CN103804416A - Phosphate derivative of acyclovir and medical application thereof - Google Patents
Phosphate derivative of acyclovir and medical application thereof Download PDFInfo
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- CN103804416A CN103804416A CN201210451606.8A CN201210451606A CN103804416A CN 103804416 A CN103804416 A CN 103804416A CN 201210451606 A CN201210451606 A CN 201210451606A CN 103804416 A CN103804416 A CN 103804416A
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- MXMAHNJOACCZGA-UHFFFAOYSA-N COCCOCN(C=NC12)C1=[N]=C(N)NC2=O Chemical compound COCCOCN(C=NC12)C1=[N]=C(N)NC2=O MXMAHNJOACCZGA-UHFFFAOYSA-N 0.000 description 1
- HWRATZQISZFJGB-UHFFFAOYSA-N NC(N1)=[N]=C2N(COCCOP(O)(O)=O)C=NC2C1=O Chemical compound NC(N1)=[N]=C2N(COCCOP(O)(O)=O)C=NC2C1=O HWRATZQISZFJGB-UHFFFAOYSA-N 0.000 description 1
- FETNWKBJGWNAPM-UHFFFAOYSA-N NC(N1)=[N]=C2N(COCCOP(O)(O)=O)C=NC2C1O Chemical compound NC(N1)=[N]=C2N(COCCOP(O)(O)=O)C=NC2C1O FETNWKBJGWNAPM-UHFFFAOYSA-N 0.000 description 1
- OVAZADLLIVKYIN-UHFFFAOYSA-N NC(N1)=[N]=C2N(COCCOP(OCOC(C3CCCCC3)=O)(OCOC(C3CCCCC3)=O)=O)C=NC2C1=O Chemical compound NC(N1)=[N]=C2N(COCCOP(OCOC(C3CCCCC3)=O)(OCOC(C3CCCCC3)=O)=O)C=NC2C1=O OVAZADLLIVKYIN-UHFFFAOYSA-N 0.000 description 1
- ZFYFSEXLXRFOLD-UHFFFAOYSA-N O=C(C1CCCCC1)OCCl Chemical compound O=C(C1CCCCC1)OCCl ZFYFSEXLXRFOLD-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention aims to provide a ring-free nucleoside phosphate derivative having an anti-hepatitis B virus activity and represented by formula I shown in the specification and a nontoxic pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1 represents H or methyl; absolute configuration of carbon atoms connected with R1 is an R or S isomer or an RS racemate; R2 represents -R3 or -OR3; R3 represents C1-C8 alkyl or cycloalkyl, and is selected from methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl and the like.
Description
Technical field
The present invention relates to have potent anti-hepatitis B virus activities and compared with the phosphate derivative of the acyclovir of low cytotoxicity, its preparation method and the purposes for the preparation of the medicine for the treatment of hepatitis B virus infection thereof.
Background technology
Hepatitis B is the major disease that threatens people's life health, and the fundamental way for the treatment of hepatitis B is antiviral therapy.Clinical effective anti-hepatic-B virus medicine is mainly lamivudine, adefovir ester, Entecavir, tenofovir disoproxil etc. at present.Lamivudine has definite anti-HBV effect, but life-time service easily produces resistance; Adefovir ester has Toxicity of Kidney, and Entecavir animal experiment has carinogenicity; Easily knock-on after tenofovir disoproxil drug withdrawal.Therefore, urgent clinical needs highly effective and safe, act on lasting anti-hepatic-B virus medicine.
Summary of the invention
The object of this invention is to provide acyclic nucleotide phosphate derivative and the non-toxicity pharmacy acceptable salt thereof of the formula I representative with anti-hepatitis B virus activities, hydrate or solvate:
Wherein,
R
1represent H or methyl;
R
2representative-R
3or-OR
3; R
3represent C
1-C
8alkyl or cycloalkyl, be selected from methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, tertiary butyl, cyclopentyl, cyclohexyl etc.The absolute configuration of the carbon atom being connected with R1 is R or S isomer, or RS raceme.
Another aspect of the present invention relates to the acyclic nucleoside phosphonate derivatives and non-toxicity pharmacy acceptable salt, hydrate or the solvate that comprise above-mentioned formula I representative.And the pharmaceutical composition of one or more pharmaceutical carrier or vehicle.
Another aspect of the present invention relates to the acyclic nucleoside phosphonate derivatives that comprises above-mentioned formula I representative and non-toxicity pharmacy acceptable salt, hydrate or solvate as effective constituent, and the pharmaceutical composition of one or more pharmaceutical carriers or vehicle.
