CN104650171A - Sofosbuvir sesquihydrate compound - Google Patents
Sofosbuvir sesquihydrate compound Download PDFInfo
- Publication number
- CN104650171A CN104650171A CN201310606264.7A CN201310606264A CN104650171A CN 104650171 A CN104650171 A CN 104650171A CN 201310606264 A CN201310606264 A CN 201310606264A CN 104650171 A CN104650171 A CN 104650171A
- Authority
- CN
- China
- Prior art keywords
- rope fluorine
- fluorine cloth
- cloth wei
- wei
- virus
- 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 CC(C)OC([C@](C)NP(*)(OC[C@]([C@@]([C@@]1(C)F)O)O[C@]1N(C=CC(N1)=O)C1=O)=O)=O Chemical compound CC(C)OC([C@](C)NP(*)(OC[C@]([C@@]([C@@]1(C)F)O)O[C@]1N(C=CC(N1)=O)C1=O)=O)=O 0.000 description 1
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a Sofosbuvir crystal and a preparation method thereof. The Sofosbuvir crystal has the following advantages: the purity is high; the stability is good, moisture absorption and weight gain are also not obvious even under the high-humidity condition. The compound is an inhibitor on RNA-independent 5RNA virus replication, and can be used as an inhibitor of HCVNS5B polymerase, and an inhibitor of HCV replication, and can be used for treating hepatitis C infection in mammal.
Description
Technical field
Openly nucleoside phosphoramidate crystal and they are as the purposes of medicament being used for the treatment of virus disease herein.These compounds are inhibitor of RNA-RNA-dependent virus replication, and can be used as the inhibitor of HCV NS5B polysaccharase, inhibitor that HCV copies and for treating hepatitis C infection in Mammals.
Background technology
It is the major health concern causing chronic hepatic diseases that hepatitis C virus (HCV) infects, such as liver cirrhosis and hepatocellular carcinoma, in the individuality of a large amount of infection substantially, is estimated as the world population of 2-15%.According to the data of the Center for Disease Control, single U.S. just estimates at the infection population of 4,500,000.According to the data of the World Health Organization, there is the infection population more than 200,000,000 in the whole world, and has at least that 300-400 ten thousand population is infected every year.Once infected, the people of about 20% removes virus, but others may will carry HCV in the life of its remainder.The chronic infection individuality of 10-20% finally develops into the destructive liver cirrhosis of liver or cancer.Virus disease is that contaminated syringe needle is propagated through parenteral by the outer blood of contaminated intestines and blood products, or by sexual behaviour with from infected mother or mother's carrier vertical transmission to its offspring.The existing treatment of HCV infection is confined to the immunotherapy of alone recombinantinterferonα or conbined usage nucleoside analogue ribavirin, and this treatment obtains limited clinical benefit.And, not yet set up the vaccine being used for HCV.Therefore, a kind of healing potion that effectively can resist the improvement of chronic HCV infection of eager needs.
HCV virosome be single oligoribonucleotide gene order with about 9600 bases have enveloped positive strand RNA viruses, about 3010 amino acid whose polyproteins of encoding.The protein product of HCV gene comprises structural protein C, E1 and E2, and Nonstructural Protein NS2, NS3, NS4A and NS4B, NS5A and NS5B.It is believed that non-structural (NS) albumen provides the katalysis of virus replication.NS3 proteolytic enzyme release NS5B, the RNA RNA-dependent polysaccharase of polyprotein chain.HCV NS5B polysaccharase be from single-stranded viral RNA synthesize double-stranded RNA necessary, single-stranded viral RNA in the replication cycle of HCV as template.Therefore, think NS5B polysaccharase be necessary component in HCV replication complex (K.Ishi, etc., Heptology (hepatology), 1999,29:1227-1235; V.Lohmann, etc., Virology (virusology), 1998,249:108-118).The suppression of HCV NS5B polysaccharase prevents from forming double-strand HCV RNA, thus forms the attractive method of exploitation HCV specificity antivirus therapy.
HCV belongs to the large section of the virus with many general character.
