CN107849075A - A kind of phosphoramidate prodrug of nucleoside analog and its application - Google Patents
A kind of phosphoramidate prodrug of nucleoside analog and its application Download PDFInfo
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- CN107849075A CN107849075A CN201680042114.XA CN201680042114A CN107849075A CN 107849075 A CN107849075 A CN 107849075A CN 201680042114 A CN201680042114 A CN 201680042114A CN 107849075 A CN107849075 A CN 107849075A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/664—Amides of phosphorus acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Abstract
The invention provides phosphate prodrugs of nucleoside analog shown in a kind of formula IV and preparation method thereof, and the purposes in prevention and/or treatment virus infection, the particularly medicine of hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection is prepared.
Description
The present invention relates to pharmaceutical fields and organic chemistry filed, more particularly to a kind of phosphate prodrugs and preparation method thereof of nucleoside analog, and the purposes in the drug of preparation prevention and/or treatment virus infection, especially hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
Nucleosides is the structural unit of nucleic acid, and the reservation, duplication and transcription of gene information are taken part in biosynthesis.And antiviral nucleoside analogue drug, the synthesis of the raw materials such as pyrimidine, purine and its nucleotide needed for its mechanism of action is substantially DNA synthesis or DNA synthesis by viral interference, to by enzyme needed for the metabolic pathway for inhibiting survival and the duplication of virocyte, and inhibition virocyte nucleic acid or generate drug action using nucleic acid as target spot.
The metabolic pathway of nucleoside analogue drugs is substantially similar, by in transporte to cells after the transfer factor identification of cell membrane, then triphosphoric acid active matter is turned to by kinase phosphorylation, mono-phosphorylated during this is speed limit, the nucleoside analogue drugs of some phosphorous acid groups can skip this mono-phosphorylated step, so that the therapeutic index of drug can be improved.But phosphate group is under physiological ph conditions, is pairs of anion, is difficult through cell membrane, oral administration biaavailability is not high, so that the drug concentration for reaching therapy target is very low, curative effect is undesirable.
Phosphate group can be esterified to form the prodrug forms of di-phosphate ester to increase the fat-soluble of the nucleoside analogue drugs of phosphorous acid groups, and then improve its permeable membrane by the characteristics of according to phosphate group, improve the bioavilability of drug.The nucleoside analog prodrug of this method exploitation has multiple successfully listings or enters III phase clinic, such as Aldoforwe ester (the adefovir dipivoxil listed, compound shown in Formulas I) and tenofovir dipivoxil (tenofovir disoproxil, compound shown in Formula II), it is currently in III phase clinic times Si Fuwei (besifovir, compound shown in formula III) etc..But after such prodrug absorbed into serum, phosphodiester group metabolism therein is very fast, is easily converted to phosphate group, limits its drug concentration that treatment target cell is further reached from blood circulation；In addition, these prodrugs are also generated to the harmful formaldehyde of body in the metabolic process.
The antiviral activity of compound times Si Fuwei (besifovir) shown in above-mentioned formula III is strong, effect and Entecavir quite and
It is not easy drug resistance, and has significant effect to the patient of lamivudine resistance, therefore Si Fuwei is expected to antiviral (the especially Anti-HBV activity and/or inhibition of HIV) drug as a new generation again.But the drug, in addition to the deficiency intrinsic there are di(2-ethylhexyl)phosphate ester prodrug, there is also the side effects of L-carnitine in consumption body.Therefore, it is necessary to develop the new prodrug of times Si Fuwei, to further enhance its antiviral activity on the basis of keeping it from the advantages such as easy drug resistance, its side effect is reduced.
Physical and chemical properties of drugs or internal pharmacokinetic property can be improved by reasonable prodrug design, improve oral administration biaavailability, this is known in those skilled in the art.Although theoretically the prodrug assumed can be rationally designed according to the chemical functional group in molecule, but what is generated after chemical modification mother's medicine is completely new molecular entity, which may show and the harmful physical chemistry or bioactive properties that are not present in parent compound.While it is contemplated that prodrug candidate compound seems simple, but due to the complexity of human body and drug interaction, it is complicated multidisciplinary task that identifying, which has physicochemical property appropriate and pharmacokinetic property, conversion and safety in vivo, and the prodrug actually obtained often through " rational design ", it often differs greatly with expected result, or even obtains physicochemical property or mother's biological activity ratio medicine is worse " prodrug ".If developing not only improves physical and chemical properties of drugs or internal pharmacokinetic property, but also can also enhance drug effect or reduce the new prodrug of side effect, then the unpredictability in development process will more greatly increase.
The present invention is in the research process of Si Fuweixin prodrug again, surprisingly have found the new structural fragrant oxygroup phosphoamide class prodrug of one kind of times Si Fuwei (containing an aromatic ester groups and a phosphinylidyne amido in its structure), the shortcomings that new prodrug of times Si Fuwei overcomes di-phosphate ester in times Si Fuwei, a times side effect for Si Fuwei consumption L-carnitine is also eliminated, while further enhancing its antiviral activity.
Summary of the invention
The present invention one is designed to provide a kind of new nucleoside analog.
Another object of the present invention is to provide the preparation methods of the novel nucleoside analogs.
Another object of the present invention is to provide the pharmaceutical composition comprising the novel nucleoside analogs.
Another object of the present invention is to provide application of the novel nucleoside analogs in the drug of preparation prevention and/or treatment virus infection.
Purpose according to the present invention, the present invention provides compound shown in a kind of formula IV or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate,
Wherein:
R1For hydrogen, C1-6Alkyl or substituted or non-substituted C6-10Aryl, 6 to 10 unit's heteroaryls or benzyl；
R2, R3Respectively C1-6Alkyl or R2、R3C is formed with connected carbon atom3-7Naphthenic base；
R4For substituted or non-substituted C6-10Aryl or 6 to 10 unit's heteroaryls.
