CN106188192A - Nucleoside phosphoramidic acid phosphate derivatives containing D-amino-acid ester and medical usage thereof - Google Patents

Nucleoside phosphoramidic acid phosphate derivatives containing D-amino-acid ester and medical usage thereof Download PDF

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CN106188192A
CN106188192A CN201510208269.3A CN201510208269A CN106188192A CN 106188192 A CN106188192 A CN 106188192A CN 201510208269 A CN201510208269 A CN 201510208269A CN 106188192 A CN106188192 A CN 106188192A
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CN106188192B (en
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刘沛
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Shenzhen Yangli Pharmaceutical Technology Co.,Ltd.
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刘沛
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Abstract

The present invention relates to novel nucleoside phosphoric acid/phosphonate prodrugs containing non-natural D amino acids ester and its production and use.Described novel nucleoside phosphoric acid/phosphonate prodrugs containing substituted benzyl is the compound shown in formula (I) or formula (II) or its isomer or officinal salt, it can be used as various nucleoside analog, the such as prodrug of acyclonucleosides, carbocyclic nucleoside, furan nucleus nucleoside etc., the biological activity of strengthening nucleoside compound, thus be applied to virus and infect and the treatment of cancer.

Description

Nucleoside phosphoramidic acid phosphate derivatives containing D-amino-acid ester and medical usage thereof
Technical field
The invention belongs to pharmaceutical technology field, in particular to a kind of novel nucleoside phosphoramidic acid containing unnatural configuration D-amino-acid ester / phosphonate prodrugs and its production and use.
Background of invention
Nucleoside compound is DNA (deoxyribonucleic acid) and ribonucleic acid, namely the structures alone of biological heredity gene DNA and RNA, thus All life entities all have critical function, and is widely used in virus infection and the treatment of cancer.Since generation nineteen sixty, many bioactive Nucleoside analog is used for treating various virus and infects, such as herpes, acquired immune deficiency syndrome (AIDS), B-mode and hepatitis C.The nucleoside of these synthetic is similar to Thing, can be by the growth of blocking virus nucleic acid chains, the duplication of break virus gene, become antiviral drugs (Fig. 1).
As it is shown in figure 1, first nucleoside must divide three steps to activate into nucleoside triphosphate, the synthesis of DNA or RNA, and then performance could be participated in Go out physiologically active.When a nucleoside analog can squeeze into the gene of virus or cancerous cell by selectivity, its nucleic acid chains is stoped to replicate breeding, Time simultaneously to host cell gene fanout free region (toxicity), this nucleoside analog just can become antiviral or cancer therapy drug.
Nucleoside triphosphate itself is the highest owing to carrying multiple negative charge, polarity, it is difficult to entered cell interior by cell wall, so can not Use directly as antiviral drugs.The form of uncleosides as antiviral agents is exactly the moderate nucleoside of polarity itself in early days, and it is after entering cell Under host cell kinases (kinase) acts on, point three step phosphorylated, eventually become nucleoside triphosphate and play drug effect.Recently as nucleoside phosphorylase The progress of ester prodrug technology, directly introduces the low polarity equivalent construction unit of monophosphate in nucleoside molecule by the method for chemistry, makes nucleoside phosphorus Acid esters prodrug discharges monophosphate nucleoside after entering cell interior again, is limited without the selectivity by nucleoside kinase.Thus, nucleoside phosphorylase Ester prodrugs just becomes the spread path of upgrading nucleoside medicine performance.
The research of nucleoside prodrugs is when previous focus, especially phosphoric acid ester prodrug are the modes of a kind of maximally effective upgrading nucleoside medicine, also Enable to some and the nucleoside of phosphorylated can not show biological activity, the phosphoric acid ester prodrug of the nucleoside of document report owing to nucleoside kinase limits Structure type mainly have seven classes (J.Am.Chem.Soc., 2004,126,5154-5163；WO2012094248, CN 102532199, CN 103980318, CN 103435672 Fig. 2), its outstanding representative be the invention such as McGuigan arylamino phosphate ester (2-5), it is to exist at present Nucleoside compound prodrug is most widely used and successful one.