Another aspect of the present invention relates to acyclic nucleoside phosphonate derivatives and the non-toxicity pharmacy acceptable salt thereof of above-mentioned formula I representative, and hydrate or solvate are for the preparation of the purposes of the medicine for the treatment of hepatitis B virus infection.
Term " pharmacologically acceptable salt " in the present invention can be the pharmaceutical salts forming with mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can be to form pharmaceutical salts, such as acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc. with organic acid.
The compounds of this invention or its pharmacologically acceptable salt can form solvate, such as hydrate, alcohol adduct etc.
As mentioned above, the compounds of this invention can be used for the medicine of preparation treatment hepatitis B virus infection.
The compounds of this invention or its pharmacologically acceptable salt can be separately or with the form administration of pharmaceutical composition.Pharmaceutical composition of the present invention can be made into various suitable formulations according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they are conducive to active compound to be processed into the preparation that can pharmaceutically use.Suitable dosage form depends on selected route of administration, can manufacture according to general knowledge well known in the art.
Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Can comprise capsule and tablet etc. by oral pharmaceutical preparation.Patient swallows while having any problem, also can adopt Sublingual tablet or other non-mode administrations of swallowing.The compounds of this invention also can be prepared for administered parenterally or transdermal administration or mucosal.It will be understood by those skilled in the art that the compounds of this invention can adopt suitable drug delivery system (DDS) to obtain more favourable effect.
It may be noted that in addition, the compounds of this invention using dosage and using method depend on factors, comprise patient's age, body weight, sex, natural health situation, nutritional status, activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of compound.Preferred using dosage is between 0.01～100mg/kg body weight/day.
Target compound shown in formula I can be prepared by following synthetic route:
Acyclovir and phosphorus oxychloride effect, then hydrolysis obtains acyclovir phosphoric acid ester (II), and II is reacting with alkanoyloxymethyl chlorine or alkoxycarbonyloxy methyl chloride, can obtain target compound I.
Embodiment
Following embodiment is for explaining particularly the present invention, but scope of the present invention is not limited to following embodiment.
The preparation of embodiment 1 acyclovir phosphoric acid ester (II)
In the reactor of sealing, add 227 grams of (1.0mol) anhydrous acyclovirs (water content is less than 0.1%), 5000ml triethyl-phosphite, passes into nitrogen, and reaction mixture is stirred and is cooled to-15 ℃ to-20 ℃.Under nitrogen, 137 grams of (1.2mol) phosphorus oxychloride are mixed with 400ml anhydrous methylene chloride, this mixed solution is cooled to-15 ℃ to-0 ℃, pump enters reactor, flow velocity 50 ml/min, cooling to keep temperature-15 ℃ of reaction mixture to-20 ℃.Continue stir until unreacted acyclovir lower than 3%.
Reaction mixture is fallen in the mixture of 2000ml deionized water and 2000 grams of ice, cooling to keep 15 ℃ of temperature.After adding, mixture temperature to 20 ℃, to 25 ℃, is stirred to 45-60 minute.Add 5000ml methylene dichloride, vigorous stirring 30 minutes, places 30 minutes, and layering, discards methylene dichloride; Add 1000ml methylene dichloride, vigorous stirring 30 minutes, places 30 minutes again, and layering, discards dichloromethane layer.Under add 10L dehydrated alcohol, keep 20 ℃ to 25 ℃, continue stir 24 hours, have solid to separate out, filter, filter cake absolute ethanol washing, in 68mmHg, 40 ℃ of vacuum-dryings, obtain II219 gram.
Embodiment 2 2-[(guanine-9-yls)-methoxyl group]-ethyl-bis-(propionyloxy methyl)-phosphoric acid ester (I
1) preparation
In 50mL dry DMF; add 3.1g (10mmoL) II and 2g (20mmoL) triethylamine; under nitrogen protection, in stirring at normal temperature 10 minutes, add 4.6g (40mmoL) propionic acid chloromethyl ester, under nitrogen protection in stirring at normal temperature reaction 24 hours.Proceed to separating funnel, add 600mL water, with ethyl acetate (3 × 200mL) extraction, merge organic layer, with saturated brine (3 × 200mL) washing.Oil reservoir is through anhydrous sodium sulfate drying, elimination siccative, and filtrate decompression is concentrated, and residue separates through silica gel column chromatography, with the methylene dichloride wash-out containing 5% methyl alcohol, collects required component, and evaporated under reduced pressure, obtains I
11.6g.
