CN109627272A - With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage - Google Patents

With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage Download PDF

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CN109627272A
CN109627272A CN201811577487.4A CN201811577487A CN109627272A CN 109627272 A CN109627272 A CN 109627272A CN 201811577487 A CN201811577487 A CN 201811577487A CN 109627272 A CN109627272 A CN 109627272A
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compound
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刘洪海
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Foshan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses one group to have the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage.Novel nucleoside phosphate analogs disclosed by the invention are significantly superior to the Suo Feibuwei of clinical application in terms of anti-hepatitis activity, on chiral phosphorus atoms, alkoxycarbonyloxyalkyl substituted-phenyl and amino acid, cytotoxicity is significantly reduced in surveyed cell line, antiviral activity is improved, there is extraordinary potential applicability in clinical practice.

Description

With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its Medicinal usage
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of novel nucleotide phosphate similar to object preparation method and Its pharmaceutical composition and purposes, especially as the purposes for the treatment of hepatitis C.
Background technique
U.S. FDA had approved multiple HCV drugs, including protease inhibitors, ucleosides and non-nucleoside polymerization in recent years Enzyme inhibitor and NS5A inhibitor etc..There are three the protease inhibitors class drugs of FDA approval: VX-950 (Telaprevir), the shortcomings that SCH-503034 (Boceprevir) and TMC435 (Simeprevir), protease inhibitors It is to be also easy to produce that mutation, toxicity is big, poor bioavailability, it is effective to a other gene type.Telaprevir is as the first generation Protease inhibitors has logged out market.The second generation of high activity and wide spectrum and third generation protease inhibitors is mainly used as and it One of the component of drug combination of his hepatitis drug.
The patient that Hepatitis C Virus (HCV) has 3-4 million newly-increased every year, the World Health Organization estimate in global sense Dye person is more than 200,000,000, and in China more than 10,000,000 patients, HCV belongs to flaviviridae hepatovirus virus.Long-term hepatitis C virus Poison infection is gently to inflammation, weight to cirrhosis, liver cancer.And when hepatitis cirrhosis patients in decompensation, various complication, such as abdomen can occur Water abdominal cavity infection, upper gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, the performance such as hepatic failure.
Hepatitis C pathogenesis is fully aware of not yet, causes liver cell structure and function when HCV is replicated in liver cell Change or interference Hepatocyte synthesizes, degeneration of liver cells can be caused downright bad, show that HCV directly damages liver, cause to fall ill Certain effect.
The polymerase inhibitors of hepatitis is generally divided into ucleosides and two kinds of non-nucleoside.Currently, clinically only having Suo Feibu One ucleosides hepatitis drug of Wei is ratified to list by FDA, and Sofosbuvir and other HCV-Ab IgGs are in the clinical examination for grinding drug combination It tests and also shows good effect.But since bioavilability is low in vivo by sofosbuvir, need with biggish to medicament Amount, hepatitis patient need to receive long-term treatment, and bring virus drug resistance and long-term safety problem can not be ignored therewith, because This, develops new bioavilability height, and the low HCV infection therapeutic agent of drug effect high toxicity is still clinical urgent need.
Summary of the invention:
The purpose of the present invention is the structures to nucleotide phosphate similar to object to be further transformed, and obtains having higher The active novel nucleoside phosphate analogs of bioavilability, more hypotoxicity and more highly resistance HCV virus, for from now on further investigation with The antiviral application of exploitation the compounds of this invention lays the foundation.
To solve the above problems, the technical solution adopted by the present invention are as follows:
The present invention provides the compound with general formula structure (Ia), salt, tautomer or free alkalis
Wherein, Base is B1, B2, B3, B4, B5；
Here, R1、R2、R3、R4、R5It is H, D, F, Cl, CH each independently3、NH2Or cyclopropylamino.
Ri is five yuan of ribose Ri1、Ri2、Ri3；
Here, X2、Y2、X3、Y3、Y4It is H, F, Cl, OH, CH each independently3Or N3。
Z1=O, C=CH2；
Z2=O, CH2；
Z3、Z4It is O or S each independently；
X, Y is H or D each independently；
A=OC (O) O, OC (O) or C (O) O；
R22=H, C1- C6Alkyl；
Rb=R0, R2, R4；Here, R0=H, C1- C6Alkyl；R2=CH2AR22；R4=aryl.
