CN101089004A - New type of phosphonate-nucleotide compound - Google Patents
New type of phosphonate-nucleotide compound Download PDFInfo
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- CN101089004A CN101089004A CN 200610027642 CN200610027642A CN101089004A CN 101089004 A CN101089004 A CN 101089004A CN 200610027642 CN200610027642 CN 200610027642 CN 200610027642 A CN200610027642 A CN 200610027642A CN 101089004 A CN101089004 A CN 101089004A
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Abstract
The present invention relates to chemical technology, and is especially one kind of phosphonate-nucleotide compounds in the structure as shown, and their salts, hydrates and solvates. These compounds and their salts, hydrates and solvates have broad spectrum and high antiviral activity, effect of treating HBV infection with lamivudine resistance, high safety, and high orally taken absorption rate, and may be used as antiviral medicine for treating hepatitis B, herpes and other diseases and as antitumor medicine.
Description
Described field
The present invention relates to chemical field, especially a kind of novel phosphonate-nucleotide compound particularly has phosphonate-nucleotide compound, its esters, hydrate or its solvate antiviral activity, that be used as medicine, and their pharmaceutical composition.
Background technology
At present, it is that one of human health threatens greatly that HBV infects, and with serious hepatic diseases necessary relation is arranged, and comprises liver cirrhosis and hepatocellular carcinoma.The whole world has 2,000,000,000 populations of surpassing to infect HBV, accounts for 1/3 of world's total population.Wherein, 300,000,000 5 thousand ten thousand people are slow virus carrier, and 1/4 the people of having an appointment dies from HBV and infects.For this reason, invent and a kind ofly have stronger antiviral activity and, be used for the treatment of HBV and infect and other disease, will make huge contribution for human beings'health to the medicine of Normocellular growth unrestraint effect.Infect though lamivudine (3TC) can be used to treat HBV, it has resistance and low seroconversion rate.And 9-(2-phosphono methoxyl group) ethyl adenine PMEA, 9-(2-phosphono methoxyl group) propyl group VITAMIN B4 PMPA, 9-(2-phosphono methoxyl group) ethyl-2, phosphonate-nucleotide compounds such as 6-diaminopurine PMDAP, because oral can not the absorption, for the performance drug effect reaches necessary Plasma Concentration, can only use non-oral administration modes such as vein and intramuscular injection.This patient for non-inpatient or need long-term treatment is difficult.
Goal of the invention
The objective of the invention is provides a kind of new phosphonate-nucleotide compound for overcoming the problems referred to above, and they have high antiviral activity, particularly the HBV to the lamivudine opposing infects effectively, they have good security to body, simultaneously, have very high oral absorption again.
Summary of the invention
Technical scheme provided by the present invention is: novel cpd comprises the phosphonate-nucleotide compound shown in the following general formula (I), its esters, hydrate or its solvate and contains the pharmaceutical composition of this compounds that they can be used as antiviral.
In the general formula (I): R1, R2 are respectively H or alkyl, described alkyl be C1--C6 alkyl promptly: methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl etc.; X1 can be O, S etc., X2 can be O, NH, S etc.When R2 was alkyl, the carbon atom C2 that links to each other with R2 can be left-handed structure, or the dextrorotation structure, also can be the racemization structure.The carbon atom C1 that links to each other with COOR1 can be left-handed structure, or the dextrorotation structure, also can be the racemization structure.Also can there be isomers on the P atom.
Phosphate nucleotide compound ' shown in the above-mentioned general formula (I) can form pharmaceutical salts.For example when acidic-group existed, this salt can be metal-salts such as lithium salts, sodium salt, sylvite, magnesium salts, calcium salt, amine salt such as ammonium salt, methylamine salt, dimethylamine salt, front three amine salt, dicyclohexyl amine salt; When basic group exists, can form inorganic acid salts such as hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, or form as organic acid salts such as mesylate, benzene sulfonate, tosilate, acetate, propionic salt, tartrate, fumarate, maleate, malate, oxalate, succinate, Citrate trianion, benzoate, mandelate, cinnamate, lactic acid salts.
Phosphate nucleotide compound ' shown in the above-mentioned general formula (I) or its salt can exist with hydrate or solvate form thereof, and the solvent that forms solvate for example has methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, methylene dichloride etc.
