CN101475594A - Liver targeted antivirus precursor medicament annular phosphoester and use thereof - Google Patents
Liver targeted antivirus precursor medicament annular phosphoester and use thereof Download PDFInfo
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- CN101475594A CN101475594A CNA2009100774035A CN200910077403A CN101475594A CN 101475594 A CN101475594 A CN 101475594A CN A2009100774035 A CNA2009100774035 A CN A2009100774035A CN 200910077403 A CN200910077403 A CN 200910077403A CN 101475594 A CN101475594 A CN 101475594A
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Abstract
The invention provides a prodrug of an antiviral drug for use in liver of cyclic phosphate of a general formula (I) and isomers, pharmaceutical salts, hydrates, solvates and pharmaceutical compositions of the same. The invention provides uses of the compounds singly or together with other antiviral drugs in the treatment of viruses, in particular of hepatitis B viruses (HBV), hepatitis C virus (HCV), HIV viruses and/or human cytomegaloviruses (HCMV).
Description
Technical field
The present invention relates to a kind of antiviral compound, particularly relate to annular phosphate class prodrug with liver targeted antivirus effect, or its all possible isomer, hydrate, solvate, pharmacologically acceptable salt and pharmaceutical composition.
Background technology
Many antiviral all are known: (Current Drug Targets-Infectious Disorders 2005 such as emtricitabine (FTC), tynofovir (Tenofovir), LB80331, LB80317, { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid, Entecavir, Torcitabine, NM-107, Viramidine, ribavirin, Racivir, Amdoxovir, MIV-210, PSI-6130, PSI-6206 for example, 5,307-400; Drugs of the Future 2004,29 (2): 163-177).
Above antiviral all belongs to ucleosides, according to its chemical structure, the glycosyl end be can simply be divided into and phosphate group and non-phosphoric acid group two classes contained, its effect base reason generally is that medicine becomes activated triphosphoric acid metabolite in the endocellular phosphorus acidifying, thereby the DNA or the rna polymerase activity that suppress virus, stop the synthetic of DNA or RNA, kill virus.
The glycosyl end contains the nucleotide medicine of phosphate group, as tynofovir, LB80331 and LB80317 etc., be highly electronegative under physiological pH, so cell leakage is poor, be difficult to arrive pharmaceutically-active target area, it is big easily to be removed weak point plasma half-life, kidney and gi tract toxic side effect by kidney simultaneously, and oral administration biaavailability is poor.In order to overcome above shortcoming; the most frequently used strategy is that the phosphate group acidylate in the medicines structure is prepared into prodrug; two (the different third oxygen acyloxy methyl) prodrug tynofovir esters of for example anti-HBV tynofovir can improve oral administration biaavailability, cell leakage and tissue distribution.But it is widely distributed in the ester hydrolase body, tynofovir ester etc. contains the ester class prodrug of phosphoric acid, before medicine arrives liver cell, major part has been metabolised to the parent drug that has the negative charge membrane permeability, be difficult for to arrive hepatocellular parent drug in the extracellular by the proximal tubule of active transport, and high density contains the parent drug of phosphoric acid and has certain renal toxicity to kidney.
Another kind of glycosyl end is the nucleotide medicine of phosphoric acid group not, as emtricitabine, Entecavir etc., can improve cell leakage, bioavailability, toxic side effect of medicine etc., but the glycosyl of medicine can not be metabolised to activated triphosphoric acid thing fully in cell, thereby has reduced curative effect.
The present invention is with the anti-viral nucleoside medicine: introduce 4-aryl-2-oxo-1 in the glycosyl structure of emtricitabine, tynofovir, LB80331, LB80317, { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid, Entecavir, torcitabine, NM-107, viramidine, ribavirin, Racivir, Amdoxovir, MIV-210, PSI-6130 and PSI-6206,3, the annular phosphate structure of 2-two oxa-phospha cyclohexane groups is prepared into the prodrug with liver targeting.
Annular phosphate (4-aryl-2-oxo-1,3,2-two oxa-phospha cyclohexanes) 4 aryl substituents in the prodrug structure can be by CYP3A specificity catalyzed oxidation in the Cytochrome P450 isozyme family in the liver cell, the result of reaction generates an intermediate that has single phosphoric acid negative charge from 4 open loops, make it be difficult for being retained in the cell by cytolemma, pass through the phosphodiester enzymatic hydrolysis again, β-elimination reaction, discharge the medicine that contains aerobic phosphoric acid or carbon phosphoric acid, continuation is changed into the ribonucleoside triphosphote medicine of biologically active by nucleoside monophosphate kinase, and another by product aryl ethylene ketone fast with liver cell in content enrich anti-oxidant the combination and be eliminated with gsh free radical, do not find side effect.(J.Am.Chem.Soc.2004，126：5154-5163；J.Pharmacol.Exp.Ther.2005，312：554-560；Curr?Opin?InvestigDrugs.2006，7：109-117)。
The present invention combines above antiviral (parent drug) and obtains the annular phosphate prodrug that a class has the liver targeting with small molecules carrier annular phosphate, it is to gi tract, blood plasma has high stability, be difficult for by the hydrolysis of body lactone hydrolase, can be before arriving liver cell after the administration by metabolism, enter the target area by the CYP3A metabolism in the liver cell after the location discharge parent drug, make the drug level in the liver cell be higher than healthy tissues, with parent drug (as emtricitabine) or other non-liver target prodrug (as the tynofovir ester) ratio, particularly resist HBV or HCV, have the curative effect height, the advantage that toxic side effect is little.
Summary of the invention
The purpose of this invention is to provide a kind of curative effect height, liver target prodrug that toxicity is low, the antiviral location is released in the liver cell, treat and prevent the disease of various virus infectiones by small molecules carrier with liver targeting.
