CN106317116A - Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition - Google Patents
Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition Download PDFInfo
- Publication number
- CN106317116A CN106317116A CN201610697576.7A CN201610697576A CN106317116A CN 106317116 A CN106317116 A CN 106317116A CN 201610697576 A CN201610697576 A CN 201610697576A CN 106317116 A CN106317116 A CN 106317116A
- Authority
- CN
- China
- Prior art keywords
- phosphamide
- acid
- compound
- alkyl
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CC(C=C)C([C@](*)NP(COCCNCNC1C(N)=NC=NC1)(OC(**1)=CC=C1C(C1=CC1)(F)F)=O)=O Chemical compound CC(C=C)C([C@](*)NP(COCCNCNC1C(N)=NC=NC1)(OC(**1)=CC=C1C(C1=CC1)(F)F)=O)=O 0.000 description 3
- LVFBTXKZKUTKBI-YFKPBYRVSA-N CC(C)OC([C@H](C)NO)=O Chemical compound CC(C)OC([C@H](C)NO)=O LVFBTXKZKUTKBI-YFKPBYRVSA-N 0.000 description 1
Classifications
-
- 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
- C07F9/65616—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 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention provides a phosphamide nucleosides compound as shown in a formula (I). Compared with the prior art, the phosphamide nucleosides compound has the advantages that the phosphamide nucleosides compound has antiviral activity which is remarkably higher than that of TAF on aspects of HIV resisting and hepatitis B resisting; the HIV resisting activity of some compounds is about 10 times higher than that of the TAF, and the hepatitis B resisting activity of the same compounds is also 2-5 times higher than that of the TAF; moreover, the phosphamide nucleosides compound has stable chemical properties and is difficult to hydrolyze by hydrolytic enzymes; compared with the TAF, the phosphamide nucleosides compound has superiority on aspect of toxicity and especially renal toxicity, and patients suffering from HIV and/or HBV can be effectively treated by the compound or isomer thereof at a low clinic dosage.
Description
Technical field
The invention belongs to medicine antivirus technology field, particularly relate to phosphamide nucleoside compound and pharmaceutically can connect
The salt being subject to and application, pharmaceutical composition.
Background technology
HIV (human immunodeficiency virus) (HIV) has two types, HIV-1 type and HIV-2 type, the patient of severe infections HIV-1
Immunologic function can be caused to lack (ARC and AIDS).HIV is as one of the most serious disease of infectiousness in the world, complete in 2012
Ball has 3,005 million people's aids infections, and newly-increased 2,700,000 cases, nearly 2,300,000 people die from acquired immune deficiency syndrome (AIDS).Current research
Show in teenager that HIV number becomes to steeply rise trend, so need nonetheless remain for developing the medicine of new high-efficiency low-toxicity and new
Drug regimen be used for treating and preventing acquired immune deficiency syndrome (AIDS).In 2015, the pharmaceutical market of HIV was 242.3 hundred million dollars, and with every year
The speed increment of 8.6%, it is contemplated that reached the market sale of 25,000,000,000 dollars in 2019.
If exploitation at present treats and prevents the key enzyme that drug main blocks or regulation inhibition of HIV replicates and the process of HIV,
As hiv reverse transcriptase, hiv protease and intergrase and the up-to-date HIV that can effectively block enter cell key glycoprotein
Medicine.The HAART (HAART) of these medicines and drug combination mainly contain two nucleoside medicines and a kind of other
Medicine.Due to existing inverase or compound recipe all can not inhibition of HIV in purged body, for long-term and life-long therapy HIV
Infected patient, the drug resistance of generation makes the pharmaceutically active treated reduce or lose activity；The additionally height of early development medicine
Toxicity and various side effect are also serious problems for the patient of long-term prescription.It is thus desirable to it is real to develop new chemistry
Body, has the structure of novelty and new model of action, and low toxicity and high activity, has produced resistance to for new compositions treatment
The patient of the property of medicine.
Hiv reverse transcriptase (RT) is a kind of important virus protease, plays a crucial role in the reproduction process of virus.
The reverse transcriptase of HIV is heterodimer, comprises two subunits of P66 and P51.The reverse transcriptase inhibitors of FDA approval is divided into nucleoside
Inhibitor (NRTIs) and non-nucleosidic inhibitors (NNRTIs).Wherein nucleoside medicine includes AZT, ddI, ddC, d4T、3TC,、
Abacavir, emtricitabine and tenofovir etc..
(R)-9-(2-phosphate methoxy propyl group)-adenine (tenofovir, PMPA, TFV) has anti-AIDS and hepatitis B
Activity, toxicity is far below adefovirdipivoxil.But due to highly acid and the polarity of TFV, it is difficult to, through cell membrane, cause bioavailability
Differing from, and the TFV of high concentration can increase the weight of the infiltration burden of glomerule, especially for the patient of renal function defect, serious kidney is little
Pipe toxicity can cause Fanconi syndrome, and the highly acid of TFV also has certain toxicity to sclerotin simultaneously.
TDF (tenofovir disoproxil fumarate) is the fumarate of PMPA dibasic acid esters prodrug, is lucky Deco
The prodrug of new generation being better than adefovir ester of company exploitation, calendar year 2001 and 2008 by U.S. video drug administration
(USFDA) approval is for the infected patient of first-line drug treatment HIV and HBV.TDF greatly improves penetrance and the mouth of cell
Clothes degree of absorbing, adds that TDF in-vitro screening has the highest AntiHIV1 RT activity and HBV activity, outstanding anti-drug resistance and good peace
Quan Xing, is widely used in various combined dosage form in terms of anti-AIDS.Wherein the Troyes of one of compound recipe reaches (Truvada) is exactly safe
Nuo Fuwei ester and emtricitabine immobilised compound, be widely used in the treatment of AntiHIV1 RT activity and HBV, and additionally Disease Control and Prevention Center of the Ye Shi U.S. is recommended
For the medicine that prevents AIDS.Truvada is 41.5 hundred million dollars the sale of 2015, accounts for HIV market sale
17.1%.But TDF equally exists shortcoming, unstable in blood plasma, easily it is hydrolyzed to TFV, on the other hand, for renal function defect
Patient, TDF may cause the risk of nephrotoxicity.
In order to reduce the TDF TFV concentration at plasma hydrolysis, the medicine that Gilid Science Co. develops metabolism more stable replaces
Nuo Fuweiaila phenol amine (Tenofovir alafenamide fumarate (TAF)), two compound recipes of TAF (Genvoya and
Odefsey) HIV is treated by FDA (Food and Drug Adminstration) (USFDA) approval for first-line drug.Two three of TAF treatment HBV
Phase clinic is successful.TAF is more stable than TDF in blood plasma, and major part TAF is absorbed into cell.Compared with TAF with TDF, at two
Aspect has significant difference: the TFV of (1) TAF metabolism concentration in blood plasma is lower by 90% than TDF；(2) TFV of TAF metabolism is exempting from
The concentration of epidemic disease cell is higher 4 times than TDF.So the nephrotoxicity that can cause with significantly reduced TDF of the TAF of low dosage and bone toxicity.
Although TAF has the low dosage of clinical practice and the highest AntiHIV1 RT activity and HBV activity, need nonetheless remain for out clinically
The compound sending out new and new model of action, invent stability more more preferable than TAF and higher external activity further, thus have
Reducing clinical drug dosage and reducing nephrotoxicity and the bone toxicity of compound further of effect, preferably plays treatment hepatitis B and Chinese mugwort
Grow sick clinical effectiveness.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of phosphamide nucleoside compound and pharmacy thereof
Upper acceptable salt and application, pharmaceutical composition, this phosphamide nucleoside compound has higher HIV (human immunodeficiency virus)-resistant activity.