1H-NMR(DMSO-d6，400MHz)δ：10.60(s，1H)，7.79(s，1H)，6.40(bs，2H)，5.63-5.68(m，4H)，5.33(s，2H)，4.06(t，2H)，3.64(t，2H)，2.37(q，4H)，1.12(t，6H)。
Embodiment 32-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(isobutyl acyl-oxygen ylmethyl)-phosphoric acid ester (I
2) preparation
With reference to the method for embodiment 2, use isopropylformic acid chloromethyl ester to replace propionic acid chloromethyl ester to react with II, reaction industry silica gel column chromatography separates, and obtains I
2, yield 27%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.65-5.70(m，4H)，5.35(s，2H)，4.1-4.0(t，2H)，3.7-3.6(t，2H)，2.53(m，2H)，1.13(d，12H)。
Embodiment 42-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(pivaloyl oxygen ylmethyl)-phosphoric acid ester (I
3) preparation
With reference to the method for embodiment 2, replace propionic acid chloromethyl ester to react with II with chloromethyl pivalate, reaction product separates through silica gel column chromatography, obtains I
3, yield 23%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.65-5.70(m，4H)，5.35(s，2H)，4.1-4.0(t，2H)，3.7-3.6(t，2H)，1.23(s，9H)，1.22(s，9H)。
Embodiment 52-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(cyclohexanecarbonyl oxygen ylmethyl)-phosphoric acid ester (I
4) preparation
With reference to the method for embodiment 2, use heptanaphthenic acid chloromethyl ester to replace propionic acid chloromethyl ester to react with II, reaction product separates through silica gel column chromatography, obtains I
4, yield 25%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.65-5.70(m，4H)，5.35(s，2H)，4.1-4.0(t，2H)，3.68(t，2H)，2.27(m，2H)，1.91(m，4H)，1.66(m，4H)；1.39-1.47(m，12H)。
Embodiment 6 2-[(guanine-9-yls)-methoxyl group]-ethyl-bis-(ethyl oxygen base ketonic oxygen ylmethyl)-phosphoric acid ester (I
5) preparation
In 12ml N-Methyl pyrrolidone, add 1.64g (4mmoL) II, 0.8g (8mmoL) triethylamine, under room temperature, stir 30 minutes, then add 2.2g (16mmol) chloromethyl ethyl carbonate ester, in 70 ℃ of stirring reactions 2 hours, cooling, add aqueous citric acid solution and the 500ml ether of 300ml1%, stir, layering, ether extraction twice for water layer, merges organic layer, dry, with silica gel column chromatography separation, with the dichloromethane solution wash-out containing 5% ethanol, collect required component, evaporated under reduced pressure, obtains I
50.92 gram.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.47-5.78(m，4H)，5.35(s，2H)，4.1-3.95(m，6H)，3.7-3.6(t，2H)，1.30(m，6H)。
Embodiment 72-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(propyl group oxygen base ketonic oxygen ylmethyl)-phosphoric acid ester (I
6) preparation
With reference to the method for embodiment 6, use chloromethyl propyl carbonate to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates with silica gel column chromatography, obtains I
6, productive rate 32%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.47-5.78(m，4H)，5.35(s，2H)，4.1-3.95(m，6H)，3.7-3.6(t，2H)，1.62(m，4H)，0.98(m，6H)。
Embodiment 82-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(sec.-propyl oxygen base ketonic oxygen ylmethyl)-phosphoric acid ester (I
7) preparation
With reference to the method for embodiment 6, use chloromethyl sec.-propyl carbonic ether to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates with silica gel column chromatography, obtains I
7, productive rate 27%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.47-5.78(m，4H)，5.35(s，2H)，4.1-3.95(m，4H)，3.7-3.6(t，2H)，1.26(s，6H)，1.24(s，6H)。
Embodiment 92-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(isobutyl-oxygen base ketonic oxygen ylmethyl)-phosphoric acid ester (I
8) preparation
With reference to the method for embodiment 6, use chloromethyl isobutyl-carbonic ether to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates with silica gel column chromatography, obtains I
8, productive rate 20%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.35(s，2H)，5.47-5.78(m，4H)，4.1-3.95(m，4H)，1.68(m，4H)，0.97(m，12H)。
Embodiment 10 2-[(guanine-9-yls)-methoxyl group]-ethyl-bis-(neo-pentyl oxygen base ketonic oxygen ylmethyl)-phosphoric acid ester (I
9) preparation
With reference to the method for embodiment 6, use chloromethyl sec.-propyl carbonic ether to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates with silica gel column chromatography, obtains I
9, productive rate 18%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.47-5.78(m，4H)，5.35(s，2H)，4.1-3.95(m，6H)，0.94(s，18H)。
Embodiment 112-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(amyl group-3-oxygen base ketonic oxygen ylmethyl)-phosphoric acid ester (I
10) preparation
With reference to the method for embodiment 6, use chloromethyl-(3-amyl group)-carbonic ether to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates to obtain I with silica gel column chromatography
10productive rate 15%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.47-5.78(m，4H)，5.35(s，2H)，4.1-3.95(m，4H)，3.7-3.6(t，2H)，1.52-1.62(m，8H)，0.92(t，12H)。
Embodiment 122-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(cyclohexyl oxygen base ketonic oxygen ylmethyl)-phosphoric acid ester (I
11) preparation
With reference to the method for embodiment 6, use chloromethyl cyclohexyl carbonic ether to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates with silica gel column chromatography, obtains I
11, productive rate 24%.
