CN1517347A - Antivirus nucleoside derivative - Google Patents
Antivirus nucleoside derivative Download PDFInfo
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- CN1517347A CN1517347A CNA03100511XA CN03100511A CN1517347A CN 1517347 A CN1517347 A CN 1517347A CN A03100511X A CNA03100511X A CN A03100511XA CN 03100511 A CN03100511 A CN 03100511A CN 1517347 A CN1517347 A CN 1517347A
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- general formula
- lamivudine
- side chain
- straight chain
- additive salt
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Abstract
An antivirus nucleoside is disclosed, which features longer half life period, higher biologic utilization rate, obvious targetting action and sure effect to decrease transaminase.
Description
Technical field
The present invention relates to antiviral nucleoside derivatives, the class lamivudine derivative of more specifically saying so.
Background technology
Lamivudine is the inhibitor of a nucleoside reverse transcriptase, is one of the most effective medicine that is used for the treatment of hepatitis B virus infection at present.In addition, lamivudine can also share the treatment AIDS with zidovudine, lamivudine is the earliest by Belleau and Bernard synthetic (EP0382526A2), simultaneously, they have synthesized a series of is the derivative of parent nucleus with the lamivudine, after this, people such as Liotta (WO91/11186) synthesized on this basis again a series of on 5 the derivative of derivatize, Charvet-faury etc. (WO95/32200) have carried out the synthetic work of a lot of derivatives on the N4 position, M, people such as Camplo (J.Med.Chem. (1994) 29,357-362) with vitamin A acid as side chain, the amino and the hydroxyl of lamivudine carried out derivatize.
Compound provided by the invention may have longer transformation period and the bioavailability of Geng Gao for lamivudine, part of compounds may have the effect that reduces transaminase in the body, and part of compounds has tangible liver targeting.
Summary of the invention
The object of the present invention is to provide the derivative of the new lamivudine of a class, i.e. antiviral nucleoside derivatives with antivirus action.
For achieving the above object, the present invention is by the following technical solutions:
The compound of representing as general formula I or general formula I I and the additive salt of medicinal acid thereof:
Wherein, R1 and R2 represent acyl group or alkoxyl formyl;
A and D represent diacyl or alcoxyl diacyl;
B and E represent the compound of nucleosides, nucleoside derivates or other classifications.
Described R
1Be C
1-C
10Straight chain or have the acyl group or the C of side chain
1-C
10Straight chain or have the acyl group alkoxy acyl of side chain.
Described A has following structure
Or
Wherein, R
3And R
4Be C
1-C
10Straight chain or have the alkyl of side chain or contain heteroatomic C
1-C
10Straight chain or have the alkyl of side chain.
Described B and D be lamivudine, zidovudine, Biphenylylmethylcarbinol, bicyclol, Shui Fei ?element, cholic acid etc.
Described C has following structure
Or
Wherein, R
5For containing heteroatomic C
1-C
10Straight chain or have the alkyl of side chain; R
6Be C
1-C
10Straight chain or have the alkyl of side chain or contain heteroatomic C
1-C
10Straight chain or have the alkyl of side chain.
Described heteroatoms is O or S or N.
The medicine of a kind of resisting HBV virus or anti-HIV, it contains the compound that the described general formula I of claim 1 or general formula I I represent.
The medicine of a kind of resisting HBV virus or anti-HIV, it contains the compound that the described general formula I of claim 1 and general formula I I represent.
Compound provided by the invention may have longer transformation period and the bioavailability of Geng Gao for lamivudine, part of compounds may have the effect that reduces transaminase in the body, and part of compounds has tangible liver targeting.
Embodiment
The preparation of embodiment 1, lamivudine hydrochloride
Get the 6.3g lamivudine and be dissolved in an amount of anhydrous methanol, feed HCl gas after drying, it is muddy that reaction solution becomes, and the adularescent precipitation generates, when not having solid to separate out, stop ventilation, filter, the solid methanol wash, vacuum-drying obtains 7.0g lamivudine hydrochloride.Yield 94%, mp.192-193 (decomposition).