The invention provides a kind of phosphamide nucleoside compound, as shown in formula (I):
Wherein, R1Selected from the alkyl of C1～C6, the cycloalkyl of C3～C6, the Heterocyclylalkyl of C4～C7,
The haloalkyl of C2～C6, the aryl of C6～C10, the aralkyl of C7～C10, C3～C10 alkanoyl oxyalkyl, C7
～C10 aroyl oxyalkyl or C3～C10 alkoxy carbonyl group oxyalkyl；
R2Aryl selected from C6～C30；
Described aryl is selected from unsubstituting aromatic yl or substituted aryl；The substituent group of described substituted aryl is selected from halogen, alkyl, ring
Alkyl, cycloheteroalkyl, haloalkyl, halogenated cycloalkyl, cycloalkyl-alkyl, cyano group, heteroaryl or alkyl silyl；Unsubstituted virtue
Base is selected from phenyl, xenyl or naphthyl.
Preferably, described R1Alkyl or the cycloalkyl of C3～C6 selected from C1～C3.
Preferably, as shown in the following structure:
Present invention also offers a kind of phosphamide nucleoside compound pharmaceutically acceptable salt, as shown in formula (II):
Wherein, R1Selected from the alkyl of C1～C6, the cycloalkyl of C3～C6, the Heterocyclylalkyl of C4～C7, the halo of C2～C6
Alkyl, the aryl of C6～C10, the aralkyl of C7～C10, C3～C10 alkanoyl oxyalkyl, C7～C10 aroyl oxyalkyl or
C3～C10 alkoxy carbonyl group oxyalkyl；
R2Aryl selected from C6～C30；
Described aryl is selected from unsubstituting aromatic yl or substituted aryl；The substituent group of described substituted aryl is selected from halogen, alkyl, ring
Alkyl, cycloheteroalkyl, haloalkyl, halogenated cycloalkyl, cycloalkyl-alkyl, cyano group, heteroaryl or alkyl silyl；Unsubstituted virtue
Base is selected from phenyl, xenyl or naphthyl；
Described acid is pharmaceutically acceptable acid.
Preferably, described acid selected from fumaric acid, half fumaric acid, citric acid, tartaric acid, oxalic acid, malic acid, methanesulfonic acid,
Hydrochloric acid, sulphuric acid and the one in phosphoric acid.
Preferably, as shown in the following structure:
Present invention also offers a kind of phosphamide nucleoside compound and/or phosphamide nucleoside compound pharmaceutically can connect
The salt being subject to application in the medicine of preparation prevention and/or treatment virus infection.
Preferably, described virus is inhibition of HIV, HBV virus, hepatitis B virus and the one or many in hepatitis B virus
Kind.
Present invention also offers a kind of pharmaceutical composition, including phosphamide nucleoside compound and/or phosphamide ucleosides
Compound pharmaceutically acceptable salt.
Preferably, other therapeutic agent and/or reinforcing agent are also included；Other therapeutic agent described presses down selected from hiv protease
Preparation, hiv reverse transcriptase non-nucleosidic inhibitors, hiv reverse transcriptase nucleosidic inhibitors, hiv reverse transcriptase nucleotide inhibitor,
Hiv integrase inhibitor, CCR5 inhibitor, HBV capsid inhibitor, cccDNA form inhibitor, cccDNA epigenetic modification
Agent and one or more in hbv rna i medicine；Described reinforcing agent selected from Tuo Nawei and/or than west he
The invention provides a kind of phosphoric acid nucleoside compounds, as shown in formula (I)；Wherein, R1Selected from C1～C6 alkyl,
The Heterocyclylalkyl of the cycloalkyl of C3～C6, C4～7, the haloalkyl of C2～C6, the aryl of C6～C10, the aralkyl of C7～C10
Base, C3～C10 alkanoyl oxyalkyl, C7～C10 aroyl oxyalkyl or C3～C10 alkoxy carbonyl group oxyalkyl；R2Selected from C6～
The aryl of C30；Described aryl is selected from unsubstituting aromatic yl or substituted aryl；The substituent group of described substituted aryl selected from halogen, alkyl,
Cycloalkyl, cycloheteroalkyl, haloalkyl, halogenated cycloalkyl, cycloalkyl-alkyl, cyano group, heteroaryl or alkyl silyl；Unsubstituted
Aryl is selected from phenyl, xenyl or naphthyl.Compared with prior art, the phosphamide nucleoside compound that the present invention provides is anti-
HIV and anti-hepatitis B aspect have the antiviral activity being significantly superior to TAF, and some compound HIV (human immunodeficiency virus)-resistant activity are up to 10 times than TAF
Left and right, same compound anti-hepatitis B activity is also superior to TAF2～5 times；And this phosphamide nucleoside compound has more stable
Chemical property, hydrolytic enzyme is more difficult to hydrolysis, particularly has superiority in terms of nephrotoxicity compared with TAF in terms of toxicity, permissible
The compounds of this invention or its isomer with lower clinical dosage effectively treat HIV and/or HBV patient.
Detailed description of the invention
The invention provides a kind of phosphoric acid nucleoside compounds, as shown in formula (I):
Wherein, R1Selected from the alkyl of C1～C6, the cycloalkyl of C3～C6, the Heterocyclylalkyl of C4～7, the alkyl halide of C2～C6
Base, the aryl of C6～C10, the aralkyl of C7～C10, C3～C10 alkanoyl oxyalkyl, C7～C10 aroyl oxyalkyl or C3
～C10 alkoxy carbonyl group oxyalkyl, the alkyl of preferably C1～C5, the cycloalkyl of C3～C6, the Heterocyclylalkyl of C4～C7, C1～C5
Haloalkyl, the aryl of C6～C10, the aralkyl of C7～C10, C3～C10 alkanoyl oxyalkyl, C7～C10 aroyl oxygen
Alkyl or C3～C10 alkoxy carbonyl group oxyalkyl, be further preferably the alkyl of C2～C4, the cycloalkyl of C4～C6, the heterocycle of C4～C7
Alkyl, the haloalkyl of C2～C4, the aryl of C6～C10, the aralkyl of C7～C10, C3～C10 alkanoyl oxyalkyl, C7～
C10 aroyl oxyalkyl or C3～C10 alkoxy carbonyl group oxyalkyl, the alkyl of most preferably C1～C3 or the cycloalkyl of C3～C6.
R2Selected from the aryl of the aryl of C6～C30, preferably C6～C20, it it is further preferably the aryl of C6～C12.
In the present invention, as described R1During for the alkyl of C1～C6, described R2It is preferably phenyl, substituted phenyl, xenyl
Or naphthyl；Substituent group in described substituted phenyl is preferably the alkyl of C1～C6, the cycloalkyl of C3～C6, the halo of C3～C6
Cycloalkyl or alkyl silyl.
In the present invention, above-mentioned aryl of stating is selected from unsubstituting aromatic yl or substituted aryl；The substituent group choosing of described substituted aryl
From halogen, alkyl, cycloalkyl, cycloheteroalkyl, haloalkyl, halogenated cycloalkyl, cycloalkyl-alkyl, cyano group, heteroaryl or alkyl
Silica-based；Unsubstituted aryl is selected from phenyl, xenyl or naphthyl.
Phosphamide nucleoside compound provided by the present invention is alternatively its stereoisomer；Stereoisomer " refer to by
Isomer produced by molecule Atom spatially arrangement mode difference.Including cis-trans-isomer, enantiomer and conformation
Isomer.All stereoisomers belong to the scope of the present invention.The compound of the present invention can be independent stereoisomer or
The mixing of other isomer such as racemic modification, or the mixing of other stereoisomers all.In the present invention shown in formula (I)
Compound in phosphorus atoms there is chirality, its configuration can be S-configuration, it is possible to for R configuration, or the mixing of S-configuration and R-configuration
Thing.
Phosphamide nucleoside compound provided by the present invention can be also its hydrate, solvate or crystallization；Solvent closes
Thing refers to the form of the compounds of this invention of the coordination compound by forming solid-state or liquid with solvent molecule coordination.Hydrate is molten
The specific form of agent compound, is wherein coordinated with water.In the present invention, solvate is preferably hydrate.Crystallization refers to this
The various solid forms that compound described in invention is formed, including crystal formation, amorphous.