Some specific embodiments according to the present invention, wherein " C1-6Alkyl " refers to the linear chain or branched chain saturated fat hydrocarbyl group of 1 to 6 carbon atom, selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, tertiary pentyl, 2- methyl butyl, 3- methyl butyl, 1- ethyl propyl, 4- methyl amyl, 3- methyl amyl, 2- methyl amyl, 1- methyl amyl, 3, 3- dimethylbutyl, 2, 2- dimethylbutyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2, 3- dimethylbutyl, 2- ethyl-butyl, n-hexyl, isohesyl etc., wherein preferred methyl, ethyl, isopropyl or tert-butyl.
Some specific embodiments according to the present invention, wherein " C6-10Aryl " refers to 6 to 10 yuan of full carbon monocycles or fused polycycle group with conjugated pi electron system, selected from phenyl, 1- naphthalene, 2- naphthalene etc..
Some specific embodiments according to the present invention, wherein, " 6 to 10 unit's heteroaryl " refers to oxygen-containing in 6 to 10 yuan of ring, the miscellaneous monocycle with conjugated pi electron system of sulphur or nitrogen heteroatom or miscellaneous fused polycycle group, selected from pyridine -2- base, pyridin-3-yl, pyridin-4-yl, pyridazine -3- base, pyridazine -4- base, pyrimidine -2-base, pyrimidine-4-yl, pyrimidine -5- base, pyrazine -2- base, pyrazine -3- base, indyl, isoindolyl, indazolyl, indolizine base, purine radicals, quinazinyl, quinolyl, isoquinolyl, cinnoline base, phthalazinyl, naphthyridines base, quinazolyl, quinoxalinyl, thieno [2, 3-b] furyl, furans simultaneously [3, 2-b]-pyranose, pyrido [2, 3-d] oxazines base, pyrazolo [4, 3-d] oxazolyl, miaow Azoles simultaneously [4, 5-d] thiazolyl, pyrazine simultaneously [2, 3-d] pyridazinyl, imidazo [2, 1-b] thiazolyl, imidazo [1, 2-b] [1, 2, 4] triazine radical, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzo dislikes heptan because of base, benzoxazinyl-, benzofuranyl, benzotriazole base, pyrrolo- [2, 3-b] pyridyl group, pyrrolo- [3, 2-c] pyridyl group, pyrrolo- [3, 2-b] pyridyl group, imidazo [4, 5-b] pyridyl group, imidazo [4, 5-c] pyridyl group, pyrazolo [4, 3-d] pyridyl group, pyrazolo [4, 3-c] pyridyl group, pyrazolo [3, 4-c] pyridyl group, pyrazolo [3, 4-d] pyridyl group, pyrazolo [3, 4-b] pyridyl group, imidazo [1 , 2-a] pyridyl group, pyrazolo [1, 5-a] pyridyl group, pyrrolo- [1, 2-b] pyridazinyl, imidazo [1, 2-c] pyrimidine radicals, pyrido [3, 2-d] pyrimidine radicals, pyrido [4, 3-d] pyrimidine radicals, pyrido [3, 4-d] pyrimidine radicals, pyrido [2, 3-d] pyrimidine radicals, pyrido [2, 3-b] pyrazinyl, pyrido [3, 4-b] pyrazinyl, pyrimido [5, 4-d] pyrimidine radicals, pyrazolo [2, 3-b] pyrazinyl, pyrimido [4, 5-d] pyrimidine radicals etc., wherein preferred pyridine -2- base, pyridin-3-yl, pyridin-4-yl, pyrimidine -2-base, pyrimidine-4-yl or pyrimidine -5- base.
Some specific embodiments according to the present invention, wherein, " substituent group " of the aryl, heteroaryl or benzyl is selected from alkyl (such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl), alkenyl (such as vinyl, acrylic), alkynyl (such as acetenyl, propinyl), hydroxyl, alkoxy (such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, tert-butoxy), acyloxy (such as formyloxy, acetoxyl group, propionyloxy, butyryl acyloxy, isopropyl
Carbonyl oxygroup, tert-butyl carbonyl oxygroup etc.), sulfydryl, alkylthio group (such as methyl mercapto, ethylmercapto group, positive rosickyite base, isopropyisulfanyl, tertiary butylthio etc.), amino, alkylamino (such as methylamino, ethylamino, dimethylamino, lignocaine, n-propylamine base, isopropylamino, tertiary fourth amino etc.), acylamino- (such as formamido group, acetylamino, propionamido, butyrylamino, i propylcarbonylamino, t-butylcarbonylamino etc.), halogen (such as fluorine, chlorine, bromine, iodine), cyano, nitro, acyl group (such as formoxyl, acetyl group, carboxyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, tertbutyloxycarbonyl, amino carbonyl, N, N- Dimethylaminocarbonyl etc.) etc., wherein preferred methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, acetoxyl group, amino, dimethylamino, acetylamino, fluorine, chlorine, cyano, Acetyl group, methoxycarbonyl group, carbethoxyl group, amino carbonyl or N, N- Dimethylaminocarbonyl.
Some specific embodiments according to the present invention, wherein " C3-7Naphthenic base " refers to the group of the aliphatic hydrocarbon containing saturated cyclic of 3 to 7 carbon atoms, selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, 2- methylcyclopropyl groups, 2- ethyl cyclopropyl, 2- propylcyclopropyl, 2- isopropyl cyclopropyl, 2- butyl cyclopropyl, 2- isobutyl cyclopropyl, 2- tert-butyl cyclopropyl, 2- methyl-cyclobutyl, 3- methyl-cyclobutyl, 2- ethylcyclobutyl, 3- ethylcyclobutyl, 2- propylcyclobutyl, 3- propylcyclobutyl, 2- isopropyl tetramethylcyclobutyl, 3- isopropyl tetramethylcyclobutyl, 2- methylcyclopentyl, 3- methylcyclopentyl, 4- methylcyclopentyl, 2- ethylcyclopentyl, 3- ethylcyclopentyl, 2- methylcyclohexyl, 3- methylcyclohexyl, 4- methylcyclohexyl, 2, 3- Dimethvlcvclopropvl, 2- methyl -3- ethyl Cyclopropyl, 2,3- diethyl cyclopropyl, 2,3- dimethylcyclobutyl, 2- methyl -3- ethylcyclobutyl, 3- methyl -2- ethylcyclobutyl, 2,3,4- front three tetramethylcyclobutyls, 2,3- dimethylcyclopentyl, 2,4- dimethylcyclopentane base etc., wherein it is preferred that cyclopropyl or cyclobutyl.