Product of the present invention has wide spectrum, high antiviral activity, as anti-hepatitis B virus HBV, immunodeficiency virus (human immunodeficiency virus HIV, simian immunodeficiency virus SIV, feline immunodeficiency virus FIV etc.), simplexvirus (hsv, varicella zoster virus, cytomegalovirus etc.), Lao Sheershi murine leukemia virus (R-MuLV), mouse cytomegalovirus (MCMV), poxvirus, adenovirus etc.Particularly the HBV to the lamivudine opposing infects effectively, and they have good security to body, simultaneously, have very high oral absorption again.They can be used as the antiviral of diseases such as treatment hepatitis B, human immune deficiency syndromes, bleb, also can be used as antitumor drug.
The synthetic method of the phosphate nucleotide compound ' of above-mentioned general formula (I) can be synthesized by following synthetic route of the present invention:
The source of the compound of general formula (II), (III), (VI) is unqualified, and they can be used as reagent and have bought, or synthesizes by known method.
The method of the compound of synthetic general formula (IV) is: general formula (II) and compound (III) in inert organic solvents, in the presence of basic catalyst, by the method that the adding condensing agent is sloughed a part water, are obtained the compound of general formula (IV).Effectively condensing agent can be selected triphen phosphorus-many methyl halides for use, triphen phosphorus-disulphide, phosphorous acid ester-pyridine-halogen, phosphorous acid ester-pyridine-mercury salt, dichloro oxidation Phenylphosphine, O, O-diethyl phosphinylidyne cyanogen, the diphenylphosphine acylazide, silicon tetrachloride, titanium tetrachloride, triethyl borate, boron trifluoride-ether, the two inferior acid amides (DCC) of dicyclohexyl carbon, N, the two imidazoles of N '-carbonyl, iodate-1-methyl-2-halogen pyridinium salt etc., organic solvent can be selected dimethyl sulfoxide (DMSO) for use, pyridine, acetonitrile, ether, dimethyl formamide, tetrahydrofuran (THF), 1-Methyl-2-Pyrrolidone, methylene dichloride, chloroform, benzene, toluene, dimethylbenzene etc., basic catalyst can be selected yellow soda ash for use, salt of wormwood, cesium carbonate, sodium hydride, potassium hydride KH, triethylamine, the diazabicyclo undecylene, N, N-dichloro hexyl-4-morpholine carboxylic acid etc.Temperature of reaction can be 20-200 ℃, preferred 50-150 ℃.Reaction times can be 0.5-72 hour, preferred 6-48 hour.Compound (II) and mol ratio (III) can be 0.5-3, preferred 1-2.The compound of the general formula that obtains (IV) can carry out separation and purification by separation and purification means commonly used such as extraction, precipitation, distillation, crystallization, chromatography etc. in case of necessity.Perhaps be directly used in next step reaction.
The method of the compound of synthetic logical formula V is: the compound and the acyl chloride reaction reagent react of general formula (IV) are formed the acyl chlorides that leads to formula V.Reaction can be carried out in the presence of inert solvent, does not perhaps add the direct chloride of inert solvent.Acyl chloride reaction reagent can be phosphorus trichloride, phosphorus pentachloride, sulfur oxychloride etc., as add inert solvent, can be dimethyl sulfoxide (DMSO), pyridine, acetonitrile, ether, dimethyl formamide, tetrahydrofuran (THF), 1-Methyl-2-Pyrrolidone, methylene dichloride, chloroform, benzene,toluene,xylene etc.Temperature of reaction can be 20-200 ℃, preferred 50-150 ℃.Reaction times can be 5min-24 hour, preferred 10min-12 hour.The compound of the logical formula V that obtains can carry out separation and purification by separation and purification means commonly used such as extraction, precipitation, distillation, crystallization, chromatography etc. in case of necessity.Perhaps be directly used in next step reaction.