1H-NMR(DMSO-d
6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.47-5.78(m，4H)，5.35(s，2H)，4.1-3.95(m，4H)，3.7-3.6(t，2H)，1.78(m，8H)，1.15-1.50(m，12H)。
Embodiment 132-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(1-pivaloyl oxygen base ethyl)-phosphoric acid ester (I
12) preparation
With reference to the method for embodiment 2, use trimethylacetic acid 1-chloro-ethyl ester to replace propionic acid chloromethyl ester to react with II, reaction product separates with silica gel column chromatography, obtains I
12, productive rate 20%.
1H-NMR(DMSO-d
6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，6.39-6.48(m，2H)，5.35(s，2H)，4.1-4.0(t，2H)，3.7-3.6(t，2H)，1.45-1.49(m，6H)，1.15(s，18H)。
Embodiment 142-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(1-benzoyloxy ethyl)-phosphoric acid ester (I
13) preparation
With reference to the method for embodiment 2, use the chloro-ethyl of phenylformic acid 1-to replace propionic acid chloromethyl ester to react with II, reaction product separates with silica gel column chromatography, obtains I
13, productive rate 15%.
1H-NMR(DMSO-d
6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，6.39-6.48(m，2H)，5.35(s，2H)，4.1-4.0(t，2H)，3.7-3.6(t，2H)，1.45-1.49(m，6H)，1.15(s，18H)。
Embodiment 152-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(1-propionyl oxygen base-2-methyl-propyl group)-phosphoric acid ester (I
14) preparation
With reference to the method for embodiment 2, use propionic acid 2-methyl isophthalic acid-chlorine-propyl ester propionic acid chloromethyl ester to react with II, reaction product separates with silica gel column chromatography, obtains I
14, productive rate 19%.
1H-NMR(DMSO-d
6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，5.35(s，2H)，6.26-6.34(m，2H)，4.1-4.0(t，2H)，3.7-3.6(t，2H)，2.34-2.46(m，4H)，1.90-2.08(m，6H)，1.15-1.18(m，6H)，0.95-1.00(m，12H)。
Embodiment 162-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(1-ethyl oxygen base ketonic oxygen base-ethyl)-phosphoric acid ester (I
15) preparation
With reference to the method for embodiment 6, use 1-chloroethyl ethyl carbonate ester to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates with silica gel column chromatography, obtains I
15, productive rate 21%.
1H-NMR(DMSO-d
6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，6.29-6.36(m，2H)，5.35(s，2H)，4.15-4.0(m，6H)，3.7-3.6(t，2H)，1.47-1.51(m，6H)，1.22-1.25(m，6H)。
Embodiment 172-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(1-sec.-propyl oxygen base ketonic oxygen base-ethyl)-phosphoric acid ester (I
16) preparation
With reference to the method for embodiment 6, use 1-chloroethyl sec.-propyl carbonic ether to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates with silica gel column chromatography, obtains I
16, productive rate 13%.
1H-NMR(DMSO-d6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，6.29-6.36(m，2H)，5.35(s，2H)，4.1-3.95(m，4H)，3.7-3.6(t，2H)，1.45-1.49(m，6H)，1.26(s，6H)，1.24(s，6H)。
Embodiment 182-[(guanine-9-yl)-methoxyl group]-ethyl-bis-(1-cyclohexyl oxygen base ketonic oxygen base-ethyl)-phosphoric acid ester (I
17) preparation
With reference to the method for embodiment 6, use 1-chloroethyl cyclohexyl carbonic ether to replace chloromethyl ethyl carbonate ester to react with II, reaction product separates with silica gel column chromatography, obtains I
17, productive rate 14%.