Flaviviridae
Viral flaviviridae comprises at least three kinds of different genus: pestivirus, and it causes the disease of ox and pig; Flavivirus, it is the major cause of the disease causing such as singapore hemorrhagic fever and yellow jack; With Hepacivirus (hepaciviruses), its unique member is HCV.Based on serological relatedness grouping, Flavivirus comprise more than 68 members (Calisher etc., J. Gen.Virol (J Gen Virol), 1993,70,37-43).Clinical symptom is different, comprises heating, encephalitis and hemorrhagic fever (Fields Virology (Fei Shi virusology), editor: Fields, B.N., Knipe, D.M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, PA, 1996, Chapter31,931-959).The Flavivirus relevant to human diseases of global concern comprises dengue haemorrhagic fever virus (DHF), yellow fever virus, shock-syndrome and japanese encephalitis virus (Halstead, S.B., Rev.Infect.Dis., 1984,6,251-264; Halstead, S.B., Science (science), 239: 476-481,1988; Monath, T.P., New Eng.J.Me work (New England Journal of Medicine) 1988,319,641-643).
Pestivirus comprises bovine viral diarrhea virus (BVDV), Pestivirus suis (CSFV, also referred to as hog cholera virus) and border disease virus (BDV) (Moennig, V. .Adv.Vir.Res.1992 is waited, 41,53-98).The pestivirus infection of domestic animal (ox, pig and sheep) causes financial loss huge in world wide.BVDV causes the mucosal disease of ox and has significant Economic Importance (Meyers, G. and Thiel, H.J., Advances in Virus Research (virus research progress), 1996,47,53-118 for cattle industries; Moennig V., etc., Adv.Vir.Res.1992,41,53-98).Not yet as animal pestivirus, fully understand people's pestivirus.But, there is considerable pestivirus to contact in the serological research display mankind.
Pestivirus and hepatitis C virus are closely-related Tobamovirus in flaviviridae.In this section, other closely-related virus comprises GB virus A, GB virus A-analogue, GB virus-B and GB virus-C (also referred to as G Hepatitis virus, HGV).Hepacivirus (hepatitis C virus; HCV) the closely related of human body is infected but the virus of different genotype forms by many.Have 6 kinds of HCV genotype at least and be greater than 50 kinds of hypotypes.Due to the similarity of pestivirus and hepatitis C virus, add that hepatitis C virus is difficult to effectively growth in cell cultures, so, in HCV virus research, usually use bovine viral diarrhea virus (BVDV) as surrogate.
The heredity group structure of pestivirus and hepatitis C virus is closely similar.These positive chain RNA viruses have single open reading frame (ORF) greatly, the viral protein of encoding needed for all virus replications.These protein expressions are polyprotein, and polyprotein, by the proteolytic enzyme of cell and encoding viral translation process or post translational processing simultaneously, produces ripe viral protein.The viral protein that responsible virus genome RNA copies is positioned at roughly within C-terminal.2/3rds of ORF is called non-structural (NS) albumen.The gene organization of the ORF nonstructural protein portion of pestivirus and hepatitis C virus and polyprotein are processed closely similar.For pestivirus and hepatitis C virus, the consecutive order of the C-terminal from the N-terminal of Nonstructural Protein coding region to ORF, ripe non-structural (NS) albumen is made up of p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B.
The NS albumen of pestivirus and hepatitis C virus has the sequence domains with specific proteins functional character.Such as, two-strain belong in virus NS3 albumen all containing have serine protease and helicase signature aa sequence motifs (Gorbalenya etc., Nature (nature), 1988,333,22; Bazan and Fletterick Virology (virusology), 1989,171,637-639; Gorbalenya etc., Nucleic Acid Res. (nucleic acids research), 1989,17,3889-3897).Similarly, the motif (Koonin, E.V. and Dolja, V.V., Crir.Rev.Biochem.Molec.Biol.1993,28,375-430) that it is feature that the NS5B albumen of pestivirus and hepatitis C virus all has with the RNA polysaccharase for RNA.