The method of the compound of synthetic general formula (I) is: will lead to formula V and compound (VI) in inert organic solvents, and react in the presence of basic catalyst, and obtain the phosphate nucleotide compound ' of general formula of the present invention (I).Organic solvent can be selected dimethyl sulfoxide (DMSO), pyridine, acetonitrile, ether, dimethyl formamide, tetrahydrofuran (THF), 1-Methyl-2-Pyrrolidone, methylene dichloride, chloroform, benzene,toluene,xylene etc. for use, basic catalyst can be selected yellow soda ash, salt of wormwood, cesium carbonate, sodium hydride, potassium hydride KH, triethylamine, Trimethylamine 99, quinoline, pyridine, diazabicyclo undecylene, N for use, N-dichloro hexyl-4-morpholine carboxylic acid etc.Temperature of reaction can be-100-100 ℃, and preferred-50-50 ℃.Reaction times can be 0.5-24 hour, preferred 1-12 hour.Compound (V) and mol ratio (VI) can be 0.5-4, preferred 1-3.The phosphate nucleotide compound ' of the general formula that obtains at last (I) can obtain the phosphate nucleotide compound ' of the general formula (I) of purity＞90% at last by further separation and purification such as separation and purification means commonly used such as extraction, precipitation, distillation, crystallization, chromatographies.
The phosphate nucleotide compound ' of general formula of the present invention (I) can be used as antiviral, also can be used as antitumor drug.Virus Type as target spot does not have special qualification, and the specific examples of processed virus comprises hepatitis b virus hbv, hepatitis C virus, immunodeficiency virus (human immunodeficiency virus HIV, simian immunodeficiency virus SIV, feline immunodeficiency virus FIV etc.), simplexvirus (hsv, varicella zoster virus, cytomegalovirus etc.), Lao Sheershi murine leukemia virus (R-MuLV), mouse cytomegalovirus (MCMV), poxvirus, adenovirus etc.Preferably to human immunodeficiency virus HIV, hepatitis b virus hbv.
The compound and the salt thereof of general formula of the present invention (I) can use separately as pharmaceuticals, also can form pharmaceutical composition with other compound by antiviral activity, synergistic agent and other pharmaceutical carrier and use.They can be the various formulations that contain these compounds, as tablet, granule, micro mist agent, powder, dragee, emulsion, gelifying agent, paste, solution, sol, macromolecular solution agent, suspensoid, injection, capsule, pill, micropill, syrup, film, suppository, aerosol, sprays, drops, liposome, microballoon, preparation capable of permeating skin etc., also can be sustained-release preparation, targeting preparation etc.The available various administering mode administration of fitting is as oral, suction, injection, transdermal, cavity and mucosa delivery etc.
Pharmaceutical carrier is used for per os, through intestines, non-during, available various suitable organic or inorganic solid or liquid vehicles through intestines or local application.The used solid carrier of preparation solid dosage for example has lactose, sucrose, starch, talcum powder, Mierocrystalline cellulose, dextrin, kaolin, lime carbonate, agar, pectin, stearic acid, Magnesium Stearate, Yelkin TTS, sodium-chlor etc.The used liquid vehicle of liquid dosage form for oral use for example has glycerine, peanut oil, polyvinylpyrrolidone, sweet oil, ethanol, phenylcarbinol, propylene glycol, physiological saline, water etc., preparation during preparation except that above-mentioned carrier, also can add auxiliary material, for example wetting agent, suspension agent, sweetener, spices, pigment or sanitas.And liquid dosage form is when placing in the capsule, and capsule will be with adsorbable material as making with gelatin.Solvent that para-oral injection is used or suspension agent can be used for example water, propylene glycol, polyoxyethylene glycol, phenylcarbinol, ethyl oleate, Yelkin TTS etc.Above-mentioned various preparation can prepare according to a conventional method.
In various pharmaceutical dosage forms, oral administration is because medication is simple, thereby application is the most general, and kind and quantity account for first of the various formulations.Because compound of the present invention has very high oral absorption, so just meeting the requirement of oral administration.
Clinical consumption, becoming the human oral The compounds of this invention generally is 1-500mg every day, is preferably 5-100mg, according to age, the state of an illness, symptom, the whether suitably increase and decrease with other medicine is simultaneously taken 1 time or be divided into 2 times or repeatedly perhaps interval medication every day.
Below the present invention is specifically described with the embodiment form, but the present invention is not limited to following embodiment.
