CN103804417B - Anti-hepatic-B virus medicine - Google Patents
Anti-hepatic-B virus medicine Download PDFInfo
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- CN103804417B CN103804417B CN201210451621.2A CN201210451621A CN103804417B CN 103804417 B CN103804417 B CN 103804417B CN 201210451621 A CN201210451621 A CN 201210451621A CN 103804417 B CN103804417 B CN 103804417B
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Abstract
The present invention relates to the new anti-hepatic-B virus medicine representated by Formulas I and its non-toxic pharmaceutically acceptable salt and its hydrate：Wherein, R1For the alkyl or cycloalkyl of carbon number 16, R2For H or the alkyl of carbon number 16.
Description
Technical field
The present invention relates to new anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt and its hydrate.
Background technology
Virus hepatitis is the major disease for threatening human health.Entecavir is current maximally effective treating hepatitis B medicine
Thing.But, Entecavir has certain cross resistance with Lamivudine, poor to lamivudine resistance patient's curative effect.In addition,
Identical with other ucleosides anti-hepatic-B virus medicines, Entecavir treatment is easily bounced after being discontinued.Therefore, it is clinical to need preferably to resist
Hepatitis B medicine.
The content of the invention
It is an object of the invention to provide the new anti-hepatic-B virus medicine representated by Formulas I and its non-toxic are pharmaceutically acceptable
Salt and its hydrate：
Wherein, R1For carbon number 1-6 a heatable brick bed base or cycloalkyl, R2For H or carbon number 1-6 alkyl.
The present invention also provides the new anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt representated by Formulas I a
And its hydrate：
Wherein, R1For carbon number 1-6 alkyl or cycloalkyl, R2For H or carbon number 1-6 alkyl.
The present invention also provide the new anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt that Formulas I b represents and
Its hydrate：
Wherein, R1For carbon number 1-6 alkyl or cycloalkyl, R2For H or carbon number 1-6 alkyl.
Present invention anti-hepatic-B virus medicine and its non-toxic new also shown in offer Formulas I or Formulas I a or Ib is pharmaceutically acceptable
Salt and its hydrate as active component pharmaceutical composition.
Anti-hepatic-B virus medicine and its non-toxic finally new also shown in offer Formulas I or Formulas I a or Ib of the invention pharmaceutically may be used
The salt and its hydrate of receiving, and include the new anti-hepatic-B virus medicine and its non-toxic pharmacy described in claim 1-3
Upper acceptable salt and its hydrate as active component pharmaceutical composition as anti-hepatic-B virus medicine purposes.
Embodiment
The present invention can be further described for the following examples, however, these embodiments should not be used as to this
The limitation of the scope of invention.
The compound of the present invention can be prepared according to following synthetic route：
Dichloride phosphoric acid phenolic ester (II) is with amino-acid ester (III) under N- methylimidazoles (NMI) catalysis, and reaction generates phosphinylidyne
Amine intermediate (IV)；Entecavir reacts the Entecavir (V) for obtaining amido protection with DMF dimethyl acetal；
IV and V reacts, and is deprotected simultaneously, obtains target compound.
React in initiation material, intermediate and target compound structural formula, R1For carbon number 1-6 alkyl or cycloalkanes
Base, R2For H or carbon number 1-6 alkyl.
Embodiment 12- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- ((methoxycarbonyl methylaminos-phenol oxygen
Base-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] and -6H- purine-6-ones (I-1) preparation
2.1 grams of (0.01mol) dichloro phosphoric acid phenol esters and 1.3 grams of (0.01mol) glycine methyl ester hydrochlorides are dissolved in
In 30mL anhydrous methylene chlorides, -78 DEG C are cooled to.Stirring is lower to be added dropwise the solution that 2 grams of triethylamines are dissolved in 20mL anhydrous methylene chlorides,
Rate of addition is controlled to keep -78 DEG C of reaction temperature.After adding, question response temperature is slow to be warmed to room temperature, and continues to stir 1 hour.Subtract
Pressure steams solvent, and 30ml absolute ethers, filtering are added in residue.Filtrate decompression is evaporated, colorless oil, as phosphorus is obtained
Amide intermediate IV-1, is directly used in the next step.