The inventor is through discovering, with the parent drug emtricitabine, tynofovir, LB80331, LB80317,2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] methane phosphonic acid, Entecavir, torcitabine, NM-107, viramidine, ribavirin, racivir, Amdoxovir, MIV-210, PSI-6130 and PSI-6206 are prepared as the annular phosphate prodrug with liver targeting, it is to gi tract, blood plasma has high stability, be difficult for by the hydrolysis of body lactone hydrolase, can be before arriving liver cell after the administration by metabolism, enter the target area by the CYP3A metabolism in the liver cell after the location discharge parent drug, therefore can improve the drug level in the liver cell, increase curative effect and reduce toxic side effect.In addition annular phosphate compound and acid-respons are prepared salify, can increase the water-soluble of this compounds,, can improve pharmacokinetic property in its body, improve oral administration biaavailability by improving the water-soluble of compound.
The invention provides compound or its all possible isomer, pharmacologically acceptable salt, hydrate or the solvate of general formula I:
Wherein:
R
1Be selected from group with following structure:
With the corresponding ucleosides antiviral compound of above-mentioned group a-o be:
A: emtricitabine (by the exploitation of Triangle company); B: tynofovir (by the exploitation of Gilead company); C:{1-[(2-amino-purine-9-yl)-methyl]-the ring propoxy-} methane phosphonic acid (LB80331) and d:{1-[(2-amino-6-hydroxyl-purine-9-yl)-methyl]-the ring propoxy-} methane phosphonic acid (LB80317) (by the exploitation of LG Life Sciences company); E:{2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] methane phosphonic acid (by the exploitation of Mitsubishi-Lilly company); F: Entecavir (by Bristol-Myers Squibb Co.'s exploitation); G:Torcitabine and h:NM-107 (by the exploitation of Idenix drugmaker); I:Viramidine (by the research and development of Valeant company); J: ribavirin (by the exploitation of Ribapharm company); K:Racivir (by the exploitation of Pharmasset company); L:Amdoxovir (by the exploitation of RFS Pharma company); M:MIV-210 (by the exploitation of Medivir AB company); N:PSI-6130 and o:PSI-6206 (by the exploitation of Pharmasset company).
R
2For independently being selected from chlorine, bromine, fluorine, iodine, nitro, hydroxyl, amino, cyano group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
6Alkylamino radical, C
1-C
6Haloalkyl or alkyloyl;
X for independently be selected from the neighbour, or the nitrogen or the carbon of contraposition;
N is 0,1,2,3,4;
R
1With 4 aromatic group cis or trans each other in the phosphoric acid ester ring structure, preferred cis-isomeride;
4 carbon atom has chirality in the phosphoric acid ester ring structure, and its configuration can be S or R-configuration, preferred S-configuration.
The present invention also provides compound or its all possible isomer, pharmacologically acceptable salt, hydrate or the solvate of general formula I I:
Wherein:
R
3Be selected from group with following structure:
R
2Be selected from chlorine, bromine, fluorine, iodine, nitro, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylamino radical, C
1-6Haloalkyl or alkyloyl;
X be selected from the neighbour, or the nitrogen or the carbon of contraposition;
N is 0,1,2,3 or 4.
The present invention also provides compound or its all possible isomer, pharmacologically acceptable salt, hydrate or the solvate of general formula III:
Wherein:
R
4Be selected from group with following structure:
R
2Be selected from chlorine, bromine, fluorine, iodine, nitro, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylamino radical, C
1-6Haloalkyl or alkyloyl;
X be selected from the neighbour, or the nitrogen or the carbon of contraposition;
N is 0,1,2,3 or 4.
Preferred compound of formula I is selected from:
(1) 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(2) 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(3) 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-4 '-[(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(4) 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(5) (2R)-and 9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(6) (2R)-and 9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(7) (2R)-9-{2-[4 '-(3-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(8) (2R)-9-{2-[4 '-(phenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(9) (2R)-9-{2-[4 '-(3 '-bromophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(10) (2R)-9-{2-[4 '-(3 '-fluorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(11) (2R)-9-{2-[4 '-(3 ', 5 '-difluorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(12) (2R)-9-{2-[4 '-(2 ', 3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(13) (2R)-9-{2-[4 '-(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(14) (2R)-9-{2-[4 '-(3 ', 5 '-xylyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(15) (2R)-9-{2-[4 '-(3 ', 5 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } VITAMIN B4
(16) 2-amino-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(17) 2-amino-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } purine
(18) 2-amino-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } purine
(19) 2-amino-6-hydroxyl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl purine
(20) 2-amino-6-hydroxyl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } purine
(21) 2-amino-6-hydroxyl-9-{2-[(2S ', 4R ')-4 '-(3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } purine
(22) 2-amino-6-to anisole sulfydryl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy ethyl purine
(23) 2-amino-6-is to anisole sulfydryl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy ethyl } purine
(24) 2-amino-6-is to anisole sulfydryl-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy ethyl } purine
(25) 2-amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-hydroxyl-3-(2 ', 4 '-cis-(4 ' S)-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl) oxygen methyl-2-methylene radical pentamethylene]-the 6H-purine-6-one.
And all possible isomer, pharmacologically acceptable salt, hydrate or solvate.
The present invention also provides compound shown in the general formula I suitable pharmaceutically useful salt, hydrate or solvate, wherein pharmaceutically useful salt include, but are not limited to salt that compound of Formula I become with mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid and with various organic acids, the salt that is become as toxilic acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, citric acid, acetate, lactic acid, methylsulfonic acid, tosic acid, palmitinic acid etc.The compounds of this invention can form pharmacologically acceptable salt with reactions such as alkali such as sodium, potassium, magnesium, calcium, lithiums.Some compounds possibility water or various organic solvent crystallization or recrystallizations among the present invention in this case, may form all kinds of SOLVENTS thing.The present invention includes those stoichiometric solvates, comprise hydrate, be also included within the compound that comprises variable water gaging that forms when preparing with lyophylization.