Practical function in viral lifecycle of the NS albumen of pestivirus and hepatitis C virus and function are directly similar.In both cases, NS3 serine protease is responsible for all proteolysis processing (Wiskerchen and Collett, Virology (virusology), 1991,184, the 341-350 of the polyprotein precursor in its downstream, position in ORF; Bartenschlager etc., J.Virol (Journal of Virology) .1993,67,3835-3844; The .Biochem.Biophys.Res.Comm. biological chemistries such as Eckart and biophysical studies comment 1993,192,399-406; Grakoui etc., J.Virol (Journal of Virology) .1993,67,2832-2843; Grakoui etc., Proc.Natl.Acad Sci.USA (institute of NAS periodical) 1993,90,10583-10587; Hijikata etc., J.Virol. (Journal of Virology) 1993,67,4665-4675; Tome etc., J.Virol. (Journal of Virology), 1993,67,4017-4026).In both cases, NS4A albumen play a part NS3 serine protease cofactor (Bartenschlager etc., J.Virol. (Journal of Virology) 1994,68,5045-5055; Failla etc., J.Virol. (Journal of Virology) 1994,68,3753-3760; Xu etc., J.Virol. (Journal of Virology), 1997,71: 5312-5322).The NS3 albumen of two-strain also all as helicase work (Kim etc., Biochem.Biophys.Res.Comm. (biological chemistry and biophysical studies comment), 1995,215,160-166; Jin and Peterson, Arch.Biochem.Biophys., 1995,323,47-53; Warrener and Collett, J.Virol. (Journal of Virology) 1995,69,1720-1726).Finally, the NS5B albumen of pestivirus and hepatitis C virus all have the RNA polysaccharase for RNA of prediction activity (Behrens etc., EMBO, 1996,15,12-22; Lechmann etc., J.Virol. (Journal of Virology), 1997,71,8416-8428; Yuan etc., Biochem.Biophys.Res.Comm (biological chemistry and biophysical studies comment) .1997,232,231-235; Hagedorn, PCTWO97/12033; Zhong etc., J.Virol. (Journal of Virology), 1998,72,9365-9369).
At present, for the individuality infecting hepatitis C virus, there is limited therapeutic choice.The therapeutic choice of current approval is the immunotherapy of alone recombinantinterferonα or conbined usage nucleoside analogue ribavirin.The limitation of this therapy is its Clinical efficacy, and only the patient for the treatment of of 50% responds for therapy.Therefore, be starved of more effective and novel therapy to solve HCV and infect the unsatisfied needs of medical treatment faced.
Identify now many potential molecule target for the drug development of direct effect antiviral agent as whose anti-HCV therapy, include but not limited to NS2-NS3 oneself protease, N3 proteolytic enzyme, N3 helicase and NS5B polysaccharase.RNA-RNA-dependent polysaccharase be single stranded positive-sense RNA genomic copy definitely required, and this enzyme causes great interest in pharmaceutical chemistry teacher.
HCV NS5B inhibitor as the potential therapy of HCV infection is summarized in the following documents: Tan, S.-L, etc., Nature Rev.Drug Discov. (drug development is commented on naturally), 2002,1,867-881; Walker, M.P. etc., Exp.Opin.Investigational Drugs (drugs experiment viewpoint), 2003,12,1269-1280; Ni, Z-J., etc., Current Opinion in Drug Discovery and Development (modern medicines find and exploitation viewpoint), 2004,7,446-459; Beaulieu, P.L, etc., Current Opinion in Investigational Drugs (modern study pharmaceutical point), 2004,5,838-850; Wu, J., etc., Current Drug Targets-Infectious Disorders (modern medicines target-infectious conditions), 2003,3,207-219; Griffith, R.C., etc., Annual Reports inMedicinal Chemistry (pharmaceutical chemistry annual report), 2004,39,223-237; Carrol, S., etc., Infectious Disorders-Drug Targets (venereal infection disease drug target), 2006,6,17-29.The possibility occurring resistance HCV bacterial strain and the medicament support needing qualification to have extensive genotype coverage keep punching to identify the novel and more effective nucleosides needs as HCV NS5B inhibitor.
The nucleosidic inhibitors of NS5B polysaccharase can play the effect of the effect of the non-natural substrates causing chain termination or the competitive inhibitor with Nucleotide competition binding polysaccharase.In order to play the effect of chain terminator, nucleoside analog must absorb by cell and be converted into triguaiacyl phosphate in body to compete the binding site of polymerase nucleotide acid.This is converted into the mediation that triguaiacyl phosphate is subject to cell kinase usually, and described cell kinase gives potential nucleoside polymerase inhibitor other structural requirement.Unfortunately, the nucleosides which has limited the inhibitor copied as HCV directly develops into can the mensuration based on cell of original position phosphorylated.