The most if no special instructions, alkyl refers to straight chain, side chain or ring-type saturated hydrocarbyl, preferably 1～20
Alkyl below carbon atom.The embodiment of alkyl includes methyl, ethyl, n-pro-pyl, isopropyl, cyclopropyl, normal-butyl, isobutyl
Base, the tert-butyl group, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohesyl, 2,2 ,-methyl butyl and 2,
3-dimethylbutyl, 16-alkyl, 18-alkyl.C1～C6 alkyl refers to the straight chain containing 1～6 carbon atom, side chain or ring-type
Saturated hydrocarbyl.Alkyl includes substituted and does not has substituted alkyl.When alkyl is replaced, substituent group can make any
Junction point on replace, substituent group can be monosubstituted or polysubstituted.Substituent group independence selected from alkyl, thiazolinyl, alkynyl, alkane
Epoxide, alkylthio group, alkyl amino, deuterium, halogen, mercaptan, hydroxyl, nitro, carboxyl, ester group, cyano group, cycloalkyl, aryl, heteroaryl
Base, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, oxo.
Cycloalkyl refers to the saturated and/or unsaturated monocycle of part or multi-ring cyclic hydrocarbon radical.Monocycle can include 3～10 carbon atoms.
The non-limiting example of monocyclic naphthenes base includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, ring
Hexadienyl, suberyl etc..Polycyclic naphthene base includes the cycloalkyl of volution, condensed ring and bridged ring.Cycloalkyl include unsubstituted and
Containing substituent group.Substituent group is selected from one or more substituted radicals, includes but are not limited to following group, independent selected from alkane
Base, cycloalkyl, alkoxyl, halogen, carboxyl, ester group, amino, amide groups, hydroxyl, cyano group, nitro, aryl, heteroaryl.
Aryl refers to 6～10 yuan of full carbon monocycles or multi-ring aromatic group, including phenyl, Nai Ji, xenyl etc..Aryl is permissible
It is substituted and unsubstituted.Substituent group independence selected from alkyl, cycloalkyl (cyclopropane base, Tetramethylene. base and Pentamethylene. base
Deng), thiazolinyl, alkynyl, nitrine, amino, deuterium, alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, heterocycle alkane
Base, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, alkyl silyl etc..
Heteroaryl refers to comprise the group of 1～10 heteroatomic miscellaneous aroma system.Hetero atom includes oxygen, sulfur, nitrogen, phosphorus etc..
Wherein single heterocyclic radical include but not limited to furan, thiophene, pyrroles, thiazole, imidazoles, 1,2,3-triazole, 1,2,4-triazole, 1,
2,3-thiadiazoles, azoles, 1,2,4-diazole, 1,3,4-diazole, pyridine, pyrimidine, pyridazine, pyrazine, oxolane, tetrahydrochysene pyrrole
Cough up, piperidines, piperazine, morpholine, isoxazolines etc..Condensed hetero ring base includes but not limited to quinoline, isoquinolin, indole, benzofuran, benzene
Bithiophene, purine, acridine, carbazole, fluorenes, chromene ketone, Fluorenone, quinoxaline, 3,4-dihydro naphthalenone, dibenzofurans, hydrogenation hexichol
And furan, benzoxazolyl group etc..Heteroaryl can be substituted and unsubstituted.Substituent group independence selected from substituent group independence
Selected from alkyl, cycloalkyl (cyclopropane base, Tetramethylene. base and Pentamethylene. base etc.), thiazolinyl, alkynyl, nitrine, amino, deuterium, alkoxyl,
Alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups,
Cycloalkylthio, heterocycle alkylthio group, alkyl silyl etc..
Halogen refers to fluorine, chlorine, bromine, iodine.
Haloalkyl refers to the alkyl at least replaced by a halogen atom.
Heterocyclic radical refers at least contain a heteroatomic cyclic group, and wherein hetero atom is nitrogen, oxygen, sulfur, sulfur etc..Heterocycle
Base includes single heterocyclic radical and many heterocyclic radicals.
In the present invention, described phosphamide nucleoside compound is the most as shown in the following structure:
The phosphamide nucleoside compound that the present invention provides has in terms of AntiHIV1 RT activity and anti-hepatitis B and is significantly superior to TAF's
Antiviral activity, some compound HIV (human immunodeficiency virus)-resistant activity are up to about 10 times than TAF, same compound anti-hepatitis B activity also superior to
TAF2～5 times；And this phosphamide nucleoside compound has more stable chemical property, hydrolytic enzyme is more difficult to hydrolysis, with TAF phase
Particularly there is superiority in terms of nephrotoxicity than in terms of toxicity, can be with the compounds of this invention of lower clinical dosage or it is different
Structure body effectively treats HIV and/or HBV patient.
The invention provides the phosphamide nucleoside compound of a kind of novel structure, the activity of AntiHIV1 RT activity be better than TAF10 times with
On, and toxicity and TAF suitable.Also superior to TAF more than 5 times in terms of anti-hepatitis B.This is because newly-designed compound is permissible
In histiocyte, metabolism is higher TFVDP.These highly active results are thought considerably beyond design at that time, so this
Bright phosphamide nucleoside compound can significantly improve the therapeutic effect to hepatitis B and acquired immune deficiency syndrome (AIDS), and reduce greatly TDF or
Nephrotoxicity that TAF causes and bone toxicity.
Present invention also offers the preparation method of a kind of above-mentioned phosphamide nucleoside compound, by the change shown in formula (III)
Compound reacts with the compound shown in formula (IV), obtains the phosphamide nucleoside compound shown in formula (I).
In the present invention, this reaction is preferably carried out under conditions of two sulfur two pyridines, triphenylphosphine exist；Described reaction
The solvent that solvent is well known to those skilled in the art, there is no special restriction, is preferably pyridine in the present invention.
Present invention also offers a kind of phosphamide nucleoside compound pharmaceutically acceptable salt, as shown in formula (II):
Wherein, R1Selected from the alkyl of C1～C6, the cycloalkyl of C3～C6, the Heterocyclylalkyl of C4～C7, the halo of C2～C6
Alkyl, the aryl of C6～C10, the aralkyl of C7～C10, C3～C10 alkanoyl oxyalkyl, C7～C10 aroyl oxyalkyl or
C3～C10 alkoxy carbonyl group oxyalkyl；
R2Aryl selected from C6～C30；
Described aryl is selected from unsubstituting aromatic yl or substituted aryl；The substituent group of described substituted aryl is selected from halogen, alkyl, ring
Alkyl, cycloheteroalkyl, haloalkyl, halogenated cycloalkyl, cycloalkyl-alkyl, cyano group, heteroaryl or alkyl silyl；Unsubstituted virtue
Base is selected from phenyl, xenyl or naphthyl；
Described acid is pharmaceutically acceptable acid.
Wherein, R1With R2The most same as above, do not repeat them here.
In the present invention, described acid be preferably phosphoric acid, sulphuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid,
Mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-methyl benzenesulfonic acid, malic acid, Loprazolam or its be similar to
In thing, more preferably fumaric acid, half fumaric acid, citric acid, tartaric acid, oxalic acid, malic acid, methanesulfonic acid, hydrochloric acid, sulphuric acid and phosphoric acid
One.
In the present invention, described phosphamide nucleoside compound pharmaceutically acceptable salt, the most as shown in the following structure:
Present invention also offers the phosphamide nucleoside compound shown in a kind of above-mentioned formula (I) and the phosphinylidyne shown in formula (II)
The application in the medicine of preparation prevention and/or treatment virus infection of the amine nucleoside compound pharmaceutically acceptable salt.
Wherein, described virus is preferably inhibition of HIV and or HBV virus.
Present invention also offers a kind of a kind of pharmaceutical composition, including shown in formula (I) phosphamide nucleoside compound
And/or the phosphamide nucleoside compound pharmaceutically acceptable salt shown in formula (II).