1H-NMR(DMSO-d
6，400MHz)δ：10.65(s，1H)，7.81(s，1H)，6.5(bs，2H)，6.29-6.36(m，2H)，5.35(s，2H)，4.1-3.95(m，4H)，3.7-3.6(t，2H)，1.78(m，8H)，1.45-1.49(m，6H)，1.15-1.50(m，12H)。
Embodiment 19 target compound In Vitro Anti HBV activity and cytotoxicity screening
With Hep G2.2.15 cells in vitro test method determination restraining effect and the cytotoxicity of target compound to HBV DNA.
Experimental technique
Measure the restraining effect of target compound to HBV DNA by quantitative real-time fluorescence PCR method: HepG2.2.15 cell cultures, in containing in the DMEM nutrient solution of 10% calf serum, is hatched in 5%CO2 incubator.Then cell is inoculated in 96 orifice plates to cell count 3X10
4, continue to cultivate, when cell density reaches 80% left and right, discard old nutrient solution, add the new nutrient solution containing different concns medicine to be measured, 3 parallel holes are set; Changed nutrient solution 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 cultures, in containing in the DMEM nutrient solution of 10% calf serum, is hatched in 5%CO2 incubator.Then cell is inoculated in 96 orifice plates to cell count 5X10
4, continue to cultivate 3 days, add the new nutrient solution that closes different concns medicine, 3 parallel holes are set; After administration the 3rd day, add MTT to 7.5mg/ml, continue to cultivate 2 hours, supernatant discarded, adds containing 10% tween X-100 Virahol, 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 1.
Table 1. target compound In Vitro Anti HBV activity and cytotoxicity the selection result
The mensuration of anti-hepatitis B virus activities in embodiment 20 bodies
By the sheldrake random packet of vertical transmission infection, the DHBV DNA detection positive, 5 every group.Gavage gives the testing compound of water, Entecavir and various dose respectively, once a day, and totally 30 days.Respectively before administration, venous blood collection the 15th day time after administration 15 days, administration 30 days and drug withdrawal, adopt outer standard TaqMan real-time fluorescence PCR method to measure serum DHBV DNA content.
Experimental result is in table 2:
Table 2 interior resisting virus activity rating result
Claims (3)
1. acyclic nucleotide phosphate derivative and the non-toxicity pharmacy acceptable salt thereof of formula I representative, hydrate or solvate:
Wherein,
R
1represent H or methyl; With R
1the absolute configuration of connected carbon atom is R or S configuration, or the mixture of RS configuration.
R
2representative-R
3or-OR
3; R
3represent C
1-C
8alkyl or cycloalkyl.
2. contain the pharmaceutical composition that compound claimed in claim 1 and atoxic pharmacy acceptable salt thereof form as activeconstituents and suitable excipient.These pharmaceutical compositions can be solution, tablet, capsule or injection; These pharmaceutical compositions can pass through injection administration or oral administration.
3. compound claimed in claim 1 and atoxic pharmacy acceptable salt thereof, and contain compound claimed in claim 1 and atoxic pharmacy acceptable salt thereof the pharmaceutical composition as activeconstituents, as the purposes for the treatment of hepatitis B medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210451606.8A CN103804416A (en) | 2012-11-13 | 2012-11-13 | Phosphate derivative of acyclovir and medical application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210451606.8A CN103804416A (en) | 2012-11-13 | 2012-11-13 | Phosphate derivative of acyclovir and medical application thereof |
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| Publication Number | Publication Date |
|---|---|
| CN103804416A true CN103804416A (en) | 2014-05-21 |
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ID=50701846
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| Application Number | Title | Priority Date | Filing Date |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113501847A (en) * | 2021-09-13 | 2021-10-15 | 南京颐媛生物医学研究院有限公司 | High-efficiency anti-hepatitis B virus compound and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5627185A (en) * | 1994-11-23 | 1997-05-06 | Gosselin; Gilles | Acyclovir derivatives as antiviral agents |
-
2012
- 2012-11-13 CN CN201210451606.8A patent/CN103804416A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5627185A (en) * | 1994-11-23 | 1997-05-06 | Gosselin; Gilles | Acyclovir derivatives as antiviral agents |
Non-Patent Citations (2)
| Title |
|---|
| 冷玲颖 等: "核苷类抗病毒前药的研究进展", 《中国药物化学杂志》 * |
| 李文保 等: "核苷类药物的前药及其研发近况", 《药学进展》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113501847A (en) * | 2021-09-13 | 2021-10-15 | 南京颐媛生物医学研究院有限公司 | High-efficiency anti-hepatitis B virus compound and preparation method and application thereof |
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