McGuigan type nucleoside prodrugs is that British scientist Christopher McGuigan is in the invention at first of generation nineteen ninety and by the most perfect Arylamino phosphate ester structure unit (3-1, Fig. 3), be structurally characterized in that it contains the phosphorus that the amino of a l-amino acid ester participates in being formed Amido link P (O)-N, and phosphide key P (the O)-O-Ar that an aryl phenol participation is formed.Have proven to the L-ammonia of McGuigan prodrug (3-1) First base acid esters key ruptures and discharges free carboxylic acid derivative (3-2), and the carboxyl functional group of generation can be catalyzed phenolic group oxygen phosphorus bond cleavage solution, is formed Five-membered ring phosphate derivative (3-3), discharges mononucleotide (3-4) subsequently, and final metabolism generates can participate in nucleic acid chains polymerization, have life The trinucleotide (3-6) of reason activity.So nucleoside prodrugs (3-1) is the equivalent of its mononucleotide (3-4), it can get around selectivity Monophosphate esterification under mononucleotide high, inefficient is kinase catalytic, directly 5 '-mono-phosphide of conveying nucleoside enters cell and produces biology Activity.Its result be McGuigan prodrug can make those because of cannot phosphorylated and lose bioactive nucleoside and there is biological activity again, or Person improves the biological activity of known nucleotide medicine.
It is known that the esterase hydrolyzed reaction of natural L-amino acids ester has caused generation monokaryon glycosides thereafter in McGuigan prodrug (3-1) molecule Acid (3-4) metabolic process, and owing to esterase is distributed widely in gastrointestinal disturbances road, so the l-amino acid ester in nucleoside phosphoramidate structure Base usually will be hydrolyzed metabolism before arriving hepatocyte in large quantities.For the nucleotide medicine for the treatment of liver disease, if using non-sky So D-amino-acid ester substitutes l-amino acid ester and participates in its phosphoramidate prodrugs of composition, it is possible to significantly delay the esterase hydrolyzed metabolism of amino-acid ester Process so that nucleoside prodrugs lipase hydrolysis loss in digestive tract greatly reduces, and then improve nucleoside prodrugs entrance hepatocellular conveying effect Rate, can reduce drug dose, exempts poisonous side effect of medicine, or improves drug effect.
Summary of the invention
Comprehensive McGuigan prodrug (Fig. 2,2-5) and HepDirect prodrug (2-6) construction features, with in HepDirect pro-drugs Substituted benzyl displaces the aromatic ring in McGuigan prodrug, and the present inventor once have devised the amino phosphorus containing natural L-amino acids ester and substituted benzyl Acid/phosphonate prodrugs (CN 102532199, CN 103980318, CN 103435672), author further describes containing non-natural on this basis The D-amino-acid ester of configuration participates in nucleoside phosphoramidate prodrugs (I) and the architectural feature of (II), the Preparation method and use constituted.
Phosphoramidic acid/the phosphonate prodrugs containing D-amino-acid ester of the present invention can strengthen the biological activity of nucleoside compound, and upgrading, it is intrinsic Antiviral or active anticancer.After nucleoside is combined with this novel phosphoric acid/phosphonate ester containing D-amino-acid ester, the nucleoside phosphoramidate of generation is to ester The metabolic stability of enzyme improves greatly relative to McGuigan prodrug, and in conjunction with the ester hydrolase stability of substituted benzyl, prodrug (I) and (II) have Significantly Liver targeting effect, is particularly suitable for exploitation treatment hepatopathy, such as the medicine of hepatocarcinoma and hepatitis etc..
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 to be similar to the phosphoric acid/phosphonate prodrugs of thing, and this prodrug is Compound shown in formula (I) or formula (II) or its isomer or officinal salt,
As shown in formula (I) and formula (II), containing a D-amino-acid ester in the phosphoramidic acid of the present invention/phosphonate prodrugs structure.In formula (I) Phosphoric acid/phosphonate function contain one participated in, by suitable substituted benzylalcohol, the phosphide key that formed and one formed by the participation of non-natural D-amino-acid ester Phosphamide key；Phosphoric acid/phosphonate function in formula (II) is contained one and is participated in the phosphide key that formed and one by suitably by suitable substituted phenol Substituted D-amino-acid ester participates in the phosphamide key formed.
Wherein, R1With R2The most independent, can be respectively selected from hydrogen, (replacement) phenyl ring, (replacement) aromatic radical, (replacement) benzyl, C1-C12 (replacement) straight or branched alkyl, C3-C8(replacement) saturated or unsaturated cycloalkyl, C2-C8(replacement) straight or branched thiazolinyl, C2-C8(replacement) straight or branched alkynyl.
R3Can be hydrogen, halogen, carboxyl, nitro, ester group, acylamino-, C1-C8(replacement) straight or branched alkyl, C1-C8(replacement) Straight or branched alkoxyl, C1-C8Amido, C2-C8(replacement) straight or branched thiazolinyl, C2-C8(replacement) straight or branched alkynyl, (replacement) C1-C12Carbon carboxylic acyloxy epoxide, (replacement) C1-C12Carbon carboxylic acyloxy Oxymethylene.