According to the present invention, described pharmaceutical composition also includes other therapeutic agent and/or reinforcing agent；Other treatment described
Agent is selected from hiv protease inhibitor, hiv reverse transcriptase non-nucleosidic inhibitors, hiv reverse transcriptase nucleosidic inhibitors, HIV reverse transcription
Enzyme nucleotide inhibitor, hiv integrase inhibitor, CCR5 inhibitor, HBV capsid inhibitor (capsid inhibitor),
CccDNA forms inhibitor, cccDNA epigenetic modification agent and one or more in hbv rna i medicine；Described reinforcing agent
Selected from Tuo Nawei and/or than west he (Cobicistat).
For making various dosage form, described pharmaceutical composition the most also includes pharmaceutically acceptable carrier；Described carrier is excellent
Elect pharmaceutically acceptable diluent, excipient, filler, binding agent, disintegrating agent, absorption enhancer, surfactant, profit as
One or more in lubrication prescription, flavouring agent and sweeting agent etc..
In the present invention, the dosage form of described pharmaceutical composition can be tablet, powder, capsule, granule, oral liquid and injection
The various ways such as preparation, there is no special restriction.
The medicine of above-mentioned various dosage form all can be prepared by the conventional method of pharmaceutical field.
Preferably, the pharmaceutical composition composition of the present invention can be made up of lower proportioning:
In order to further illustrate the present invention, the phosphamide nucleoside compound that the present invention provided below in conjunction with embodiment and
Its pharmaceutically acceptable salt is described in detail with application, pharmaceutical composition.
Reagent used in following example is commercially available.
(R) synthesis of-9-[2-[(phenyl) phosphoric acid methoxy] propyl group] adenine (intermediate-1)
By tenofovir (14.6g, 50.8mmol) and phenol (9.6g, 102mmol) after vacuum drying half an hour, it is dissolved in
N-Methyl pyrrolidone (39g), under nitrogen protection, is warming up to 85 DEG C, after stirring 30 minutes, addition triethylamine (6.3g,
62.3mmol), react 10 minutes, be warming up to 100 DEG C, be slowly added dropwise the N-Methyl pyrrolidone of DCC (17.1g, 82.9mmol)
(16g) solution, dropping in 6 hours is complete, continues reaction 20h.Reactant liquor is cooled to room temperature, filters, and filtrate concentrates, and residue adds
Methanol (30mL) stirs, and it is (middle that the solid filtration drying of precipitation obtains (R)-9-[2-[(phenyl) phosphoric acid methoxy] propyl group] adenine
Body-1) (11.3g, 61.4%).
Utilizing nuclear magnetic resonance, NMR to be analyzed the intermediate-1 obtained, obtain its proton nmr spectra, result is1H NMR
(400MHz,DMSO-d6):δ0.99-1.11(d,3H),3.71-3.85(m,2H),3.92-4.01(m,1H),4.14-4.35
(m, 2H), 6.98-7.36 (m, 5H), 7.58 (s, 2H), 8.14 (s, 2H), 8.15 (s, 2H).
Utilizing mass spectrograph to be analyzed the intermediate-1 obtained, obtaining its mass spectral results is ESI-MS:[M+H]+:
364.1；[M+Na]+: 386.1.
Reaction scheme 1
Embodiment 1
1-(((cyclohexyloxy) carbonyl) epoxide) ethyl (((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) oxygen
Base) methyl) (phenoxy group) phosphoryl)-ALANINE ethyl ester fumarate (6)
The synthesis of step 1:1-(((cyclohexyloxy) carbonyl) epoxide) ethyl (tert-butoxycarbonyl)-ALANINE (3)
Under nitrogen protection, DMF (15ml) solution of Boc-L-alanine (2.0g, 10.5mmol) is added drop-wise to the carbon of 0 DEG C
In DMF (16mL) reactant liquor of acid potassium (2.9g, 21.1mmol), drip and finish, react 30 minutes under room temperature, be cooled to 0 DEG C, compound 2
(4.3g, 21.1mmol) is added drop-wise in reactant liquor, is warmed to room temperature reaction overnight.Reactant liquor is poured in frozen water, extracts by ethyl acetate
Taking, organic facies anhydrous sodium sulfate is dried, and concentrates, residue petroleum ether: ethyl acetate=20:1 column chromatography, obtains compound
3,2.0g, 53%.
Utilize nuclear magnetic resonance, NMR that the compound 3 obtained is analyzed, obtain result1H NMR(400MHz,CDCl3):δ
1.21-1.76(m,25H),4.32-4.33(m,1H),4.60-4.67(m,1H),5.02(m,1H),6.75-6.85(m,1H)。
Step 2:1-(((cyclohexyloxy) carbonyl) epoxide) ethyl ALANINE hydrochlorate (4)
At room temperature, compound 3 (1.5g, 4.17mmol) is added to the diethyl ether solution (8mL) of hydrogen chloride, and reactant liquor is stirred
At night, decompression boils off solvent, and column chromatography (eluent: ethyl acetate: ethanol=8:1) obtains two isomers of compound 4, two
The ratio of isomer is close to 1:1.
Isomer 4-1,0.42g, 34%.1H NMR(400MHz,CDCl3):δ1.25-1.91(m,16H),4.25(m,
1H), 4.61 (m, 1H), 6.82 (m, 1H), 8.71 (brs, 3H).
Isomer 4-2,0.47g, 38%.1H NMR(400MHz,CDCl3):δ1.25-1.91(m,16H),4.27(m,
1H), 4.63 (m, 1H), 6.87 (m, 1H), 8.75 (brs, 3H).
Step 3:1-(((cyclohexyloxy) carbonyl) epoxide) ethyl (((((R)-1-(6-amino-9H-purine-9-base) acrylate-
2-yl) epoxide) methyl) (phenoxy group) phosphoryl) synthesis (5) of-ALANINE ethyl ester
(R)-9-[2-[(phenyl) phosphoric acid methoxy] propyl group] adenine (intermediate-1) (0.46g, 1.28mmol), compound
4-1 or compound 4-2 (0.72g, 2.56mmol), two sulfur two pyridine (0.56g, 2.56mmol), triphenyl phosphorus (0.67g,
2.56mmol) it is added in 10mL pyridine, under nitrogen protection, after 72 DEG C of stirrings are reacted 30 minutes, addition triethylamine (1.76mL,
12.8mmol) reaction is overnight, and reactant liquor concentrates, and silica gel column chromatography (eluent: ethyl acetate: methanol=20:1-5) obtains chemical combination
Thing 5,0.36g, 48%.
Isomer 5-1,1H NMR(400MHz,CDCl3):δ1.47-1.51(m,15H),1.72-1.90(m,4H),3.63-
3.98(m,4H),4.09-4.14(m,2H),4.32-4.48(m,1H),4.61(m,1H),5.98(brs,2H),6.68-6.73
(m,1H),6.99-7.30(m,5H),7.97(2s,1H),8.33(2s,1H)。ESI-MS:[M+H]+: 605.3.
Isomer 5-2,1H NMR(400MHz,CDCl3):δ1.26-1.54(m,15H),1.71-1.72(m,2H),1.90
(m,2H),3.57-3.78(m,2H),3.92-3.97(m,2H),4.09-4.21(m,2H),4.30-4.62(m,2H),5.97
(brs,2H),6.68-6.77(m,1H),6.95-7.30(m,5H),8.00(2s,1H),8.31and 8.33(2s,1H)。ESI-
MS:[M+H]+: 605.3.
Step 4:1-(((cyclohexyloxy) carbonyl) epoxide) ethyl (((((R)-1-(6-amino-9H-purine-9-base) acrylate-
2-yl) epoxide) methyl) (phenoxy group) phosphoryl)-ALANINE ethyl ester fumarate (6)
Compound 5-1 (100mg, 0.16mmol) joins in acetonitrile (2mL), is heated to 80 DEG C to clarification, addition richness horse
Acid (17.4mg, 0.15mmol), after stirring 15 minutes, hot sucking filtration, filtrate is cooled to room temperature, continues to place 12 hours at-12 DEG C
Separating out crystallization, filter, filter cake washs with cold acetonitrile, and drying at room temperature is positioned over after 6 hours in the vacuum drying oven of 35 DEG C and is dried 12h
Fumarate 6,95mg, 79%.