The invention still further relates to the various isomer of compound of Formula I.The isomer of The compounds of this invention comprises tautomer, cis-trans-isomer, conformer, meso compound and has mapping or the optical isomer of non-enantiomorphic relationship.
Compound may exist with the form of cis-trans-isomer, optical isomer or tautomer among the present invention, the present invention includes the form of its all existence forms, particularly pure isomer.Different isomeric forms can or split with the isomer separation of the means of various routines and other form, and perhaps synthetic method or the three-dimensional method single-minded or asymmetric synthesis that certain isomer can various routines obtains.Since compound of Formula I is to be purpose with medicinal, be appreciated that they preferably provide with pure form, at least 60% purity for example, more suitably 75%, better 85%, best at least 98% purity (% is meant weight percent).The preparation method of pure compound not can be used to be used for the purer form of medicinal compositions.At least contain 1% in these pure inadequately products, be more suitable for 5%, better at least 10% the compound shown in general formula I or its pharmaceutically useful derivative.
The present invention also provides the preparation method of preparation compound of Formula I or its pharmaceutically useful salt, hydrate or solvate, is described respectively at general formula I substructure (general formula I I and general formula III) below, wherein R
1, R
2, R
3, R
4, X and n have aforesaid definition.
1. the preparation method of general formula I I compound is as follows:
At N, in the dinethylformamide solution, add R
3CH
2OH, 4S-phosphoramidite derivative and 5-methylthio group tetrazole are cooled to subzero 45 ℃, slowly drip tertbutanol peroxide, behind the reaction 1h, are warming up to room temperature and react 24h again, remove solvent under reduced pressure, and silica gel column chromatography obtains cis and trans general formula I I compound.
2. the preparation method of compound of formula III is as follows:
Method 1:
At N, in the dinethylformamide solution, add R
4OCH
2PO (OH)
2, 1, ammediol derivative, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, stirring at room 30min is warming up to about 100 ℃ and reacts 24h, reaction finishes.Reaction solution is dissolved in ethyl acetate, uses citric acid, sodium bicarbonate, water, saturated common salt water washing successively, anhydrous sodium sulfate drying removes solvent under reduced pressure, and silica gel column chromatography obtains compound of formula III.
Method 2:
With R
4OCH
2PO (OH)
2, N, the N-diethylformamide joins in the dichloromethane solution, slowly drips oxalyl chloride, reheat is to back flow reaction 3h.Reaction solution is cooled to-78 ℃, adds triethylamine, R or S-3-aryl-1 successively, ammediol, reaction is reacted 1h after slowly being warming up to 0 ℃ behind the 1h again, drips trifluoroacetic acid, stirs 30min post-heating back flow reaction 2h, and reaction finishes.Add the neutralization of yellow soda ash frozen water solution, organic layer is washed to neutrality, and anhydrous sodium sulfate drying filters, and removes solvent under reduced pressure, and silica gel column chromatography obtains compound of formula III.
The applicant has invented preparation method's (method 2) of a kind of " cooking different foods in one pot " synthetic general formula III: with tynofovir (LB80331, LB80317 or { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid), priority and N, after N-diethylformamide, the oxalyl chloride reaction, add 3-aryl-1, ammediol prepares 4-aryl-2-oxo-1,3,2-two oxa-phospha cyclohexane derivatives, use the trifluoracetic acid hydrolysis again, obtain compound of formula III.This method and the disclosed annular phosphate synthetic method ratio of patent CN1964967, synthesis step is few, simple to operate, yield is high, economical environment-protective, uses this novel method and has prepared a class annular phosphate prodrug.
See embodiment about the more detailed data of preparation compound of Formula I.
The present invention also provides a kind of medicinal compositions, comprises compound of Formula I, or its isomer, pharmacologically acceptable salt, hydrate or solvate and pharmaceutically acceptable auxiliary, diluent or carrier.
The compound of general formula I of the present invention or its pharmaceutically useful salt can use separately; or use with the form of pharmaceutical composition with pharmaceutically useful carrier or vehicle; when using with the form of pharmaceutical composition; usually with the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or thinner in conjunction with making suitable administration form or dosage form, this program comprises by suitable manner component mixing, granulation, compression or dissolving.Therefore, the invention provides pharmaceutical composition, it comprises compound, its all possible isomer, prodrug, pharmacologically acceptable salt, solvate or hydrate and at least a pharmaceutically useful carrier of general formula I.
The pharmaceutical composition of The compounds of this invention, any-mode that can following aspect is granted: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone or intracranial injection or input, or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenously application method.In addition, effectively treat central nervous system disease for the pharmaceutical composition that makes The compounds of this invention or contain it, preferably the approach medication can overcome the hemato encephalic barrier transmitance that compound may be low in the ventricle.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. for example.
Can also contain carrier commonly used in the pharmaceutical composition of the present invention, pharmaceutically acceptable carrier described here is including, but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum protein, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, wool grease etc.The content of carrier in pharmaceutical composition can be 1 weight %-98 weight %, accounts for 80 weight % usually greatly.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in the carrier.
Oral tablet and capsule can contain vehicle such as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent is as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil, lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli, disintegrating agent, as yam starch, or acceptable dibutyl phthalate, as bay sodium alkoxide vitriol.Tablet can be with known method dressing on the pharmacopedics.
Oral liquid can be made the suspension of water and oil, solution, and emulsion, syrup or elixir also can be made dry product, with preceding make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, hydrogenant food oils, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (may comprise edible oil), as Prunus amygdalus oil, grease such as glycerine, ethylene glycol, or ethanol; Sanitas is as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.Can add seasonings or tinting material as needs.
