CN100396689C - Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity - Google Patents
Tenoforv monoester compounds with HIV-1/HBV virus copying inhibiting activity Download PDFInfo
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Abstract
The present invention relates to a group of Tenofovir PMPA monoester compounds, alkali/acid composites, a synthesis process and antiviral application thereof. Extracorporeal experiment shows that the compounds of the present invention have HIV-1 virus copy and HBV virus copy inhibiting activity. The present invention lays a foundation for the deep research and development of the compounds in the antiviral application.
Description
Technical field:
The present invention relates to one group of tynofovir (Tenofovir, PMPA) mixture of monoester compound and above-mentioned monoester compound and alkali/acid; The invention still further relates to the synthetic method of said compound and in the application of anti-virus aspect.
Background technology:
Tynofovir is non-nucleolus glycoside antiviral compound, and retrovirus is had strong restraining effect, and does not have cross resistance with other nucleoside medicine that uses clinically.But the tynofovir bioavailability of strongly hydrophilic is poor, influences its exploitation as clinical medicine.For improving its bioavailability, usually they are made ester class prodrug.The fumaric acid mixture tenofovir DF (WO99/05150) of the different third oxygen carbonyl oxygen methyl ester of tynofovir, the medicine that infects as HIV was gone on the market by the FDA approval in calendar year 2001, was the hiv reverse transcriptase inhibitor class AIDS medicine that antiviral activity is the strongest up to now, renal toxicity is lower again.The tenofovir DF oral administration biaavailability be improved significantly, enter intravital tenofovir DF but absorb, have only the hydrolysis competence exertion effect behind the active structure tynofovir that dissociates.
For synthetic screening can improve the fat-soluble novel tynofovir derivative that keeps former compound activity again, the present invention has carried out the synthetic and antiviral activity research of phosphate monoester compound of tynofovir, obtains the novel antiviral compound in the hope of screening.
Tend to change physicochemical property such as its crystallinity, solvability, also can be more convenient for preparing behind the salify preparation or administration behind organic basic or the acidic cpd salify.For this reason, the present invention has carried out the preparation and the antiviral activity research of the salt mixture of the phosphate monoester compound of tynofovir and alkali/acid.
Tynofovir phosphate monoester compound provided by the present invention and with the salt mixture of alkali/acid, be the new compound that there is no relevant report so far.
Summary of the invention:
The present invention is lead compound with the tynofovir, has carried out the synthetic of phosphoric acid long-chain monoester compound and antiviral activity research; Also having carried out the preparation of the mixture (1: 1) of the phosphoric acid long-chain monoester compound of tynofovir and alkali or acid studies with antiviral activity.The in vitro tests result of study shows that The compounds of this invention all shows the activity that suppresses the HIV-1 virus replication and suppress the HBV virus replication, for the further investigation from now on and the antiviral application of the said compound of exploitation are laid a good foundation.
One group provided by the invention has the active tynofovir monoester compound of the HIV-1/HBV virus replication of inhibition, and its structure is suc as formula shown in (I):
Wherein, x=0-8, y=1-20.
The invention provides tynofovir monoester compound pharmacy acceptable salt, shown in (II):
Wherein, x=0-8, y=1-20, Base comprise can with the salifiable sodium hydroxide of phosphate acid group part, potassium hydroxide, calcium hydroxide, Methionin, Histidine, arginine and other common mineral alkali or organic amine; Acid comprise can with mineral acids commonly used such as the salifiable hydrochloric acid of purine amino bases base section, sulfuric acid, phosphoric acid, or organic acid pharmaceutically commonly used such as fumaric acid, lactic acid, Citric Acid.
The invention provides the preparation method of above-mentioned tynofovir monoester compound or its pharmacy acceptable salt, its reaction formula is as follows:
Wherein: x, y, Acid and Base are the same; M is halogen, methanesulfonic base, tosic acid base.
The step that this preparation method comprises is as follows: with tynofovir is raw material, at alkaline reagents (as yellow soda ash, hydrolith, triethylamine, pyridine or 4-N, the N-lutidine) effect down, with halo or sulphur acyloxy for the side chain condensation, obtain tynofovir monoester compound (I), with acid or alkali reaction, obtain the salt (II) of tynofovir monoester compound again.
