CN106188192B - Nucleosides phosphoramidic acid/the phosphate derivatives and its medical usage of the amino-acid ester containing D- - Google Patents
Nucleosides phosphoramidic acid/the phosphate derivatives and its medical usage of the amino-acid ester containing D- Download PDFInfo
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Abstract
The present invention relates to novel nucleoside phosphoric acid/phosphonate prodrugs and its preparation method and application containing non-natural D amino acids ester.Novel nucleoside phosphoric acid/the phosphonate prodrugs containing substituted benzyl are formula (I) or formula (II) compound represented or its isomers or officinal salt, it can be used as various nucleoside analogs, such as the pro-drug of acyclonucleosides, carbocyclic nucleoside, furan nucleus nucleosides etc., strengthen the bioactivity of nucleoside compound, to be applied to the treatment of virus infection and cancer.
Description
Technical field
The invention belongs to pharmaceutical technology fields, contain the new of unnatural configuration D- amino-acid ester in particular to a kind of
Type nucleosides phosphoramidic acid/phosphonate prodrugs and its preparation method and application.
Background of invention
Nucleoside compound is DNA and ribonucleic acid namely biological heredity gene DNA and the structure list of RNA
Body, thus all have critical function in all life entities, and be widely used in the treatment of virus infection and cancer.Nineteen sixty generation with
Come, the nucleoside analog of many bioactivity be used to treat various virus infections, such as bleb, AIDS, B-mode and the third type liver
It is scorching.These artificial synthesized nucleoside analogs can destroy the duplication of viral gene by the growth of blocking virus nucleic acid chains,
As antiviral drugs (Fig. 1).
As shown in Figure 1, nucleosides must divide the activation of three steps at nucleoside triphosphate first, the synthesis of DNA or RNA could be participated in,
And then show physiological activity.When a nucleoside analog can selectively squeeze into the gene of virus or cancer cell, prevention
The duplication breeding of its nucleic acid chains, while when to host cell gene fanout free region (toxicity), this nucleoside analog can become disease-resistant
Poison or anticancer drug.
Nucleoside triphosphate itself is very high due to carrying multiple negative electrical charges, polarity, it is difficult to enter cell by cell wall
Inside, so cannot be used directly as antiviral drugs.The form of early stage uncleosides as antiviral agents is exactly that polarity is moderate
Nucleosides, its point three step phosphorylated under host cell kinases (kinase) effect after entering cell itself, eventually becomes three phosphorus
Sour nucleosides and play drug effect.Recently as the progress of nucleoside phosphoric acid ester prodrug technologies, with the method for chemistry directly by monophosphate
Low polarity equivalent construction unit be introduced into nucleoside molecule, make nucleoside phosphorylase ester prodrugs enter cell interior after release list again
Phosphoric acid nucleoside is limited without the selectivity by nucleoside kinase.Nucleoside phosphorylase ester prodrugs just become upgrading ucleosides medicine as a result,
The spread path of physical performance.
The research of nucleoside prodrugs is when previous hot spot, and especially phosphoric acid ester prodrug is a kind of most effective upgrading ucleosides
The mode of drug, it is also possible that some nucleosides for being unable to phosphorylated due to nucleoside kinase limitation show bioactive, document
The structure type of the phosphoric acid ester prodrug of the nucleosides of report mainly have seven classes (J.Am.Chem.Soc., 2004,126,5154-
5163；103435672 Fig. 2 of WO2012094248, CN 102532199, CN 103980318, CN), outstanding representative is
The inventions such as McGuigan arylamino phosphate (2-5), be most widely used in nucleoside compound prodrug at present and
Successful one.
McGuigan type nucleoside prodrugs be British scientist Christopher McGuigan in the invention at first of generation nineteen ninety,
And the arylamino phosphate ester structure unit (3-1, Fig. 3) constantly improve, it is structurally characterized in that it contains a l-amino acid
- N and aryl phenol of phosphinylidyne amine key P (O) that the amino of ester participates in being formed participates in phosphide key P (the O)-O-Ar to be formed.It has demonstrate,proved
The l-amino acid ester bond of real McGuigan prodrug (3-1) is broken first releases free carboxylic acid derivative (3-2), the carboxyl of generation
Functional group can be catalyzed phenolic group oxygen phosphorus bond cleavage solution, formed five-membered ring phosphate derivative (3-3), then release mononucleotide
(3-4), final metabolism, which generates, can participate in nucleic acid chain polymerization, the trinucleotide (3-6) with physiological activity.So nucleoside prodrugs
(3-1) is the equivalent of its mononucleotide (3-4), and it is kinase catalytic that it can get around selective height, inefficient mononucleotide
Under monophosphate esterification, the 5 '-mono- phosphides for directly transporting nucleosides enter cell and generate bioactivity.As a result,
McGuigan prodrug can make those because can not phosphorylated due to lose bioactivity nucleosides there is bioactivity again, or improve
The bioactivity of known nucleotide medicine.