" isomers " includes the optical isomer with mapping or diastereomeric relationship, tautomer, cis-trans-isomer, conformer, mesomeric compound etc. or their mixture.In one embodiment, due in the Formulas I compound represented phosphorus atoms have chirality, configuration be selected from S type, R type or S type and R type mixture.
In one embodiment, compound shown in formula IV is selected from the isomers of the compound of flowering structure or these compounds, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate:
In another embodiment, compound shown in formula IV is selected from the isomers of the compound of flowering structure or these compounds, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate:
In another embodiment, compound shown in formula IV is selected from the isomers of the compound of flowering structure or these compounds, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate:
The definition of " salt " be it is well known to those skilled in the art of the present technique, refer to by cation and the compound that is formed by the effect of ionic bond of anion.
" eutectic " (Co-Crystals) refers to a kind of multicomponent crystal with fixed stoichiometric ratio, and each component is to be coexisted with molecular level by the effect combination of hydrogen bond or other non-covalent bonds, nonionic key in the crystal.In pharmaceutical co-crystals, active pharmaceutical ingredient and one or more eutectic forming bodies (Co-crystal former) are generally comprised.When individual pure eutectic forming body at room temperature with liquid in the presence of, which is also referred to as " solvate ", is referred to as " hydrate " when wherein solvent is water." eutectic " further includes the multicomponent crystal more in this way with fixed stoichiometric ratio, between these crystal pharmaceutical active ingredients and other components, a part is by hydrogen bond or other non-covalent bond effects, and another part is by ionic bond or between hydrogen bond in conjunction with the active force between ionic bond.
" salt " or " eutectic " further include the forms such as the solvate of salt or eutectic, hydrate.When salt or eutectic are prepared in certain solvent, pulp or crystallization when, which is likely to enter in salt or eutectic crystal, formed solvate；When the solvent is water, that is, it is likely to form hydrate.
The method for determining " eutectic " or " salt " is well known to those skilled in the art of the present technique, such as with Advances in crystal X-ray diffraction analysis.
" officinal salt " or " pharmaceutically acceptable eutectic " includes: the compounds of this invention and pharmaceutically acceptable inorganic acid, as hydrochloric acid,
Salt formed by sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid, nitric acid etc. or eutectic, or the compounds of this invention and pharmaceutically acceptable organic acid, the salt as formed by maleic acid, malic acid, fumaric acid, succinic acid, tartaric acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, p-methyl benzenesulfonic acid etc. or eutectic.
Purpose according to the present invention, this hair provide the preparation method of compound shown in formula IV or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate, this method comprises:
(1), compound shown in Formula V is reacted under the suitable conditions to obtain compound shown in Formula VII with compound shown in Formula IV,
Wherein R4It is defined as above；
(2), compound shown in Formula VII is reacted under the suitable conditions to obtain IV compound shown in formula with compound shown in Formula VIII,
Wherein R1、R2、R3And R4It is defined as above；
(3), optional, compound shown in formula IV is subjected to chiral resolution as needed, salt is made, eutectic is made, hydrate is made or solvate is made.
In the preparation method step (1), compound shown in the Formula V can be prepared by method disclosed in CN1487949A etc.；Compound shown in the Formula IV is generally commercially viable to be bought, it is also possible to which corresponding chloro thing, bromo-derivative are converted into hydroxylate with the conventional methods in the field.
In the preparation method step (1), the reaction is generally required to be carried out in the presence of condensing agent.
Some specific embodiments according to the present invention, wherein, the condensing agent of step (1) includes N, the carbodiimides such as N- dicyclohexyl carbodiimide (DCC), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimides (EDCI).Carbodiimides condensing agent need to generally be applied in combination with the reagents such as such as triethylamine, dimethylamino naphthyridine (DMAP), I-hydroxybenzotriazole (HOBT).
The molar ratio of compound shown in the condensing agent and Formula V of step (1) is generally 0.8:1~2:1.
In the preparation method step (1), the molar ratio of compound shown in compound shown in the Formula V and Formula IV is generally 1:1~1:3.
In the preparation method step (1), the solvent of the reaction is generally aprotic solvent, such as N-Methyl pyrrolidone, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide.
In the preparation method step (2), compound shown in the Formula VIII is generally commercially viable to be bought or by Arch.Pharm. (Weinheim) 314,44-51 (1980), Bioorganic&Medicinal Chemistry16 (17), 8054-8062 (2008), WO2006123145, WO2011089396, WO2009158393, WO the pertinent literatures such as 2007020193, WO2014033617 be made.
In the preparation method step (2), the reaction is generally required to be carried out in the presence of condensing agent.
Some specific embodiments according to the present invention, wherein the condensing agent of step (2) includes thionyl chloride (SOCl2), phosphorus oxychloride (POCl3), hexafluorophosphoric acid N- [(dimethylamino) -1H-1,2,3- triazol [4,5-b] pyridine -1- methylene]-N- methyl first amine n-oxide (HATU), hexafluorophosphoric acid N- [(1H- benzotriazole -1- base) (dimethylamino) methylene]-N- methyl first amine n-oxide (HBTU),-three (pyrrolidinyl) Phosphonium (PyBOP) of hexafluorophosphoric acid benzotriazole -1- base-N- oxygroup, wherein it is preferred that thionyl chloride (SOCl2) or phosphorus oxychloride (POCl3)。
The molar ratio of compound shown in the condensing agent and Formula VII of step (2) is generally 1:1~5:1.