The preparation of embodiment 2,5 '-acetyl lamivudine hydrochloride
Getting 7.3g lamivudine hydrochloride and 73ml Glacial acetic acid joins in the three-necked bottle of 250ml, stir the Acetyl Chloride 98Min. that drips 36.5ml down, after dripping, reaction solution continues to stir 23 hours under 30 ℃ condition, after having reacted, evaporated under reduced pressure solution gets a white solid, uses the anhydrous diethyl ether repetitive scrubbing, vacuum-drying, get 5 '-acetyl lamivudine hydrochloride 8.8g, yield 86%, mp.195 (decomposition).
The preparation of embodiment 3, hexanedioyl (two (5 '-acetyl lamivudine) amine)
Get hexanodioic acid 1.9g, be suspended in the thionyl chloride of 20ml, splash into 1 DMF, at room temperature stir then and spend the night, the reaction solution clarification that becomes, the thionyl chloride that the pressure reducing and steaming unreacted is intact adds toluene 30ml, evaporated under reduced pressure, remove residual thionyl chloride, be chilled to room temperature, add the 20ml methylene dichloride and get the hexanedioyl chlorine solution, other gets 5 '-acetyl lamivudine hydrochloride 4.0g and is suspended in the 30ml methylene dichloride, add N-methylmorpholine 1.5ml, solid all dissolves, and adds 1 hour again, evaporated under reduced pressure, the methylene dichloride dissolving that adds 50ml again, water successively then, 5% citric acid solution, saturated sodium bicarbonate solution |, organic layer is told in the saturated nacl aqueous solution washing, use anhydrous sodium sulfate drying, concentrate, silica gel is leant on chromatography, and eluent is a methylene dichloride: methyl alcohol=15: 1, obtain white powder 5.2g, yield 61.2%.
Its nuclear magnetic data is: 10.883 (s, 2H), 8.170 (d, 2H, J=7Hz), 7.252 (t, 2H, J=7.5Hz), 6.225 (d, 2H, J=7.5Hz), 5.416 (t, 2H, J=4Hz), 4.426 (d, 4H, J=5Hz), 3.568 (m, 2H), 3.229 (m, 2H), 2.349 (m, 4H), 2.065 (s, 6H), 1.540 (s, 4H).
The preparation of embodiment 4, hexanedioyl (two lamivudine amine)
(two (5 '-acetyl lamivudine) amine 1g is dissolved in the methyl alcohol, slowly splashes into 1ml ammoniacal liquor under the ice bath to get hexanedioyl, stirred then 1 hour, and added dilute hydrochloric acid and regulate PH, boil off solvent to neutral, the methylene dichloride recrystallization gets white crystal 0.4g, yield: 51%, and mp.195-196 (decomposition).
Its nuclear magnetic data is: 10.879 (s, 2H), 8.170 (d, 2H, J=7Hz), 7.254 (t, 2H, J=7.5Hz), 6.230 (d, 2H, J=7.5Hz), 5.412 (t, 2H, J=4Hz), 5.521 (s, 2H), 4.420 (d, 4H, J=5Hz), 3.572 (m, 2H), 3.226 (m, 2H), 2.321 (m, 4H), 1.535 (s, 4H).