As further preferred scheme, compound (Ia) of the present invention, salt, tautomer or free alkali, It is preferred that A=OC (O) O；R22It is preferred that isopropyl, isobutyl group, neopentyl；R4It is preferred that phenyl.
As further preferred scheme, compound of the present invention, salt, tautomer or free alkali, phosphorus Atom is chiral atom, preferably its single configuration S(P)Configuration or R(P)Configuration or S(P)Configuration and R(P)Configuration any proportion mixes Close object.
As scheme still more preferably, compound of the present invention, salt, tautomer or free alkali, institute Preferred structural formula of compound is as follows:
The synthetic route of nucleoside phosphorylase ester compounds of the present invention is as follows:
Here: Base, Ri, X, Y, A, R22、RbDefinition is the same as claim 1.
Under alkaline condition, R is added with after phosphorus oxychloride reaction in K2bOH reaction, adds Pentafluorophenol reaction Close object F2B-1 and F2B-2；Under cryogenic, compound F2B-1 or F2B-2 are reacted with nucleosides, respectively obtain chemical combination Object N2B-2 or N2B-1.
Nucleoside phosphorylase ester compounds of the present invention mix system with pharmaceutically acceptable carrier, diluent or excipient It is standby at pharmaceutical preparation and nanometer formulation, to be suitable for oral or parenteral；Medication include, but are not limited to it is intradermal, In intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.
A kind of medical composition comprising nucleoside phosphorylase ester compounds of the present invention.
Medical composition of the present invention also contains the other therapeutic agents independently selected from following drug: Ribavirin (Ribavirin), interferon, hepatitis NS3 protease inhibitors, HCV reverse transcriptase NS5B non-nucleosidic inhibitors, HCV reverse transcription Enzyme NS5B nucleosidic inhibitors, the synergist of NS5A inhibitor and NS5A inhibitor, entry inhibitor, cyclosporine immunosupress Agent, NS4A antagonist, NS4B inhibitor, cyclophilin inhibitor.
Nucleoside phosphorylase ester compounds and its Pharmaceutical composition of the present invention are in the drug for preparing anti-Flaviviridae In application, the flaviviridae is Hepatitis C Virus.
The dosage form of pharmaceutical composition of the present invention is tablet, injection or capsule.
Specific embodiment
The present invention is further elaborated by the following examples, but the present invention is not limited to these Examples.This hair Reagent used in bright embodiment and raw material are the commercially available gained in market.
Embodiment 1
(R)-(isopropoxy carbonyl oxygroup) methyl pentafluorophenyl group phosphate (FP020-1) and (S)-(isopropoxy Carbonyloxy group) methyl pentafluorophenyl group phosphate (FP020-2) synthesis.
Phosphorus oxychloride (5g, 3.04ml, 32.6mmol) is added in reaction flask, adds acetonitrile 200mL, is cooled to -70 DEG C, Acetonitrile (60mL) solution of K2 (4.37g, 32.6mmol) and triethylamine (3.3g, 4.53ml, 32.6mmol) is slowly added dropwise, drips It adds complete, is slowly increased to room temperature, after reaction overnight, is cooled to 0 DEG C, by Pentafluorophenol (5.4g, 29.4mmol) and triethylamine The acetonitrile solution 60mL liquid of (7.3g, 10ml, 72mmol) is added drop-wise in above-mentioned solution, is stirred 1 hour at 0 DEG C, is risen to room Temperature after being stirred overnight, is added 100ml methylene chloride and 100ml water, separates organic phase, dense with depressurizing after anhydrous sodium sulfate drying Contracting, residue obtain 6.2g white solid, 10% tert-butyl of solid with silica gel post separation (0-30% ethyl acetate/n-hexane) Methyl ether/n-hexane recrystallization, obtains white solid FP020-2 (2.5g), mother liquor with silica gel post separation (50% ethyl acetate/oneself Alkane) FP020-1 (1.8g) and FP020-2 (0.3g), FP020-2 and FP020-1 purity are all larger than 99%.
FP020-1:1H NMR (400MHz, CDCl3) δ (ppm): 1.12-1.23 (6H, m, 2 × CH3), 4.68- 4.79 (1H, m, OCH), 5.31-5.43 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -1.57.