1H NMR(400MHz,DMSO-d6):δ1.01-1.39(m,15H),1.62(m,2H),1.80(m,2H),3.85-
3.96(m,4H),4.21-4.27(m,2H),4.52(m,1H),5.71-5.81(m,1H),6.57-6.63(m,3H),7.11-
7.33(m,7H),8.11-8.13(m,2H),13.16(brs,2H)。
Reaction scheme 2
Embodiment 2 ((isopropyl) epoxide) methyl (((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) epoxide)
Methyl) (phenoxy group) phosphoryl)-ALANINE (10)
Step 1:((butyloxycarbonyl) synthesis of epoxide (tertbutyloxycarbonyl)-ALANINE (8)
DMF (10ml) solution of N-Boc-L-alanine (2.5g, 13.2mmol) be added drop-wise to ice bath potassium carbonate (3.65g,
26.4mmol) with in DMF (30mL) mixture of sodium iodide (3.96g, 26.4mmol), it is stirred at room temperature reaction 30 minutes
After, it is cooled to 0 DEG C, adds compound 7 (4.03g, 26.4mmol), stirred overnight at room temperature.Reactant liquor pours in water, ethyl acetate
Extraction, the organic facies anhydrous Na obtained2SO4Being dried, silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20:1) is changed
Compound 8,2.46g, 61%.1H NMR(400MHz,CDCl3): δ 1.31-1.44 (m, 18H), 4.35-4.39 (m, 1H), 4.91-
4.94 (m, 1H), 5.03-5.04 (m, 1H), 5.74-5.84 (m, 2H).
Step 2:((butyloxycarbonyl) epoxide) synthesis of methyl ALANINE (9)
Compound 8 (2.0g, 6.55mmol) is added the diethyl ether solution (18mL) of hydrogen chloride, stirred overnight at room temperature, concentrates
Reactant liquor, residue over silica gel chromatogram column technique purification (ethyl acetate: methanol=10:1) hydrochlorate 9,1g, 65%.1H NMR
(400MHz,DMSO-d6):δ1.24-1.26(d,6H),1.42-1.44(d,3H),4.15-4.18(m,1H),4.82(m,1H),
5.78-5.80(m,2H),8.77(s,3H)。
Step 3:((isopropyl) epoxide) methyl (((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) epoxide)
Methyl) (phenoxy group) phosphoryl) synthesis of-ALANINE (10)
(R)-9-[2-[(phenyl) phosphoric acid methoxy] propyl group] adenine (intermediate-1) (0.5g, 1.3mmol), compound 9
(0.66g, 2.7mmol), two sulfur two pyridine (0.59g, 2.7mmol), triphenyl phosphorus (0.7g, 2.7mmol) add 14mL pyridine,
N2Under protection, after 72 DEG C of stirrings are reacted 0.5 hour, add triethylamine (1.78mL, 16mmol) and react overnight.Concentrate, column chromatography
(eluent: ethyl acetate: ethanol=20:1) obtains compound 10,0.21g, and 28%.1H NMR(400MHz,CDCl3):δ
1.29-1.31(m,12H),3.56-3.67(m,2H),3.91-3.99(m,2H),4.11-4.16(m,2H),4.31-4.49(m,
1H),4.88-4.91(m,1H),5.64-5.77(m,2H),6.07(s,2H),6.95-7.33(m,5H),7.98(s,1H),
8.29-8,32(2s,1H)。ESI-MS:[M+H]+: 551.2.
Reaction scheme 3
Embodiment 3:(((((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) epoxide) methyl) (phenoxy group) phosphorus
Acyl group)-L-alanyl) epoxide) methyl pivalate (14)
Step 1:(((tertbutyloxycarbonyl)-L-alanyl) epoxide) synthesis of methyl pivalate (12)
DMF (9mL) solution of Boc-L-alanine (2g, 10.5mmol) be added drop-wise to ice bath potassium carbonate (2.92g,
21.1mmol) with in DMF (28mL) mixture of sodium iodide (3.16g, 21.1mmol), it is stirred at room temperature reaction 30 minutes
After, it is cooled to 0 DEG C, adds compound 11 (3.18g, 21.1mmol), stirred overnight at room temperature.Reactant liquor pours in water, acetic acid second
Ester extracts, the organic facies anhydrous Na obtained2SO4Being dried, silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20:1) obtains
Compound 12,1.49g, 47%.1H NMR(400MHz,CDCl3): δ 1.18-1.58 (m, 21H), 4.22-4.31 (m, 1H),
4.99 (m, 1H), 5.72-5.84 (m, 2H).
Step 2:((L-alanyl) epoxide) synthesis of methyl pivalate hydrochlorate (13)
Compound 12 (1g, 3.29mmol) is added the diethyl ether solution (10mL) of hydrogen chloride, stirred overnight at room temperature, concentrates anti-
Answer liquid, residue over silica gel chromatogram column technique purification (ethyl acetate: methanol=10:1) hydrochlorate 13,0.4g, 51%.1H NMR
(400MHz,CDCl3): δ 1.21 (brs, 12H), 4.33-4.42 (m, 1H), 5.82-5.96 (m, 2H), 6.74 (brs, 3H).
Step 3:(((((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) epoxide) methyl) (phenoxy group) phosphinylidyne
Base)-L-alanyl) epoxide) synthesis of methyl pivalate (14)
(R)-9-[2-[(phenyl) phosphoric acid methoxy] propyl group] adenine (intermediate-1) (0.5g, 1.3mmol), compound 13
(0.65g, 2.7mmol), two sulfur two pyridine (0.59g, 2.7mmol), triphenyl phosphorus (0.7g, 2.7mmol) add 14ml pyridine,
Under nitrogen protection, after 72 DEG C of stirrings are reacted 0.5 hour, add triethylamine (1.78mL, 16mmol) and react overnight.Concentrate, post layer
Analysis (eluent: ethyl acetate: ethanol=20:1) obtains compound 14,0.2g, and 30%.1H NMR(400MHz,CDCl3):δ
1.22-1.31 (m, 15H), 3.62-3.68 (m, 2H), 3.91-3.99 (m, 2H), 4.01-4.15 (m, 2H), 4.33-4.49 (m,
1H), 5.64-5.79 (m, 2H), 6.19 (s, 2H), 6.96-7.31 (m, 5H), 7.99-8.00 (2s, 1H), 8.29-8.32 (2s,
1H)。ESI-MS:[M+H]+: 549.2.
Same method has synthesized the compound in table 1.
Table 1 compound 15～19 structural formula and testing result
Reaction scheme 4
Embodiment 4 isopropyl (((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) epoxide) methyl) (4-(three
Methylsilyl) phenoxy group) phosphoryl)-ALANINE ethyl ester fumarate (24)
The synthesis of step 1:4-(trimethylsilyl) phenol (21)
N-BuLi (18mL, 2.5M in hexane, 45mmol) be slowly dropped to-78 DEG C 4-bromophenol (3.46g,
In oxolane (60mL) solution 20.0mmol), continue reaction 2 hours at this temperature, drip trim,ethylchlorosilane
(6.6mL, 52mmol), after reacting 30 minutes, reactant liquor is slowly increased to room temperature, is stirred overnight.Anti-with 1N HCl (30mL) cancellation
Should, stirring 1 hour, add water (60mL), ethyl acetate extracts, and organic facies is respectively with saturated sodium bicarbonate aqueous solution, saline solution
Washing, be dried, concentrate, silica gel column chromatography (eluting phase: petroleum ether: ethyl acetate=100:4) obtain compound 21,2.5g,
75%, compound 21 water is recrystallized to give colourless crystal.1H NMR(400MHz,CDCl3): δ 0.25 (s, 9H), 4.70 (s,
1H), 6.84 (d, J=8.5Hz, 2H), 7.41 (d, J=8.5Hz, 2H).