The preparation of embodiment 5, glycol ether acyl (two (5 '-acetyl lamivudine) amine)
Get diglycollic acid 1.75g, be suspended in the thionyl chloride of 20ml, splash into 1 DMF, at room temperature stir then and spend the night, the reaction solution clarification that becomes, the thionyl chloride that the pressure reducing and steaming unreacted is intact adds toluene 30ml, evaporated under reduced pressure, remove residual thionyl chloride, be chilled to room temperature, add the 20ml methylene dichloride and get the hexanedioyl chlorine solution, other gets 5 '-acetyl lamivudine hydrochloride 4.0g and is suspended in the 30ml methylene dichloride, add N-methylmorpholine 1. 5ml, solid all dissolves, and adds pyridine 20ml again, drips the hexanedioyl chlorine solution under ice-water bath, dropwised at 20 minutes, restir 1 hour at room temperature then, evaporated under reduced pressure adds the methylene dichloride dissolving of 50ml again, water successively then, 5% citric acid solution, saturated sodium bicarbonate solution |, the saturated nacl aqueous solution washing, tell organic layer, use anhydrous sodium sulfate drying, concentrate, silica gel is leant on chromatography, eluent is a methylene dichloride: methyl alcohol=15: 1 obtains white powder 1.2g, yield 29%.
Its nuclear magnetic data is: 10.790 (s, 2H), 8.214 (d, 2H, J=7Hz), 7.215 (t, 2H, J=7.5Hz), 6.238 (d, 2H, J=7.5Hz), 5.437 (t, 2H, J=4Hz), 4.473 (d, 4H, J=5Hz), 4.257 (s, 4H), 3.584 (m, 2H), 3.251 (m, 2H), 2.506 (s, 6H).
The preparation of embodiment 6, glycol ether acyl (two lamivudine amine)
(two (5 '-acetyl lamivudine) amine 1g is dissolved in the methyl alcohol, slowly splashes into 1ml ammoniacal liquor under the ice bath, stirs then 1 hour, adds dilute hydrochloric acid and regulates pH to neutral, boils off solvent, and the methylene dichloride recrystallization gets white crystal 0.5g, and yield is 62% to get the glycol ether acyl.
Its nuclear magnetic data is: 10.765 (s, 2H), 8.210 (d, 2H, J=7Hz), 7.214 (t, 2H, J=7.5Hz), 6.242 (d, 2H, J=7.5Hz), 5.433 (t, 2H, J=4Hz), 5.532 (s, 2H), 4.469 (d, 4H, J=5Hz), 4.254 (s, 4H), 3.580 (m, 2H), 3.256 (m, 2H).
Embodiment 7,1, the preparation of the 3-third dioxy carbonyl diurethane lamivudine amine
Getting 5 '-acetyl lamivudine hydrochloride 4.0g is suspended in the 30ml methylene dichloride, add N-methylmorpholine 3ml, stir and make it dissolving, add the 10ml pyridine again, it is slowly splashed in the 10% phosgene toluene solution, drip off the back and continue to stir 1 hour, other gets 1, ammediol 1.2ml, add the 10ml methylene dichloride, slowly be added drop-wise in the solution of above-mentioned preparation, stir then and spend the night, after reacting completely, boil off solvent, add the dissolving of 30ml methylene dichloride, successively water, 5% citric acid solution, saturated sodium bicarbonate solution, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrate, add dissolve with ethanol, add ammoniacal liquor, stirred one hour, add dilute hydrochloric acid and regulate pH to neutral, be concentrated into driedly, lean on chromatography, obtain white solid 1.7g.Yield 31%.
Its nuclear magnetic data is: 10.760 (s, 2H), 8.214 (d, 2H, J=7Hz), 7.220 (t, 2H, J=7.5Hz), 6.244 (d, 2H, J=7.5Hz), 5.430 (t, 2H, J=4Hz), 5.532 (s, 2H), 4.464 (d, 4H, J=5Hz), 4.238 (s, 4H), 4.127 (m, 4H), 3.541 (m, 2H), 3.238 (m, 2H), 1.841 (m, 2H).
The contract preparation of diethoxy carbonyl diurethane lamivudine amine of embodiment 8,
Replace 1 with a diethyl acetal, ammediol, reaction conditions are with embodiment 7, and yield is 33%.