It is well known that the esterase hydrolyzed reaction of natural L-amino acids ester has caused it in McGuigan prodrug (3-1) molecule
Mononucleotide (3-4) metabolic process is generated afterwards, and since esterase is distributed widely in gastrointestinal disturbances road, so nucleosides phosphoramidic acid
L-amino acid ester group in ester structure will be usually metabolized before reaching liver cell by hydrolysis in large quantities.For treatment liver disease
For the nucleotide medicine of change, if participated in front of constituting its phosphoramidate using unnatural D amino acids ester substitution l-amino acid ester
Medicine, so that it may delay the esterase hydrolyzed metabolic process of amino-acid ester significantly, so that nucleoside prodrugs are in lipase hydrolysis in the digestive tract
Loss greatly reduces, and then improves the transfer efficiency that nucleoside prodrugs enter liver cell, can reduce drug dose, exempts drug
Toxic side effect, or improve drug effect.
Summary of the invention
Synthesis McGuigan prodrug (Fig. 2,2-5) and HepDirect prodrug (2-6) design feature, before HepDirect
Substituted benzyl in medicine structure displaces the aromatic ring in McGuigan prodrug, and the present inventor once had devised containing natural L- amino
Phosphoramidic acid/phosphonate prodrugs (CN 102532199, CN 103980318, CN 103435672) of acid esters and substituted benzyl,
Before author further describes the nucleoside phosphoramidate that the D- amino-acid ester containing unnatural configuration participates in composition on this basis
Structure feature, the Preparation method and use of medicine (I) and (II).
The biology that can strengthen nucleoside compound containing phosphoramidic acid/phosphonate prodrugs of D- amino-acid ester of the invention
Activity upgrades its intrinsic antiviral or anticancer activity.When phosphoric acid/phosphonate ester knot of nucleosides and this novel amino-acid ester containing D-
After conjunction, the nucleoside phosphoramidate of generation improves greatly, in conjunction with substitution the metabolic stability of esterase with respect to McGuigan prodrug
The ester hydrolase stability of benzyl, prodrug (I) and (II) have significant Liver targeting effect, treat liver particularly suitable for exploitation
Disease, such as the drug of liver cancer and hepatitis.
The present invention is achieved through the following technical solutions.
On the one hand, the present invention provides a kind of novel nucleoside containing non-natural D- amino-acid ester similar to phosphoric acid/phosphine of object
Acid esters prodrug, the prodrug are formula (I) or formula (II) compound represented or its isomers or officinal salt,
As shown in formula (I) and formula (II), a D- amino acid is contained in phosphoramidic acid of the invention/phosphonate prodrugs structure
Ester.Phosphoric acid/phosphonate function in formula (I) contain one by the benzylalcohol suitably replaced participate in the phosphide key formed and one by
Non-natural D- amino-acid ester participates in the phosphinylidyne amine key to be formed；Phosphoric acid/phosphonate function in formula (II) contains one by fitting
When substituted phenol participates in the phosphinylidyne amine key that the phosphide key to be formed and one are participated in by the D- amino-acid ester suitably replaced being formed.
Wherein, R1With R2It is respectively independent, it can be respectively selected from hydrogen, (substitution) phenyl ring, (substitution) aromatic radical, (substitution) benzyl
Base, C1-C12(substitution) linear or branched alkyl group, C3-C8(substitution) saturation or unsaturated ring alkyl, C2-C8(substitution) it is straight
Chain or branched-chain alkenyl, C2-C8(substitution) linear chain or branched chain alkynyl.
R3It can be hydrogen, halogen, carboxyl, nitro, ester group, acylamino-, C1-C8(substitution) linear or branched alkyl group, C1-C8
(substitution) straight or branched alkoxyl, C1-C8Amido, C2-C8(substitution) linear chain or branched chain alkenyl, C2-C8(substitution)
Linear chain or branched chain alkynyl, (substitution) C1-C12Carbon carboxylic acid acyloxy, (substitution) C1-C12Carbon carboxylic acyloxy Oxymethylene.
Nucleoside refers to various nucleoside analogs, including common furan nucleus nucleosides, carbocyclic nucleoside and acyclic core
Glycosides has following structure general formula:
Wherein, X1It can be not present or be CH2Or CHCH3。
X2Selected from O, CH2, C=CH2、CHCH3Or cyclopropyl alkyl
X3It can be not present or be methylene CH2。
T1、T2Independently of each other, H and CH be can be2R4, and R4For H, OH or F；T1、T2It can also structure together bonding to each other
At following functional group:
Wherein, R5、R6、R7、R8Independently of each other, hydrogen, hydroxyl, halogen, cyano, nitrine, amino or C be can be1-C4Alkane
Base, C1-C4Alkenyl, C1-C4Alkynyl or C1-C4Alkoxy.
Base is purine perhaps pyrimidine base analog or its chemistry and metabolic derivative, has following structure general formula:
Wherein, X4Can selected from hydrogen, halogen (F, Cl, Br, I), hydroxyl, methyl, amino, vinyl, 2- bromoethylene base,
C1-8(substitution) linear or branched alkyl group, (substitution) acetenyl；
X5、X6And X7It is respectively independent, hydrogen, halogen (F, Cl, Br, I), hydroxyl, amino, C can be selected from1-C4Alkoxy or C1-
C4Alkylamino.
Z is nitrogen, CH or CX4, X4It is defined as described above.
