% is controlled in forced air drying; In dry granule, add the magnesium stearate of recipe quantity, cross 20 mesh sieves, granulate; Select the circular punch die that diameter is 8mm, debugging tablet weight adjuster, heavily meets the requirements the sheet of simvastatin element sheet, and theoretical value is 200 ± 15mg.Regulating pressure regulator to make slice, thin piece hardness is 60～80 newton (6～8kg) again, tabletting.
Table 10-1 prescription screening table (100 consumptions) (unit: gram)
Experimental result through prescription screenings such as dissolution, homogeneity and repeatability shows, No. 1 prescription indices all meets designing requirement.According to 3 batch samples of No. 1 formula preparation, carry out accelerated stability test, the results are shown in Table 10-2.
Table 10-2 acceleration environment (40 ℃ ± 2 ℃, RH75% ± 5%) stability test result
The capsule compositions of embodiment 12 80mg/ grains
Select lactose as diluent, crospovidone (PVP XL) as disintegrating agent, polyvidone (K30) as binding agent, magnesium stearate as lubricant, carry out prescription screening by the unit dose of 80mg/ grain IHCl, in Table 11-1.
Preparation technology: IHCl and adjuvant lactose, crospovidone, magnesium stearate are crossed respectively to 80 mesh sieves, for subsequent use; By the IHCl of recipe quantity, lactose, crospovidone, by volume the progressively increase principle of method of equivalent is fully mixed, crosses 60 mesh sieve 3 times; Get the polyvidone that model is K30 (K30) appropriate, the stirring and dissolving that adds water, is mixed with the solution that concentration is 5% (W/V), for subsequent use; Above-mentioned mixture is added to appropriate binding agent (35～45ml), and limit edged is mixed, makes soft material, granulates twice through 40 mesh sieves, and wet granular is put 60 ± 5 ℃ of oven dry; Regulate loading amount; In dry granule, add the magnesium stearate of recipe quantity, cross 40 mesh sieves mixed 2 times, granulate; Fill.
Table 11-1 prescription screening table (100 consumptions) (unit: gram)
The prescription screening evaluation test results such as mobility of particle, homogeneity and technique repeatability show, No. 2 prescription indices all meets designing requirement.According to 3 batch samples of No. 2 formula preparations, carry out accelerated stability test, the results are shown in Table 11-2.
Table 11-2 acceleration environment (40 ℃ ± 2 ℃, RH75% ± 5%) stability test result
Claims (5)
- Acyclic nucleoside acid derivative shown in formula I and non-toxicity pharmaceutically acceptable salt thereof as treatment hepatitis medicament purposes:
- 2. the purposes as treatment hepatitis B medicine according to the acyclic nucleoside acid derivative shown in the formula I of claim 1 and non-toxicity pharmaceutically acceptable salt thereof.
- Acyclic nucleoside acid derivative shown in contained I and non-toxicity pharmaceutically acceptable salt thereof as the pharmaceutical composition of pharmaceutical excipient conventional in active component and pharmaceutical field the purposes as treatment hepatitis medicament.
- 4. compositions claimed in claim 3, wherein, comprises the acyclic nucleotide derivant analog shown in the formula I of 1mg to 500mg and non-toxicity pharmaceutically acceptable salt thereof as pharmaceutical excipient conventional in active component and pharmaceutical field in per unit dosage.