Suppository can comprise conventional suppository base, and this vehicle at room temperature is solid state, and fusing disengages medicine under body temperature, as theobroma oil, and other glyceryl ester or beeswax.
Stomach is offerd medicine outward, and liquid formulation is made by compound and a kind of disinfectant carrier usually.The first-selected water of carrier.Different according to selected carrier and drug level, compound had both dissolved in and also can be made into aaerosol solution in the carrier, and was earlier that compound is soluble in water when making injection solution, packed into after the filter-sterilized and sealed in bottle or the ampoule.
When topical application, The compounds of this invention can be made suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more the carrier.Wherein the operable carrier of ointment formulation is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
According to the difference of administering mode, can contain weight ratio 0.1% in the component, or the active ingredient of weight ratio 10-60% more suitably.But when comprising unitary dose in the component, each unit preferably comprises 1-500 milligram activeconstituents.
It may be noted that in addition, The compounds of this invention is decided by all multifactor at different patients' specific using dosage and using method, comprise patient's age, body weight, sex, the natural health situation, nutritional status, the activity intensity of compound, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the person in charge judges.Here preferred using dosage is between the 0.01-100mg/Kg body weight/day.
Must recognize, the best dosage of compound of Formula I and be at interval by compound property with such as the decision of the external conditionss such as form, path and position of administration, and this best dosage can be determined with conventional technology.Must recognize also simultaneously that the best course of treatment, promptly compound of Formula I is at the nominal dosage of every day in the time, available method well known in the art is determined.
The present invention further provides The compounds of this invention, or its isomer, pharmacologically acceptable salt, hydrate or solvate treat and/or prevent the application that acute and Chronic HBV or HIV or HCV or HCMV infect the medicine of the disease that causes, the disease that described medicine is used for the treatment of and pre-anti-virus causes being used for preparing.Described disease is including, but not limited to diseases such as following disease: HBV, HCV, HIV and HCMV.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
The fusing point of compound is measured by RY-1 fusing point instrument, and thermometer is calibration not.Mass spectrum is measured by Micromass ZabSpec mass spectrograph.
1H-NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR instrument, operating frequency
1H-NMR 400MHz.
Embodiment 1 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } preparation of cytosine(Cyt)
At N, in dinethylformamide (30ml) solution, add FTC (741.6mg, 3.0mmol), 4S-4-(3-chloro-phenyl-)-N, N-di-isopropyl-1,3, (1.45g is 4.5mmol) with 5-methylthio group tetrazole (527mg for 2-two oxa-s phospha cyclohexane-2-amine, 4.5mmol), be cooled to subzero 45 ℃, slowly drip tertbutanol peroxide, behind the reaction 1h, be warming up to room temperature and react 24h again, remove solvent under reduced pressure, silica gel column chromatography is used methyl alcohol: methylene dichloride=1:18 wash-out, obtain 0.30g white powder solid, yield 21.0%, fusing point 98-100 ℃, R
f=0.38 (methyl alcohol: methylene dichloride=1:9).
1HNMR(400MHz，DMSO)，δ(ppm)：1.98-2.45(m，2H)，2.91-3.22(m，1H)，3.20-3.47(m，1H)，4.19-4.62(m，4H)，5.21-5.60(m，2H)，6.16-6.32(m，1H)，7.20-7.51(m，4H)，8.22(S，1H)；ESI-MS：478.0(M+1)。
Embodiment 2 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } preparation of cytosine(Cyt)
Adopt 1 identical method preparation, obtain 0.25g white powder solid, yield 17.5%, fusing point 92-94 ℃, R with embodiment
f=0.42 (methyl alcohol: methylene dichloride=1:9).
1HNMR(400MHz，DMSO)，δ(ppm)：2.01-2.48(m，2H)，2.89-3.25(m，1H)，3.20-3.49(m，1H)，4.09-4.68(m，4H)，5.22-5.59(m，2H)，6.18-6.30(m，1H)，7.20-7.51(m，4H)，8.22(S，1H)；ESI-MS：478.0(M+1)。
Embodiment 3 5-fluoro-1-(2R, 5S)-2 ', 4 '-cis-(4 ' S)-[4 '-(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl } the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl] preparation of cytosine(Cyt)
Adopt method preparation similar to Example 1, with FTC (741.6mg, 3.0mmol), 4S-4-(4-pyridyl)-N, N-di-isopropyl-1,3,2-two oxa-s phospha cyclohexane-2-amine (1.27g, 4.5mmol) and 5-methylthio group tetrazole (527mg, 4.5mmol) reaction obtains 0.28g brown ceramic powder shape solid, yield 21.0%, R
f=0.40 (methyl alcohol: methylene dichloride=1:6).
1HNMR(400MHz，DMSO)，δ(ppm)：
1HNMR(400MHz，DMSO)，δ(ppm)：2.01-2.38(m，2H)，2.91-3.26(m，1H)，3.22-3.50(m，1H)，4.10-4.67(m，4H)，5.20-5.63(m，2H)，6.19-6.35(m，1H)，7.34(d，J＝9.6Hz，2H)，8.24(s，1H)，8.56(d，J＝9.6Hz，2H)；ESI-MS：445.1(M+1)。
Embodiment 4 5-fluoro-1-(2R, 5S)-2 ', 4 '-trans-(4 ' S)-4 '-[(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] the oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } preparation of cytosine(Cyt)
Adopt 3 identical method preparations, obtain 0.23g brown ceramic powder shape solid, yield 17.2%, R with embodiment
f=0.45 (methyl alcohol: methylene dichloride=1:6).