In the preparation method step (2), the molar ratio of compound shown in compound shown in the Formula VII and Formula VIII is generally 1:1~1:5.
In the preparation method step (2), the solvent of the reaction is generally aprotic solvent, such as acetonitrile, methylene chloride, chloroform, tetrahydrofuran.
In the preparation method step (3), the chiral resolution can be carried out by chiral post separation, chiral acid selectivity at the conventional method in the art such as salt or eutectic segregation, by chiral resolution, compound shown in formula IV can be converted into compound shown in compound shown in its isomers formula IV 1 or formula IV 2.
Compound shown in Formula V described in the preparation method, compound shown in compound and Formula VIII shown in compound, Formula VII shown in Formula IV can be transformed by corresponding salt, eutectic, hydrate or solvate, the conversion can carry out before the reaction, it can also be carried out in reaction or post-processing, these method for transformation can be carried out with the conventional method of the art.
In the preparation method step (1), step (2) and step (3), isolating and purifying for product can be carried out by the conventional method of the art, such as according to reaction system situation, isolated or purifieds are carried out using one of the methods of concentration of reaction solution, pH adjusting, extraction, crystallization, column chromatography or a variety of pairs of products therefroms.
Purpose according to the present invention, the present invention provides compound shown in a kind of formula IV comprising therapeutically effective amount or its isomeries
The pharmaceutical composition of body, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate and pharmaceutic adjuvant.
In one embodiment, the pharmaceutical composition or preparation selected from formula a~formula l compound represented or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate and pharmaceutic adjuvant comprising therapeutically effective amount that the present invention provides a kind of.
In another embodiment, the pharmaceutical composition or preparation selected from formula a1~formula l1 compound represented or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate and pharmaceutic adjuvant comprising therapeutically effective amount that the present invention provides a kind of.
In one embodiment, the pharmaceutical composition or preparation selected from formula a2~formula l2 compound represented or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate and pharmaceutic adjuvant comprising therapeutically effective amount that the present invention provides a kind of.
Aforementioned pharmaceutical compositions or preparation can oral or not oral administrations.When oral administration, conventional preparation technique can be used, tablet, capsule, pill, granule, solution, syrup, suspension, powder, sustained release preparation or controlled release preparation etc. is made.When non-oral administration, conventional preparation technique can be used and be made into preparation capable of permeating skin, injection, infusion solution or suppository etc..
The various dosage forms of aforementioned pharmaceutical compositions can be prepared according to the conventional method of pharmaceutical field.Such as compound shown in the formula IV by therapeutically effective amount or selected from formula a~formula l compound represented or selected from formula a1~formula l1 compound represented or be selected from formula a2~formula l2 compound represented, or their isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate, optionally with the active constituent of one or more therapeutically effective amounts, it mixes or contacts with one or more pharmaceutic adjuvants, be then made into required dosage form.
Aforementioned pharmaceutical compositions or preparation preferred peroral dosage form, including tablet, capsule, pill, granule, solution, syrup, dry suspensoid agent, suspension, powder, sustained release preparation or controlled release preparation etc..The wherein solid orally ingestibles such as preferred tablet, capsule, granule, dry suspensoid agent and sustained release preparation or controlled release preparation, wherein more preferable tablets and capsules.Currently preferred pharmaceutical composition or preparation can be prepared according to any one conventional method used by solid orally ingestible is prepared.Such as tablet can be used wet granule compression tablet mode and prepare, and can carry out any form of coating as needed, such as any releasing pattern (such as quick-release, enteric ease up controlled release) can be made in tablet；Capsule can be used the modes such as encapsulated dose of wet granulation and prepare, and any releasing pattern (such as quick releasing formulation, enteric coated preparations and sustained-release preparation) can be made in Capsule content.
In one embodiment, compound shown in formula IV provided by the invention is selected from formula a~formula l compound represented or is selected from formula a1~formula l1 compound represented or is selected from formula a2~formula l2 compound represented, or they isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate particle diameter distribution control 95% less than 200 μm, it is preferably small
In 180 μm, more preferably less than 150 μm, more preferably less than 100 μm.The pharmaceutic adjuvant of this field routine in peroral dosage form, including filler, disintegrating agent, adhesive, dispersing agent, lubricant or retention agent and all types of coating materials etc..
The filler generally comprises pregelatinized starch, starch, lactose, dextrin, calcium monohydrogen phosphate, calcium carbonate, mannitol, microcrystalline cellulose, sorbierite, glucose etc., they, which can be used alone, to be used in mixed way, wherein preferably one of pregelatinized starch, lactose, microcrystalline cellulose and mannitol or a variety of.
The disintegrating agent generally comprises cross-linked carboxymethyl cellulose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose etc., they, which can be used alone, to be used in mixed way, wherein preferably one of cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, microcrystalline cellulose and low-substituted hydroxypropyl cellulose or a variety of.
Described adhesive generally comprise microcrystalline cellulose, pre-paying starch, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, povidone, starch slurry, Arabic gum, Macrogol 4000, polyvinyl alcohol, alginates, water, various concentration ethanol solution, they, which can be used alone, to be used in mixed way, wherein preferably one of hydroxypropyl methyl cellulose, hydroxypropylcellulose, povidone and starch slurry or a variety of.
The lubricant generally comprises magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, stearic acid Potassium fumarate, palmitinic acid, differential silica gel, stearmide, talcum powder, solid polyethylene glycol, glyceryl triacetate etc..They, which can be used alone, to be used in mixed way, wherein preferably one of magnesium stearate, stearic acid, talcum powder, differential silica gel and glyceryl triacetate or a variety of.