In above-mentioned statement, (substitution) alkyl is common name substitution or unsubstituted alkyl.
Preferably, formula (I) is the compound of the amino-acid ester containing D- of following formula:
Wherein, R1、R2、R3It is defined as described above with Nucleoside.
Preferably, formula (I) is the benzylamino phosphate derivative of acyclonucleosides tenofovir, i.e., formula (I) is following formula
Compound:
Wherein, R1、R2、R3It is defined as described above.It is preferred that are as follows:
Wherein, R1、R2It is defined as described above.Or preferably are as follows:
Wherein, R1、R2It is defined as described above.
Nucleosides Nucleoside in formula (I) can also be furan nucleus nucleosides, such as 2 '-methyl -2 '-fluorodeoxyuridine replaces
Benzylphosphate compound, i.e., formula (I) be lower formula (VII) compound:
Wherein, R1、R2、R3It is defined as described above.It is preferred that are as follows:
Wherein, R1、R2It is defined as described above.
Preferably, formula (II) is the compound of following formula:
Wherein, R1、R2、R3It is defined as described above with Nucleoside.
Preferably, formula (II) compound represented is tenofovir derivative:
Wherein, R1、R2、R3It is defined as described above.
Preferably, formula (II) compound represented are as follows:
Wherein, R1、R2It is defined as described above.
Preferably, compound above-mentioned (such as formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI) and (XII)) in, R1Selected from benzyl or C1-C12(substitution) linear or branched alkyl group.
Preferably, compound above-mentioned (such as formula (I), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), (X), (XI) and (XII)) in, R2Selected from substituted or unsubstituted C1-C8Linear or branched alkyl group.
Preferably, in compound above-mentioned (such as formula (I), (II), (III), (IV), (V), (VII), (IX) and (X))
In, R3It can be independently selected from hydrogen, C1-C12(substitution) linear or branched alkyl group, C1-C12(substitution) linear or branched alkyl group
Oxygroup, (substitution) C1-C12Carbon carboxylic acid acyloxy, (substitution) C1-C12Carbon carboxylic acyloxy Oxymethylene etc..
Preferably, in compound above-mentioned (such as formula (I), (II), (III), (IX)), Nucleoside is selected from following
Group:
Preferably, Nucleoside are as follows:
But it is not limited only to these nucleosides.
In a specific embodiment, aforesaid compound are as follows:
But it is not limited only to these nucleosides.
Isomers of the present invention includes tautomer, cis-trans-isomer, conformer and optical isomer.
Officinal salt of the present invention refer to the compound of phosphate prodrugs formula (I) or formula (II) of the invention with it is inorganic
The salt that acid or organic acid are formed, it is preferable that the organic acid is fumaric acid；It is highly preferred that the officinal salt is selected from:
On the other hand, the present invention provides a kind of preparation method of aforesaid compound.Specifically, D containing non-natural of the invention
The Phosphoramidate derivatives (I) of amino acids ester and (II) can be by the phenol leaving groups rolled into a ball containing strong electron-withdrawing group
Phosphate intermediate (1) or (3) and the unprotected nucleoside analog of 5 '-hydroxyls (2) under the catalysis of organic base, organic molten
Reaction is carried out in agent to be prepared.Reaction molecular formula is as follows:
Wherein R1、R2、R3, Nucleoside, Base it is defined as described above；X is strong electron-withdrawing group group, can be one,
It is also possible to multiple, NO can be selected from2,Cl,F；Y is oxygen atom, methylene, C=CH2Or cyclopropyl alkylN be 1,2,3,
4 or 5.
Preferably, the organic base is mainly tert-butyl magnesium chloride.
Preferably, formula (2) nucleoside analog and the phenol leaving group containing strong electron-withdrawing group phosphate (1) or
(3) and the molar ratio of organic base be 1: 1-5: 1-10, usually increase organic base dosage reaction is not hindered.
Preferably, using preparation method of the invention, reaction temperature is -78 DEG C to solvent reflux temperature, is recommended as 0 DEG C extremely
Room temperature.
Preferably, the reaction time is monitored by TLC, and usually 5-100 hours.
Preferably, the organic solvent of the reaction is selected from methylene chloride, tetrahydrofuran, chloroform, dioxane, benzene, toluene, second
One of ether, acetonitrile, DMF etc. or a variety of are recommended as methylene chloride, dioxane or tetrahydrofuran.
The amino-acid ester containing D- benzylphosphate intermediate (1) can by phosphorus oxychloride respectively with the substituted benzyl alcohol of equivalent
(4a), D- amino-acid ester (6) and strong electron-withdrawing group fortified phenol (7) reaction, in the presence of appropriate alkaline acid binding agent, appropriate
Organic solvent in be prepared.
Preferably, alkaline acid binding agent can be triethylamine, diisopropyl ethyl amine or pyridine.
Preferably, organic solvent can be benzene, toluene, chloroform, methylene chloride, ether, tetrahydrofuran, dioxane, second
One of acetoacetic ester, acetonitrile etc. are a variety of, are recommended as methylene chloride, benzene or tetrahydrofuran.
Preferably, reaction temperature is -78 DEG C to solvent reflux temperature, is recommended as -78 DEG C to room temperature.