Nucleoside refers to various nucleoside analog, and including common furan nucleus nucleoside, carbocyclic nucleoside and acyclonucleosides, it has following structure Formula:
Wherein, X1Can not exist or CH2Or CHCH3。
X2Selected from O, CH2, C=CH2、CHCH3Or cyclopropane base
X3Can not exist or methylene CH2。
T1、T2Separate, can be H and CH2R4, and R4For H, OH or F；T1、T2The composition that can also be bonded together mutually is as follows Functional group:
Wherein, R5、R6、R7、R8Separate, can be hydrogen, hydroxyl, halogen, cyano group, nitrine, amino or C1-C4Alkyl, C1-C4 Thiazolinyl, C1-C4Alkynyl or C1-C4Alkoxyl.
Base is purine or miazines base, or its chemistry and metabolic derivative, and it has a following general structure:
Wherein, X4Hydrogen, halogen (F, Cl, Br, I), hydroxyl, methyl, amino, vinyl, 2-bromoethylene base, C can be selected from1-8(take Generation) straight or branched alkyl, (replacement) acetenyl；
X5、X6And X7The most independent, hydrogen, halogen (F, Cl, Br, I), hydroxyl, amino, C can be selected from1-C4Alkoxyl or C1-C4Alkane Amino.
Z is nitrogen, CH or CX4, X4Defined as described above.
In above-mentioned statement, (replacement) alkyl is that common name replaces or unsubstituted alkyl.
Preferably, formula (I) is the compound containing D-amino-acid ester of following formula:
Wherein, R1、R2、R3Defined as described above with Nucleoside.
Preferably, formula (I) is the benzylamino phosphate derivative of acyclonucleosides tenofovir, i.e. formula (I) is the compound of following formula:
Wherein, R1、R2、R3Defined as described above.It is preferably:
Wherein, R1、R2Defined as described above.Or it is preferably:
Wherein, R1、R2Defined as described above.
Nucleoside Nucleoside in formula (I) is alternatively furan nucleus nucleoside, such as 2 '-methyl-2 '-fluorodeoxyuridine substituted benzylphosphate compound, I.e. formula (I) is the compound of lower formula (VII):
Wherein, R1、R2、R3Defined as described above.It is preferably:
Wherein, R1、R2Defined as described above.
Preferably, formula (II) is the compound of following formula:
Wherein, R1、R2、R3Defined as described above with Nucleoside.
Preferably, the compound shown in formula (II) is tenofovir derivant:
Wherein, R1、R2、R3Defined as described above.
Preferably, the compound shown in formula (II) is:
Wherein, R1、R2Defined as described above.
Preferably, aforesaid compound (such as formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII)) in, R1Selected from benzyl or C1-C12(replacement) straight or branched alkyl.
Preferably, aforesaid compound (such as formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII)) in, R2Selected from substituted or unsubstituted C1-C8Straight or branched alkyl.
Preferably, in aforesaid compound (such as formula (I), (II), (III), (IV), (V), (VII), (IX) and (X)), R3Can With independently selected from hydrogen, C1-C12(replacement) straight or branched alkyl, C1-C12(replacement) straight or branched alkyl oxy, (replacement) C1-C12 Carbon carboxylic acyloxy epoxide, (replacement) C1-C12Carbon carboxylic acyloxy Oxymethylene etc..
Preferably, in aforesaid compound (such as formula (I), (II), (III), (IX)), Nucleoside is selected from following group:
Preferably, Nucleoside is:
But it is not limited only to these nucleoside.
In a specific embodiment, aforesaid compound is:
But it is not limited only to these nucleoside.
Isomer of the present invention includes tautomer, cis-trans-isomer, conformer and optical isomer.
Officinal salt of the present invention refers to what the phosphate prodrugs formula (I) of the present invention or the compound of formula (II) and mineral acid or organic acid were formed Salt, it is preferable that described organic acid is fumaric acid；It is highly preferred that described officinal salt is selected from:
On the other hand, the present invention provides the preparation method of a kind of aforesaid compound.Specifically, the ammonia containing non-natural D amino acids ester of the present invention Base phosphate derivative (I) and (II) can by the phenol leaving group rolled into a ball containing strong electron-withdrawing group phosphate intermediate (1) or (3) and 5 '- The unprotected nucleoside analog of hydroxyl (2) under the catalysis of organic base, carry out reaction in organic solvent and be prepared.Reaction molecular formula is as follows:
Wherein R1、R2、R3, Nucleoside, Base defined as described above；X is strong electron-withdrawing group group, can be one, it is also possible to be many Individual, NO can be selected from2、Cl、F；Y is oxygen atom, methylene, C=CH2Or cyclopropane baseN is 1,2,3,4 or 5.