If necessary, other auxiliary materials can also be added into above-mentioned composition or preparation, such as sweetener (such as aspartame, Steviosin), colorant (such as lemon yellow, iron oxide various medicinal or edible pigment), stabilizer (such as calcium carbonate, calcium bicarbonate, sodium bicarbonate, sodium carbonate, calcium phosphate, calcium monohydrogen phosphate, glycine), surfactant (such as Tween 80, lauryl sodium sulfate) coating material (such as Opadry, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin copolymer etc..
In one embodiment, the present invention provides a kind of composition or preparations, wherein active constituent is selected from compound shown in the formula IV of therapeutically effective amount or selected from formula a~formula l compound represented or selected from formula a1~formula l1 compound represented or selected from formula a2~formula l2 compound represented or their isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate.The composition or the preferred oral preparation of preparation, more preferable tablets and capsules；In unit composition or preparation, their weight content is generally 1mg to 200mg, preferably 5mg to 100mg.
Purpose according to the present invention, the present invention provides the application of compound shown in formula IV or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate in the drug of preparation prevention and/or treatment virus infection.
Specifically, the present invention provides compound shown in formula IV or its isomers, officinal salt, pharmaceutically acceptable eutectics, hydration
The application of object or solvate in the drug of preparation prevention and/or treatment hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
In one embodiment, the present invention provides compound shown in formula IV or the applications selected from formula a~formula l compound represented or selected from formula a1~formula l1 compound represented or selected from formula a2~formula l2 compound represented or their isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate in the drug of preparation prevention and/or treatment hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
The experiment proved that, compound shown in formula IV provided by the invention, for example selected from formula a~formula l compound represented or selected from formula a1~formula l1 compound represented or it is selected from formula a2~formula l2 compound represented, or their isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate etc., in viral infection resisting, there is higher activity and better safety than the prior art (such as times Si Fuwei) especially in terms of anti-hepatitis B virus (HBV), human immunodeficiency virus (HIV) infection.
The technical solution that the present invention will be described in detail with reference to the accompanying drawings and embodiments, but protection scope of the present invention includes but is not limited to this.
The preparation of 1 compound a of embodiment
Step 1
1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (compound V) 5.0g (16.7mmol), phenol (compound 1) 3.1g (33.4mmol), triethylamine 2.7ml are mixed with 1-Methyl-2-Pyrrolidone 50ml, it is heated to about 90 DEG C, DCC 5.5g (26.7mmol) is added, is stirred to react overnight.After completion of the reaction, it is cooled to room temperature, water 30ml is added, it is filtered to remove solid, filtrate adds water 30ml, with 25% sodium hydrate aqueous solution tune pH to about 11 through being concentrated under reduced pressure in concentrate, it is filtered through diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to about 3, filtering, filter cake obtains compound 2 through column chromatographic purifying.
Step 2
2 3.5g of compound (9.3mmol) is mixed with acetonitrile 10ml, thionyl chloride 1.5ml (21.0mmol) is added, is heated to about 80 DEG C, is stirred to react, the evaporating solvent under reduced pressure after solution becomes clear；Methylene chloride 25ml dissolution is added after gained residue is cooling, it is cooled to about -20 DEG C, solution and triethylamine 2.4ml that α-isobutyl propylhomoserin isopropyl ester (compound 3) 2.7g (18.6mmol) is dissolved in methylene chloride 15ml is added, is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer is dried over anhydrous sodium sulfate, is concentrated under reduced pressure, and gained concentrate obtains compound a through column chromatographic purifying.
1H-NMR (δ): 8.34 (s, 1H), 8.05 (s, 1H), 7.63~6.95 (m, 5H), 6.49 (b, 2H), 4.35~4.00 (m, 5H), 3,74 (m, 2H), 1.52~1.18 (m, 13H), 0.92 (t, 2H).
MS (m/z): 503.2 (MH+)。
The preparation of embodiment 2 chipal compounds a1 and a2
The resulting compound a of embodiment 1 is subjected to HPLC preparative separation by the following conditions, obtains compound a 1 (retention time 15.5min) and compound a 2 (retention time 16.7min).
Instrument: Instrument:Thar analytical SFC
Chromatographic column: Chiralpak AS-H, 250 × 4.6mm
Mobile phase: A:CO2；B: ethyl alcohol (0.05% diethanol amine)
Gradient: B 40%
Flow velocity: 2.4mL/min
Column pressure: 100bar
Column temperature: 35 DEG C
Wavelength: 220nm.
The preparation of 3 compound b of embodiment
Referring to the preparation method of embodiment 1, the difference lies in that replacing α-isobutyl propylhomoserin isopropyl ester (compound 3) with compound 4, compound b is obtained.
1H-NMR (δ): 8.32 (s, 1H), 8.07 (s, 1H), 7.62~6.93 (m, 5H), (6.49 b, 2H), 4.35~4.04 (m, 5H), 3,71 (m, 2H), 1.51~1.19 (m, 9H), 0.96 (m, 4H).
MS (m/z): 501.1 (MH+)。
The preparation of embodiment 4 chipal compounds b1 and b2
The resulting compound b of embodiment 3 is separated as described in Example 2, obtains compound b1 (retention time 17.3min) and compound b2 (retention time 18.9min).
The preparation of 5 compound c of embodiment
Compound c is obtained the difference lies in that replacing phenol with p-methyl phenol referring to the preparation method of embodiment 1.
1H-NMR (δ): 8.31 (s, 1H), 8.21 (s, 1H), 7.35~6.61 (m, 4H), 6.21 (b, 2H), 4.41~4.01 (m, 5H), 3,83 (m, 2H), 1.51~1.31 (m, 16H), 0.96 (m, 2H).
MS (m/z): 517.3 (MH+)。
The preparation of embodiment 6 chipal compounds c1 and c2
The resulting compound c of embodiment 5 is separated as described in Example 2, obtains compound c1 (retention time 18.4min) and compound c2 (retention time 19.8min).
The preparation of 7 compound d of embodiment
Referring to the preparation method of embodiment 1, the difference lies in that 6- xylenol replaces phenol with 2, compound d is obtained.