Preferably, the reaction time is 3-12 hours, recommends to monitor reaction end with TLC.
Reaction equation is as follows:
Wherein, X, n, R1、R2And R3It is defined as described above.
Under certain condition, phosphorus oxychloride and substituted benzyl alcohol (4a) reaction product (5) can need not separate and be directly used in
It reacts in next step, i.e., replace with D- amino-acid ester or its hydrochloride and strong electron-withdrawing group (7) stepwise condensation, generation ammonia containing D-
Base acid esters benzylamino phosphate product (1).Multistep reaction can be handled with one pot, and synthetic method is simple, and yield is very high, can be with
Industrialized production.Benzyl phenolic group phosphate (1) stability it is high, can be handled with column chromatographic purifying.
The amino-acid ester containing D- phenolic group phosphoramidate intermediate (3) can by phosphorus oxychloride respectively with the phenol of equivalent
Derivative (4b), D- amino-acid ester or its hydrochloride (6) and strong electron-withdrawing group replace phenol (7) reaction, in appropriate alkalinity
In the presence of acid binding agent, in a suitable organic solvent it is prepared.
Preferably, alkaline acid binding agent can be triethylamine, diisopropyl ethyl amine or pyridine.
Preferably, organic solvent can be benzene, toluene, chloroform, methylene chloride, ether, tetrahydrofuran, dioxane, second
One of acetoacetic ester, acetonitrile etc. are a variety of, are recommended as methylene chloride, benzene or tetrahydrofuran.
Preferably, reaction temperature is -78 DEG C to solvent reflux temperature, is recommended as -78 DEG C to room temperature.
Preferably, the reaction time is 3-12 hours.
Reaction equation is as follows:
Wherein, X, n, R1、R2And R3It is defined as described above.
Under certain condition, phosphorus oxychloride and fortified phenol (4b) reaction product (8) can need not separate and be directly used in
In next step react, i.e., with D- amino-acid ester (6) and strong electron-withdrawing group replace phenol derivatives (7) stepwise condensation, generate contain D-
Amino-acid ester phenolic group phosphoramidic acid ester products (3).Multistep reaction can be handled with one pot, and synthetic method is simple, and yield is higher, can
With industrialized production.Phosphate (3) stability it is high, can be handled with column chromatographic purifying.
Another aspect, the present invention provide a kind of pharmaceutical composition, which includes compound above-mentioned or its is different
Structure body or officinal salt.
In another aspect, before aforementioned nucleoside analog of the invention, phosphoramidate containing unnatural D amino acids ester
Medicine or its isomers or officinal salt, can be used for upgrading various uncleosides as antiviral agents or anticancer drug.I.e. the present invention mentions
It in preparation prevention and/or is treated by virus, such as HIV, HBV and HCV for compound above-mentioned or its isomers or officinal salt
The drug of disease caused by Deng infecting；Or the purposes in the drug of preparation prevention and/or treating cancer.
Detailed description of the invention
Attached drawing Fig. 1 is the polymerization process of nucleosides, nucleotide and nucleic acid；
Attached drawing Fig. 2 is common nucleotide prodrug；
Attached drawing Fig. 3 is McGuigan type arylamine group phosphate (3-1) and its metabolism mechanism.
Specific embodiment
In following embodiment, all water sensitive reactions carry out in dry conditions.Benzene, tetrahydrofuran or methylene chloride exist
It flows back in the presence of metallic sodium, is dry, being saved for use after distillation.Nucleoside analog reference literature method
(Org.Proc.Res.Dev., 2010,14,1194；J.Org.Chem., 2003,68,6799；WO 2010075549A2) it closes
At nucleoside analog uses preceding preferably under vacuum 50 DEG C or so dryings.The amino phosphorus of the amino-acid ester containing D- of nucleoside compound
Acid ester derivant is separated using silica gel column chromatography method, and what is obtained is benzylamino phosphate (I) either phenolic group phosphoramidic acid
The epimeric mixture of ester (II), can by further by chiral resolution or recrystallization or chiral column column chromatograph etc. in a manner of point
From.
Facilitate to understand the present invention by following embodiments, but is not intended to limit the contents of the present invention.
Embodiment 1
By compound (9, 12.8g, 50mmol) and it is dissolved in methylene chloride (100mL) and is cooled at -78 DEG C, in 20 minutes
Methylene chloride (100mL) solution of o-methyl benzyl alcohol (6.1g, 50mmol) and triethylamine (7.7mL, 55mmol) is slowly added dropwise.Instead
Answer liquid to stir 30 minutes at -78 DEG C, be then warming up to 0 DEG C, be slowly added into dry D-alanine isopropyl ester hydrochloride (7.68g,
Methylene chloride (100 mL) solution 50mmol), then to be slowly added dropwise in above-mentioned reaction solution triethylamine (14.7mL,
105mmol), it is added dropwise within 90 minutes, and makes to continue stirring 3 hours under reaction solution zero degree.Rotary evaporation removes solvent, and second is added
Acetoacetic ester levigation, filtering, filtrate concentration, residue (petroleum ether: ethyl acetate=7: 3) are obtained with silica gel column chromatography separating purification
Colorless oil as product (11) (17.7g, 84%), be long placed in and can slowly solidify.