55 grams of (0.2mmol) anhydrous Entecavirs, 24 grams of (0.2mmol) DMF contracting methanol are added to
In 800ml dimethylformamides, it is stirred overnight at room temperature.Vacuum steams solvent, obtains the Entecavir derivative V of amido protection,
It is directly used in the next step.
0.33 gram of (1mmol) intermediate V, 0.66 gram of (8mmol) N- methylimidazole are dissolved in 6ml anhydrous tetrahydro furans, it is acute
The solution that 1.6 grams of (6mmol) IV-1 are dissolved in 6ml anhydrous tetrahydro furans is added dropwise under strong stirring, is stirred overnight at room temperature.Evaporated under reduced pressure is molten
Agent.Residue is separated with silica gel column chromatography, with the dichloromethane eluent containing 2% methanol, component needed for collecting, evaporated under reduced pressure,
Obtain I-10.13 grams of target compound.Proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.62 (bs, 1H), 7.68
(s, 1H), 7.37-7.40 (m, 2H), 7.18-7.26 (m, 3H), 6.44 (s, 2H), 6.05 (m, 1H), 5.37 (m, 1H), 5.12
(m, 1H)；4.89 (d, 1H), 4.85 (m, 1H), 4.57 (m, 1H), 4.42 (m, 1H), 4.25-4.29 (m, 2H), 3.60 (s, 3H)
3.56 (m, 2H), 2.52 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H).
2- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- ((the ethoxy carbonyl methylaminos-phenol of embodiment 2
Epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] and -6H- purine-6-ones (I-2) preparation
2.1 grams of (0.01mol) dichloro phosphoric acid phenol esters and 1.4 grams of (0.01mol) glycine ethyl ester hydrochlorides are dissolved in
In 30mL anhydrous methylene chlorides, -78 DEG C are cooled to.Stirring is lower to be added dropwise the solution that 2 grams of triethylamines are dissolved in 20mL anhydrous methylene chlorides,
Rate of addition is controlled to keep -78 DEG C of reaction temperature.After adding, question response temperature is slow to be warmed to room temperature, and continues to stir 1 hour.Subtract
Pressure steams solvent, and 30ml absolute ethers, filtering are added in residue.Filtrate decompression is evaporated, colorless oil, as phosphorus is obtained
Amide intermediate IV-2, is directly used in the next step.
0.33 gram of (1mmol) intermediate V, 0.66 gram of (8mmol) N- methylimidazole are dissolved in 6ml anhydrous tetrahydro furans, it is acute
The solution that 1.75 grams of (6mmol) IV-2 are dissolved in 6ml anhydrous tetrahydro furans is added dropwise under strong stirring, is stirred overnight at room temperature.Evaporated under reduced pressure
Solvent.Residue is separated with silica gel column chromatography, with the dichloromethane eluent containing 2% ethanol, component needed for collecting, decompression is steamed
It is dry, obtain I-20.15 grams of target compound.Proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.60 (bs, 1H),
7.67 (s, 1H), 7.37-7.40 (m, 2H), 7.18-7.27 (m, 3H), 6.43 (s, 2H), 6.04 (m, 1H), 5.38 (m, 1H),
5.11 (m, 1H)；4.88 (d, 1H), 4.85 (m, 1H), 4.57 (m, 1H), 4.42 (m, 1H), 4.25-4.29 (m, 2H), 3.70-
3.90 (m, 2H), 3.56 (m, 2H), 2.52 (m, 1H), 2.23 (m, 1H), 2.05 (m, 1H), 1.15 (m, 3H).