1H-NMR (δ): 8.42 (s, 1H), 8.12 (s, 1H), 7,83~6.32 (m, 3H), 6.22 (b, 2H), 4.31~4.01 (m, 5H), 3,84 (m, 2H), 1.54~1.41 (m, 19H), 0.94 (m, 2H).
MS (m/z): 531.3 (MH+)。
The preparation of embodiment 8 chipal compounds d1 and d2
The resulting compound d of embodiment 7 is separated as described in Example 2, obtains compound d1 (retention time 20.1min) and compound d2 (retention time 22.4min).
The preparation of 9 compound e of embodiment
Compound e is obtained the difference lies in that replacing phenol with 1- naphthols referring to the preparation method of embodiment 1.
1H-NMR (δ): 8.31 (s, 1H), 8.11 (s, 1H), 7,88~6.61 (m, 7H), 6.22 (b, 2H), 4.34~4.10 (m, 5H), 3,74 (m, 2H), 1.53~1.42 (m, 13H), 0.93 (m, 2H).
MS (m/z): 553.3 (MH+)。
The preparation of embodiment 10 chipal compounds e1 and e2
The resulting compound e of embodiment 9 is separated as described in Example 2, obtains compound e1 (retention time 21.2min) and compound e2 (retention time 22.9min).
The preparation of 11 compound f of embodiment
Compound f is obtained the difference lies in that replacing phenol with beta naphthal referring to the preparation method of embodiment 1.
1H-NMR (δ): 8.22 (s, 1H), 8.14 (s, 1H), 7,85~6.81 (m, 7H), 6.21 (b, 2H), 4.35~4.11 (m, 5H), 3,72 (m, 2H), 1.51~1.41 (m, 13H), 0.93 (m, 2H).
MS (m/z): 553.3 (MH+)。
The preparation of embodiment 12 chipal compounds f1 and f2
The resulting compound f of embodiment 11 is separated as described in Example 2, obtains compound f1 (retention time 21.8min) and compound f2 (retention time 22.7min).
The preparation of 13 compound g of embodiment
Compound g is obtained the difference lies in that replacing phenol with p-fluorophenol referring to the preparation method of embodiment 1.
1H-NMR (δ): 8.21 (s, 1H), 8.11 (s, 1H), 7.65~6.91 (m, 4H), 6.31 (b, 2H), 4.43~4.02 (m, 5H), 3,81 (m, 2H), 1.54~1.33 (m, 13H), 0.91 (m, 2H).
MS (m/z): 521.3 (MH+)。
The preparation of embodiment 14 chipal compounds g1 and g2
The resulting compound g of embodiment 13 is separated as described in Example 2, obtains compound g1 (retention time 16.4min) and compound g2 (retention time 17.2min).
The preparation of 15 compound h of embodiment
Compound h is obtained the difference lies in that replacing phenol with parachlorophenol referring to the preparation method of embodiment 1.
1H-NMR (δ): 8.22 (s, 1H), 8.14 (s, 1H), 7.65~6.91 (m, 4H), 6.31 (b, 2H), 4.33~4.02 (m, 5H), 3,75 (m, 2H), 1.54~1.31 (m, 13H), 0.98 (m, 2H).
MS (m/z): 537.2 (MH+)。
The preparation of embodiment 16 chipal compounds h1 and h2
The resulting compound h of embodiment 15 is separated as described in Example 2, obtains compound h1 (retention time 17.0min) and compound h2 (retention time 18.3.min).
The preparation of 17 compound i of embodiment
Compound i is obtained the difference lies in that replacing phenol with 4- pyridone referring to the preparation method of embodiment 1.
1H-NMR (δ): 8.48~6.61 (m, 6H), 6.21 (b, 2H), 4.34~4.04 (m, 5H), 3,84 (m, 2H), 1.54~1.41 (m, 13H), 0.94 (m, 2H).
MS (m/z): 504.1 (MH+)。
The preparation of embodiment 18 chipal compounds i1 and i2
The resulting compound i of embodiment 17 is separated as described in Example 2, obtains compound i1 (retention time 15.4min) and compound i2 (retention time 16.1min).
The preparation of 19 compound j of embodiment
Compound j is obtained the difference lies in that replacing phenol with p methoxy phenol referring to the preparation method of embodiment 1.
1H-NMR (δ): 8.24 (s, 1H), 8.12 (s, 1H), 7.61~6.93 (m, 4H), 6.35 (b, 2H), 4.32~4.01 (m, 5H), 3,75 (m, 5H), 1.51~1.21 (m, 13H), 0.95 (m, 2H).
MS (m/z): 533.2 (MH+)。
The preparation of embodiment 20 chipal compounds j1 and j2
The resulting compound j of embodiment 19 is separated as described in Example 2, obtains compound j1 (retention time 17.9min) and compound j2 (retention time 19.0min).
The preparation of 21 compound k of embodiment
Compound k is obtained the difference lies in that replacing phenol with ethyl-para-hydroxybenzoate referring to the preparation method of embodiment 1.
1H-NMR (δ): 8.32 (s, 1H), 8.13 (s, 1H), 7.31~6.21 (m, 4H), 6.21 (b, 2H), 4.11~4.02 (m, 7H), 3,85 (m, 2H), 1.54~1.12 (m, 16H), 0.95 (m, 2H).
MS (m/z): 575.1 (MH+)。
The preparation of embodiment 22 chipal compounds k1 and k2
The resulting compound k of embodiment 21 is separated as described in Example 2, obtains compound k1 (retention time 16.8min) and compound k2 (retention time 18.1min).
The preparation of 23 compound l of embodiment
Compound l is obtained the difference lies in that replacing α-isobutyl propylhomoserin isopropyl ester (compound 3) with α-isobutyl propylhomoserin benzyl ester referring to the preparation method of embodiment 1.