Preferably, described organic base is mainly tert-butyl group magnesium chloride.
Preferably, formula (2) nucleoside analog and phenol leaving group containing strong electron-withdrawing group phosphate ester (1) or (3) and organic The mol ratio of alkali is 1: 1-5: 1-10, and reaction is not hindered by the consumption generally increasing organic base.
Preferably, use the preparation method of the present invention, reaction temperature be-78 DEG C to solvent reflux temperature, it is recommended that be 0 DEG C to room temperature.
Preferably, the response time is monitored by TLC, usually 5-100 hour.
Preferably, the organic solvent of this reaction is selected from dichloromethane, oxolane, chloroform, dioxane, benzene, toluene, ether, acetonitrile, DMF One or more in Deng, it is recommended that for dichloromethane, dioxane or oxolane.
Benzylphosphate intermediate containing D-amino-acid ester (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 suitably alkalescence acid binding agent, it is prepared in suitable organic solvent.
Preferably, alkalescence acid binding agent can be triethylamine, diisopropyl ethyl amine or pyridine.
Preferably, organic solvent can be benzene, toluene, chloroform, dichloromethane, ether, oxolane, dioxane, ethyl acetate, acetonitrile One or more in Deng, it is recommended that for dichloromethane, benzene or oxolane.
Preferably, reaction temperature be-78 DEG C to solvent reflux temperature, it is recommended that for-78 DEG C to room temperature.
Preferably, the response time is 3-12 hour, it is recommended that monitor reaction end with TLC.
Reaction equation is as follows:
Wherein, X, n, R1、R2And R3Defined as described above.
Under certain condition, phosphorus oxychloride and substituted benzyl alcohol (4a) product (5) can separate and be directly used in next step reaction, i.e. Substituted with D-amino-acid ester or its hydrochlorate and strong electron-withdrawing group (7) stepwise condensation, generate containing D-amino-acid ester benzylamino phosphate ester produce Thing (1).Multistep reaction can one pot of process, synthetic method is simple, and productivity is the highest, can be with industrialized production.Benzyl phenolic group phosphate ester (1) Stability is high, can be with column chromatography purification process.
Phenolic group phosphoramidate intermediate containing D-amino-acid ester (3) can by phosphorus oxychloride respectively with the phenol derivatives of equivalent (4b)、D- Amino-acid ester or its hydrochlorate (6) and the substituted phenol of strong electron-withdrawing group (7) reaction, in the presence of suitably alkalescence acid binding agent, have suitable Machine solvent is prepared.
Preferably, alkalescence acid binding agent can be triethylamine, diisopropyl ethyl amine or pyridine.
Preferably, organic solvent can be benzene, toluene, chloroform, dichloromethane, ether, oxolane, dioxane, ethyl acetate, acetonitrile One or more in Deng, it is recommended that for dichloromethane, benzene or oxolane.
Preferably, reaction temperature be-78 DEG C to solvent reflux temperature, it is recommended that for-78 DEG C to room temperature.
Preferably, the response time is 3-12 hour.
Reaction equation is as follows:
Wherein, X, n, R1、R2And R3Defined as described above.
Under certain condition, phosphorus oxychloride and fortified phenol (4b) product (8) can separate and be directly used in next step reaction, i.e. With D-amino-acid ester (6) and the substituted phenol derivatives of strong electron-withdrawing group (7) stepwise condensation, generate containing the phenolic group phosphoramidic acid of D-amino-acid ester Ester products (3).Multistep reaction can one pot of process, synthetic method is simple, and productivity is higher, can be with industrialized production.Phosphate ester (3) stablize Property high, can be with column chromatography purification process.
Another aspect, the present invention provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises aforesaid compound or its isomer or officinal salt.
Another further aspect, the aforementioned nucleoside analog of the present invention, phosphoramidate prodrugs containing unnatural D amino acids ester or its isomer or can medicine With salt, may be used for upgrade various uncleosides as antiviral agents or cancer therapy drug.The i.e. present invention provides aforesaid compound or its isomer or pharmaceutically acceptable Salt is infected the medicine of the disease caused in preparation prevention and/or treatment by virus, such as HIV, HBV and HCV etc.；Or preparation prevention and/ Or the purposes in the medicine for the treatment of cancer.
Accompanying drawing explanation
Accompanying drawing Fig. 1 is the polymerization process of nucleoside, nucleotide and nucleic acid；
Accompanying drawing Fig. 2 is common nucleotide prodrug；
Accompanying drawing Fig. 3 is McGuigan type arylamine group phosphate ester (3-1) and metabolism mechanism thereof.