- 5. compositions claimed in claim 3, wherein, comprises the acyclic nucleoside acid derivative thing shown in the formula I of 10mg to 100mg and non-toxicity pharmaceutically acceptable salt thereof as pharmaceutical excipient conventional in active component and pharmaceutical field in per unit dosage.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210505773.6A CN103845345A (en) | 2012-12-03 | 2012-12-03 | Hepatitis treatment medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210505773.6A CN103845345A (en) | 2012-12-03 | 2012-12-03 | Hepatitis treatment medicament |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103845345A true CN103845345A (en) | 2014-06-11 |
Family
ID=50853750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210505773.6A Pending CN103845345A (en) | 2012-12-03 | 2012-12-03 | Hepatitis treatment medicament |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103845345A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923124A (en) * | 2013-01-15 | 2014-07-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Crystalline-state anti-hepatitis B virus drug |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110218241A1 (en) * | 2010-03-06 | 2011-09-08 | Cacao Bio-Technologies, Llc | Antiviral epicatechins, epicatechin oligomers, or thiolated epicatechins from theobroma cacao for treatment of genital warts |
| CN102417521A (en) * | 2010-09-28 | 2012-04-18 | 中国医学科学院医药生物技术研究所 | Preparation method of acyclic nucleoside antiviral drug phosphoric acid monoester compound |
| CN102485229A (en) * | 2010-12-02 | 2012-06-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Antiviral medicine |
-
2012
- 2012-12-03 CN CN201210505773.6A patent/CN103845345A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110218241A1 (en) * | 2010-03-06 | 2011-09-08 | Cacao Bio-Technologies, Llc | Antiviral epicatechins, epicatechin oligomers, or thiolated epicatechins from theobroma cacao for treatment of genital warts |
| CN102417521A (en) * | 2010-09-28 | 2012-04-18 | 中国医学科学院医药生物技术研究所 | Preparation method of acyclic nucleoside antiviral drug phosphoric acid monoester compound |
| CN102485229A (en) * | 2010-12-02 | 2012-06-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Antiviral medicine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| CN103923124A (en) * | 2013-01-15 | 2014-07-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Crystalline-state anti-hepatitis B virus drug |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI789695B (en) | Methods for treating sars cov-2 infections | |
| CA2856529C (en) | Compositions and methods for treating hepatitis c virus | |
| CN107530348A (en) | A kind of pharmaceutical composition containing jak kinase inhibitor or its officinal salt | |
| CN110248951A (en) | For treating the nucleotide Hemisulphate of Hepatitis C Virus | |
| JP2024513571A (en) | Thionucleosides as antiviral agents | |
| US20140187627A1 (en) | Uses of c15-substituted andrographolide derivatives in the preparation of anti-hepatitis b virus medicament | |
| CN101869633B (en) | Enteric-coated medicament combination containing epigallocatechin gallate | |
| CN101671337B (en) | Citric acid aildenafil crystal form A and preparation method and usage thereof | |
| CN104000789A (en) | Adefovir dipivoxil dispersible tablet and preparation method thereof | |
| CN1872853A (en) | Derivative of purine | |
| ES2844848T3 (en) | Pharmaceutical compositions comprising Lonafarnib and Ritonavir | |
| CN103845345A (en) | Hepatitis treatment medicament | |
| CN1857418A (en) | Chinese medicine powder inhalant and its preparing method and application | |
| CN101698668B (en) | Crystal form V of Aildenafil citrate and preparation method and application thereof | |
| CN101361869A (en) | Quality control method of tables for treating asthma | |
| CN101953773B (en) | Lamivudine liposome solid preparation | |
| CN111096954B (en) | A pharmaceutical composition for resisting viral infection and its preparation method | |
| CN1528759A (en) | Radix bupleuri stem-leaf extract and preparing method and use thereof | |
| CN101774921A (en) | Method for preparing dicaffeoylquinic acid methyl compound and composition thereof | |
| CN102070691B (en) | Metacavir crystal form, preparation method thereof and medicinal composition containing metacavir crystal form | |
| CN102485229B (en) | antiviral drugs | |
| CN105267232A (en) | Pharmaceutical preparation for treating hepatitis C and preparing method thereof | |
| Corbo et al. | In silico prediction of the inhibitory effect of phytochemical components extracted from Knautia sarajevensis on the main protease of SARS-CoV-2 virus | |
| ES2908500B2 (en) | ANDROGRAFOLIDE DERIVATIVE FOR USE IN THE TREATMENT OF INFLAMMATORY DISEASES ASSOCIATED WITH A CYTOKINE STORM | |
| Rajesh et al. | Related substances method development and validation of Atazanavir and Ritonavir in tablet dosage form by high performance liquid chromatography |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140611 |