In some cases, the biological activity of nucleosides is subject to the obstruction of its poor substrate specificities, and described characteristic is used for one or more and needs the kinases being translated into active triguaiacyl phosphate form.Usually the rate-limiting step of three phosphorylated events is considered to by nucleoside kinase formation phosplate.In order to avoid following needs, report the phosphate prodrugs that preparation is stable: initial phosphorylation step is to active triguaiacyl phosphate analogue in the metabolism of nucleosides.Nucleoside phosphoramidate prodrugs has been shown as the precursor of active nucleoside triphosphate, and when being applied to the full cell of virus infection suppress virus copy (McGuigan, C., Deng., J.Med.Chem. (medical science and the Chemicals), 1996,39,1748-1753; Valette, G., etc., J.Med.Chem. (medical science and the Chemicals), 1996,39,1981-1990; Balzarini, J., etc., Proc.National AcadSci USA (institute of NAS periodical), 1996,93,7295-7299; Siddiqui, A.Q., etc., J.Med.Chem. (medical science and the Chemicals), 1999,42,4122-4128; Eisenberg, E.J., etc., Nucleosides, Nucleotides and Nucleic Acids (nucleosides, Nucleotide and nucleic acid), 2001,20,1091-1098; Lee, W.A., etc., Antimicrobial Agents and Chemotherapy (biocide and chemotherapy), 2005,49,1898); US2006/0241064 and WO 2007/095269.
In addition restriction nucleosides is used as the effectiveness of feasible viral therapy agent is their sometimes poor physical chemistry and pharmacokinetic properties.These poor character can limit the intestinal absorption of medicament and limit picked-up in target tissue or cell.In order to improve their character, use the prodrug of nucleosides.Confirm that the preparation of nucleoside phosphoramidate improves the systemic Absorption of nucleosides, and the phosphoramidate of these " front Nucleotide (pronucleotide) " shelter by neutral lipophilic group to obtain suitable partition ratio, thus the picked-up be optimized in cell and transhipment, and then relative to only using parent nucleotide, improve the IC of Nucleotide monophosphates ester analogs significantly.The hydrolysis of the enzyme mediation of phosphonate moiety produces single-nucleotide phosphate, and wherein the initial phosphorylated of speed limit is unwanted.For this reason, U.S. Patent application 12/053,015, corresponding to WO2008/121634 and US 2010/0016251, discloses multiple nucleoside phosphoramidate prodrugs, wherein many hepatitis C detect in demonstrate activity.Some compounds disclosed in US2010/001625 are tested as the potential clinical material standed for of FDA approval.
Summary of the invention
One object of the present invention, discloses a kind of rope fluorine cloth Wei times semihydrate.
Another object of the present invention, discloses the preparation method of rope fluorine cloth Wei times semihydrate.
Another object of the present invention, discloses the pharmaceutical composition comprising rope fluorine cloth Wei times semihydrate.
The invention also discloses rope fluorine cloth Wei times semihydrate and prepare treatment use.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of rope fluorine cloth Wei times semihydrate (shown in formula I),
(formula I)
Karl_Fischer method (Karl Fischer method) a kind ofly measures in all kinds of chemical processes of moisture in material, and, method the most accurately the most single-minded to water, has been listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through multiple batches of mensuration, the moisture that described invention compound contains is between 4.50%-5.50% (weight percent).In rope fluorine cloth Wei times semihydrate, the theoretical content of water is 4.85%, can assert that invention compound contains a hypocrystalline water.
Wherein the measurement result of 6 batches is as follows:
This rope fluorine cloth Wei times hemi-hydrate crystalline, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ), D value and relative intensity are as follows.
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two) annex VI C first method, the fusing point recorded is 215.7 DEG C-217.0 DEG C.
Another object of the present invention, discloses the preparation method of rope fluorine cloth Wei times hemi-hydrate crystalline, by being dissolved at propyl carbinol-piperidines-heated in water solution by rope fluorine cloth Wei, naturally cools to room temperature, then is incubated for some time and obtains.
Specifically comprise the following steps: that rope fluorine cloth Wei hydrate adds in the mixed solution of 6-8 times of (weight or measurement (WM) ratio) propyl carbinol-piperidines-water=3-5:0.1-0.3:3-6, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
A large amount of experiments proves: the adding of piperidines, the proportioning of mixed solution, standing temperature and time are most important to obtaining rope fluorine cloth Wei times hemi-hydrate crystalline of the present invention.
Another object of the present invention, provides the composition comprising the rope fluorine cloth Wei times semihydrate that rope fluorine cloth Wei times hemi-hydrate crystalline and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
Allow people surprisingly, identical prescription and technique, wait rope fluorine cloth Wei times semihydrate tablet and the rope fluorine cloth Wei tablet of dosage (rope fluorine cloth Wei times semihydrate is converted into rope fluorine cloth Wei), to hematoblastic restraining effect, the former exceeds the latter about 20%.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 30%(weight of composition).