Step 2:4-(TMS) phenyl hydrogen ((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) oxygen
Base) methyl) synthesis of phosphonic acids (22)
By tenofovir (7.3g, 25.4mmol) and phenol (8.4g, 51mmol), it is dissolved in N-Methyl pyrrolidone (20g),
Under nitrogen protection, it is warming up to 85 DEG C, after stirring 30 minutes, adds triethylamine (3.2g, 31.1mmol), react 10 minutes, rise
Temperature, to 100 DEG C, is slowly added dropwise N-Methyl pyrrolidone (8g) solution of DCC (8.6g, 41.4mmol), drips complete follow-up continuous anti-
Answer 20h.Reactant liquor is cooled to room temperature, filters, and filtrate concentrates, and residue adds methanol (15mL) stirring, and the solid of precipitation filters
It is dried to obtain the monoesters 4.6g of tenofovir, 42%.1H NMR(400MHz,DMSO-d6): δ 0.21 (s, 9H), 1.05 (d, J=
6Hz, 3H), 3.73-3.79 (m, 2H), 3.99 (d, 1H), 4.19-4.29 (m, 3H), 7.03 (d, J=7.6Hz, 2H), 7.39
(d, J=8Hz, 2H), 7.88 (s, 2H), 8.17 (s, 1H), 8.20 (s, 1H).ESI-MS:[M+H]+: 436.1.
Step 3:(((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) epoxide) methyl) (4-(trimethyl silicane
Base) phenoxy group) phosphoryl) synthesis of-ALANINE isopropyl ester (23)
The monophosphate phenyl ester 22 (0.55g, 1.28mmol) of tenofovir, ALANINE isopropyl ester hydrochlorate (0.43g,
2.56mmol), two sulfur two pyridine (0.56g, 2.56mmol), triphenyl phosphorus (0.67g, 2.56mmol) be added in 10 ml pyridines,
Under nitrogen protection, after 72 DEG C of stirrings are reacted 30 minutes, adding triethylamine (1.76ml, 12.8mmol) and react overnight, reactant liquor is dense
Contracting, silica gel column chromatography (eluent: ethyl acetate: methanol=20:1-5) obtains compound 23,0.24g, and 35%.
1H NMR(400MHz,CDCl3):δ0.22-0.24(m,9H),1.17-1.32(m,12H),3.51-4.15(m,
6H),4.33-4.42(m,1H),4.90-5.00(m,1H),5.97(m,2H),6.97-7.45(m,4H),8.02and 8.03
(2s,1H),8.33and 8.35(2s,1H)。ESI-MS:[M+H]+:549.2.
Step 4:(((((R)-1-(6-amino-9H-purine-9-base) acrylate-2-yl) epoxide) methyl) (4-(trimethyl silicane
Base) phenoxy group) phosphoryl) synthesis of-ALANINE isopropyl ester fumarate (24)
Compound 23 (120mg, 0.21mmol) joins in acetonitrile (2mL), is heated to 80 DEG C to clarification, addition fumaric acid
(16.3mg, 0.19mmol), after stirring 15 minutes, hot sucking filtration, filtrate is cooled to room temperature, continues to place analysis in 12 hours at-12 DEG C
Going out crystallization, filter, filter cake washs with cold acetonitrile, and drying at room temperature is positioned in the vacuum drying oven of 35 DEG C dry 12 little after 6 hours
Time obtain fumarate 24,100mg, 72%.
1H NMR(400MHz,DMSO-d6):δ0.22(m,9H),1.06-1.14(m,12H),3.76-4.26(m,6H),
4.80-4.83(m,1H),5.55-5.67(m,1H),6.63(m,2H),7.02-7.47(m,6H),8.11-8.14(m,2H),
13.14(m,2H)。ESI-MS:[M+H]+:549.2。
Same method can prepare the compound in table 2.
The structural formula of table 2 compound 25～29 and testing result
Embodiment 9: the compound antiviral activity detection of the present invention
1.HIV active testing
1.1 compound preparations
The data of the toxicity of the compound according to detection, determine the maximal non-toxic concentration of compound, by 1:2 dilution totally 11
Gradient, it is standby that every hole 10 μ l adds 384 porocyte culture plates.
1.2ATP method measures the test medicine half toxic concentration (TC to MT-2 cell50)
Taking the compound solution prepared, 1:2 dilutes, totally 11 gradients.Store plate from sample to take 10 μ l to add 384 holes thin
Born of the same parents' culture plate, the multiple hole of each compound 2,11 gradient dilutions.Addition MT-2 cell suspension 90 μ l, 37 DEG C, 5%CO2Cultivate
3d.By Celltiter Glo Luminescent Assay test kit detection Luminescence activity, Reed-Muench method
Calculate TC50。
1.3 measure test medicine antiviral activity
After MT-2 cell 250 × g is centrifuged 10min, suspend with fresh growth medium, piping and druming mixing, Trypan
Blue dyeing after count, determine cell concentration, percentage cell survival must > 95% can be used for next step test.Take aequum
MT-2 cell, add HIV-1 III B virus so that it is infectious multiple MOI (multiplicityof infection)=
0.01TCID50, dilution MT-2 cell suspension makes its final concentration of 1.5 × 105/ml.Above-mentioned cell suspension 90 μ l is added and contains
384 porocyte culture plates of compound, 37 DEG C, 5%CO2Cultivate 3d.Shift with Precision Power v2 liquid working station
The culture supernatant of 20 μ l is to a new black 384 porocyte culture plate.Adjustment cell concentration is 4 × 105/ml, and every hole adds 40 μ
L, 37 DEG C, 5% cultivation 24h.At Wallac 1420 readout instrument detection Umbelliferone (355nm/460nm, 0.1s).Test
It is repeated 3 times.The half-inhibition concentration IC of drug on viral is calculated by Reed-Muench method50。
The HIV (human immunodeficiency virus)-resistant activity evaluation of synthesis compound is shown in Table 3.
The HIV (human immunodeficiency virus)-resistant activity evaluation result of table 3 compound
Experiment conclusion: the compound of synthesis has the strongest HIV (human immunodeficiency virus)-resistant activity, reaches nanomolar range.The compound of synthesis is complete
Match in excellence or beauty the HIV (human immunodeficiency virus)-resistant activity of TAF and TDF entirely, compound 5-2, and 6,10,15,16,24,26,28 activity than TAF are high 2～10 times,
In the cell line surveyed, do not show toxicity.
2. the Anti-HBV effect evaluation of synthesis compound:
The chromosomal integration of HepG2 2.2.15 cell (SELLS, PNAS, 1987and SELLS, JV, 1988) has completely
HBV gene group, and stably express viral RNA, cccDNA and virus protein.Additionally, this cell is also secreted in culture medium
Ripe hepatitis B virus granule.The method being quantified virion DNA by qPCR can measure viral duplication.Testing compound
It is dissolved as the storage liquid of 30mM with DMSO and is saved in-20 DEG C.10,000, every hole HepG2 is added in 96 porocyte culture plates
2.2.15 cell, every hole 200 μ L cell culture medium, at 37 DEG C, 5%CO2Cell culture incubator is cultivated and within 3 days, covers with to cell.Abandon
Fall old culture medium and add 200 detection culture medium (5%FBS) fresh for μ L.The compound 1 μ L of addition 100%DMSO dilution:
It is diluted to the different test concentrations specified, at CO2Hatching in incubator 10 days, every other day (the 2nd, 4,6,8,10 day) changes one
Not good liquor (5%FBS), and add the compound of Fresh concentration.At the 11st day, every hole took 150 μ L of supernatant and extracts viral DNA.Carefully
Cellular toxicity detection plate is also carried out similar process: maximum concentration is 150 μMs.The extraction test kit of virus genom DNA is QIAamp
96DNA Blood Kit.Through conventional centrifugal and QPCR process.With plasmid (viral copy number: the 2* comprising HBV gene group
10E6,2*10E5,2*10E4,2*10E3) do standard curve, and calculate viral copy number with standard curve.The meter of suppression ratio
Calculation formula is as follows: the suppression ratio=100-(detected value-HPE meansigma methods) of antiviral/(ZPE meansigma methods-HPE meansigma methods) * 100
(ZPE: least concentration compound well meansigma methods, HPE: maximum concentration compound well meansigma methods). suppression ratio data are passed through
Graphpad Prism 5 software processes also draws curve, EC50Calculated by four parameter nonlinear regression models.Cytotoxicity %
=100-(detected value/DMSO control wells meansigma methods * 100).Cytotoxicity % data are by Graphpad Prism 5 software
Manage and draw curve, CC50By the Anti-HBV effect evaluation of four parameter nonlinear regression model computerized compounds, the results are shown in Table 4.