Embodiment 32- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- ((isopropoxy carbonyl methylaminos-phenol
Epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] and -6H- purine-6-ones (I-3) preparation
2.1 grams of (0.01mol) dichloro phosphoric acid phenol esters and 1.53 grams of (0.01mol) glycine isopropyl ester hydrochlorides are dissolved in
In 30mL anhydrous methylene chlorides, -78 DEG C are cooled to.Stirring is lower to be added dropwise the solution that 2 grams of triethylamines are dissolved in 20mL anhydrous methylene chlorides,
Rate of addition is controlled to keep -78 DEG C of reaction temperature.After adding, question response temperature is slow to be warmed to room temperature, and continues to stir 1 hour.Subtract
Pressure steams solvent, and 30ml absolute ethers, filtering are added in residue.Filtrate decompression is evaporated, colorless oil, as phosphorus is obtained
Amide intermediate IV-3, is directly used in the next step.
0.33 gram of (1mmol) intermediate V, 0.66 gram of (8mmol) N- methylimidazole are dissolved in 6ml anhydrous tetrahydro furans, it is acute
The solution that 1.9 grams of (6mmol) IV-3 are dissolved in 6ml anhydrous tetrahydro furans is added dropwise under strong stirring, is stirred overnight at room temperature.Evaporated under reduced pressure is molten
Agent.Residue is separated with silica gel column chromatography, with the dichloromethane eluent containing 2% isopropanol, component needed for collecting, decompression is steamed
It is dry, obtain I-30.10 grams of target compound.Proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.59 (bs, 1H),
7.66 (s, 1H), 7.36-7.40 (m, 2H), 7.16-7.22 (m, 3H), 6.41 (s, 2H), 6.03 (m, 1H), 5.37 (m, 1H),
5.11 (m, 1H)；4.86 (d, 1H), 4.83 (m, 1H), 4.55 (m, 1H), 4.42 (m, 1H), 4.26 (m, 1H), 4.21 (m, 1H),
3.78 (m, 2H), 3.55 (m, 2H), 2.54 (m, 1H), 2.25 (m, 1H), 2.02 (m, 1H), 1.18 (m, 6H).
Embodiment 42- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- (((S) -1- ethoxy carbonyl ethamine
Base-phenol epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] and -6H- purine-6-ones (I-4) preparation
21 grams of (0.1mol) dichloro phosphoric acid phenol esters and 15.3 grams of (0.1mol) ALANINE carbethoxy hydrochlorides are dissolved in
In 300mL anhydrous methylene chlorides, -78 DEG C are cooled to.Stirring 20 grams of triethylamines of lower dropwise addition are dissolved in the molten of 100mL anhydrous methylene chlorides
Liquid, controls rate of addition to keep -78 DEG C of reaction temperature.After adding, question response temperature is slow to be warmed to room temperature, and continues to stir 1 hour.
Decompression steams solvent, and 250ml absolute ethers, filtering are added in residue.Filtrate decompression is evaporated, colorless oil is obtained, i.e.,
For phosphamide intermediate compound IV -4, the next step is directly used in.
3.3 grams of (10mmol) intermediate V, 6.6 grams of (80mmol) N- methylimidazoles are dissolved in 50ml anhydrous tetrahydro furans, it is acute
The solution that 17.5 grams of (60mmol) IV-4 are dissolved in 50ml anhydrous tetrahydro furans is added dropwise under strong stirring, is stirred overnight at room temperature.Decompression is steamed
Dry solvent.Residue is separated with silica gel column chromatography, with the dichloromethane eluent containing 2% ethanol, component needed for collecting, decompression is steamed
It is dry, obtain I-41.5 grams of target compound.Proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.54 (bs, 1H), 7.66
(s, 1H), 7.35-7.39 (m, 2H), 7.18-7.23 (m, 3H), 5.84-6.15 (m, 2H), 6.42 (s, 2H), 5.36 (m, 1H),
5.10 (m, 1H), 4.87 (d, 1H), 4.83-4.86 (m, 1H), 4.84 (m, 1H), 4.56 (m, 1H), 4.20-4.45 (m, 1H),
4.23 (m, 1H), 3.70-3.90 (m, 2H), 3.53 (m, 2H), 2.52 (m, 1H), 2.22 (m, 1H), 2.04 (m, 1H), 1.13-
1.28 (m, 6H).