Present invention also offers rope fluorine cloth Wei times semihydrate and manufacture the application in treatment third liver medicine.
On the impact of the third hepatomegaly mouse model
Test medicine: rope fluorine cloth Wei times semihydrate; Physiological saline; Ribavirin; Rope fluorine cloth Wei.
The SD rat of animal subject: body weight 300-400g 96, male and female half and half, are divided into 1. blank group (physiological saline) at random; 2. rope fluorine cloth Wei times semihydrate; 3. ribavirin; 4. rope fluorine cloth Wei; Often organize 10 animal subjects.
Experimental technique: by rat administration, give each group of medicine by grouping, gavage solvent is 6ml/kg, every day 1 time, totally 180 days.During administration, every day observes rat outward appearance sign data, and tail venous blood sampling is checked and measured body weight change weekly, within after administration the last day 2 hours, puts to death rat, carries out anatomic observation.Use statistical method, blood test data are added up, calculate medicine to the inhibiting rate of hepatitis C virus.
Experimental result
The each administration group of table 1 on rat body inner virus impact (
± s)
Note: compare with saline control group
※ ※p < 0.01
Compare with rope fluorine cloth Wei group,
△ △p < 0.01
stability test
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in hydrate crystal of the present invention:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in rope fluorine cloth Wei:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), rope fluorine cloth Wei has moisture absorption to increase weight, to moist lability.
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
In the 10L reactor that stirring, thermometer, condenser are housed, add 300 grams of rope fluorine cloth Weis and 970.0ml isopropylcarbinol, 16.5ml piperidines, 980.0ml water, starts stirring, is heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, then leaves standstill insulation 4 hours, crystallization, filter, through indoor seasoning, obtain rope fluorine cloth Wei times semihydrate white crystals 254.6 grams, fusing point is the fusing point recorded is 115.7 DEG C-117.0 DEG C, content 99.76%, single contaminant is less than 0.06%.Measure through Karl_Fischer method, the moisture containing 4.86% (weight percent).
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
embodiment 2
Tablet containing rope fluorine cloth Wei times semihydrate
Prescription: rope fluorine cloth Wei times semihydrate 10.7 grams, Microcrystalline Cellulose 12 g, pregelatinized Starch 16g, carboxymethylstach sodium 5 g, lactose 210 grams, 25 grams of PEG-4000, Magnesium Stearate 6 grams, 30 grams of PVP K30s, croscarmellose sodium 33 grams, distilled water is appropriate, makes 10000.
Technique:
The preparation of label: mixed with auxiliary material by main ingredient by determined prescription, granulate, particle air seasoning below 40 DEG C, with the whole grain of l6 mesh sieve, adds Magnesium Stearate and remaining starch, compressing tablet, to obtain final product.
Sealing coat dressing: added by talcum powder in 5% polyvinylpyrrolidone (PVP) anhydrous alcohol solution, stir, is mixed with the suspension of 20% as sealing coat coating liquid.In fluidized-bed, carry out dressing, its processing condition are as follows: spray pressure 0.3 MPa, feed liquor speed 5mL/min, inlet temperature 37 DEG C, temperature out 31 DEG C, dry air flow 200 m
3/ h, sealing coat weightening finish for essence blade heavy 9%.
Enteric layers dressing: No. II resin is dissolved in dehydrated alcohol, clothing liquid concentration is 10% (w/v), its processing condition except spray speed be except 4mL/min, all the other are with sealing coat coating conditions, enteric layers weightening finish for wrap isolate synusia heavy 6%.
Claims (6)
1. times semihydrate of the cloth of rope fluorine shown in formula I Wei,
（Ⅰ）
Measure with Karl_Fischer method, described hydrate contains the moisture of weight percent 4.50%-5.50%;
The crystal of described rope fluorine cloth Wei times semihydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle, spacing (d value) and relative intensity (I/I
0),
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of rope fluorine cloth Wei times hemi-hydrate crystalline described in claim 1, by being dissolved at propyl carbinol-piperidines-heated in water solution by rope fluorine cloth Wei, naturally cools to room temperature, then is incubated for some time and obtains.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that rope fluorine cloth Wei adds in the mixed solution of 6-8 times of (weight or measurement (WM) ratio) propyl carbinol-piperidines-water=3-5:0.1-0.3:3-6, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
4. one kind forms the composition of rope fluorine cloth Wei times semihydrate containing rope fluorine cloth Wei times hemi-hydrate crystalline according to claim 1 and one or more pharmaceutically acceptable carriers.