1H NMR(CDCl3, 400MHz) and δ 8.21 (dd, J1=9.2Hz, J2=2.2Hz, 2H), 7.20-7.38 (m, 6H),
5.19 (t, J=7.6Hz, 2 H), 4.98-5.03 (m, 1H), 3.93-3.99 (m, 1H), 3.73-3.78 (m, 1H), 3.10-
3.13 (m, 1H), 2.36 (s, 1.5H), 2.35 (s, 1.5H), 1.35-1.43 (m, 3H), 1.17-1.25 (m, 6H)；31P NMR
(CDCl3) δ 2.03,1.96；MS(m/z)437(M+H).
Embodiment 2
By 2- xylyl alcohol (122mg, 1mmol) and POCl3Methylene chloride (5mL) solution of (95 μ L, 1mmol) is cooling
To -78 DEG C, triethylamine (140 μ L, 1mmol) is slowly added dropwise, is added dropwise and continues stirring 4 hours.To reaction solution at -78 DEG C
Middle dropwise addition D-alanine isopropyl ester hydrochloride (168mg, 1mmol), the methylene chloride (5mL) of triethylamine (280 μ L, 2mmol) are molten
Liquid, reaction make reaction solution slowly be warming up to 0 DEG C in 1.5 hours after sixty minutes.
Methylene chloride (5mL) solution of Pentafluorophenol (184mg, 1mmol) is added into reaction flask, then in 1 hour
Triethylamine (140 μ L, 1mmol) slowly is added dropwise, reaction solution is slowly increased to be stirred overnight at room temperature.Triethylamine hydrochloride is filtered to remove,
Filter cake is washed with a small amount of methylene chloride, combined organic phase dry (Na after being washed with water2SO4), residue column chromatography can be with after concentration
Obtain two epimers13aWith13bEtc. compare mixture13, two epimers13aWith13bIt can use acetic acid second
Ester-petroleum ether mixed solvent is recrystallized and is separated.
13:1H NMR(CDCl3, 400MHz) and δ 7.17-7.37 (m, 4H), 5.22-5.24 (m, 2H), 4.98-5.03 (m,
1H), 3.98-4.02 (m, 1 H), 3.74-3.78 (m, 1H), 2.38 (s, 1.5H), 2.37 (s, 1.5H), 1.22-1.43 (m,
9H)；31P NMR(CDCl3) δ 5.69,5.01；MS (m/z)482(M+H).
13a:1H NMR(CDCl3, 400MHz) and δ 7.17-7.34 (m, 4H), 5.21-5.23 (m, 2H), 4.99-5.02 (m,
1H), 3.99-4.01 (m, 1H), 3.71-3.75 (m, 1H), 2.37 (s, 3H), 1.22-1.43 (m, 9H)；31P NMR(CDCl3)
δ5.69；MS(m/z)482(M+H).
13b:1H NMR(CDCl3, 400MHz) and δ 7.18-7.39 (m, 4H), 5.19-5.22 (m, 2H), 4.99-5.03 (m,
1H), 3.99-4.03 (m, 1H), 3.74-3.77 (m, 1H), 2.38 (s, 3H), 1.22-1.43 (m, 9H)；31P NMR(CDCl3)
δ5.01；MS(m/z)482(M+H).
Embodiment 3
Compound14(260mg, 1mmol) is dissolved in 20mL anhydrous tetrahydro furan, and tert-butyl chloride Grignard is added at 0 DEG C
Reaction 30 minutes is stirred at room temperature in reagent (1.0M, 2 mL, 2mmol).It is slowly added dropwise into compound11The four of (870mg, 2mmol)
Hydrogen tetrahydrofuran solution (4mL), reaction mixture stir 24 hours at room temperature, and saturated ammonium chloride solution (20mL) quenching reaction is added,
Ethyl acetate extracts (20mLx3), and organic phase merges, dry, and concentration, residue purifies (methylene chloride: first with silica gel column chromatography
Alcohol=20: 1) so that obtain white foam product (15a) and (15b)。
(15a)1H NMR(CD3OD, 400MHz) δ 7.54 (d, J=8.0Hz, 1H), 7.12-7.42 (m, 4H), 6.18 (s,
Br, 1H), 5.66 (d, J=8.0Hz, 1H), 4.94-5.30 (m, 6H), 3.74-4.43 (m, 5H), 2.36 (s, 3H), 1.33-
1.42 (m, 6H), 1.15-1.23 (m, 6H)；31P NMR(CD3OD)δ8.58；MS(m/z)558(M+H).
(15b)1H NMR(CD3OD, 400MHz) δ 7.41 (d, J=8.0Hz, 1H), 7.12-7.42 (m, 4H), 6.20 (s,
Br, 1H), 5.43 (d, J=8.0Hz, 1H), 4.94-5.30 (m, 6H), 3.74-4.43 (m, 5H), 2.41 (s, 3H), 1.33-
1.42 (m, 6H), 1.15-1.23 (m, 6H)；31P NMR(CD3OD)δ8.43；MS(m/z)558(M+H).