Embodiment of the present invention
Embodiment 1: o.1 synthetic of compound N
The structural formula of No.1 compound is as shown below, and wherein carbon atom C1 is left-handed structure:
In reactor, add 9-(2-phosphono methoxyethyl) VITAMIN B4 (PMEA) 10g, phenol 7g, triethylamine 5g and tetrahydrofuran (THF) 30g, reflux.Add N then, the two imidazoles 15g of N '-carbonyl.Continued back flow reaction 24 hours.Reaction solution is cooled to 25 ℃.Under reduced pressure reaction solution is condensed into filemot soup compound, adds water 18g then, and to regulate pH value with 25% NaOH solution be 11.Suspended solids is removed by the 1.5g diatomite filtration, then uses the 3g water wash.Mix filtrate and use ethyl acetate extraction.Water is adjusted to PH3.1 with 37% HCl solution, and 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 precipitation is filtered separation, and washs with methyl alcohol 10g.Product is pulp in 40g methyl alcohol, is filtered separation then, uses the 6g methanol wash again, and drying under reduced pressure obtains 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 (7.2g, productive rate 56%, the purity: 99%) of white solid.Mass spectrum M
+ H=350, fusing point: 215-217 ℃.
In reactor, add 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 7.2g, DMF30g.Keep adding thionyl chloride 6g under mixture temperature＜50 ℃.With mixture heating up, back flow reaction 2 hours.Volatile matter 12g is collected in distillation under normal pressure.Resistates is cooled to 25 ℃, with the dilution of 40g methylene dichloride, and is chilled to-10 ℃.Methylene dichloride (35g) solution that adds L-ethyl lactate 7g then.Then add triethylamine 8g down at-10-0 ℃.Reaction mixture is heated to room temperature and with the dihydrogen phosphoric acid sodium solution of 10% concentration washing three times, consumption 20g at every turn.Organic solution 20g anhydrous sodium sulfate drying, filtration, and use the 30g eluent methylene chloride, under reduced pressure be condensed into-oily matter.20g acetone is added in the oily matter.Acetone soln is carried out separation and purification by column chromatography (230 to 400 silica gel 60).Chromatography column carries out wash-out with 500g acetone.Product behind the purifying under reduced pressure is condensed into oily.Add acetonitrile 20g in oily matter, mixture under reduced pressure concentrates.Add the 70g acetonitrile again, solution is cooled to 0-5 ℃ of 20h.Solid is filtered to be removed.Filtrate under reduced pressure concentrates and obtains light yellow solid (2.8g, productive rate 30%).
The light yellow solid (2.8g) that obtains above in reactor, adding, fumaric acid (0.64g), and acetonitrile (55g).Mixture heating up refluxes, and makes the solid dissolving, and heat filtering is chilled to 5 degree, 16 hours, and product is filtered separation, with the drip washing of 20g acetonitrile, drying, the fumarate solid of 2.9g (productive rate 84%, purity 98.8%) white powder No.1 compound.Mass spectrum M
+ H=450, fusing point: 139-141 ℃, specific optical rotation: solubleness: solubleness is 0.03g/ml in the ethanol, and solubleness is 0.1g/ml in the methyl alcohol, and solubleness is 0.01g/ml in the water.
Embodiment 2: o.2 synthetic of compound N
The structural formula of No.2 compound is as shown below, and wherein carbon atom C1 is left-handed structure:
According to the same method of embodiment 1, in reactor, add 9-(2-phosphono methoxyethyl) VITAMIN B4 (PMEA) 10g, phenol 7g, triethylamine 5g and tetrahydrofuran (THF) 30g, reflux.Add N then, the two imidazoles 15g of N '-carbonyl.Continued back flow reaction 24 hours.Reaction solution is cooled to 25 ℃.Under reduced pressure reaction solution is condensed into filemot soup compound, adds water 18g then, and to regulate pH value with 25% NaOH solution be 11.Suspended solids is removed by the 1.5g diatomite filtration, then uses the 3g water wash.Mix filtrate and use ethyl acetate extraction.Water is adjusted to PH3.1 with 37% HCl solution, and 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 precipitation is filtered separation, and washs with methyl alcohol 10g.Product is pulp in 40g methyl alcohol, is filtered separation then, uses the 6g methanol wash again, and drying under reduced pressure obtains 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 (7.2g, productive rate 56%, the purity: 99%) of white solid.Mass spectrum M
+ H=350, fusing point: 215-217 ℃.