FP020-2:1H NMR (400MHz, CDCl3) δ (ppm): 1.16-1.28 (6H, m, 2 × CH3), 4.71- 4.79 (1H, m, OCH), 5.32-5.49 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -1.83.
Embodiment 2
The synthesis of two ((isopropoxy carbonyl oxygroup) methyl) pentafluorophenyl group phosphates (FP2020).
Phosphorus oxychloride (5g, 3.04ml, 32.6mmol) is added in reaction flask, adds acetonitrile 200mL, is cooled to -70 DEG C, Acetonitrile (60mL) solution of K2 (8.7g, 65.2mmol) and triethylamine (6.6g, 9.06ml, 65.2mmol) is slowly added dropwise, is added dropwise It finishes, is slowly increased to room temperature, after reaction overnight, be cooled to 0 DEG C, by Pentafluorophenol (5.4g, 29.4mmol) and triethylamine (7.3 Gram, 10ml, 72mmol) acetonitrile solution 60mL liquid be added drop-wise in above-mentioned solution, 0 DEG C stir 1 hour, be warmed to room temperature, stir After mixing overnight, 100 milliliters of methylene chloride and 100 milliliters of water are added, separate organic phase, it is dense with being depressurized after anhydrous sodium sulfate drying Contracting, residue obtain 8.3g white solid, 10% tert-butyl first of solid with silica gel post separation (0-30% ethyl acetate/hexane) Base ether/hexane recrystallization, obtains white solid FP11 (3.2g), mother liquor with silica gel post separation (50% ethyl acetate/hexane) again FP11 (2.1g), FP11 purity are greater than 99%.
1H NMR (400MHz, CDCl3) δ (ppm): 1.10-1.25 (12H, m, 4 × CH3), 4.61-4.81 (2H, m, 2 × OCH), 5.30-5.46 (4H, m, 2 × OCH2O)。
Embodiment 3
The synthesis of two ((neopentyl oxygen carbonyl oxygroup) methyl) pentafluorophenyl group phosphates (FP2323).
FP2323 is closed in the similar method of embodiment 2.
1H NMR (400MHz, CDCl3) δ (ppm): 0.82-0.95 (18H, m, 6 × CH3), 4.30-4.49 (4H, m, 2 ×COOCH2), 5.33-5.48 (4H, m, 2 × OCH2O)。
Embodiment 4
(R)-((phenyl-pentafluoride oxygroup) (phenoxy group) phosphoryl oxygroup) methyl carbonic acid isopropyl ester (FP24-1) and (S)- The synthesis of ((phenyl-pentafluoride oxygroup) (phenoxy group) phosphoryl oxygroup) methyl carbonic acid isopropyl ester (FP24-2).
Dichloro-phenyl phosphate (6.88g, 3.04ml, 32.6mmol) is added in reaction flask, adds acetonitrile 200mL, it is cooling To -70 DEG C, the acetonitrile of K2 (4.37g, 32.6mmol) and triethylamine (3.3 grams, 4.53ml, 32.6mmol) is slowly added dropwise (60mL) solution, is added dropwise, and is slowly increased to room temperature, after reaction overnight, is cooled to 0 DEG C, by Pentafluorophenol (5.4g, It 29.4mmol) is added drop-wise in above-mentioned solution with the acetonitrile solution 60mL liquid of triethylamine (7.3 grams, 10ml, 72mmol), at 0 DEG C Stirring 1 hour, is warmed to room temperature, after being stirred overnight, 100 milliliters of methylene chloride and 100 milliliters of water is added, organic phase are separated, with nothing It is concentrated under reduced pressure after aqueous sodium persulfate is dry, residue obtains 7.6g white with silica gel post separation (0-30% ethyl acetate/hexane) and consolidates Body, solid are recrystallized with 10% t-butyl methyl ether/hexane, are obtained white solid FP24-2 (3g), mother liquor silica gel post separation (50% ethyl acetate/hexane) obtains FP24-1 (2.3g) and FP24-2 (0.4g), FP24-2 and FP24-1 purity are all larger than 99%.
FP24-1:1H NMR (400MHz, CDCl3) δ (ppm): 1.12-1.23 (6H, m, 2 × CH3), 4.68-4.79 (1H, m, OCH), 5.31-5.43 (2H, m, OCH2O), 7.17-7.30 (H in 3H, m, OPh ortho para position), 7.33-7.37 (H in 2H, m, OPh meta position).31P NMR (162MHz, CDCl3) δ -1.62.