Detailed description of the invention
In following example, the reaction of all water sensitive is carried out the most in dry conditions.Benzene, oxolane or dichloromethane reflux in the presence of metallic sodium, Be dried, distillation after preserve stand-by.Nucleoside analog reference literature method (Org.Proc.Res.Dev., 2010,14,1194；J.Org.Chem., 2003, 68,6799；WO 2010075549A2) synthesis, nucleoside analog use before the most under vacuo about 50 DEG C be dried.Nucleoside compound containing D- The Phosphoramidate derivatives of amino-acid ester utilizes silica gel column chromatography method to separate, and obtain is benzylamino phosphate ester (I) or phenolic group amino phosphorus The epimeric mixture of acid esters (II), can be to separate by modes such as chiral separation or recrystallization or chiral column column chromatographies further.
Contribute to understanding the present invention by following embodiment, but be not limiting as present disclosure.
Embodiment 1
By compound (9, 12.8g, 50mmol) be dissolved in dichloromethane (100mL) and be cooled to-78 DEG C at, be slowly added dropwise neighbour in 20 minutes Dichloromethane (100mL) solution of xylyl alcohol (6.1g, 50mmol) and triethylamine (7.7mL, 55mmol).Reactant liquor is at-78 DEG C Stir 30 minutes, be then warmed up to 0 DEG C, be slowly added into the dichloromethane (100 of dry D-alanine isopropyl ester hydrochlorate (7.68g, 50mmol) ML) solution, is slowly added dropwise triethylamine (14.7mL, 105mmol) subsequently in above-mentioned reactant liquor, and dropping in 90 minutes is complete, and makes reactant liquor zero Degree is lower continues stirring 3 hours.Rotary evaporation removes solvent, adds ethyl acetate levigation, filters, and filtrate concentrates, and residue over silica gel column chromatography divides From purification (petroleum ether: ethyl acetate=7: 3) obtain 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 POCl3Dichloromethane (5mL) solution of (95 μ L, 1mmol) is cooled to-78 DEG C, It is slowly added dropwise triethylamine (140 μ L, 1mmol), drips complete continuation and stir 4 hours.D-alanine isopropyl is dripped in-78 DEG C of downhill reaction liquid Ester hydrochloride (168mg, 1mmol), dichloromethane (5mL) solution of triethylamine (280 μ L, 2mmol), make reaction after reacting 60 minutes Liquid was slowly warmed up to 0 DEG C in 1.5 hours.
In reaction bulb, add dichloromethane (5mL) solution of Pentafluorophenol (184mg, 1mmol), in 1 hour, slowly drip three subsequently Ethamine (140 μ L, 1mmol), reactant liquor is slowly increased to stirred overnight at room temperature.Being filtered to remove triethylamine hydrochloride, filter cake washs with a small amount of dichloromethane, (Na it is dried after the organic phases washed with water merged2SO4), after concentration, residue column chromatography can obtain two epimers13aWith13bGeometric ratio Mixture13, two epimers13aWith13bEthyl acetate-light petrol mixed solvent recrystallization can be utilized to separate.
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(mn/z)482(M+H).
Embodiment 3
Compound14(260mg, 1mmol) is dissolved in 20mL anhydrous tetrahydro furan, at 0 DEG C add tert-butyl group chloride Grignard reagents (1.0M, 2 ML, 2mmol), reaction 30 minute is stirred at room temperature.It is slowly added dropwise into compound11The tetrahydrofuran solution (4mL) of (870mg, 2mmol), Stirring 24 hours under reactant mixture room temperature, add saturated ammonium chloride solution (20mL) cancellation reaction, ethyl acetate extracts (20mL x 3), Organic facies merges, and is dried, and concentrates, and residue is with silica gel column chromatography purification (dichloromethane: methanol=20: 1) and then obtains 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 80mLN, the solvent of dinethylformamide, add (R)-9-[2-(phosphonylmethoxy base) propyl group]-adenine16(3.5g, 8.9mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (1.9g, 10mmol), triethylamine (3.8mL, 27mmol), 4-(N, N- Dimethylamino) pyridine (320mg, 2.6mmol) and 2-xylyl alcohol (1.8g, 14.7mmol), after being stirred at room temperature 30 minutes, in 100 