1HNMR(400MHz，DMSO)，δ(ppm)：1.95-2.30(m，2H)，2.90-3.27(m，1H)，3.25-3.56(m，1H)，4.08-4.69(m，4H)，5.17-5.63(m，2H)，6.22-6.34(m，1H)，7.34(d，J＝9.6Hz，2H)，8.24(s，1H)，8.56(d，J＝9.6Hz，2H)；ESI-MS：445.1(M+1)。
Embodiment 5 (2R)-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
With (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (2.87g, 10mmol), N, N-diethylformamide (1.01g, 10mmol) join in the 250ml dichloromethane solution, under the condition of anhydrous and oxygen-free, slowly drip oxalyl chloride (3.81g, 30mmol), reheat is to back flow reaction 3h, then reaction solution is cooled to-78 ℃, add successively triethylamine (6.06g, 60mmol), S-3-(3-chloro-phenyl-)-1, ammediol (1.87g, 10mmol), reaction is reacted 1h after slowly being warming up to 0 ℃ behind the 1h again, drips the 8.0g trifluoroacetic acid, stir 30min post-heating back flow reaction 2h, reaction finishes.Add the neutralization of yellow soda ash frozen water solution, organic layer is washed to neutrality, and anhydrous sodium sulfate drying filters, and removes solvent under reduced pressure, silica gel column chromatography, and use methyl alcohol: methylene dichloride=1:20 wash-out obtains 1.84g yellow powder shape solid, yield 42.0%, fusing point 90-92 ℃, R
f=0.40 (methyl alcohol: methylene dichloride=1:10).
1HNMR(400MHz，DMSO)，δ(ppm)：1.16d，(d，3H)，1.75-2.04(m，2H)，3.45-3.96(m，3H)，4.05-4.26(m，1H)，4.26-4.55(m，3H)，5.57(m，1H)，7.19-7.43(m，4H)，8.07(s，1H)，8.12(s，1H)；ESI-MS：438.1(M+1)。
Embodiment 6 (2R)-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method similar to Example 5 preparation, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (2.87g, 10mmol), N, the N-diethylformamide (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol), triethylamine (6.06g, 60mmol), R-3-(3-chloro-phenyl-)-1, ammediol (1.87g, 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 1.34g yellow powder shape solid, yield 30.6%, fusing point 88-90 ℃, R
f=0.40 (methyl alcohol: methylene dichloride=1:10).
1HNMR(400MHz，DMSO)，δ(ppm)：1.18(d，3H)，1.75-2.04(m，2H)，3.40-3.96(m，3H)，4.05-4.25(m，1H)，4.26-4.58(m，3H)，5.57(m，1H)，7.19-7.47(m，4H)，8.07(s，1H)，8.10(s，1H)；ESI-MS：438.1(M+1)。
Embodiment 7 (2R)-9-{2-[4 '-(3-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
At 20ml N, in the dinethylformamide solution, add (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3-chloro-phenyl-)-1, ammediol (0.37g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol), stirring at room 30min is warming up to about 100 ℃ and reacts 24h, and reaction finishes.Reaction solution is dissolved in ethyl acetate, uses 10% citric acid, 4% sodium hydrogen carbonate solution, water, saturated common salt water washing successively, anhydrous sodium sulfate drying, remove solvent under reduced pressure, silica gel column chromatography obtains 0.40g yellow powder shape solid, yield 45.6%, fusing point 87-89 ℃, R
f=0.40 (methyl alcohol: methylene dichloride=1:10).
1HNMR(400MHz，DMSO)，δ(ppm)：1.12-1.22(m，3H)，1.78-2.10(m，2H)，3.36-4.86(m，7H)，5.20-5.60(m，1H)，7.09-7.47(m，4H)，8.05-8.20(s，2H)；ESI-MS：438.1(M+1)。
Embodiment 8 (2R)-9-{2-[4 '-(phenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method preparation similar to Example 7, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-phenyl-1, ammediol (0.30g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finishes, and obtains the 0.30g pulverulent solids, yield 37.5%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.10-1.21(m，3H)，1.78-2.20(m，2H)，3.36-4.90(m，7H)，5.22-5.60(m，1H)，7.09-7.40(m，5H)，8.05-8.25(s，2H)；ESI-MS：404.1(M+1)。
Embodiment 9 (2R)-9-{2-[4 '-(3 '-bromophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method preparation similar to Example 7, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3-bromophenyl)-1, ammediol (0.46g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finishes, and obtains the 0.38g pulverulent solids, yield 36.6%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.13-1.25(m，3H)，1.75-2.20(m，2H)，3.36-4.95(m，7H)，5.22-5.50(m，1H)，7.04-7.60(m，4H)，8.05-8.20(s，2H)；ESI-MS：482.1(M+1)。
Embodiment 10 (2R)-9-{2-[4 '-(3 '-fluorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method preparation similar to Example 7, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3-fluorophenyl)-1, ammediol (0.34g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finishes, and obtains the 0.26g pulverulent solids, yield 30.9%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.10-1.25(m，3H)，1.65-2.23(m，2H)，3.32-4.96(m，7H)，5.16-5.40(m，1H)，7.00-7.48(m，4H)，8.02-8.19(s，2H)；ESI-MS：422.1(M+1)。
Embodiment 11 (2R)-9-{2-[4 '-(3 ', 5 '-difluorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method preparation similar to Example 7, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3, the 5-difluorophenyl)-1, ammediol (0.38g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finish, obtain the 0.22g pulverulent solids, yield 25.0%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.10-1.28(m，3H)，1.60-2.24(m，2H)，3.36-4.98(m，7H)，5.06-5.49(m，1H)，6.74-7.20(m，3H)，7.80-8.40(s，2H)；ESI-MS：440.1(M+1)。
Embodiment 12 (2R)-9-{2-[4 '-(2 ', 3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method preparation similar to Example 7, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(2, the 3-dichlorophenyl)-1, ammediol (0.44g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finish, obtain the 0.31g pulverulent solids, yield 32.8%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.11-1.30(m，3H)，1.62-2.20(m，2H)，3.35-4.97(m，7H)，5.26-5.89(m，1H)，7.05-7.65(m，3H)，8.05-8.20(s，2H)；ESI-MS：472.1(M+1)。