Wherein, starting raw material tynofovir reference literature (Antonin Holy, Collect.Czech.Chem.Commun., 1197-1211,1995) is synthetic obtains; Side chain MCH
2(CH
2) xCH
2OCH
2(CH
2) yCH
3Reference literature (Susumu Tsushima, Chem.Pharm.Bull.30 (9) 3260-3270,1982) is synthetic to be obtained.
The pharmaceutical composition of above-claimed cpd provided by the invention, can contain the above-claimed cpd for the treatment of significant quantity is activeconstituents, and contains one or more pharmaceutically acceptable carriers.
The invention provides the application in the preparation antiviral of said compound and pharmaceutical composition.
The various formulations of aforementioned pharmaceutical compositions provided by the invention can for example make activeconstituents mix with one or more carriers according to the conventional production method preparation of pharmaceutical field, are made into required formulation then.
The invention provides aforementioned pharmaceutical compositions and preferably contain the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contain the activeconstituents that weight ratio is 0.5%-99.5%.
The invention effect:
According to above said route and method, can stablize, repeatable synthesizing obtain The compounds of this invention.
The present invention adopts cell culture method to measure the extracorporeal antivirus effect activity and the antiviral spectrum of The compounds of this invention, and the result shows that The compounds of this invention is stronger to the restraining effect of retrovirus HIV-1 and HBV, and the determination of activity result of each compound is as shown in table 1.Wherein, the anti-HIV-1 of 16 alkoxyethyls/propyl diester and 18 alkoxyethyls/propyl diester and anti-HBV activity all are better than the precursor tynofovir, the anti-HIV-1 activity of 14 alkoxyethyls/propyl diester is strong than tynofovir, but anti-HBV activity is weaker than or is equivalent to tynofovir.
Table 1: the antiviral activity of invention compound
Embodiment:
Following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.The equal warp of the structure of all compounds
1H NMR or MS determine.
Embodiment 1: (R)-and 9-[2-[(n-Hexadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 (5)
With (R)-9-[2-(phosphoric acid methoxy) propyl group] VITAMIN B4 1.44g (PMPA 5.0mmol), DMF20ml, 1-bromo-3-n-Hexadecane Ethylene Oxide 1.82g (5.0mol), triethylamine 0.61g (6.0mmol) mix, be heated to 80 ℃ of stirring reaction 6h, get yellow oil after being spin-dried for, adding methylene dichloride and methyl alcohol are that 1: 1 mixed solvent 100ml fully dissolves after-filtration, filtrate is spin-dried for, and the resistates silica gel column chromatography obtains light yellow solid 2.04 (71.5%) after separating.
1HNMR (DMSO) δ, (ppm): 0.838 (3H, t, CH
3), 0.919-0.933 (3H, d, CH
3), 1.134-1.225 (26H, m, 13 * CH
2), 1.414-1.475 (2H, m, CH
2), 1.606-1.638 (2H, m, CH
2), 3.128-3.416 (6H, m, 3 * OCH
2), 3.642 (2H, s, OCH
2P), and 3.837-3.850 (1H, m, CH), 4.084-4.269 (2H, m, NCH
2), 7.109 (2H, s, NH
2), 8.098,8.345 (2H, s are respectively the H on the purine skeleton).
Embodiment 2: (R)-and 9-[2-[(n-Hexadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 fumarate (6)
(R)-9-[2-[(n-Hexadecane oxygen propyl group with equivalent) phosphoric acid methoxy] propyl group] VITAMIN B4 and the fumaric acid Virahol that is dissolved in heat stirs 0.5h, cooling crystallization under the room temperature, leach the solid of separating out and with ether wash white solid.