degree Reacting by heating 24 hours, reacts complete, and concentrating under reduced pressure removes solvent, and residue is soluble in water, inverted C-18 column chromatography (methanol: water=1: 9) purification, 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), adds thionyl chloride (33 μ L, 0.25mmol) under 50 DEG C of stirrings, Then react two hours at 75-80 DEG C.Solvent being evaporated off under nitrogen protection subsequently, residue is dissolved in dry dichloromethane (2mL) and is cooled to -30℃.D-alanine isopropyl ester hydrochlorate (30mg, 0.2mmol) and the dichloro of triethylamine (30 μ L, 0.22mmol) is slowly added in one hour Dichloromethane (0.5mL), reactant liquor is slowly warmed to room temperature overnight.Question response terminates, and adds 10% sodium dihydrogen phosphate cancellation reaction, adds Dichloromethane (10mL) dilutes, extracts, organic facies saturated common salt solution washing, be dried (sodium sulfate), filter then concentrate, residue with Column chromatography purification, obtains white solid product18(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 hydrochlorate (1g, 6mmol) and triethylamine (0.84mL, 6mmol) Pyridine (8mL) solution is heated to 60 DEG C 5 minutes, subsequently will be by triphenyl phosphorus (1.84g, 7mmol) and compound19(1.54g, 7mmol) In pyridine (8mL), the bright yellow solution of fresh preparation joins above-mentioned nucleoside17With the reactant liquor of D-amino-acid ester, react overnight at 60 DEG C. Reaction terminates rear concentrating under reduced pressure, and residue distributes between ethyl acetate and sodium bicarbonate aqueous solution, and organic facies anhydrous sodium sulfate is dried, filters, dense Contracting, residue chirality preparative hplc (Diacel ' s Chiralpak AS) separates, and chromatographs with the acetonitrile mobile phase containing 25% methanol, obtain product (18a) (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, is subsequently added TMSBr (0.66mL, 5mmol) And make reactant liquor be stirred at room temperature overnight.Removing solvent under reduced pressure, residue is dissolved in anhydrous triethylamine (2mL) and pyridine (8mL) mixed solvent In, it is subsequently added D-alanine isopropyl ester hydrochlorate (250mg, 1.5mmol) and benzylalcohol20(270mg, 1.5mmol) stirring and dissolving.Additionally By compound in one reaction bulb19(1.1g, 5mmol) and PPh3(1.31g, 5mmol) be mixing in the anhydrous pyridine (50mL), generation bright orange Color solution is transferred in the reaction bulb of PMPA immediately with double needle, and reactant liquor heats 5 hours in 50-60 DEG C.After reactant liquor cooling, add first The each 15mL of alcohol, water, toluene and hexane, stirring layering, the water-methanol of lower floor washs with 1: 1 toluene-hexane (10mLx3), then uses Dichloromethane (30mLx3) extracts, and is merged by dichloromethane extract, is dried (anhydrous sodium sulfate), filters, concentrates, and residue is with column chromatography Separation can obtain 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
Use the synthetic method of embodiment 7, by compound16With D-alanine isopropyl ester hydrochlorate and benzylalcohol22Condensation, obtains colourless foam solid Body 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
Use the synthetic method of embodiment 7, by compound16With D-alanine isopropyl ester hydrochlorate and phenol24Condensation, column chromatography method purification obtains To colorless foamy solid product25aWith25bMixture25.Product25aWith25bTwo kinds of epimers can use D-tartaric acid to split Method separate, its concrete grammar is as follows:
Column chromatography is obtained25aWith25bThe mixture 10g of two kinds of isomers is dissolved in 100mL acetonitrile, adds 3.78g D-tartaric acid, heating Reactant liquor keeps 3 hours to 60-65 DEG C, and cooled and filtered collects the white precipitate obtained, for product25Mixture salt tartaric with D-.
1.2g is above-mentioned25Tartrate be suspended in 10mL water-acetonitrile (10: 1) solvent, be heated to 60-65 DEG C keep 1 hour, obtain Be precipitated as PRConfiguration25aTartrate.