Embodiment 4
In the solvent of 80mL n,N-Dimethylformamide, (R) -9- [2- (phosphonylmethoxy base) propyl]-adenine is added16(3.5g, 8.9mmol), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (1.9g, 10mmol), three second
Amine (3.8mL, 27mmol), 4- (N, N- dimethylamino) pyridine (320mg, 2.6mmol) and 2- xylyl alcohol (1.8g,
14.7mmol), it after being stirred at room temperature 30 minutes, is reacted 24 hours in 100 degree of heating, end of reaction, is concentrated under reduced pressure and removes solvent, it is residual
Excess is soluble in water, inverted C-18 column chromatography (methanol: water=1: 9) purifying, obtain product (17, 69%).
31P NMR(MeOH-d4)δ-30.98；1H NMR(MeOH-d4) δ 8.32 (s, 1H), 8.25 (s, 1H), 7.07-7.23
(m, 4H), 4.88-4.96 (m, 2H), 4.39-4.43 (m, 1H), 4.20-4.25 (m, 1H), 3.92-3.96 (m, 1H), 3.80-
3.85 (m, 1H), 3.64-3.69 (m, 1H), 2.27 (s, 3H), 1.16 (d, J=6Hz, 3H)；13C NMR(MeOH-d4)δ
15.59,17.66,62.29,63.92,65.50,65.55,75.84,75.86,118.03,125.73,128.09,128.20,
130.03,136.49,143.91,145.23,149.19,150.46.
Embodiment 5
By compound17(45mg, 0.11mmol) is suspended in acetonitrile (1mL), and 50 DEG C are added with stirring thionyl chloride (33 μ
L, 0.25mmol), then reacted two hours at 75-80 DEG C.Solvent is evaporated off under subsequent nitrogen protection, residue is dissolved in dry two
In chloromethanes (2mL) and it is cooled to -30 DEG C.Slowly add D-alanine isopropyl ester hydrochloride (30mg, 0.2mmol) in one hour
With the dichloromethane solution (0.5mL) of triethylamine (30 μ L, 0.22mmol), reaction solution is slowly warmed to room temperature overnight.Wait react knot
10% sodium dihydrogen phosphate quenching reaction is added in beam, and methylene chloride (10mL) dilution, extraction, organic phase saturation food is added
Then brine, drying (sodium sulphate), filtering are concentrated, residue obtains white solid product with column chromatographic purifying18
(72%).
1H NMR(CDCl3) δ 8.29 (s, 0.5H), 8.28 (s, 0.5H), 7.90 (s, 0.5H), 7.89 (s, 0.5H),
7.15-7.29 (m, 4H), 6.52 (s, 2H), 5.27 (s, 1H), 4.88-5.02 (m, 3H), 4.31-4.36 (m, 1H), 3.56-
4.12 (m, 6H), 2.29 (s, 1.5H), 2.28 (s, 1.5H), 1.28-1.32 (m, 3H), 1.09-1.22 (m, 9H)；31P NMR
(CDCl3) δ 24.76,23.95；MS(m/z)505(M+H).
Embodiment 6
By compound17(0.78g, 2mmol), D-alanine isopropyl ester hydrochloride (1g, 6mmol) and triethylamine
Pyridine (8mL) solution of (0.84mL, 6mmol) is heated to 60 DEG C 5 minutes, then will by triphenyl phosphorus (1.84g, 7mmol) with
Compound19(1.54g, 7mmol) freshly prepared bright yellow solution in pyridine (8mL) is added to above-mentioned nucleosides17With D- ammonia
In the reaction solution of base acid esters, reacted overnight at 60 DEG C.It is concentrated under reduced pressure after reaction, residue is in ethyl acetate and sodium bicarbonate
It is distributed between aqueous solution, organic phase is dry with anhydrous sodium sulfate, filtering, is concentrated, the chiral preparation chromatography (Diacel ' s of residue
Chiralpak AS) separation, with containing 25% methanol acetonitrile mobile phase chromatograph, obtain product (18a) and (18b)。
18a:1H NMR(CDCl3) δ 8.36 (s, 1H), 7.92 (s, 1H), 7.17-7.37 (m, 4H), 5.70 (s, 2H),
5.00-5.14 (m, 3H), 4.32-4.36 (m, 1H), 4.09-4.14 (m, 1H), 3.52-4.00 (m, 5H), 2.36 (s, 3H),
1.85 (s, 3H), 1.13-1.31 (m, 9H)；31P NMR(CDCl3)δ23.73；MS(m/z)505(M+H).