1HNMR (DMSO) δ, (ppm): 0.833 (3H, t, CH
3), 0.910-0.926 (3H, d, CH
3), 1.136-1.219 (26H, m, 13 * CH
2), 1.428-1.476 (2H, m, CH
2), 1.601-1.630 (2H, m, CH
2), 3.127-3.419 (6H, m, 3 * OCH
2), 3.642 (2H, s, OCH
2P), and 3.835-3.853 (1H, m, CH), 4.096-4.267 (2H, m, NCH
2), 6.63 (2H, s, the H on the two keys of fumaric acid), 6.998 (2H, s, NH
2), 8.103,8.339 (2H, s are respectively the H on the purine skeleton).
Embodiment 3: (R)-and 9-[2-[(n-Hexadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 sodium salt (7)
(R)-9-[2-[(n-Hexadecane oxygen propyl group with equivalent) phosphoric acid methoxy] propyl group] VITAMIN B4 and the water-soluble stirring of NaOH 0.5h, lyophilize gets white cotton-shaped solid.
Embodiment 4: (R)-and 9-[2-[(n-Hexadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 Histidine salt (8)
With synthetic (the R)-9-[2-[(n-Hexadecane oxygen propyl group that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] VITAMIN B4 Histidine salt.
1HNMR (DMSO) δ, (ppm): 0.833 (3H, t, CH
3), 0.910-0.926 (3H, d, CH
3), 1.136-1.219 (26H, m, 13 * CH
2), 1.428-1.476 (2H, m, CH
2), 1.601-1.630 (2H, m, CH
2), 2.961-3.086 (2H, m, CH on the Histidine
2), 3.127-3.419 (6H, m, 3 * OCH
2), 3.642 (2H, s, OCH
2P), and 3.835-3.853 (1H, m, CH), 3.880 (1H, t, CH on the Histidine), 4.096-4.267 (2H, m, NCH
2), 6.998 (2H, s, NH
2), 7.665,8.477 (2H, s, CH on the Histidine five-ring), 8.103,8.339 (2H, s are respectively the H on the purine skeleton).
Embodiment 5: (R)-and 9-[2-[(tetradecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 (1)
With synthetic (the R)-9-[2-[(tetradecane oxygen propyl group that obtains of embodiment 1 similar approach) the phosphoric acid methoxy] propyl group] VITAMIN B4.
1HNMR (DMSO) δ, (ppm): 0.838 (3H, t, CH
3), 0.944-0.955 (3H, d, CH
3), 1.151-1.227 (22H, m, 11 * CH
2), 1.379-1.394 (2H, m, CH
2), 1.637 (2H, m, CH
2), 3.196-3.416 (6H, m, 3 * OCH
2), 3.709 (2H, s, OCH
2P), and 3.843-3.856 (1H, m, CH), 4.138-4.209 (2H, m, NCH
2), 7.122 (2H, s, NH
2), 8.098 (2H, s, the H on the purine skeleton).
Embodiment 6: (R)-and 9-[2-[(tetradecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 hydrochloride (2)
With the synthetic R that obtains of embodiment 2 similar approach)-9-[2-[(tetradecane oxygen propyl group) the phosphoric acid methoxy] propyl group] the VITAMIN B4 hydrochloride.
Embodiment 7: (R)-and 9-[2-[(tetradecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 sodium salt (3)
With the synthetic R that obtains of embodiment 3 similar approach)-9-[2-[(tetradecane oxygen propyl group) the phosphoric acid methoxy] propyl group] the VITAMIN B4 sodium salt.
Embodiment 8: (R)-and 9-[2-[(tetradecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 lysine salt (4)
With synthetic (the R)-9-[2-[(tetradecane oxygen propyl group that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] the VITAMIN B4 lysine salt.
1HNMR (DMSO) δ, (ppm): 0.838 (3H, t, CH
3), 0.944-0.956 (3H, d, CH
3), 1.151-1.227 (24H, m, 12 * CH
2), 1.379-1.394 (4H, m, 2 * CH
2), 1.637 (4H, m, 2 * CH
2), 2.011 (2H, t, NH on the Methionin
2), 2.570 (2H, t, NCH on the Methionin
2), 3.196-3.416 (6H, m, 3 * OCH
2), 3.709 (2H, s, OCH
2P), 3.767 (2H, t, CH on the Methionin), 3.843-3.856 (1H, m, CH), 4.138-4.209 (2H, m, NCH
2), 7.122 (2H, s, NH
2), 8.098 (2H, s, the H on the purine skeleton).