Nuclear magnetic data is: 10.870 (s, 2H), 8.224 (d, 2H, J=7Hz), 7.280 (t, 2H, J=7.5Hz), 6.254 (d, 2H, J=7.5Hz), 5.468 (t, 2H, J=4Hz), 5.578 (s, 2H), 4.476 (d, 4H, J=5Hz), 4.234 (s, 4H), 4.176 (m, 4H), 3.549 (m, 2H), 3.406 (m, 4H), 3.238 (m, 2H).
Embodiment 9, N, the preparation of N-dimethylamino methylene lamivudine
In the three-necked bottle of 100ml, add the 10g lamivudine, the DMF-DMA of 9ml, the 150ml methylene dichloride stirred 21 hours at 50 times, and reaction solution becomes clarification, the pressure reducing and steaming solvent adds the ether of 10ml and the alcoholic acid mixing solutions of 10ml, and the adularescent solid is separated out, filter, washing, drying obtains N, N-dimethylamino methylene lamivudine 11g, yield 90%.
The preparation of embodiment 10, glycol ether acyl (two lamivudine esters)
Get diglycollic acid 1.75g, be suspended in the thionyl chloride of 20ml, splash into 1 DMF, at room temperature stir then and spend the night, the reaction solution clarification that becomes, the thionyl chloride that the pressure reducing and steaming unreacted is intact, add toluene 30ml, evaporated under reduced pressure is removed residual thionyl chloride, is chilled to room temperature, add the 20ml methylene dichloride and get the glycol ether solution of acid chloride, other gets N, N-dimethylamino methylene lamivudine 2g, pyridine 10ml, DMAPO.2g, join in the three-necked bottle of 50ml, drip the glycol ether solution of acid chloride down at 0 ℃, after dripping, at room temperature continue to stir 2 hours, reaction solution is concentrated into dried, adds the dissolving of 50ml methylene dichloride, successively water, 5% citric acid solution, saturated sodium bicarbonate solution, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrated methylene chloride solution adds 5ml methyl alcohol to 15ml then, stirs the acetum that adds 5ml 80% down, reaction is spent the night, boil off solvent, add the acetone of 20ml in residual oily matter, the adularescent solid is separated out, filter, washing, dry diglycollic acid (two lamivudine esters) 0.2g, the yield 26% of getting.
Its nuclear magnetic data is: 7.683 (d, 2H, J=7.5Hz), 7.200 (d, 4H, J=25Hz), 6.239 (t, 2H, J=6Hz), 5.761 (d, 2H, J=7.5Hz), 5.379 (t, 2H, J=4Hz), 4.443 (d, 4H, J=5Hz), 4.301 (s, 4H), 3.420 (m, 2H), 3.101 (m, 2H).
The preparation of embodiment 11, sulfurous base diacetyl (two lamivudine esters)
Replace diglycollic acid with thiodiglycolic acid, by last method operation, yield is 22%.
Its nuclear magnetic data is: 7.675 (d, 2H, J=7.5Hz), 7.195 (d, 4H, J=25Hz), 6.227 (t, 2H, J=6Hz), 5.761 (d, 2H, J=7.5Hz), 5.360 (t, 2H, J=4Hz), 4.424 (d, 4H, J=5Hz), 4.376 (s, 4H), 3.418 (m, 2H), 3.091 (m, 2H).