Take 0.6g compound25aTartrate be suspended between 2mL dichloromethane and 1mL water, add ammonia regulation pH 8-9 between, extraction Taking layering, organic facies concentrates, and add water 1mL stirring a hour between 55-60 DEG C, though the compound that cooled and filtered is free25a。
Use L-TARTARIC ACID to mixture25Split and then obtain 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
Use the synthetic method of embodiment 7, by compound16With D-alanine isopropyl ester hydrochlorate and phenol26Condensation, obtains colourless foam solid Body 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, adds fumaric acid (10mg, 0.9eq), is heated to reflux 30 minutes Obtaining settled solution, filtered while hot after being cooled between 45-50 DEG C, filtrate separates out white solid after being cooled to room temperature, filters solvent, and filter cake is with cold Acetonitrile washs, and obtains white solid product28。
Embodiment 12
By compound18a(50mg, 0.1mmol) is dissolved in anhydrous acetonitrile (2mL), adds fumaric acid (10mg, 0.09mmol) post-heating Reflux 1 hour, be cooled to room temperature and slowly separate out solid, filter, with 0-5 DEG C of cold acetonitrile washing filter cake, obtain white powder solid28a。
Embodiment 13
By compound18b(50mg, 0.1mmol) is dissolved in anhydrous acetonitrile (2mL), adds fumaric acid (10mg, 0.09mmol) post-heating Reflux 4 hours, be cooled to room temperature and slowly separate out solid, filter, with 0-5 DEG C of cold acetonitrile washing filter cake, obtain white powder solid28b。
Embodiment 14
By compound25a(48mg, 0.1mmol) is dissolved in anhydrous acetonitrile (1mL), adds fumaric acid (10mg, 0.09mmol) post-heating Reflux 4 hours, be cooled to room temperature and slowly separate out solid, filter, with 0-5 DEG C of cold acetonitrile washing filter cake, obtain white powder solid29a。
Embodiment 15(HCV activity)
Method of testing list of references report (WO2007/027248) of the anti-HCV activity of compound is carried out in human hepatocytes Huh-7, to be measured The activity of compound is assessed by the duplication situation of the HCV replicon with luciferase genes.Here, the signal intensity of luciferase is direct Duplication amount corresponding to viral RNA.Nucleoside phosphorylase ester prodrugs is configured to wait the DMSO solution of variable concentrations from 0.14 to 300 μMs, then executes It is added on 96-orifice plate, is subsequently added replicon cell (6000, every hole cell).Cell hatches 48 hours in the presence of nucleoside prodrugs, then Measure luciferase intensity.The weakening of luciferase signal indicates weakening of HCV replicon rna in cell, it can so that anti-in order to calculate Virus activity index EC50。
After tested, compound15aWith15bShow preferable anti-hepatitis C virus activity, such as compound15aEC50It it is 1.0 μMs, 100 To cells such as PBM, CEM all without any toxicity under μM.
Embodiment 16(HIV activity)
Method of testing list of references report (Antimicrob.Agents Chemother., 1992,36,2423) of the Anti-HIV-1 Active of compound exists PBM lymphocyte is carried out.Nucleoside phosphorylase ester prodrugs is configured to the DMSO solution of (20-40mM), is then diluted to a series of different dense With HIV-1 after degreeLAIThe PBM cell co-culture that virus has infected.HIV-1LAIVirus with PBM cell quantity than MOI=0.01, DMSO Virus breeding is not affected by solvent itself, and AZT is reference, antiviral activity index EC50Calculate according to suppression ratio-concentration curve and obtain (Adv. Enzyme Regul., 1984,22,27).
Confirm after tested, compound18a、18b、21、23、25a、25bAnd27All showing preferable anti-HIV activity, result sees below Table.
Embodiment 17Zoopery
By 6 healthy beasle dogs, it is divided into 3 groups, often each 1 of male and female of group.1st treated animal takes TDF, takes compound for the 2nd group25a, the 3rd Group takes compound18a.All animals are administered front fasting 12h, and dosage is 10mg kg-1, respectively at be administered after 0,2,4,8 and 24 Hour being taken a blood sample 2mL by foreleg vein, centrifugation goes out peripheral blood lymphocytes (PBM), and the quantitative determination of the intracellular PMPA of PBM uses HPLC-MS method (Clin.Chem, 1992,480-485).Plasma drug concentration data, through DAS2.0 software processes, calculates two medicines thin at PBM Intracellular metabolism goes out the medicine of PMPA for parameter AUC0-24。
Experimental result find three groups of beasle dogs oral TDF,18aWith25aAfter, PMPA AUC in peripheral blood lymphocytes0-24It is respectively 3.8,101 and 89 μ g.h/mL, namely oral administration of compound18a、25aThe PMPA amount of the intracellular generation of rear PMB exceedes oral TDF's respectively 26 times and 23 times, compound18aWith25aConveying PMPA reaches the ability of lymphocyte apparently higher than a current line anti-acquired immunodeficiency syndrome drug TDF.

Claims (9)

1. formula (I) or the compound shown in formula (II) or its isomer or an officinal salt,
As shown in formula (I) and formula (II), containing a D-amino-acid ester in the phosphoramidic acid of the present invention/phosphonate prodrugs structure: in formula (I) Phosphoric acid/phosphonate function contain one participated in, by suitable substituted benzylalcohol, the phosphide key that formed and one formed by the participation of non-natural D-amino-acid ester Phosphamide key；Phosphoric acid/phosphonate function in formula (II) is contained one and is participated in the phosphide key that formed and one by suitably by suitable substituted phenol Substituted D-amino-acid ester participates in the phosphamide key formed.