Embodiment 9: (R)-and 9-[2-[(octadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 (9)
With synthetic (the R)-9-[2-[(octadecane oxygen propyl group that obtains of embodiment 1 similar approach) the phosphoric acid methoxy] propyl group] VITAMIN B4.
1HNMR (DMSO) δ, (ppm): 0.842 (3H, t, CH
3), 0.915 (3H, d, CH
3), 1.091-1.220 (30H, m, 15 * CH
2), 1.418-1.475 (2H, m, CH
2), 1.652 (2H, m, CH
2), 3.153-3.472 (6H, m, 3 * OCH
2) 3.650 (2H, s, OCH
2P), 3.783 (1H, m, CH), 4.338 (2H, m, NCH
2), 7.111 (2H, s, NH
2), 8.100,8.238 (2H, s, the H on the purine skeleton).
Embodiment 10: (R)-and 9-[2-[(octadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of adenine sulfate (10)
With the synthetic R that obtains of embodiment 2 similar approach)-9-[2-[(octadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] adenine sulfate.
Embodiment 11: (R)-and 9-[2-[(octadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 sylvite (11)
With synthetic (the R)-9-[2-[(octadecane oxygen propyl group that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] VITAMIN B4 sylvite.
Embodiment 12: (R)-and 9-[2-[(octadecane oxygen propyl group) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 lysine salt (12)
With synthetic (the R)-9-[2-[(octadecane oxygen propyl group that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] the VITAMIN B4 lysine salt.
1HNMR (DMSO) δ, (ppm): 0.841 (3H, t, CH
3), 0.947-0.958 (3H, d, CH
3), 1.149-1.228 (32H, m, 16 * CH
2), 1.381-1.396 (4H, m, 2 * CH
2), 1.638-1.960 (4H, m, 2 * CH
2), 2.013 (2H, t, NH on the Methionin
2), 2.565 (2H, t, NCH on the Methionin
2), 3.203-3.409 (6H, m, 3 * OCH
2), 3.707 (2H, s, OCH
2P), 3.758 (2H, t, CH on the Methionin), 3.839-3.849 (1H, m, CH), 4.142-4.211 (2H, m, NCH
2), 7.119 (2H, s, NH
2), 8.081 (2H, s, the H on the purine skeleton).
Embodiment 13: (R)-and 9-[2-[(tetradecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 (13)
With synthetic (the R)-9-[2-[(tetradecane oxygen ethyl that obtains of embodiment 1 similar approach) the phosphoric acid methoxy] propyl group] VITAMIN B4.
1HNMR (DMSO) δ, (ppm): 0.823 (3H, t, CH
3), 0.943-0.946 (3H, d, CH
3), 1.087-1.216 (22H, m, 11 * CH
2), 1.420-1.455 (2H, m, CH
2), 3.147-3.465 (6H, m, 3 * OCH
2), 3.639 (2H, s, OCH
2P), 3.778 (1H, m, CH), 4.327 (2H, m, NCH
2), 7.108 (2H, s, NH2), 8.096,8.211 (2H, s, the H on the purine skeleton).
Embodiment 14: (R)-and 9-[2-[(tetradecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of adenine sulfate (14)
With synthetic (the R)-9-[2-[(tetradecane oxygen ethyl that obtains of embodiment 2 similar approach) the phosphoric acid methoxy] propyl group] adenine sulfate.
Embodiment 15: (R)-and 9-[2-[(tetradecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 sodium salt (15)
With synthetic (the R)-9-[2-[(tetradecane oxygen ethyl that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] the VITAMIN B4 sodium salt.
Embodiment 16: (R)-and 9-[2-[(n-Hexadecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 (16)
With synthetic (the R)-9-[2-[(n-Hexadecane oxygen ethyl that obtains of embodiment 1 similar approach) the phosphoric acid methoxy] propyl group] VITAMIN B4.