Table 4 compound Anti-HBV effect evaluation result
Experiment conclusion: the compound of all synthesis has the strongest Anti-HBV effect, part of compounds activity to be significantly better than
TAF and TDF.The compound of partial synthesis, such as compound 5-2,6,10,24,26,28 all high 2-5 of Anti-HBV effect than TAF
About times.In the cell line surveyed, do not show toxicity.
More than test result indicate that, the compound of the present invention has efficient AntiHIV1 RT activity and the ability of HBV virus, with the positive
Comparison medicine TDF with TAF compares, and part of compounds has more excellent antiviral activity, and nephrotoxicity is little, and safety is good, has and controls
Treat the good clinical landscapes that HIV and HBV virus infects.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For Yuan, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. a phosphamide nucleoside compound, as shown in formula (I):
Wherein, R1Selected from the alkyl of C1～C6, the cycloalkyl of C3～C6, the Heterocyclylalkyl of C4～C7, the haloalkyl of C2～C6,
The aryl of C6～C10, the aralkyl of C7～C10, C3～C10 alkanoyl oxyalkyl, C7～C10 aroyl oxyalkyl or C3～
C10 alkoxy carbonyl group oxyalkyl；
R2Aryl selected from C6～C30；
Described aryl is selected from unsubstituting aromatic yl or substituted aryl；The substituent group of described substituted aryl is selected from halogen, alkyl, cycloalkanes
Base, cycloheteroalkyl, haloalkyl, halogenated cycloalkyl, cycloalkyl-alkyl, cyano group, heteroaryl or alkyl silyl；Unsubstituted aryl
Selected from phenyl, xenyl or naphthyl.
Phosphamide nucleoside compound the most according to claim 1, it is characterised in that described R1Alkyl selected from C1～C3
Or the cycloalkyl of C3～C6.
Phosphamide nucleoside compound the most according to claim 1, it is characterised in that as shown in the following structure:
4. a phosphamide nucleoside compound pharmaceutically acceptable salt, as shown in formula (II):
Wherein, R1Selected from the alkyl of C1～C6, the cycloalkyl of C3～C6, the Heterocyclylalkyl of C4～C7, the haloalkyl of C2～C6,
The aryl of C6～C10, the aralkyl of C7～C10, C3～C10 alkanoyl oxyalkyl, C7～C10 aroyl oxyalkyl or C3～
C10 alkoxy carbonyl group oxyalkyl；
R2Aryl selected from C6～C30；
Described aryl is selected from unsubstituting aromatic yl or substituted aryl；The substituent group of described substituted aryl is selected from halogen, alkyl, cycloalkanes
Base, cycloheteroalkyl, haloalkyl, halogenated cycloalkyl, cycloalkyl-alkyl, cyano group, heteroaryl or alkyl silyl；Unsubstituted aryl
Selected from phenyl, xenyl or naphthyl；
Described acid is pharmaceutically acceptable acid.
Phosphamide nucleoside compound pharmaceutically acceptable salt the most according to claim 4, it is characterised in that described
Acid is in fumaric acid, half fumaric acid, citric acid, tartaric acid, oxalic acid, malic acid, methanesulfonic acid, hydrochloric acid, sulphuric acid and phosphoric acid
A kind of.
Phosphamide nucleoside compound pharmaceutically acceptable salt the most according to claim 4, as shown in the following structure:
7. phosphamide nucleoside compound and/or claim 4～6 described in a claims 1 to 3 any one are any one
Phosphamide nucleoside compound pharmaceutically acceptable salt described in Xiang is at preparation prevention and/or the medicine for the treatment of virus infection
Application in thing.
Application the most according to claim 7, it is characterised in that described virus is inhibition of HIV, HBV virus, hepatitis B
Poison and one or more in hepatitis B virus.
9. a pharmaceutical composition, it is characterised in that include the phosphamide ucleosides described in claims 1 to 3 any one
Phosphamide nucleoside compound pharmaceutically acceptable salt described in compound and/or claim 4～6 any one.
Pharmaceutical composition the most according to claim 9, it is characterised in that also include other therapeutic agent and/or enhancing
Agent；Other therapeutic agent described is selected from hiv protease inhibitor, hiv reverse transcriptase non-nucleosidic inhibitors, hiv reverse transcriptase core
Glycosides inhibitor, hiv reverse transcriptase nucleotide inhibitor, hiv integrase inhibitor, CCR5 inhibitor, HBV capsid inhibitor,
CccDNA forms inhibitor, cccDNA epigenetic modification agent and one or more in hbv rna i medicine；Described reinforcing agent
Selected from Tuo Nawei and/or than west he.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610697576.7A CN106317116A (en) | 2016-08-19 | 2016-08-19 | Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610697576.7A CN106317116A (en) | 2016-08-19 | 2016-08-19 | Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106317116A true CN106317116A (en) | 2017-01-11 |
Family
ID=57741240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610697576.7A Pending CN106317116A (en) | 2016-08-19 | 2016-08-19 | Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106317116A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2647576C1 (en) * | 2017-02-28 | 2018-03-16 | Васильевич Иващенко Александр | Cyclobutyl (s)-2-[[[r)-2-(6-aminopurin-9-yl)-1-methyl-etoxy]methyl-phenoxy-phosphoryl]amino]-propanoates, method of their production and application |
| CN108101943A (en) * | 2018-02-28 | 2018-06-01 | 顾世海 | A kind of tenofovir prodrug or officinal salt and its application in medicine |
| RU2659388C1 (en) * | 2017-02-28 | 2018-07-02 | Васильевич Иващенко Александр | Nucleotides including n-[(s)-1-cyclobutoxycarbonyl]phosphoramidate fragment, their analogs and their application |
| WO2019237957A1 (en) * | 2018-06-12 | 2019-12-19 | 四川科伦博泰生物医药股份有限公司 | Phosphonamide ester compound, salt thereof, related crystal form thereof, preparation method therefor and use thereof |
| CN111065379A (en) * | 2017-07-03 | 2020-04-24 | 亚历山大·瓦西里耶维奇·伊瓦切恩科 | Combination pharmaceutical formulation for the treatment of viral infections |
| JP2021511305A (en) * | 2018-01-10 | 2021-05-06 | ヌクオリオン ファーマシューティカルズ インコーポレイテッド | Phosphoramidite acetal and phosphatidylsetal compounds |
| CN113121600A (en) * | 2021-03-31 | 2021-07-16 | 澳门科技大学 | Remdesivir dimer, preparation method and application thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| WO2005042772A1 (en) * | 2003-10-24 | 2005-05-12 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
| CN104151360A (en) * | 2013-05-14 | 2014-11-19 | 北京美倍他药物研究有限公司 | Phosphoric acid/phosphonic acid derivatives and medical applications thereof |
| CN104804042A (en) * | 2014-01-24 | 2015-07-29 | 齐鲁制药有限公司 | Nucleotide phosphonate compound, pharmaceutical composition, preparation method and uses thereof |
| CN105001262A (en) * | 2014-04-18 | 2015-10-28 | 四川海思科制药有限公司 | Aryl-substituted phosphonaminate and application in medical science thereof |
| CN105669751A (en) * | 2015-03-05 | 2016-06-15 | 洛阳聚慧医药科技有限公司 | Preparation of non-cyclic nucleotide phosphoamides and salts thereof and application of non-cyclic nucleotide phosphoamides and salts thereof in aspect of antivirus |
| CN106866737A (en) * | 2015-12-11 | 2017-06-20 | 南京圣和药业股份有限公司 | Phosphonate derivative and its application |
-
2016