FP24-2:1H NMR (400MHz, CDCl3) δ (ppm): 1.16-1.25 (6H, m, 2 × CH3), 4.70-4.83 (1H, m, OCH), 5.32-5.48 (2H, m, OCH2O), 7.18-7.34 (H in 3H, m, OPh ortho para position), 7.37-7.41 (H in 2H, m, OPh meta position).31P NMR (162MHz, CDCl3) δ -1.98.
Embodiment 5
(((2R, 3R, 4R, 5R) -5- (2,4 (1H, 3H)-hybar X -1- base) fluoro- 3- hydroxyl-of -4- 4- methyltetrahydrofuran -2- base) methyl) two ((isopropoxy carbonyl oxygroup) methyl) phosphotriesters (SOF2020) synthesis
Nucleosides SOF (260.2mg, 1mmol) and the anhydrous THF of 5.0mL are added into 50mL flask, mixture is in ice-water bath It is cooled to 0 DEG C.It is added dropwise tert-butyl magnesium chloride 1.0MinTHF solution (3.0mL, 3.0mmol), reaction mixture stirs at 0 DEG C The solution of phosphorus reagent FP2020 (794mg, 1.6mmol) in 5mLTHF is then added dropwise in 30min at 0 DEG C.It will be obtained clear Clearance response solution is warmed to room temperature, and after stirring 20 hours, saturation NH is added4Cl (15mL) is stirred 5 minutes, by mixture acetic acid Ethyl ester (200mL) dilution, separates organic phase, aqueous layer with ethyl acetate (30mL) is extracted twice.Combined organic layer water (30mL), saturation NaHCO3The washing of (2x30mL), salt water (30mL), and through Na2SO4Decompression boils off solvent, residue after drying It is purified via silica gel column chromatography (methylene chloride of 0-10% methanol), obtains white solid product SOF2020 (315mg), yield 55%).
1H NMR (400MHz, CDCl3) δ (ppm): 1.09-1.39 (15H, m, 5 × CH3), 4.09-4.14 (1H, m, H on saccharide ring 3 '-position), 4.28 (1H, brs, the OH on saccharide ring 3 '-position), 4.34-4.41 (1H, m, on saccharide ring 4 '-position H), 4.47-4.52 (2H, m, the H on saccharide ring 5 '-position), 4.87-4.99 (2H, m, 2 × COOCH), 5.55-5.72 (5H, M, 2 × OCH2H on O and pyrimidine ring 5), 6.19 (1H, s, the H on saccharide ring 1 '-position), 7.22-7.51 (1H, d, pyrimidine H on 6, ring), 9.75 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.27；
ESI+MS:(M+H)+573.4。
Embodiment 6
(R)-(((2S, 3S, 5R) -5- (5- methyl -2,4 (1H, 3H)-hybar X -1- base) -3- nitrine Tetrahydrofuran -2- base) methyl) ((isopropoxy carbonyl oxygroup) methyl) phosphate (AZT020-2) synthesis.
AZT020-1 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 1.09-1.39 (6H, m, 2 × CH3), 1.95 (3H, s, pyrimidine rings 5 CH on position3), 2.30-2.53 (3H, m, the H on 3 '-position of Hand saccharide ring on saccharide ring 2 '-position, 4.06-4.23 (1H, m, H on saccharide ring 4 '-position), 4.27-4.44 (2H, m, the H on saccharide ring 5 '-position), 4.87-4.99 (1H, m, COOCH), 5.55-5.72 (2H, m, OCH2O), 6.15 (1H, t, the H on saccharide ring 1 '-position, 7.25 (1H, s, the H on pyrimidine ring 6), 9.25 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.79；
ESI+MS:(M+H)+464.3。
Embodiment 7
(S)-(((2S, 3S, 5R) -5- (5- methyl -2,4 (1H, 3H)-hybar X -1- base) -3- nitrine Tetrahydrofuran -2- base) methyl) ((isopropoxy carbonyl oxygroup) methyl) phosphate (AZT020-2) synthesis.