1HNMR (DMSO) δ, (ppm): 0.822 (3H, t, CH
3), 0.920-0.934 (3H, d, CH
3), 1.136-1.223 (26H, m, 13 * CH
2), 1.416-1472 (2H, m, CH
2), 3.028-3.409 (6H, m, 3 * OCH
2), 3.645 (2H, s, OCH
2P), and 3.836-3.852 (1H, m, CH), 4.079-4.262 (2H, m, NCH
2), 7.102 (2H, s, NH
2), 8.097,8.333 (2H, s, the H on the purine skeleton).
Embodiment 17: (R)-and 9-[2-[(n-Hexadecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 sylvite (17)
With synthetic (the R)-9-[2-[(n-Hexadecane oxygen ethyl that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] VITAMIN B4 sylvite.
Embodiment 18: (R)-and 9-[2-[(n-Hexadecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 sodium salt (18)
With synthetic (the R)-9-[2-[(n-Hexadecane oxygen ethyl that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] the single sodium salt of VITAMIN B4.
Embodiment 19: (R)-and 9-[2-[(octadecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 (19)
With synthetic (the R)-9-[2-[(octadecane oxygen ethyl that obtains of embodiment 1 similar approach) the phosphoric acid methoxy] propyl group] VITAMIN B4.
1HNMR (DMSO) δ, (ppm): 0.828 (3H, t, CH
3), 0.918-0.930 (3H, d, CH
3), 1.091-1.220 (30H, m, 15 * CH
2), 1.420-1.466 (2H, m, CH
2), 3.039-3.411 (6H, m, 3 * OCH
2), 3.663 (2H, s, OCH
2P), and 3.822-3.842 (1H, m, CH), 4.068-4.257 (2H, m, NCH
2), 7.101 (2H, s, NH
2), 8.088,8.229 (2H, s, the H on the purine skeleton).
Embodiment 20: (R)-and 9-[2-[(octadecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 sodium salt (20)
With synthetic (the R)-9-[2-[(octadecane oxygen ethyl that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] the VITAMIN B4 sodium salt.
Embodiment 21: (R)-and 9-[2-[(octadecane oxygen ethyl) the phosphoric acid methoxy] propyl group] preparation of VITAMIN B4 arginic acid salt (21)
With synthetic (the R)-9-[2-[(octadecane oxygen ethyl that obtains of embodiment 3 similar approach) the phosphoric acid methoxy] propyl group] the VITAMIN B4 arginic acid salt.
1HNMR (DMSO) δ, (ppm): 0.828 (3H, t, CH
3), 0.918-0.930 (3H, d, CH
3), 1.091-1.220 (30H, m, 15 * CH
2), 1.420-1.466 (4H, m, 2 * CH
2), 1.781-1.853 (4H, m, the NCH on the arginine
2), 3.039-3.411 (6H, m, 3 * OCH
2), 3.492 (1H, t, the NCH on the arginine), 3.663 (2H, s, OCH
2P), and 3.822-3.842 (1H, m, CH), 4.068-4.257 (2H, m, NCH
2), 7.101 (2H, s, NH
2), 7.822 (1H, s, the NH on the arginine), 8.088,8.229 (2H, s, the H on the purine skeleton).
Embodiment 22: the active mensuration of resisting HBV virus
Adopt cell culture method, measured The compounds of this invention in external influence to hepatitis B virus and HIV virus replication.In the anti-hepatitis B virus activities research, sample cell toxicity test method is: will test cell and be mixed with every milliliter of 100,000 cell inoculation Tissue Culture Plates, the every hole 100 μ l of 96 orifice plates, 37 ℃ of 5%CO
2Cultivated 24 hours, cell experimentizes after growing up to individual layer.Add 96 porocyte culture plates after target compound and the medicinal nutrient solution of contrast are mixed with desired concn, every concentration 4 holes were changed with concentration liquid once in per 4 days, established no drug cell control group simultaneously.With the observation of cell pathology is index, 8 days microscopically observation of cell lesion degrees.Sample suppresses hepatitis virus activity test method: 100,000 every milliliter test cell inoculation 96 porocyte culture plates, every hole 100 μ l, 37 ℃ of 5%CO
2Cultivated 24 hours, and added medicine, establish the cell control group simultaneously, changed original content soup or contrast culture liquid in 4 days once.Press molecular cloning experimental technique method after the lysis and extract HBV DNA.After the A value of each hybridization point of each sample dot hybridization, radioautograph, measurement, utilize the HBV dna content of the regression equation calculation cell contrast of typical curve and administration group after, calculating medium effective concentration (IC
50) (table 1).