The separation of embodiment 5I-4 isomers
I-41.1 grams is taken, is dissolved with the acetonitrile containing 15% ethanol, chromatographic isolation is prepared with chirality, chromatographic column is Diacel ' s
Chiralpak AS, mobile phase is the acetonitrile solution containing 15% ethanol, and flow velocity 8ml/min collects first component, and decompression is steamed
It is dry, obtain 2- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- ((R)-((S) -1- ethoxy carbonyls ethylamino-s-phenol
Epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] 0.55 gram of -6H- purine-6-ones (I-4-A)；Collect second group
Point, evaporated under reduced pressure obtains 2- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- ((S)-((S) -1- isopropoxy carbonyls
Base ethylamino--phenol epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] 0.45 gram of -6H- purine-6-ones (I-4-B).
I-4-A proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.50 (bs, 1H), 7.63 (s, 1H),
7.38-7.33 (m, 2H), 7.18-7.12 (m, 3H), 6.07 (m, 1H), 6.40 (s, 2H), 5.35 (m, 1H), 5.08 (m, 1H)；
4.87 (d, 1H), 4.85 (m, 1H), 4.82 (m, 1H), 4.53 (m, 1H), 4.21 (m, 1H), 3.70-3.90 (m, 2H), 3.50
(m, 2H), 2.51 (m, 1H), 2.23 (m, 1H), 2.01 (m, 1H) .1.21 (d, 3H), 1.14 (t, 3H).
I-4-B proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.51 (bs, 1H), 7.62 (s, 1H),
7.37-7.34 (m, 2H), 7.20-7.15 (m, 3H), 6.41 (s, 2H), 6.01 (m, 1H), 5.80 (m, 1H), 5.35 (m, 1H),
5.12 (m, 1H)；4.88 (d, 1H), 4.84-4.80 (m, 2H), 4.53 (m, 1H), 4.21 (m, 1H), 3.71-3.90 (m, 2H),
3.50 (m, 2H), 2.53 (m, 1H), 2.18 (m, 1H), 2.00 (m, 1H) 1.24 (d, 3H), 1.13 (t, 3H).
Embodiment 62- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- (((S) -1- isopropoxy carbonyl second
Amido-phenol epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] and -6H- purine-6-ones (I-5) preparation
21 grams of (0.1mol) dichloro phosphoric acid phenol esters and 16.7 grams of (0.1mol) ALANINE isopropyl ester hydrochlorides are dissolved in
In 250mL anhydrous methylene chlorides, -78 DEG C are cooled to.Stirring 20 grams of triethylamines of lower dropwise addition are dissolved in the molten of 150mL anhydrous methylene chlorides
Liquid, controls rate of addition to keep -78 DEG C of reaction temperature.After adding, question response temperature is slow to be warmed to room temperature, and continues to stir 1 hour.
Decompression steams solvent, and 250ml absolute ethers, filtering are added in residue.Filtrate decompression is evaporated, colorless oil is obtained, i.e.,
For phosphamide intermediate compound IV -5, the next step is directly used in.
3.3 grams of (10mmol) intermediate V, 6.6 grams of (80mmol) N- methylimidazoles are dissolved in 60ml anhydrous tetrahydro furans, it is acute
The solution that 18.3 grams of (60mmol) IV-5 are dissolved in 50ml anhydrous tetrahydro furans is added dropwise under strong stirring, is stirred overnight at room temperature.Decompression is steamed
Dry solvent.Residue is separated with silica gel column chromatography, with the dichloromethane eluent containing 2% isopropanol, component needed for collecting, decompression
It is evaporated, obtains I-51.4 grams of target compound.Proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.50 (bs, 1H),
7.65 (s, 1H), 7.33-7.38 (m, 2H), 7.15-7.25 (m, 3H), 6.40 (s, 2H), 6.08 (m, 1H), 5.33 (m, 1H),
5.07 (m, 1H)；4.85-4.82 (m, 2H), 4.53 (m, 1H), 4.19-4.40 (m, 2H), 3.70-3.90 (m, 2H), 3.55 (m,
2H), 2.56 (m, 1H), 2.20 (m, 1H), 2.04 (m, 1H), 1.23 (m, 3H), δ 1.15 (m, 6H).