Embodiment 12,1, the 3-third dioxy carbonyl diurethane lamivudine ester
Get N, N-dimethylamino methylene lamivudine 4.0g is suspended in the 30ml methylene dichloride, adds N-methylmorpholine 3ml, stirs and makes it dissolving, add the 10ml pyridine again, it is slowly splashed in the 10% phosgene toluene solution, drip off the back and continue to stir 1 hour, other gets 1, ammediol 1.2ml, add the 10ml methylene dichloride, slowly be added drop-wise in the solution of above-mentioned preparation, stir then and spend the night, after reacting completely, seized with terror desolvating adds the dissolving of 30ml methylene dichloride, successively water, 5% citric acid solution, saturated sodium bicarbonate solution, the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, concentrated methylene chloride solution adds 5ml methyl alcohol to 15ml, stirs the acetum that adds 5ml 80% down, reaction is spent the night, boil off solvent, add the acetone of 20ml in residual oily matter, the adularescent solid is separated out, filter, washing, dry 0.2g, the yield: 27% of getting
Its nuclear magnetic data is: 7.668 (d, 2H, J=7.5Hz), 7.178 (d, 4H, J=25Hz), 6.232 (t, 2H, J=6Hz), 5.758 (d, 2H, J=7.5Hz), 5.366 (t, 2H, J=4Hz), 4.428 (d, 4H, J=5Hz), 4.231 (m, 4H), 3.432 (m, 2H), 3.096 (m, 2H), 1.852 (m, 2H).
The contract preparation of diethoxy carbonyl diurethane lamivudine ester of embodiment 13,
Press embodiment 12 operations, replace 1 with a diethyl acetal, ammediol, the yield of reaction is: 21%.
Nuclear magnetic data be 7.673 (d, 2H, J=7.5Hz), 7.205 (d, 4H, J=25Hz), 6.230 (t, 2H, J=6Hz), 5.777 (d, 2H, J=7.5Hz), 5.373 (t, 2H, J=4Hz), 4.435 (d, 4H, J=5Hz), 4.106 (m, 4H), 3.436 (m, 2H), 3.410 (m, 4H), 3.102 (m, 2H).
The contract prescription of diethoxy carbonyl diurethane lamivudine ester sheet of embodiment 14,
The one diethoxy carbonyl diurethane lamivudine ester 300mg that contracts
Starch 100mg
Microcrystalline Cellulose 60mg
L-HPC 54.6mg
Magnesium Stearate 5.4mg
CMC-Na 20mg
4%HPMC is an amount of
The 540mg/ sheet
Respectively mistake 80 mesh sieves are standby to get starch/Microcrystalline Cellulose, L-HPC, supplementary material is weighed up the back with the equivalent method mixing that progressively increases by prescription, add an amount of HPMC solution, make softwood, cross 16 mesh sieves, make wet grain, in 60 times ℃ loft drier, dry 3 hours, the whole grain of 18 mesh sieves, add Magnesium Stearate and CMC-Na as recipe quantity, mix, compressing tablet promptly.
Embodiment 15, glycol ether acyl (two lamivudine esters) are tested the inhibition of HBV DNA in the 2.2.15 cell culture fluid
2.2.15 HBV-DNA extracts in cell (institute of oncology, Beijing provides) culture supernatant: 2.2.15 cell inoculation 6 porocyte culture plates, cultivate and added different concns in back 24 hours, changed the original content soup in per 4 days, cultivate and collected supernatant liquor on the 8th day, add polyethylene glycol precipitation, the centrifugal supernatant that goes, add the Proteinase K lysing cell, add yeast T-RNA enzyme, use phenol: chloroform: primary isoamyl alcohol (25: 24: 1) extracting 2 times, 10000g is centrifugal, get supernatant, add the dehydrated alcohol precipitate nucleic acids, vacuum is drained, and heavily is dissolved in the TE damping fluid making sample.
Dot hybridization: get 20ul (dna content 25ug), add the sex change of sex change liquid, it is neutralized with neutralizer, and with 20 * SSC damping fluid two-fold dilution to 1: 128 times, point sample is put to be placed on after room temperature is dried to do in 80 ℃ of baking boxs and is baked, with fixed dna on nitrocellulose filter.Nitrocellulose filter is loaded on adds prehybridization solution in the plastics bag, be positioned over that prehybridization added 5 * 10 in 2 hours in the water-bath
7CPM α
32The sex change HBV-DNA probe of P-dCTP mark, hybridization is 14-18 hour in 42 ℃ of water-baths.Intermediate plate, the exposure, with ordinary method towards the X-ray sheet developing radioautograph.The scanner scanning mating plate is measured the IOD value with gel-pro software (PowerLab company provides), calculates inhibiting rate and IC
50
2.2.15 HBV-DNA inhibition=CIOD-TIOD/CIOD * 100% in the cell culture fluid
Annotate: CIOD: dosing group IOD value TIOD: no medicine control group IOD value
Statistics and analysis: HBV-DNA is suppressed effect and gel-pro gel analysis software analysis mating plate relative density, calculate inhibiting rate and median effective dose (IC
50).