MS (m/z): 551.2 (MH+)。
The preparation of embodiment 24 chipal compounds l1 and l2
The resulting compound l of embodiment 23 is separated as described in Example 2, obtains compound l1 (retention time 19.0min) and compound l2 (retention time 20.2min).
The thin membrane coated tablet of 25 compound a 1 of embodiment and its preparation
| Component | Content (mg/ piece) |
| Label: | |
| Compound a 1 | 50.0 |
| Lactose monohydrate | 100.0 |
| Microcrystalline cellulose | 60.0 |
| Cross-linked carboxymethyl cellulose sodium | 15.0 |
| Magnesium stearate | 3.0 |
| Thin film coating material: | |
| Opadry II | 10.0 |
It is weighed according to supplementary material each in upper table, microcrystalline cellulose is mixed with cross-linked carboxymethyl cellulose sodium, lactose monohydrate mixing is then added, add the mixing of compound a 1；Add Purified Water q. s wet granulation；It is dry；Whole grain；Additional magnesium stearate mixes, tabletting；Then by coating material with 75% ethyl alcohol be made into suspension coating to get.
The preparation of 1 compound V of preparation example
It is prepared by method disclosed in embodiment 5 in CN1487949A.
The preparation of 2 compound III of preparation example
It is prepared by method disclosed in embodiment 6 in CN1487949A.
The preparation of 3 compound VI of preparation example
It is prepared by method disclosed in embodiment 1 in CN104119385A.
The preparation of 4 compound VII of preparation example
It is prepared by method disclosed in embodiment 2 in CN104119385A.
The screening of test case anti-hepatitis B virus activity
With the anti-hepatitis B activity of HepG2.2.15 raji cell assay Raji compound.The material used and instrument are as follows: HepG2.2.15 cell, RPMI 1640 culture medium, fetal calf serum, 96 orifice plates, DMSO, QIAamp 96DNA Blood Kit, Cell-titer blue, microplate reader, Applied Biosystems 7900real-time PCR system.
Each compound is dissolved to 20mM with DMSO, the 20mM of each compound is stored liquid 3 times of gradient dilutions of DMSO, totally 9 concentration by -20 DEG C of storages.200 times are diluted with the RPMI 1640 culture medium containing 2.0%FBS again.Final concentration of 100 μM of the highest test of compound.Experimental procedure simultaneously calculates EC referring to QIAamp 96DNABlood Kit (QIAGEN 51161) specification, qPCR method measurement compound anti-hepatitis B activity50(half effective inhibition concentration).Analyze data and calculate suppression percentage: the following formula of application calculates suppression percentage: inhibiting rate (%)=(HBV total amount-test sample group HBV total amount of DMSO control group)/DMSO control group total amount × 100 HBV.The EC of compound is finally calculated using GraphPad Prism software50Value.
The cytotoxicity of Cell-titer blue method measurement compound simultaneously calculates CC50(causing 50% cytotoxic concentration).Analyze data and calculate versus cell vigor: the following formula of application calculates cell activity percentage: cells survival rate (%)=(given the test agent
Fluorescence values-background fluorescence numerical value)/(fluorescence values of DMSO control group-background fluorescence numerical value) × 100.The CC of compound is finally calculated using GraphPad Prism software50Value.Experimental result is as follows:
Experiment show formula a1~formula l1 compound represented, formula a2~formula l2 compound represented compared with formula III compound represented, EC50It is worth considerably lower, hence it is evident that there is better anti-hepatitis B activity, CC50> 100 μM, without cytotoxicity in the concentration range of test.
It will be understood by those skilled in the art that some modifications or variation can be made to the present invention under the introduction of this specification.These modifications and variations should also be as within the scope of the claims in the present invention.
Claims (10)
- Compound or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate shown in a kind of formula IV,Wherein:R1For hydrogen, C1-6Alkyl or substituted or non-substituted C6-10Aryl, 6 to 10 unit's heteroaryls or benzyl；R2, R3Respectively C1-6Alkyl or R2、R3C is formed with connected carbon atom3-7Naphthenic base；R4For substituted or non-substituted C6-10Aryl or 6 to 10 unit's heteroaryls.
- Compound according to claim 1 or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate, which is characterized in that the wherein C1-6Alkyl is selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, tertiary pentyl, 2- methyl butyl, 3- methyl butyl, 1- ethyl propyl, 4- methyl amyl, 3- methyl amyl, 2- methyl amyl, 1- methyl amyl, 3,3- dimethylbutyl, 2,2- dimethylbutyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 1,3- dimethylbutyl, 2,3- dimethylbutyl, 2- ethyl-butyl, n-hexyl or isohesyl；6 to 10 unit's heteroaryl is selected from pyridine -2- base, pyridin-3-yl, pyridin-4-yl, pyridazine -3- base, pyridazine -4- base, pyrimidine -2-base, pyrimidine-4-yl, pyrimidine -5- base, pyrazine -2- base, pyrazine -3- base, indyl, isoindolyl, indazolyl, indolizine base, purine radicals, quinazinyl, quinolyl, isoquinolyl, cinnoline base, phthalazinyl, naphthyridines base, quinazolyl, quinoxalinyl, thieno [2, 3-b] furyl, furans simultaneously [3, 2-b]-pyranose, pyrido [2, 3-d] oxazines base, pyrazolo [4, 3-d] oxazolyl, imidazo [4, 5-d] thiazolyl, pyrazine simultaneously [2, 3-d] pyridazinyl, imidazo [2, 1-b] thiazolyl, imidazo [1, 2-b] [1, 2, 4] triazine Base, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzo dislikes heptan because of base, benzoxazinyl-, benzofuranyl, benzotriazole base, pyrrolo- [2, 3-b] pyridyl group, pyrrolo- [3, 