The separation of embodiment 7I-5 isomers
I-51.0 grams is taken, is dissolved with the acetonitrile containing 20% isopropanol, chromatographic isolation is prepared with chirality, chromatographic column is
Diacel ' s Chiralpak AS, mobile phase is the acetonitrile solution containing 20% isopropanol, and flow velocity 8ml/min collects first group
Point, evaporated under reduced pressure obtains 2- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- ((R)-((S) -1- ethoxy carbonyls
Ethylamino--phenol epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] 0.5 gram of -6H- purine-6-ones (I-5-A)；Collect the
Two components, evaporated under reduced pressure obtains 2- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- ((S)-((S) -1- isopropyls
Epoxide carbonyl ethylamino--phenol epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] -6H- purine-6-ones (I-5-B) 0.4
Gram.
I-5-A proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.51 (bs, 1H), 7.63 (s, 1H),
7.39-7.35 (m, 2H), 7.22-7.17 (m, 3H), 6.09 (m, 1H), 6.45 (s, 2H), 5.32 (m, 1H), 5.06 (m, 1H)；
4.89 (d, 1H), 4.85-4.83 (m, 2H), 4.52 (m, 1H), 4.40 (m, 1H), 4.23 (m, 1H), 3.51 (m, 2H), 2.52
(m, 1H), 2.22 (m, 1H), 2.04 (m, 1H) .1.19 (d, 3H), 1.16 (d, 6H).
I-5-B proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.54 (bs, 1H), 7.67 (s, 1H),
7.38-7.33 (m, 2H), 7.21-7.15 (m, 3H), 6.45 (s, 2H), 6.03 (m, 1H), 5.80 (m, 1H), 5.32 (m, 1H),
5.07 (m, 1H)；4.87-4.83 (m, 3H), 4.58 (m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 3.51 (m, 2H), 2.50
(m, 1H), 2.21 (m, 1H), 2.03 (m, 1H), 1.21 (d, 3H), 1.13 (d, 6H).
Embodiment 82- amino -1,9- dihydros -9- [(1S, 3R, 4S) -4- hydroxyls -3- (((S) -1- cyclohexyloxy carbonyl second
Amido-phenol epoxide-phosphoryl)-oxygen methyl) -2- methylenecyclopentyls] and -6H- purine-6-ones (I-6) preparation
2.1 grams of (0.01mol) dichloro phosphoric acid phenol esters and 1.67 grams of (0.01mol) ALANINE hexamethylene ester hydrochlorides are molten
In 30mL anhydrous methylene chlorides, -78 DEG C are cooled to.Stirring 2 grams of triethylamines of lower dropwise addition are dissolved in the molten of 20mL anhydrous methylene chlorides
Liquid, controls rate of addition to keep -78 DEG C of reaction temperature.After adding, question response temperature is slow to be warmed to room temperature, and continues to stir 1 hour.
Decompression steams solvent, and 30ml absolute ethers, filtering are added in residue.Filtrate decompression is evaporated, colorless oil is obtained, is
Phosphamide intermediate compound IV -6, are directly used in the next step.
0.33 gram of (1mmol) intermediate V, 0.66 gram of (8mmol) N- methylimidazole are dissolved in 6ml anhydrous tetrahydro furans, it is acute
The solution that 2.07 grams of (6mmol) IV-6 are dissolved in 6ml anhydrous tetrahydro furans is added dropwise under strong stirring, is stirred overnight at room temperature.Evaporated under reduced pressure
Solvent.Residue is separated with silica gel column chromatography, with the dichloromethane eluent containing 2% isopropanol, component needed for collecting, decompression is steamed
It is dry, obtain I-60.14 grams of target compound.Proton nmr spectra δ (ppm, DMSO-d6,400MHz)：10.54 (bs, 1H),
7.66 (s, 1H), 7.32-7.36 (m, 2H), 7.15-7.20 (m, 3H), 6.42 (s, 2H), 5.51 (t, 1H), 5.32 (m, 1H),
5.07 (m, 1H), 5.03 (m, 1H), 4.87 (d, 1H), 4.83 (m, 1H), 4.57-4.55 (m, 2H), 4.35 (m, 1H), 4.22
(m, 1H), 3.51 (m, 2H), 2.50 (m, 1H), 2.23 (m, 1H), 2.01 (m, 1H) 1.63 (m, 4H), 1.18-1.41 (m, 9H).