Result: the IC of glycol ether acyl (two lamivudine esters)
50Be 10.25ug, inhibiting rate is 80%.
Claims (9)
1, the compound of representing as general formula I or general formula I I and the additive salt of medicinal acid thereof:
Wherein, R1 and R2 represent acyl group or alkoxyl formyl;
A and D represent diacyl or alcoxyl diacyl;
B and E represent the compound of nucleosides, nucleoside derivates or other classifications.
2, the additive salt of compound according to claim 1 and medicinal acid thereof is characterized in that: described R
1Be C
1-C
10Straight chain or have the acyl group or the C of side chain
1-C
10Straight chain or have the acyl group alkoxy acyl of side chain.
3, the additive salt of compound according to claim 1 and medicinal acid thereof is characterized in that: described A has following structure
Wherein, R
3And R
4Be C
1-C
10Straight chain or have the alkyl of side chain or contain heteroatomic C
1-C
10Straight chain or have the alkyl of side chain.
4, the additive salt of compound according to claim 1 and medicinal acid thereof is characterized in that: described B and D be lamivudine, zidovudine, Biphenylylmethylcarbinol, bicyclol, Shui Fei ?element, cholic acid etc.
5, the additive salt of compound according to claim 1 and medicinal acid thereof is characterized in that: described C has following structure
Or
Wherein, R
5For containing heteroatomic C
1-C
10Straight chain or have the alkyl of side chain; R
6Be C
1-C
10Straight chain or have the alkyl of side chain or contain heteroatomic C
1-C
10Straight chain or have the alkyl of side chain.
6, the additive salt of compound according to claim 3 and medicinal acid thereof is characterized in that: described heteroatoms is O or S or N.
7, the additive salt of compound according to claim 5 and medicinal acid thereof is characterized in that: described heteroatoms is O or S or N.
8, the medicine of a kind of resisting HBV virus or anti-HIV is characterized in that it contains the compound that the described general formula I of claim 1 or general formula I I represent.
9, the medicine of a kind of resisting HBV virus or anti-HIV is characterized in that it contains the compound that the described general formula I of claim 1 and general formula I I represent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA03100511XA CN1517347A (en) | 2003-01-16 | 2003-01-16 | Antivirus nucleoside derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA03100511XA CN1517347A (en) | 2003-01-16 | 2003-01-16 | Antivirus nucleoside derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1517347A true CN1517347A (en) | 2004-08-04 |
Family
ID=34281202
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA03100511XA Pending CN1517347A (en) | 2003-01-16 | 2003-01-16 | Antivirus nucleoside derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1517347A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009522270A (en) * | 2005-12-29 | 2009-06-11 | シェーリング−プラウ・リミテッド | Phenicol antibiotic carbonate |
| US20150368232A1 (en) * | 2013-02-07 | 2015-12-24 | Tobira Therapeutics, Inc. | Lamivudine salts |
-
2003
- 2003-01-16 CN CNA03100511XA patent/CN1517347A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009522270A (en) * | 2005-12-29 | 2009-06-11 | シェーリング−プラウ・リミテッド | Phenicol antibiotic carbonate |
| US20150368232A1 (en) * | 2013-02-07 | 2015-12-24 | Tobira Therapeutics, Inc. | Lamivudine salts |
| US9688666B2 (en) * | 2013-02-07 | 2017-06-27 | Tobira Therapeutics, Inc. | Lamivudine salts |
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