AZT020-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 1.12-1.43 (6H, m, 2 × CH3), 1.95 (3H, s, pyrimidine rings 5 CH on position3), 2.32-2.55 (3H, m, the H on 3 '-position of Hand saccharide ring on saccharide ring 2 '-position, 4.09-4.26 (1H, m, H on saccharide ring 4 '-position), 4.30-4.45 (2H, m, the H on saccharide ring 5 '-position), 4.89-5.01 (1H, m, COOCH), 5.58-5.75 (2H, m, OCH2O), 6.17 (1H, t, the H on saccharide ring 1 '-position, 7.27 (1H, s, the H on pyrimidine ring 6), 9.25 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.92；
ESI+MS:(M+H)+464.3。
Embodiment 8
(((2R, 5S) -5- (fluoro- -2 (1H)-pyrimidone -1- base of 4- amino of 5-) -1,3- oxygen sulphur Polymorphs Alkane -2- base) methyl) two ((neopentyl oxygen carbonyl oxygroup) methyl) phosphotriesters (FTC2323) synthesis.
FTC2323 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.89 (18H, m, 6 × CH3), 3.06-3.51 (2H, m, saccharide ring H on 2 '-positions), 3.86-4.06 (4H, m, 2 × COOCH2), 4.26-4.47 (1H, m, the H on saccharide ring 4 '-position), 5.29-5.42 (2H, m, the H on saccharide ring 5 '-position), 5.55-5.72 (5H, m, 2 × OCH2On 1 '-position of O and saccharide ring H), 5.81-6.21 (2H, dbrs, the NH on pyrimidine ring 42), 7.92-8.16 (1H, s, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ4.52；
ESI+MS:(M+H)+616.6。
Embodiment 9
((S)-(((2R, 5S) -5- (4- amino -2 (1H)-pyrimidone -1- base) -1,3- oxygen sulphur Polymorphs Alkane -2- base) methyl oxygroup) (phenoxy group) phosphoryl oxygroup) and methyl carbonic acid isopropyl ester (3TC24-1) synthesis.
3TC24-1 is synthesized in the similar method of embodiment 5
1H NMR (400MHz, CDCl3) δ (ppm): 1.08-1.39 (6H, m, 2 × CH3), 3.06-3.51 (2H, m, sugar H on ring 2 '-position), 4.26-4.47 (1H, m, the H on saccharide ring 4 '-position), 4.87-4.99 (1H, m, COOCH), 5.29- 5.42 (3H, m, the H on saccharide ring 5 '-position and pyrimidine ring 5), 5.55-5.72 (3H, m, OCH2On 1 '-position of O and saccharide ring H), 5.81-6.21 (2H, dbrs, the NH on pyrimidine ring 42), 7.23-7.29 (2H, m, the H on phenyl ring ortho position), 7.32-7.39 (3H, m, the H between phenyl ring in contraposition), 8.32-8.72 (1H, d, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ4.28；
ESI+MS:(M+H)+502.5。
Embodiment 10
((R)-(((2R, 5S) -5- (4- amino -2 (1H)-pyrimidone -1- base) -1,3- oxygen sulphur Polymorphs Alkane -2- base) methyl oxygroup) (phenoxy group) phosphoryl oxygroup) and methyl carbonic acid isopropyl ester (3TC24-2) synthesis.
3TC24-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 1.10-1.42 (6H, m, 2 × CH3), 3.09-3.55 (2H, m, sugar H on ring 2 '-position), 4.29-4.42 (1H, m, the H on saccharide ring 4 '-position), 4.90-5.03 (1H, m, COOCH), 5.31- 5.44 (3H, m, the H on saccharide ring 5 '-position and pyrimidine ring 5), 5.58-5.74 (3H, m, OCH2On 1 '-position of O and saccharide ring H), 5.85-6.24 (2H, dbrs, the NH on pyrimidine ring 42), 7.27-7.31 (2H, m, the H on phenyl ring ortho position), 7.36-7.47 (3H, m, the H between phenyl ring in contraposition), 8.34-8.64 (1H, d, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ4.57；
ESI+MS:(M+H)+502.5。
Embodiment 11
Biological assessment
1. antiviral activity detection of the compound of the present invention in HCV replicon (HCVpp) system
HCV replicon mensuration program