In reactor, add 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 7.2g, DMF30g.Keep adding thionyl chloride 6g under mixture temperature＜50 ℃.With mixture heating up, back flow reaction 2 hours.Volatile matter 12g is collected in distillation under normal pressure.Resistates is cooled to 25 ℃, with the dilution of 40g methylene dichloride, and is chilled to-10 ℃.Methylene dichloride (35g) solution that adds L-isopropyl lactate 7.8g then.Then add triethylamine 8g down at-10-0 ℃.Reaction mixture is heated to room temperature and with the dihydrogen phosphoric acid sodium solution of 10% concentration washing three times, consumption 20g at every turn.Organic solution 20g anhydrous sodium sulfate drying, filtration, and use the 30g eluent methylene chloride, under reduced pressure be condensed into an oily matter.20g acetone is added in the oily matter.Acetone soln is carried out separation and purification by column chromatography (230 to 400 silica gel 60).Chromatography column carries out wash-out with 500g acetone.Product behind the purifying under reduced pressure is condensed into oily.Add acetonitrile 20g in oily matter, mixture under reduced pressure concentrates.Add the 70g acetonitrile again, solution is cooled to 0-5 ℃ of 20h.Solid is filtered to be removed.Filtrate under reduced pressure concentrates and obtains light yellow solid (2.9g, productive rate 30%).
The light yellow solid (2.9g) that obtains above in reactor, adding, fumaric acid (0.64g), and acetonitrile (55g).Mixture heating up refluxes, and makes the solid dissolving, and heat filtering is chilled to 5 degree, 16 hours, and product is filtered separation, with the drip washing of 20g acetonitrile, drying, the fumarate solid of 3.0g (productive rate 84%, purity 99.8%) white powder No.1 compound.Mass spectrum M
+ H=464, fusing point: 140-142 ℃, specific optical rotation: solubleness: solubleness is 0.03g/ml in the ethanol, and solubleness is 0.1g/ml in the methyl alcohol, and solubleness is 0.01g/ml in the water.
Effect of the present invention
Test example 1: compound N o.1, the research of the external anti-hepatitis B virus activity of No.2
With HepG 2.2.15 cell is the hepatitis B poisonous carrier, measures compound and suppresses the ability that hepatitis B virus carries out dna replication dna.
Testing method: HepG 2.2.15 cell kind 96 well culture plates, add sample and positive control drug respectively by above extent of dilution after 36 hours, establish cell control well simultaneously, change the nutrient solution that contains different weaker concn samples after the dosing after 96 hours respectively, the 8th day respectively collecting cell supernatant and 2.2.15 cell after dosing, adopt the method for dot blot to detect HBV dna replication dna degree in the cell, calculate IC respectively
50And SI.
| Compound | TC 50(μg/ml) | The HBV dna replication dna | |
| IC 50 (μg/ml) | SI | ||
| No.1 | 13.87 | 1.49 | 9.31 |
| No.1 | 20 | 1.002 | 19.96 |
Annotate: TC
50The poisonous concentration of pair cell half; IC
50To viral half-inhibition concentration; SI: selectivity index, SI=TC
50/ IC
50
Experiment conclusion: o.2 compound N has restraining effect to the HBV dna replication dna of HepG 2.2.15 cell.The test example 2: compound N o.1, the anti-hepatitis B virus animal experiment study of No.2
Adopt Chongqing sheldrake hepatitis B animal model, observe anti-duck hepatitis B virus (duck hepatitis B virus, effect DHBV) in No.1 and the No.2 body.The No.1 and the No.2 (10mg.Kg of three kinds of dosage adopted in test respectively
-1.D
-1, 25mg.Kg
-1.D
-1, 50mg.Kg
-1.D
-1) oral cavity irritate to feed 28 days, drug withdrawal was observed 7 days, detected DHBV DNA in the forward and backward serum of medication and the change situation of DHBsAg.The visible No.1 small dose group of result medication to 28 day relatively has remarkable reduction (P＜0.01) before DNA titre and the medication; Among the No.1, the medication of heavy dose of group begins to have serum DHBV DNA titre and significantly reduces (P＜0.05 or P＜0.01) after 7 days, though DHBV DNA titre rise trend is arranged after the drug withdrawal, and relatively still have remarkable reduction before the medication.All there is serum DHBV DNA titre extremely significantly to reduce (P＜0.01) during each dosage group medication of No.2.In addition, all there is serum DHBsAgO.D value significantly to reduce (P＜0.05 or P＜0.01) after each dosage group medication of No.1, to the drug withdrawal 7 days, relatively still has reduction (P＜0.01) extremely significantly before serum DHBsAgO.D value and the medication.No.2 small dose group medication 28 days, in, the medication of heavy dose of group began to occur the significantly reduction (P＜0.05 or P＜0.01) of serum DHBsAg O.D value in 7 days, after drug withdrawal 7 days, relatively still have before serum DHBsAgO.D value and the medication and reduce (P＜0.01) extremely significantly.Therefore, test-results shows that No.1 and No.2 have the effect that suppresses duck hepatitis B virus in the duck body.