Embodiment 13 (2R)-9-{2-[4 '-(4 '-pyridyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method preparation similar to Example 7, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(4-pyridyl)-1, ammediol (0.31g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finishes, and obtains the 0.22g pulverulent solids, yield 27.2%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.08-1.28(m，3H)，1.65-2.24(m，2H)，3.38-5.04(m，7H)，5.20-5.62(m，1H)，7.08-7.38(m，2H)，8.04-8.60(s，4H)；ESI-MS：405.1(M+1)。
Embodiment 14 (2R)-9-{2-[4 '-(3 ', 5 '-xylyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method preparation similar to Example 7, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3, the 5-xylyl)-1, ammediol (0.36g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finish, obtain the 0.28g pulverulent solids, yield 32.5%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.08-1.28(m，3H)，1.65-2.34(m，8H)，3.46-4.95(m，7H)，5.05-5.45(m，1H)，6.75-7.30(m，3H)，8.00-8.20(s，2H)；ESI-MS：432.2(M+1)。
Embodiment 15 (2R)-9-{2-[4 '-(3 ', 5 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy-propyl } preparation of VITAMIN B4
Adopt method preparation similar to Example 7, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (0.57g, 2mmol), 3-(3, the 5-dichlorophenyl)-1, ammediol (0.44g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) and 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finish, obtain the 0.38g pulverulent solids, yield 40.2%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.10-1.28(m，3H)，1.70-2.26(m，2H)，3.46-5.04(m，7H)，5.20-5.46(m，1H)，7.28-7.58(m，3H)，8.02-8.25(s，2H)；ESI-MS：472.1(M+1)。
Embodiment 16 2-amino-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt method preparation similar to Example 7, will 1-[(2-amino-purine-9-yl)-methyl]-the ring propoxy-} methane phosphonic acid (0.60g, 2mmol), 3-(3-chloro-phenyl-)-1, ammediol (0.44g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finishes, and obtains the 0.48g pulverulent solids, yield 53.5%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.83-1.16(m，4H)，1.78-2.20(m，2H)，3.66-4.86(m，6H)，5.20-5.60(m，1H)，7.09-7.47(m，4H)，8.05(s，1H)，8.70(s，1H)；ESI-MS：450.1(M+1)。
Embodiment 17 2-amino-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt method preparation similar to Example 5, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (2.99g, 10mmol), N, N-diethylformamide (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol), and triethylamine (6.06g, 60mmol), S-3-(3-chloro-phenyl-)-1, ammediol (1.87g, 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 1.04g yellow powder shape solid, yield 23.2%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.84-1.16(m，4H)，1.76-2.23(m，2H)，3.64-4.96(m，6H)，5.28-5.60(m，1H)，7.06-7.48(m，4H)，8.01(s，1H)，8.68(s，1H)；ESI-MS：450.1(M+1)。
Embodiment 18 2-amino-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt method preparation similar to Example 5, with (R)-9-[2-(phosphono methoxyl group) propyl group]-VITAMIN B4 (2.99g, 10mmol), N, N-diethylformamide (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol), and triethylamine (6.06g, 60mmol), R-3-(3-chloro-phenyl-)-1, ammediol (1.87g, 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 1.24g yellow powder shape solid, yield 27.6%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.90-1.12(m，4H)，1.78-2.22(m，2H)，3.66-4.88(m，6H)，5.30-5.63(m，1H)，7.08-7.50(m，4H)，8.02(s，1H)，8.70(s，1H)；ESI-MS：450.1(M+1)。
Embodiment 19 2-amino-6-hydroxyl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt method preparation similar to Example 7, will 1-[(2-amino-6-hydroxyl-purine-9-yl)-methyl]-the ring propoxy-} methane phosphonic acid (0.63g, 2mmol), 3-(3-chloro-phenyl-)-1, ammediol (0.44g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finishes, and obtains the 0.18g pulverulent solids, yield 19.3%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.82-1.18(m，4H)，1.76-2.25(m，2H)，3.68-4.88(m，6H)，5.20-5.61(m，1H)，7.06-7.50(m，4H)，8.05(s，1H)；ESI-MS：466.1(M+1)。
Embodiment 20 2-amino-6-hydroxyl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt method preparation similar to Example 5, will 1-[(2-amino-6-hydroxyl-purine-9-yl)-methyl]-the ring propoxy-} and methane phosphonic acid (3.15g, 10mmol), N, N-diethylformamide (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol), and triethylamine (6.06g, 60mmol), S-3-(3-chloro-phenyl-)-1, ammediol (1.87g, 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 0.46g yellow powder shape solid, yield 9.9%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.80-1.12(m，4H)，1.77-2.23(m，2H)，3.62-4.98(m，6H)，5.23-5.65(m，1H)，7.09-7.51(m，4H)，8.04(s，1H)；ESI-MS：466.1(M+1)。
Embodiment 21 2-amino-6-hydroxyl-9-{2-[(2S ', 4R ')-4 '-(3 '-dichlorophenyl)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxyl group-2-ethylene group ethyl } preparation of purine
Adopt method preparation similar to Example 5, will 1-[(2-amino-6-hydroxyl-purine-9-yl)-methyl]-the ring propoxy-} and methane phosphonic acid (3.15g, 10mmol), N, N-diethylformamide (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol), and triethylamine (6.06g, 60mmol), R-3-(3-chloro-phenyl-)-1, ammediol (1.87g, 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 0.51g yellow powder shape solid, yield 10.1%.