18b:1H NMR(CDCl3) δ 8.31 (s, 1H), 7.94 (s, 1H), 7.14-7.28 (m, 4H), 6.11 (s, 2H),
4.99-5.08 (m, 2H), 4.88-4.94 (m, 1H), 4.28-4.33 (m, 1H), 3.80-4.14 (m, 4H), 3.55-3.64 (m,
2H), 2.29 (s, 3H), 1.35 (d, 3H), 1.12-1.26 (m, 9H),31P NMR(CDCl3)δ24.80；MS(m/z)505(M+
H)。
Embodiment 7
Under nitrogen protection, by PMPA16(287mg, 1mmol) is dissolved in 10mL acetonitrile, and TMSBr is then added
(0.66mL, 5mmol) is simultaneously stirred at room temperature overnight reaction solution.Evaporating solvent under reduced pressure, residue are dissolved in anhydrous triethylamine
D-alanine isopropyl ester hydrochloride (250mg, 1.5mmol) and benzylalcohol is then added in (2mL) and pyridine (8mL) in the mixed solvent20(270mg, 1.5mmol) stirring and dissolving.By compound in another reaction flask19(1.1g, 5mmol) and PPh3
(1.31g, 5mmol) mixing, bright yellow solution of generation in anhydrous pyridine (50mL) is transferred to PMPA's with double-ended needle immediately
In reaction flask, reaction solution heats 5 hours in 50-60 DEG C.After reaction solution is cooling, it is each that methanol, water, toluene and hexane is added
The water-methanol of 15mL, stirring layering, lower layer are mutually washed with 1: 1 toluene-hexane (10mL x3) again, then use methylene chloride
(30mLx3) extraction, dichloromethane extract is merged, and dry (anhydrous sodium sulfate), filtering, concentration, residue is with column chromatography point
From available product21。
1H NMR(CDCl3) δ 8.34 (s, 0.5H), 8.33 (s, 0.5H), 7.94 (s, 0.5H), 7.91 (s, 0.5H),
7.33-7.42 (m, 4H), 5.75 (s, 2H), 4.89-5.27 (m, 5H), 4.30-4.43 (m, 1H), 3.19-4.16 (m, 6H),
2.13 (s, 1.5H), 2.12 (s, 1.5H), 1.13-1.35 (m, 12H)；31P NMR(CDCl3) δ 24.96,23.96；MS(m/z)
563(M+H)。
Embodiment 8
Using the synthetic method of embodiment 7, by compound16With D-alanine isopropyl ester hydrochloride and benzylalcohol22Condensation, obtains
To colorless foamy solid product23(58%).1H NMR(CDCl3) δ 8.33 (s, 0.5H), 8.32 (s, 0.5H), 7.93 (s,
0.5H), 7.91 (s, 0.5H), 7.33-7.42 (dd, 4H), 5.73 (s, 2H), 4.89-5.27 (m, 3H), 4.30-4.43 (m,
1H), 3.19-4.16 (m, 6H), 2.12 (s, 1.5H), 2.11 (s, 1.5H), 1.13-1.35 (m, 12H)；MS(m/z)549(M+
H)。
Embodiment 9
Using the synthetic method of embodiment 7, by compound16With D-alanine isopropyl ester hydrochloride and phenol24Condensation, column
Chromatography method purifies to obtain colorless foamy solid product25aWith25bMixture25.Product25aWith25bTwo kinds of epimerisms
The method separation of D- tartaric acid fractionation can be used in body, and the specific method is as follows:
Column is chromatographed25aWith25bThe mixture 10g of two kinds of isomers is dissolved in 100mL acetonitrile, and 3.78g is added
D- tartaric acid, heating reaction solution to 60-65 DEG C keep 3 hours, the white precipitate that cooled and filtered is collected, be product25With
The mixture salt of D- tartaric acid.
1.2g is above-mentioned25Tartrate be suspended in 10mL water-acetonitrile (10: 1) solvent, be heated to 60-65 DEG C holding
1 hour, what is obtained was precipitated as PRConfiguration25aTartrate.
Take 0.6g compound25aTartrate be suspended between 2mL methylene chloride and 1mL water, be added ammonium hydroxide adjust pH
Between 8-9, extracting and demixing, organic phase concentration adds water 1mL and stirs one hour between 55-60 DEG C, even if cooled and filtered is swum
From compound25a。
Using L-TARTARIC ACID to mixture25Fractionation then obtains pure PSConfiguration25b。
25a:1H NMR(CDCl3) δ 8.35 (s, 1H), 7.99 (s, 1H), 7.11-7.32 (m, 5H), 6.04 (s, 2H),
4.97-5.03 (m, 1H), 4.34-4.39 (m, 1H), 4.14-4.20 (m, 1H), 3.99-4.12 (m, 4H), 3.63-3.69 (m,
1H), 1.04-1.29 (m, 12H)；31P NMR (CDCl3)δ20.91；MS(m/z)477(M+H).
25b:1H NMR(CDCl3) δ 8.29 (s, 1H), 7.94 (s, 1H), 6.97-7.22 (m, 5H), 6.52 (s, 2H),
4.93-4.97 (m, 1H), 4.30-4.34 (m, 1H)；4.05-4.14 (m, 3H), 3.88-3.93 (m, 2H), 3.66-3.72 (m,
1H), 1.13-1.24 (m, 12H)；31P NMR (CDCl3)δ21.98；MS(m/z)477(M+H).
Embodiment 10
Using the synthetic method of embodiment 7, by compound16With D-alanine isopropyl ester hydrochloride and phenol26Condensation, obtains
To colorless foamy solid product (27, 48%).
1H NMR(CDCl3) δ 8.34 (s, 0.5H), 8.33 (s, 0.5H), 7.94 (s, 0.5H), 7.91 (s, 0.5H), 7.31
(s, 2H), 6.46-6.77 (m, 3H), 5.98 (s, 2H), 4.36-4.40 (m, 1H), 3.45-3.92 (m, 6H), 1.12-1.26
(m, 12H)；MS(m/z)521(M+H).