5. the composition of rope fluorine cloth Wei times semihydrate according to claim 4, is characterized in that said composition is for the preparation of oral preparations.
6. rope fluorine cloth Wei times semihydrate according to claim 1 is manufacturing the application in anti-hepatitis virus medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310606264.7A CN104650171A (en) | 2013-11-25 | 2013-11-25 | Sofosbuvir sesquihydrate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310606264.7A CN104650171A (en) | 2013-11-25 | 2013-11-25 | Sofosbuvir sesquihydrate compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104650171A true CN104650171A (en) | 2015-05-27 |
Family
ID=53241857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310606264.7A Pending CN104650171A (en) | 2013-11-25 | 2013-11-25 | Sofosbuvir sesquihydrate compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104650171A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084237A (en) * | 2016-11-23 | 2018-05-29 | 广东东阳光药业有限公司 | Monohydrate of Suo Feibuwei and preparation method thereof |
| WO2019025600A1 (en) * | 2017-08-03 | 2019-02-07 | Sandoz Ag | Sofosbuvir hydrate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008121634A2 (en) * | 2007-03-30 | 2008-10-09 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
| CN102858790A (en) * | 2010-03-31 | 2013-01-02 | 吉利德制药有限责任公司 | Nucleoside Phosphoramidates |
-
2013
- 2013-11-25 CN CN201310606264.7A patent/CN104650171A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008121634A2 (en) * | 2007-03-30 | 2008-10-09 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
| CN102858790A (en) * | 2010-03-31 | 2013-01-02 | 吉利德制药有限责任公司 | Nucleoside Phosphoramidates |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084237A (en) * | 2016-11-23 | 2018-05-29 | 广东东阳光药业有限公司 | Monohydrate of Suo Feibuwei and preparation method thereof |
| WO2019025600A1 (en) * | 2017-08-03 | 2019-02-07 | Sandoz Ag | Sofosbuvir hydrate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102753563A (en) | Nucleoside analogs | |
| KR101432860B1 (en) | Nucleoside phosphoramidate prodrugs | |
| CN102695513A (en) | Nucleoside phosphoramidates | |
| TW201136945A (en) | Purine nucleoside phosphoramidate | |
| US20100003217A1 (en) | Compounds and Pharmaceutical Compositions for the Treatment of Viral Infections | |
| TW201329096A (en) | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections | |
| CN104017020A (en) | Nucleoside phosphoramidates | |
| EA035439B1 (en) | Amide compound and use thereof as agent for the treatment and prevention of diseases caused by rna- and/or dna-containing viruses and concomitant diseases | |
| CN113491700B (en) | Application of taurolidine in antivirus | |
| CN109689063A (en) | Nucleotide containing alkynes and nucleosides therapeutic combination and its associated uses | |
| CN104644607A (en) | Sofosbuvir sesquihydrate capsule and preparation method thereof | |
| CN104650171A (en) | Sofosbuvir sesquihydrate compound | |
| US20180193322A1 (en) | Thienopyridine derivative for the treatment of hepatitis c infections | |
| CN108129366B (en) | Antiviral compounds, methods of preparation and uses thereof | |
| CN112516150B (en) | Application of tripterygium triterpenic acid in preparation of medicine for preventing and treating white spot syndrome virus | |
| CN106588764B (en) | Inhibitors of hepatitis c virus | |
| AU2014233579B2 (en) | Nucleoside phosphoramidate prodrugs | |
| Lee et al. | Intestinal Organoid as a Research Platform for the Virus-host Interaction | |
| CN104478872A (en) | Compound for resisting infection | |
| CN117503776A (en) | Pharmaceutical composition and application thereof | |
| CN113456637A (en) | Quinoline derivative of anti-RNA virus medicine and application thereof | |
| CN116350643A (en) | Application of 2' fucosyllactose in preparation of coxsackie virus inhibitor | |
| CN104496984A (en) | Anti-infection compound | |
| Stoyanova et al. | ACTA MICROBIOLOGICA BULGARICA | |
| CN104478873A (en) | Compound for resisting infection |
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 |
Application publication date: 20150527 |
|
| WD01 | Invention patent application deemed withdrawn after publication |