1HNMR(400MHz，DMSO)，δ(ppm)：0.87-1.20(m，4H)，1.74-2.21(m，2H)，3.65-4.96(m，6H)，5.26-5.67(m，1H)，7.06-7.49(m，4H)，8.04(s，1H)；ESI-MS：466.1(M+1)。
Embodiment 22 2-amino-6-to anisole sulfydryl-9-{2-[4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy ethyl the preparation of purine
Adopt method preparation similar to Example 7, will 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] methane phosphonic acid (0.82g, 2mmol), 3-(3-chloro-phenyl-)-1, ammediol (0.44g, 2mmol), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.46g, 3mmol) with 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2mmol) reaction finishes, and obtains the 0.38g pulverulent solids, yield 33.9%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.70-2.10(m，2H)，3.36-4.86(m，11H)，5.20-5.60(m，1H)，6.95-8.06(m，9H)；ESI-MS：562.1(M+1)。
Embodiment 23 2-amino-6-are to anisole sulfydryl-9-{2-[(2R ', 4S ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy ethyl } preparation of purine
Adopt method preparation similar to Example 5, will { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid (4.11g, 10mmol), N, N-diethylformamide (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol), and triethylamine (6.06g, 60mmol), S-3-(3-chloro-phenyl-)-1, ammediol (1.87g, 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 0.93g yellow powder shape solid, yield 16.6%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.73-2.16(m，2H)，3.38-4.80(m，11H)，5.20-5.62(m，1H)，6.90-8.08(m，9H)；ESI-MS：562.1(M+1)。
Embodiment 24 2-amino-6-are to anisole sulfydryl-9-{2-[(2S ', 4R ')-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl] methoxy ethyl } preparation of purine
Adopt method preparation similar to Example 5, will { 2-[2-amino-6-(4-anisole sulfydryl) purine-9-yl)-oxyethyl group] } methane phosphonic acid (4.11g, 10mmol), N, N-diethylformamide (1.01g, 10mmol), oxalyl chloride (3.81g, 30mmol), and triethylamine (6.06g, 60mmol), R-3-(3-chloro-phenyl-)-1, ammediol (1.87g, 10mmol), drip the reaction of 8.0g trifluoroacetic acid, obtain 1.03g yellow powder shape solid, yield 18.4%.
1HNMR(400MHz，DMSO)，δ(ppm)：1.72-2.19(m，2H)，3.40-4.87(m，11H)，5.22-5.60(m，1H)，6.91-8.08(m，9H)；ESI-MS：562.1(M+1)。
Embodiment 25 2-amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-hydroxyl-3-(2 ', 4 '-cis-(4 ' S)-4 '-(3 '-chloro-phenyl-)-2 '-oxo-1 ', 3 ', 2 '-two oxa-phospha cyclohexanes-2 '-yl) oxygen methyl-2-methylene radical pentamethylene]-preparation of 6H-purine-6-one
Adopt method preparation similar to Example 1, with entecavir (1.664g, 6.0mmol), 4S-4-(4-pyridyl)-N, N-di-isopropyl-1,3,2-two oxa-s phospha cyclohexane-2-amine (2.54g, 9.0mmol) and 5-methylthio group tetrazole (1.054g, 9.0mmol) reaction, obtain the 0.13g pulverulent solids, yield 4.3%.
1HNMR(400MHz，DMSO)，δ(ppm)：1HNMR(400MHz，DMSO)，δ(ppm)：7.67(s，1H)，7.15-7.43(m，4H)，5.26-5.64(m，3H)，4.18-4.65(m，4H)，3.31-3.75(m，2H)，1.75-2.54(m，5H)；ESI-MS：508.1(M+1)。
The pharmacologically active evaluation of anti-duck hepatitis B virus (DHBV) in experimental example 26 bodies
Animal model: 1 age in days duckling of the egg incubation that the Chongqing sheldrake of employing healthy adult produces, through abdominal cavity inoculation 0.1ml DHBV DNA positive-virus serum.After inoculating for 1 week, respectively external jugular vein blood drawing detects to filter out through dot hybridization with the DHBV dna probe of digoxigenin labeled and infects positive duck, raise to 2 all ages as laboratory animal.
Measuring method: will infect 55 of positive ducks and be divided into 11 groups at random, and be divided into: 1. virus control group, use the starch capsule; 2. positive drug control group: use emtricitabine, dosage is 100mg/ (kg.d) and tynofovir ester, and dosage is 150mg/ (kg.d); 3. embodiment 1 and embodiment 3, dosage is 100mg/ (kg.d); 4. embodiment 5 and embodiment 6, dosage is 150mg/ (kg.d); 5. embodiment 17 and embodiment 20, dosage is 30mg/ (kg.d); 6. embodiment 23, and dosage is 5mg/ (kg.d); 7. embodiment 25, and dosage is 0.5mg/ (kg.d).The experiment administration time is 14 days, and drug withdrawal was observed 7 days.Observation index: serum DHBV DNA changes situation: before medication, medication 7 days, medication 14 days, drug withdrawal external jugular vein blood drawing respectively in 7 days, separation of serum is to be checked in-20 ℃ of preservations.Adopt spot hybridization, prepare with the digoxigenin labeled test kit of Roche Holding Ag that the DHBV dna probe is unified to be detected, carry out diaphragm with Vuego can (Brisa-620ST) scanner and scan; With the Discovery Series Quantity One software spot is carried out quantitative analysis, the spot value is volume (volume=intensity * mm
2).