Embodiment 11
By compound18(50mg, 0.1mmol) is dissolved in 1mL acetonitrile, is added fumaric acid (10mg, 0.9eq), is heated to reflux
It obtaining clear solution within 30 minutes, is filtered while hot after being cooled between 45-50 DEG C, white solid is precipitated after being cooled to room temperature in filtrate,
Solvent is filtered out, filter cake is washed with cold acetonitrile, obtains white solid product28。
Embodiment 12
By compound18a(50mg, 0.1mmol) is dissolved in anhydrous acetonitrile (2mL), addition fumaric acid (10mg,
It is heated to reflux after 0.09mmol) 1 hour, is cooled to room temperature and solid is slowly precipitated, filtered, wash filter cake with 0-5 DEG C of cold acetonitrile, obtain
To white powder solid28a。
Embodiment 13
By compound18b(50mg, 0.1mmol) is dissolved in anhydrous acetonitrile (2mL), addition fumaric acid (10mg,
It is heated to reflux after 0.09mmol) 4 hours, is cooled to room temperature and solid is slowly precipitated, filtered, wash filter cake with 0-5 DEG C of cold acetonitrile, obtain
To white powder solid28b。
Embodiment 14
By compound25a(48mg, 0.1mmol) is dissolved in anhydrous acetonitrile (1mL), addition fumaric acid (10mg,
It is heated to reflux after 0.09mmol) 4 hours, is cooled to room temperature and solid is slowly precipitated, filtered, wash filter cake with 0-5 DEG C of cold acetonitrile, obtain
To white powder solid29a。
Embodiment 15(HCV activity)
The test method bibliography report (WO2007/027248) of the anti-HCV activity of compound is in human hepatocytes
It is carried out in Huh-7, the activity of untested compound is assessed by the duplication situation of the HCV replicon with luciferase genes.
Here, the signal strength of luciferase corresponds directly to the duplication amount of viral RNA.Nucleoside phosphorylase ester prodrugs be configured to from 0.14 to
The DMSO solution of 300 μM of equal various concentrations, is then applied on 96- orifice plate, and replicon cell is then added, and (every hole is 6000 thin
Born of the same parents).Cell is hatched 48 hours in the presence of nucleoside prodrugs, then measures luciferase intensity.The decrease of luciferase signal
Indicate the decrease of HCV replicon rna in cell, it can be in turn to calculate antiviral activity index EC50。
After tested, compound15aWith15bShow preferable anti-hepatitis C virus activity, such as compound15aEC50For
1.0 μM, to cells such as PBM, CEM without any toxicity under 100 μM.
Embodiment 16(HIV activity)
The test method bibliography of the Anti-HIV-1 Active of compound reports (Antimicrob.Agents
Chemother., it 1992,36,2423) is carried out in PBM lymphocyte.Nucleoside phosphorylase ester prodrugs are configured to (20-40mM's)
Then DMSO solution is diluted to after a series of different concentration and HIV-1LAIThe PBM cell co-culture of virus infection.
HIV-1LAIVirus does not influence virus breeding with PBM cell quantity ratio MOI=0.01, DMSO solvent itself, and AZT is ginseng
According to antiviral activity index EC50Obtained according to inhibiting rate-concentration curve calculating (Adv. Enzyme Regul., 1984,22,
27)。
It confirms after tested, compound18a、18b、21、23、25a、25bAnd27It is living to show preferable anti AIDS virus
Property, as a result it see the table below.
Embodiment 17Zoopery
By 6 healthy beasle dogs, it is divided into 3 groups, every group of male and female each 1.1st group of animal takes TDF, and the 2nd group is taken chemical combination
Object25a, the 3rd group is taken compound18a.Fasting 12h before all animals are administered, dosage is 10mgkg-1, respectively at
It 0 after administration, is taken a blood sample 2mL by foreleg vein within 2,4,8 and 24 hours, is centrifugated out peripheral blood mononuclear cells (PBM), PBM cell
The quantitative determination of interior PMPA uses HPLC-MS method (Clin.Chem, 1992,480-485).Plasma drug concentration data is through DAS2.0
Software processing, calculates two drugs in PBM endocellular metabolism and goes out the medicine of PMPA for parameter AUC0-24。
Experimental result find three groups of beasle dogs oral TDF,18aWith25aAfterwards, PMPA is in peripheral blood mononuclear cells
AUC0-24The μ g.h/mL of respectively 3.8,101 and 89 namely oral administration of compound18a、25aThe PMPA amount that PMB is generated into the cell afterwards point
26 times and 23 times of TDF, compound Chao Guo not taken orally18aWith25aThe ability of conveying PMPA up to lymphocyte is apparently higher than at present
A line AIDS drugs TDF.
Claims (3)
1. a kind of formula (18), formula (21), formula (25) and formula (27) compound represented or its officinal salt,
2. compound or pharmaceutically acceptable salt thereof according to claim 1, which is characterized in that the compound are as follows:
3. according to right want 1 or 2 described in compound or pharmaceutically acceptable salt thereof, which is characterized in that the salt be fumarate:
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