Embodiment 23: medicine suppresses the antigenic effect of HIV-1P24 in the chronically infected H9 cell cultures of HIV-1IIIB
Add the soup and the positive control soup of 8 different weaker concns in 96 porocytes are cultivated, each extent of dilution repeats 2 holes, establishes the cell contrast; Again with 2 * 10
5Cell/ml 100 μ l are inoculated in the pastille 96 porocyte culture plates.Put 37 ℃, 5%CO
2With cultivate in the saturated humidity incubator, every day the observation of cell pathology.By the operation steps that the HIV-1P24 antigenic reagent box provides, the 4th day (96 hours) cells and supernatant HIV-1 P24 antigenic content after the mensuration dosing calculates medicine medium effective concentration (EC
50) (table 1).
Claims (9)
1. one group of tynofovir monoester compound, it has the activity that suppresses the HIV-1/HBV virus replication, and its structure is suc as formula shown in (I):
Wherein, x=0-8, y=1-20.
2. the described tynofovir monoester compound of claim 1 pharmacy acceptable salt, its structure is suc as formula shown in (II):
Wherein: x=0-8, y=1-20, Base be can with the salifiable sodium hydroxide of phosphate acid group part, potassium hydroxide, Methionin, Histidine, arginine; Acid be can with the salifiable hydrochloric acid of purine amino bases base section, sulfuric acid, fumaric acid.
3. method for preparing the described formula of claim 1 (I) compound, its reaction formula is as follows:
Wherein: x, y are the same; M is halogen, methanesulfonic base, tosic acid base; This preparation method comprises the steps: that with tynofovir be raw material, under the alkaline reagents effect, replaces the-oxyl condensation with M, obtains tynofovir monoester compound (I).
4. method for preparing the described formula of claim 2 (II) salt, its reaction formula is as follows:
Wherein, x, y, Acid and Base are the same; This preparation method's step is: with tynofovir monoester compound (I) and acid or the alkali reaction that obtains, promptly obtain the salt (II) of tynofovir monoester compound.
5. the pharmaceutical composition of the described compound of claim 1, containing the above-claimed cpd for the treatment of significant quantity is activeconstituents, and contains one or more pharmaceutically acceptable carriers.
6. the application of the described compound of claim 1 in the preparation antiviral.
7. the application of the described composition of claim 5 in the preparation antiviral.
8. the various formulations of the described pharmaceutical composition of claim 5, the conventional production method preparation according to pharmaceutical field makes activeconstituents mix with one or more carriers, is made into required formulation then.
9. the described pharmaceutical composition of claim 5, it contains the activeconstituents that weight ratio is 0.1%-99.5%.
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| FR2908133B1 (en) | 2006-11-08 | 2012-12-14 | Centre Nat Rech Scient | NOVEL NUCLEOTIDE ANALOGUES AS ANTIVIRAL PRECURSOR MOLECULES |
| AU2008246195B2 (en) * | 2007-04-27 | 2014-06-05 | Emergent Biodefence Operations Lansing Llc | Methods of Reducing Nephrotoxicity in Subjects Administered with Nucleoside Phosphonates |
| US8993542B2 (en) * | 2008-01-25 | 2015-03-31 | Chimerix Inc. | Methods of treating viral infections |
| AU2011216243B2 (en) | 2010-02-12 | 2015-07-09 | Chimerix, Inc. | Nucleoside phosphonate salts |
| CA2797601A1 (en) | 2010-04-26 | 2011-11-10 | Chimerix, Inc. | Methods of treating retroviral infections and related dosage regimes |
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