Wherein, R1With R2The most independent, can be respectively selected from hydrogen, (replacement) phenyl ring, (replacement) aromatic radical, (replacement) benzyl, C1-C12 (replacement) straight or branched alkyl, C3-C8(replacement) saturated or unsaturated cycloalkyl, C2-C8(replacement) straight or branched thiazolinyl, C2-C8(replacement) straight or branched alkynyl.
R3Can be hydrogen, halogen, carboxyl, nitro, ester group, acylamino-, C1-C8(replacement) straight or branched alkyl, C1-C8(take Generation) straight or branched alkoxyl, C1-C8Amido, C2-C8(replacement) straight or branched thiazolinyl, C2-C8(replacement) straight or branched Alkynyl, (replacement) C1-C12Carbon carboxylic acyloxy epoxide, (replacement) C1-C12Carbon carboxylic acyloxy Oxymethylene.
Nucleoside refers to various nucleoside analog, and including common furan nucleus nucleoside, carbocyclic nucleoside and acyclonucleosides, it has following structure Formula:
Wherein, X1Can not exist or CH2Or CHCH3。
X2Selected from O, CH2, C=CH2、CHCH3Or cyclopropane base
X3Can not exist or methylene CH2。
T1、T2Separate, can be H and CH2R4, and R4For H, OH or F；T1、T2Composition can also be bonded together mutually such as Lower functional group:
Wherein, R5、R6、R7、R8Separate, can be hydrogen, hydroxyl, halogen, cyano group, nitrine, amino or C1-C4Alkyl, C1-C4 Thiazolinyl, C1-C4Alkynyl or C1-C4Alkoxyl.
Base is purine or miazines base, or its chemistry and metabolic derivative, and it has a following general structure:
Wherein, X4Hydrogen, halogen (F, Cl, Br, I), hydroxyl, methyl, amino, vinyl, 2-bromoethylene base, C can be selected from1-8(take Generation) straight or branched alkyl, (replacement) acetenyl；
X5、X6And X7The most independent, hydrogen, halogen (F, Cl, Br, I), hydroxyl, amino, C can be selected from1-C4Alkoxyl or C1-C4Alkane Amino.
Z is nitrogen, CH or CX4, X4Defined as described above.
Compound the most according to claim 1 or its isomer or officinal salt, it is characterised in that formula (I) is the compound of following formula:
Preferably, formula (I) is the compound of following formula:
More preferably:
Or preferably, the compound of formula (I) alternatively following formula:
It is preferably:
Wherein, R1、R2、R3, Nucleoside, Base definition as claimed in claim 1.
Compound the most according to claim 1 or its isomer or officinal salt, it is characterised in that formula (II) is the compound of following formula:
Preferably, the compound shown in formula (II) is:
Wherein, R1、R2Definition as claimed in claim 1.
Compound the most according to any one of claim 1 to 3 or its isomer or officinal salt, it is characterised in that R1With R2Each Independently selected from benzyl or C1-C8Substituted or non-substituted straight or branched alkyl；
R3Can be independently selected from hydrogen, C1-C12(replacement) straight or branched alkyl, C1-C12(replacement) straight or branched alkyl oxy, C1-C12(replacement) straight or branched acyloxy etc..
Preferably, R3Selected from hydrogen, methyl, C1-C12Carbon carboxylic acyloxy Oxymethylene, C1-C12Alkoxyl or C1-C12Carbon carboxylic acyloxy epoxide；Enter one Preferably, Nucleoside is selected from following group for step:
Preferably, Nucleoside is:
Compound the most according to any one of claim 1 to 4 or its isomer or officinal salt, it is characterised in that described compound is:
Compound the most according to any one of claim 1 to 5 or its isomer or officinal salt, it is characterised in that described isomer bag Include tautomer, cis-trans-isomer, conformer and optical isomer.
7. want the compound according to any one of 1 to 6 or its isomer or officinal salt according to right, it is characterised in that described officinal salt is The salt that the compound of formula (I) or formula (II) is formed with mineral acid or organic acid, it is preferable that described organic acid is fumaric acid；It is highly preferred that it is described Officinal salt is selected from:
8. a pharmaceutical composition, this pharmaceutical composition comprises the compound according to any one of claim 1 to 7 or its isomer or pharmaceutically acceptable Salt.
9. compound according to any one of claim 1 to 7 or its isomer or officinal salt in preparation prevention and/or treatment by virus, such as HIV, HBV and HCV etc. infect the medicine of the disease caused；Or the purposes in the medicine of preparation prevention and/or treatment cancer.
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