Test example 3: compound N studies on acute toxicity o.2
Experimental basis: " the chemicals acute toxicity test technical director principle " of state food and drug administration issue in 2005 on March 18.
The experiment grouping:
| Route of administration | Grouping (mg/kg) | Measurement result | Mean body weight increases (g) | |
| Male | Female | |||
| Intravenous injection | 50 | O.2, there is no compound N exists overt toxicity anti- | 77 | 47.8 |
| 125 | 91.8 | 55.2 | ||
| 250 | Should, do not see the rats death that o.2 causes by compound N yet. | 88.4 | 65.2 | |
| 375 | 119.0 | 50.2 | ||
| Irritate stomach | 200 | There is no compound N and o.2 have the overt toxicity reaction, also do not see the rats death that o.2 causes by compound N. | 123.4 | 37.4 |
| 500 | 120.6 | 37.6 | ||
| 1000 | 136.2 | 27.6 | ||
| 2000 | 130.0 | 16.8 |
Experimental result:
1, to 40 cleaning level SD rat (male and female half and half, body weight 200-250g) divide four groups, intravenous injection 50-375mg/kg compound N o.2 after, observed continuously 14 days, do not see that o.2 compound N exists the overt toxicity reaction, does not see the rats death that is o.2 caused by compound N yet.
2, to 40 cleaning level SD rat (male and female half and half, body weight 200-250g) divide four groups, gastric infusion 200-2000mg/kg compound N o.2 after, observed continuously 14 days, do not see that o.2 compound N exists the overt toxicity reaction, does not see the rats death that is o.2 drawn Wei by compound N yet.
In a word, o.2 compound N has lower toxicity.
Phosphonate-nucleotide compound of the present invention has good antiviral activity and lower toxicity, and oral absorption is good, and it will become effective medicine.
Claims (7)
1, a kind of novel phosphonate-nucleotide compound is characterized in that their structural formula is:
In the formula: R1, R2 are respectively H or alkyl, described alkyl be C1--C6 alkyl promptly: methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl; X1 can be O, S etc., X2 can be O, NH, S.
2, a kind of novel phosphonate-nucleotide compound according to claim 1 is characterized in that: when R2 was alkyl, the carbon atom C2 that links to each other with R2 can be left-handed structure or dextrorotation structure or racemization structure.
3, a kind of novel phosphonate-nucleotide compound according to claim 1 is characterized in that: with COOR
1The carbon atom C that links to each other
1, can be left-handed structure or dextrorotation structure or racemization structure.
4, a kind of novel phosphonate-nucleotide compound according to claim 1 is characterized in that: it can be independent a kind of isomer or the mixture of isomers that exists on the P atom of isomer.
5, a kind of novel phosphonate-nucleotide compound according to claim 1, the salt that it is characterized in that this compound is: metal-salts such as lithium salts, sodium salt, sylvite, magnesium salts, calcium salt, various inorganic acid salts such as amine salt, hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt such as ammonium salt, methylamine salt, dimethylamine salt, front three amine salt, dicyclohexyl amine salt; Or various organic acid salts such as mesylate, benzene sulfonate, tosilate, acetate, propionic salt, tartrate, fumarate, maleate, malate, oxalate, succinate, Citrate trianion, benzoate, mandelate, cinnamate, lactic acid salt.
6, according to claim 1 and 5 described a kind of novel phosphonate-nucleotide compounds, it is characterized in that this compound and its salt can have compound, synergistic agent and other pharmaceutical carrier etc. of antiviral activity to mix separately or with other, make tablet, granule, micro mist agent, powder, dragee, emulsion, gelifying agent, paste, suspension agent, injection, capsule, syrup, film, sprays, liposome, microballoon, preparation capable of permeating skin, also can be made into sustained-release preparation, targeting preparation etc.
7, according to claim 1 and 5 described a kind of novel phosphonate-nucleotide compound and salt thereof, can hydrate or solvate form thereof exist, form the solvent methanol of solvate, ethanol, Virahol, acetone, ethyl acetate, methylene dichloride etc.
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| US11572377B2 (en) | 2015-09-15 | 2023-02-07 | The Regents Of The University Of California | Nucleotide analogs |
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