The measure of the effect on hepatitics B virus in vitro of embodiment 9 activity and cytotoxicity
By Hep G 2.2.15 cell culture in the DMEM nutrient solutions containing 10% calf serum, it is inoculated in 96 orifice plates,
Cell number 3X104/ hole, is incubated in 5%CO2 incubators, when cell density reaches 80%, abandons old nutrient solution, adds containing not
With the new nutrient solution of concentration medicine to be measured, 200 μ l/ holes set 3 parallel holes；Nutrient solution was changed every 2 days.Upon administration
10 days, 100 μ l supernatants are taken, HBV DNA content is determined with the method for quantitative PCR, calculates 50% inhibition concentration, as IC50Value.
In 96 orifice plates for taking 100 μ l supernatants, 7.5mg/ml MTT is added, 30 μ l/ holes are continued to cultivate 3 hours, abandoned
After supernatant, the acid isopropyl alcoholic solution containing 10% tween X-100 is added, 120 μ l/ holes determine the suction at 540nm with enzyme-linked instrument
Receive, calculate 50% inhibition concentration, as CC50Value.
Experimental result is shown in Table 1：
The effect on hepatitics B virus in vitro of table 1 activity and cytotoxicity
The measure of anti-hepatitis B activity in the body of embodiment 10
Vertical transmission is infected, the sheldrake that DHBV DNA detections are positive is grouped at random, every group 5.Respectively gavage give water,
The testing compound of Entecavir and various dose, once a day, totally 30 days.Respectively before administration, administration 15 days, administration 30 days
With venous blood collection at the 15th day after drug withdrawal, serum DHBV DNA contents are determined using outer standard TaqMan real-time fluorescence PCRs method.
Experimental result is shown in Table 2：
The interior resisting virus Activity evaluation of table 2
Claims (5)
1. anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt representated by Formulas I：
Wherein, R1For ethyl, isopropyl or cyclohexyl, R2For methyl.
2. anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt representated by Formulas I a：
Wherein, R1For ethyl, isopropyl, R2For methyl.
3. anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt representated by Formulas I b：
Wherein, R1For ethyl, isopropyl, R2For methyl.
4. the anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt described in claim any one of 1-3 are used as activity
The pharmaceutical composition of composition.
5. anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt described in claim any one of 1-3, and bag
Anti-hepatic-B virus medicine and its non-toxic pharmaceutically acceptable salt described in any one of 1-3 containing claim are used as active component
Purposes of the pharmaceutical composition in anti-hepatic-B virus medicine is prepared.
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| KR101996229B1 (en) * | 2016-10-07 | 2019-07-04 | 단국대학교 천안캠퍼스 산학협력단 | Fatty acid conjugated entecavir analogs and pharmaceutical use thereof |
| CA3122410A1 (en) * | 2018-12-12 | 2020-06-18 | Janssen Biopharma, Inc. | Cyclopentyl nucleoside analogs as anti-virals |
| CN113493481A (en) | 2020-04-08 | 2021-10-12 | 北京君科华元医药科技有限公司 | Entecavir monophosphate alaninamide phenol ester and medical application thereof |
| CN113501847B (en) * | 2021-09-13 | 2022-01-11 | 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100503628C (en) * | 2003-05-30 | 2009-06-24 | 法莫赛特股份有限公司 | Modified fluorinated nucleoside analogues |
| CN102119167A (en) * | 2008-06-11 | 2011-07-06 | 法莫赛特股份有限公司 | Nucleoside cyclicphosphates |
| CN102725302A (en) * | 2009-11-16 | 2012-10-10 | 乔治亚大学研究基金公司 | 2'-fluoro-6'-methylene carbocyclic nucleosides and methods of treating viral infections |
| TW201242974A (en) * | 2010-11-30 | 2012-11-01 | Gilead Pharmasset Llc | Compounds |
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