- 2016-08-19 CN CN201610697576.7A patent/CN106317116A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443189A (en) * | 2000-07-21 | 2003-09-17 | 吉里德科学公司 | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| WO2005042772A1 (en) * | 2003-10-24 | 2005-05-12 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
| WO2005047898A2 (en) * | 2003-10-24 | 2005-05-26 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
| CN104151360A (en) * | 2013-05-14 | 2014-11-19 | 北京美倍他药物研究有限公司 | Phosphoric acid/phosphonic acid derivatives and medical applications thereof |
| CN104804042A (en) * | 2014-01-24 | 2015-07-29 | 齐鲁制药有限公司 | Nucleotide phosphonate compound, pharmaceutical composition, preparation method and uses thereof |
| CN105001262A (en) * | 2014-04-18 | 2015-10-28 | 四川海思科制药有限公司 | Aryl-substituted phosphonaminate and application in medical science thereof |
| CN105669751A (en) * | 2015-03-05 | 2016-06-15 | 洛阳聚慧医药科技有限公司 | Preparation of non-cyclic nucleotide phosphoamides and salts thereof and application of non-cyclic nucleotide phosphoamides and salts thereof in aspect of antivirus |
| CN106866737A (en) * | 2015-12-11 | 2017-06-20 | 南京圣和药业股份有限公司 | Phosphonate derivative and its application |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020509046A (en) * | 2017-02-28 | 2020-03-26 | アラ・ケム・エルエルシー | Cyclobutyl (S) -2-[[[(R) -2- (6-aminopurin-9-yl) -1-methyl-ethoxy] methyl-phenoxy-phosphoryl] amino] -propanoate, and production and use thereof how to |
| WO2018160088A1 (en) * | 2017-02-28 | 2018-09-07 | Александр Васильевич ИВАЩЕНКО | Nucleotides containing an n-[(s)-1-cyclobutoxycarbonyl]phosphoramidate fragment, analogs thereof, and use thereof |
| RU2647576C1 (en) * | 2017-02-28 | 2018-03-16 | Васильевич Иващенко Александр | Cyclobutyl (s)-2-[[[r)-2-(6-aminopurin-9-yl)-1-methyl-etoxy]methyl-phenoxy-phosphoryl]amino]-propanoates, method of their production and application |
| WO2018160091A1 (en) * | 2017-02-28 | 2018-09-07 | Александр Васильевич ИВАЩЕНКО | Cyclobutyl (s)-2-[[[(r)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]-propanoates, and method for producing and using same |
| US20200079814A1 (en) * | 2017-02-28 | 2020-03-12 | Alexandre Vasilievich Ivachtchenko | Nucleotides comprising an N-[(S)-1-cyclobutoxycarbonyl]phosphoramidate moiety and analogs and application thereof |
| CN110300758A (en) * | 2017-02-28 | 2019-10-01 | 亚历山大·瓦西里耶维奇·伊瓦切恩科 | (S) -2- [[[(R) -2- (adenine -9- base) -1- methyl-ethoxy] methyl-phenoxv-phosphoryl] amino]-propionic acid ring butyl ester and its production and application method |
| RU2659388C1 (en) * | 2017-02-28 | 2018-07-02 | Васильевич Иващенко Александр | Nucleotides including n-[(s)-1-cyclobutoxycarbonyl]phosphoramidate fragment, their analogs and their application |
| CN111065379A (en) * | 2017-07-03 | 2020-04-24 | 亚历山大·瓦西里耶维奇·伊瓦切恩科 | Combination pharmaceutical formulation for the treatment of viral infections |
| JP2021511305A (en) * | 2018-01-10 | 2021-05-06 | ヌクオリオン ファーマシューティカルズ インコーポレイテッド | Phosphoramidite acetal and phosphatidylsetal compounds |
| JP7181938B2 (en) | 2018-01-10 | 2022-12-01 | ヌクオリオン ファーマシューティカルズ インコーポレイテッド | Phosphoro(n)amidate acetal and phospha(hona)toarcetal compounds |
| CN108101943A (en) * | 2018-02-28 | 2018-06-01 | 顾世海 | A kind of tenofovir prodrug or officinal salt and its application in medicine |
| CN108101943B (en) * | 2018-02-28 | 2020-11-24 | 顾世海 | Tenofovir prodrug or pharmaceutically acceptable salt and application thereof in medicine |
| CN111989335A (en) * | 2018-06-12 | 2020-11-24 | 四川科伦博泰生物医药股份有限公司 | Phosphonamide ester compounds and salts and related crystal forms, preparation methods and uses thereof |
| WO2019237957A1 (en) * | 2018-06-12 | 2019-12-19 | 四川科伦博泰生物医药股份有限公司 | Phosphonamide ester compound, salt thereof, related crystal form thereof, preparation method therefor and use thereof |
| JP2021528363A (en) * | 2018-06-12 | 2021-10-21 | シチュアン ケルン−バイオテック バイオファーマシューティカル カンパニー リミテッド | Phosphonamide ester compound, its salt, its related crystals, its production method and its use |
| US11186599B2 (en) | 2018-06-12 | 2021-11-30 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Phosphonamide ester compound, salt thereof, related crystal form thereof, preparation method therefor and use thereof |
| CN113121600A (en) * | 2021-03-31 | 2021-07-16 | 澳门科技大学 | Remdesivir dimer, preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106317116A (en) | Phosphamide nucleosides compound, pharmaceutically acceptable salt and application thereof, and pharmaceutical composition | |
| JP6932394B2 (en) | Nitrogen-containing heterocyclic compounds, production methods, intermediates, pharmaceutical compositions and applications | |
| CN104017020B (en) | Nucleoside phosphoramidates | |
| CN102459299B (en) | N-[(2 ' R)-2 '-deoxidation-2 '-fluoro-2 '-methyl-P-phenyl-5 '-uridine acyl group]-ALANINE 1-methylethyl ester and preparation method thereof | |
| EP3290428B1 (en) | Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate | |
| CN104135859B (en) | substituted benzaldehyde compound and its method for increasing tissue oxygenation | |
| US20130288997A1 (en) | Nucleoside phosphoramidates | |
| CN110088104A (en) | For treating and preventing hepatitis b virus infected new tetrahydropyridine and pyrimidine compound | |
| CN106167504A (en) | Acyclonucleosides phosphamide D amino acid ester derivative and the preparation of salt thereof and in the application of anti-virus aspect | |
| KR20150046315A (en) | Tenofovir prodrug and pharmaceutical uses thereof | |
| CN113105454A (en) | FGFR4 inhibitor, preparation method and application thereof | |
| CN102863428A (en) | Spiro-compounds taken as hepatitis c virus (HCV) inhibitor | |
| CN105829334A (en) | Uracil nucleotide analogs, preparation methods therefor and uses thereof | |
| CN112979679B (en) | Fluoroheterocyclic derivative having macrocyclic structure and use thereof | |
| CN112384519A (en) | Synthesis and application of peptide borate compound | |
| CN107759600A (en) | Crystallization as the Pyrrolopyrimidine compounds of JAK inhibitor | |
| CN106543253A (en) | Anti-viral nucleoside phosphoramidate and its drug regimen and purposes | |
| CN104804042B (en) | Phosphonate-nucleotide ester class compound, its pharmaceutical composition, Preparation method and use | |
| CN108350007B (en) | Substituted adenine compound and pharmaceutical composition thereof | |
| CN108350008B (en) | Novel acyclic nucleoside analogue and pharmaceutical composition thereof | |
| CN104804001B (en) | 4 substituted azoles simultaneously [2,3 d] pyrimidine compound and application thereof | |
| CN103221415B (en) | Oxazolo [5, 4 -] pyridin-5-yl compounds and their use for the treatment of cancer | |
| CN112125908A (en) | CDK kinase inhibitor, preparation method, pharmaceutical composition and application thereof | |
| CN113501847B (en) | High-efficiency anti-hepatitis B virus compound and preparation method and application thereof | |
| CN110382514A (en) | The prodrug of HCV NS5B polymerase inhibitors and its production and application method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170111 |
|
| RJ01 | Rejection of invention patent application after publication |