Serum DHBV dna level comparison before and after table 1 treatment (x ± s)
Annotate:
aP＜0.05,
bP＜0.01
Interpretation of result: table 1 is classified mean number and the standard deviation of respectively organizing DNA spot volume value as, and statistics adopts before and after the treatment self paired t-test, is the comparison of dna level before medication group different time dna level and the medication on the same group.Wherein the activity of embodiment 3 anti-DHBV and positive control emtricitabine or tynofovir ester are suitable; The activity of the anti-DHBV of embodiment 1, embodiment 5, embodiment 17, embodiment 20, embodiment 23 and embodiment 25 obviously is better than positive control emtricitabine or tynofovir ester.
Claims (9)
1, the compound of following general formula I, or its isomer, pharmacologically acceptable salt, hydrate or solvate:
Wherein:
R
1Be selected from group with following structure:
R
2Be selected from chlorine, bromine, fluorine, iodine, nitro, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylamino radical, C
1-6Haloalkyl or alkyloyl;
X be selected from the neighbour, or the nitrogen or the carbon of contraposition;
N is 0,1,2,3 or 4.
2, compound according to claim 1, or its isomer, pharmacologically acceptable salt, hydrate or solvate is characterized in that, R in the described general formula I
1With 4 aromatic group cis or trans each other in the phosphoric acid ester ring structure.
3, compound according to claim 1, or its isomer, pharmacologically acceptable salt, hydrate or solvate is characterized in that, in the described general formula I in the phosphoric acid ester ring structure 4 carbon atom have chirality, its configuration is S or R-configuration.
According to each described compound of claim 1-3, it is characterized in that 4, described isomer comprises tautomer, cis-trans-isomer, conformer, meso compound and has mapping or the optical isomer of non-enantiomorphic relationship.
5, according to each described compound of claim 1-3, it is characterized in that described compound is:
(1) 5-fluoro-1-(2R, 5S)-{ 2 ＇, 4 ＇-cis-(4 ＇ S)-4 ＇-[(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(2) 5-fluoro-1-(2R, 5S)-{ 2 ＇, 4 ＇-trans-(4 ＇ S)-4 ＇-[(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(3) 5-fluoro-1-(2R, 5S)-{ 2 ＇, 4 ＇-cis-(4 ＇ S)-4 ＇-[(4 ＇-pyridyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(4) 5-fluoro-1-(2R, 5S)-{ 2 ＇, 4 ＇-trans-(4 ＇ S)-4 ＇-[(4 ＇-pyridyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] oxygen methyl isophthalic acid, 3-oxygen sulphur ring-5-acyl } cytosine(Cyt)
(5) (2R)-and 9-{2-[(2R ＇, 4S ＇)-4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(6) (2R)-and 9-{2-[(2S ＇, 4R ＇)-4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(7) (2R)-and 9-{2-[4 ＇-(3-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(8) (2R)-and 9-{2-[4 ＇-(phenyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(9) (2R)-and 9-{2-[4 ＇-(3 ＇-bromophenyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(10) (2R)-and 9-{2-[4 ＇-(3 ＇-fluorophenyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(11) (2R)-and 9-{2-[4 ＇-(3 ＇, 5 ＇-difluorophenyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(12) (2R)-and 9-{2-[4 ＇-(2 ＇, 3 ＇-dichlorophenyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(13) (2R)-and 9-{2-[4 ＇-(4 ＇-pyridyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(14) (2R)-and 9-{2-[4 ＇-(3 ＇, 5 ＇-xylyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(15) (2R)-and 9-{2-[4 ＇-(3 ＇, 5 ＇-dichlorophenyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy-propyl } VITAMIN B4
(16) 2-amino-9-{2-[4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxyl group-2-ethylene group ethyl } purine
(17) 2-amino-9-{2-[(2R ＇, 4S ＇)-4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxyl group-2-ethylene group ethyl } purine
(18) 2-amino-9-{2-[(2S ＇, 4R ＇)-4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxyl group-2-ethylene group ethyl } purine
(19) 2-amino-6-hydroxyl-9-{2-[4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxyl group-2-ethylene group ethyl } purine
(20) 2-amino-6-hydroxyl-9-{2-[(2R ＇, 4S ＇)-4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxyl group-2-ethylene group ethyl } purine
(21) 2-amino-6-hydroxyl-9-{2-[(2S ＇, 4R ＇)-4 ＇-(3 ＇-dichlorophenyl)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxyl group-2-ethylene group ethyl } purine
(22) 2-amino-6-is to anisole sulfydryl-9-{2-[4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy ethyl } purine
(23) 2-amino-6-is to anisole sulfydryl-9-{2-[(2R ＇, 4S ＇)-4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy ethyl } purine
(24) 2-amino-6-is to anisole sulfydryl-9-{2-[(2S ＇, 4R ＇)-4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl] methoxy ethyl } purine
(25) 2-amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-hydroxyl-3-(2 ＇, 4 ＇-cis-(4 ＇ S)-4 ＇-(3 ＇-chloro-phenyl-)-2 ＇-oxo-1 ＇, 3 ＇, the oxygen methyl-2-methylene radical pentamethylene of 2 ＇-two oxa-phospha cyclohexane-2 ＇-yl)]-the 6H-purine-6-one.
According to each described compound of claim 1-3, it is characterized in that 6, the salt of described compound is and mineral acid or the formed pharmacologically acceptable salt of organic acid.
According to each described compound of claim 1-3, it is characterized in that 7, the salt of described compound is and the formed pharmacologically acceptable salt of alkali reaction.
8, a kind of medicinal compositions is characterized in that, comprises each described formula I compound of claim 1-3, or its isomer, pharmacologically acceptable salt, hydrate or solvate and pharmaceutically acceptable auxiliary, diluent or carrier.
9, according to each described compound of claim 1-3, or its isomer, pharmacologically acceptable salt, hydrate or solvate treat and/or prevent the application that acute and Chronic HBV or HIV or HCV or HCMV infect the medicine of the disease that causes being used for preparing.
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