2-c] pyridyl group, pyrrolo- [3, 2-b] pyridyl group, imidazo [4, 5-b] pyridyl group, imidazo [4, 5-c] pyridyl group, pyrazolo [4, 3-d] pyridyl group, pyrazolo [4, 3-c] pyridyl group, pyrazolo [3, 4-c] pyridyl group, pyrazolo [3, 4-d] pyridyl group, pyrazolo [3, 4-b] pyridyl group, imidazo [1, 2-a] pyridyl group, pyrazolo [1, 5-a] pyridyl group, pyrrolo- [1, 2-b] pyridazinyl, imidazo [1, 2-c] pyrimidine radicals, pyrido [3, 2-d ] pyrimidine radicals, pyrido [4,3-d] pyrimidine radicals, pyrido [3,4-d] pyrimidine radicals, pyrido [2,3-d] pyrimidine radicals, pyrido [2,3-b] pyrazinyl, pyrido [3,4-b] pyrazinyl, pyrimido [5,4-d] pyrimidine radicals, pyrazolo [2,3-b] pyrazinyl or pyrimido [4,5-d] pyrimidine radicals；When the aryl, heteroaryl or benzyl are to replace, the substituent group of the aryl, heteroaryl or benzyl is selected from alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, acyloxy, sulfydryl, alkylthio group, amino, alkylamino, acylamino-, halogen, cyano, nitro or acyl group；The C3-7Naphthenic base is selected from cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, suberyl, 2- methylcyclopropyl groups, 2- ethyl cyclopropyl, 2- propylcyclopropyl, 2- isopropyl cyclopropyl, 2- butyl cyclopropyl, 2- isobutyl cyclopropyl, 2- tert-butyl cyclopropyl, 2- methyl-cyclobutyl, 3- methyl-cyclobutyl, 2- ethylcyclobutyl, 3- ethylcyclobutyl, 2- propylcyclobutyl, 3- propylcyclobutyl, 2- isopropyl tetramethylcyclobutyl, 3- isopropyl tetramethylcyclobutyl, 2- methylcyclopentyl, 3- methylcyclopentyl, 4- methylcyclopentyl, 2- ethylcyclopentyl, 3- ethylcyclopentyl, 2- methylcyclohexyl, 3- methylcyclohexyl, 4- methylcyclohexyl, 2, 3- Dimethvlcvclopropvl, 2- methyl -3- ethyl cyclopropyl, 2, 3- diethyl cyclopropyl, 2, 3- dimethylcyclobutyl, 2- methyl -3- Ethylcyclobutyl, 3- methyl -2- ethylcyclobutyl, 2,3,4- front three tetramethylcyclobutyls, 2,3- dimethylcyclopentyls or 2,4- dimethylcyclopentane base.
- Compound according to claim 2 or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate, which is characterized in that the wherein C1-6Alkyl is selected from methyl, ethyl, isopropyl or tert-butyl；The C6-10Aryl is selected from phenyl, 1- naphthalene or 2- naphthalene；6 to 10 unit's heteroaryl is selected from pyridine -2- base, pyridin-3-yl, pyridin-4-yl, pyrimidine -2-base, pyrimidine-4-yl or pyrimidine -5- base；When the aryl, heteroaryl or benzyl are to replace; the substituent group of the aryl, heteroaryl or benzyl is selected from methyl, ethyl, hydroxyl, methoxyl group, ethyoxyl, acetoxyl group, amino, dimethylamino, acetylamino, fluorine, chlorine, cyano, acetyl group, methoxycarbonyl group, carbethoxyl group, amino carbonyl or N, N- Dimethylaminocarbonyl；The C3-7Naphthenic base is selected from cyclopropyl or cyclobutyl.
- Described in any item compounds or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate according to claim 1~3, which is characterized in that the compound is selected from:
- Described in any item compounds or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate according to claim 1~3, which is characterized in that the compound is selected from:
- Described in any item compounds or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate according to claim 1~3, which is characterized in that the compound is selected from:
- A kind of preparation method of compound shown in formula IV or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate, this method comprises:(1), compound shown in Formula V is reacted under the suitable conditions to obtain compound shown in Formula VII with compound shown in Formula IV,Wherein R4Definition with claim 1；(2), compound shown in Formula VII is reacted under the suitable conditions to obtain IV compound shown in formula with compound shown in Formula VIII,Wherein R1、R2、R3And R4Definition with claim 1；(3), optional, compound shown in formula IV is subjected to chiral resolution as needed, salt is made, eutectic is made, hydrate is made or solvate is made.
- A kind of pharmaceutical composition, it includes the compound according to any one of claims 1 to 6 of therapeutically effective amount or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvates and pharmaceutic adjuvant.
- The application of compound according to any one of claims 1 to 6 or its isomers, officinal salt, pharmaceutically acceptable eutectic, hydrate or solvate in the drug of preparation prevention and/or treatment virus infection.
- Application according to claim 9, which is characterized in that the virus infection is selected from hepatitis b virus infected and/or HIV infection.
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|---|---|---|---|---|
| CN101816664A (en) * | 2003-12-30 | 2010-09-01 | 吉里德科学公司 | The phosphonate ester, mono phosphonic acid amidate, the two phosphonic acid amide thing that are used for the treatment of viral disease |
| WO2012142075A1 (en) * | 2011-04-13 | 2012-10-18 | Merck Sharp & Dohme Corp. | 2'-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
| CN104119385A (en) * | 2014-07-24 | 2014-10-29 | 廖国超 | Phosphate prodrug of nucleoside analog and application of phosphate prodrug |
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| CN101816664A (en) * | 2003-12-30 | 2010-09-01 | 吉里德科学公司 | The phosphonate ester, mono phosphonic acid amidate, the two phosphonic acid amide thing that are used for the treatment of viral disease |
| WO2012142075A1 (en) * | 2011-04-13 | 2012-10-18 | Merck Sharp & Dohme Corp. | 2'-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases |
| CN104119385A (en) * | 2014-07-24 | 2014-10-29 | 廖国超 | Phosphate prodrug of nucleoside analog and application of phosphate prodrug |
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