General procedure: make the cell in the source Huh-7 with HCV genotype 1b replicon and luciferase reporter gene It is (Zluc) in supplement 10% fetal calf serum, 2mMGlutaMAX, 1%MEM nonessential amino acid, 100IU/mL penicillin, 100 μ The Dulbecco of g/mL streptomysin and 0.5mg/mL (G418) improve growth in Eagle culture medium (DMEM).By using being based on Lipid/histone transfection process transiently transfects Zluc cell with mankind's carbonyl acid ester enzyme 1 (CES1).After transfection 24 and 48 hours, Using anti-CES1 and anti-tag antibody, the expression of CES1 is confirmed by Western blotting (Westernblot).For dose response Test, with 7.5xl03 cells/well, in 50 μ L volumes, by cell inoculation in 96 orifice plates, and in 37 DEG C/5%CO2Under incubate It educates.Fresh drug solution is as 2X liquid storage in Huh-7 culture medium.From these liquid storage systems in the DMEM without G418 Standby 10 5 times of other dilutions.At least 3 hours after being inoculated with Huc cell, by being added 50 μ L's in duplicate into plate Drug dilution liquid is to start drug-treated.The range of drug final concentration is 100nM-0.0000512n Μ.Then cell is existed 37 DEG C/5%CO2Lower incubation.Or compound is tested with two kinds of concentration (10nM and 100nM).In all cases, Huh-7 (it is not with HCV replicon) is used as negative control.It, will by Fluc by quantization after being incubated for 72 hours 5 '-fluorine luciferin list oxygen synthesize the photon that oxygroup fluorine luciferin (oxyfIuoroluciferin) is emitted, to measure HCV The inhibition of duplication.For this purpose, removing culture medium from plate by tapping, 50 microlitres of ONE-glo luciferase assay kits being added Enter each hole.Plate is gently vibrated 3 minutes at room temperature, using 700nm cut-off filter, there is 1 second readout time It measures and shines on Victor3V1420 multiple labeling counter (PerkinElmer).By Microsoft Excel and The dose-effect curve for the gained best fit equation formula that XLfit4.1 software is found out calculates EC50Value.
For Cytotoxic evaluation, Zluc cell is handled with above compound, using CellTiter-Blue cell It survives amylograph (Promega), 20 μ L measurement solution is added in each hole, to monitor cell viability.Then by plate 37 DEG C/5%CO2It is lower to be incubated at least 3 hours.It is more in Victor3V1420 respectively with the excitation and launch wavelength of 560 and 590nm The fluorescence for marking detection plate in counter (Perkin Elmer), finds out using Microsoft Excel and XLfit4.1 software CC50Value.
The compound that following table provides is measured according to above-mentioned replicon measuring method.
+++ indicate 1-10nM；++ indicate 10-100nM；+ indicate 0.1-1 μM；
* Suo Feibuwei is according to bibliography J.Org.Chem.2011,76,8311 preparations.

Claims (10)

1. the compound with structure (Ia), salt, tautomer or free alkali
Wherein, Base is B1, B2, B3, B4, B5；
Here, R1、R2、R3、R4、R5It is H, D, F, Cl, CH each independently3、NH2Or cyclopropylamino；
Ri is five yuan of ribose Ri1、Ri2、Ri3；
Here, X2、Y2、X3、Y3、Y4It is H, F, Cl, OH, CH each independently3Or N3；
Z1=O, C=CH2；
Z2=O, CH2；
Z3、Z4It is O or S each independently；
X, Y is H or D each independently；
A=OC (O) O, OC (O) or C (O) O；
R22=H, C1- C6Alkyl；
Rb=R0, R2, R4；Here, R0=H, C1- C6Alkyl；R2=CH2AR22；R4=aryl.
2. compound (Ia) as described in claim 1, salt, tautomer or free alkali, which is characterized in that preferred A= OC(O)O；R22It is preferred that isopropyl, isobutyl group, neopentyl；R4It is preferred that phenyl.
3. such as compound claimed in claims 1-2, salt, tautomer or free alkali, which is characterized in that phosphorus atoms are Chiral atom, preferably its single configuration S(P)Configuration or R(P)Configuration or S(P)Configuration and R(P)The mixture of configuration any proportion.
4. the compound as described in claim 1-3, salt, tautomer or free alkali, which is characterized in that institute is preferred Structural formula of compound is as follows:
5. a kind of method for preparing nucleoside phosphorylase ester compounds described in claim 1-4, which is characterized in that the method Synthetic route is as follows:
Here: Base, Ri, X, Y, A, R22、RbDefinition is the same as claim 1；
Under alkaline condition, R is added with after phosphorus oxychloride reaction in K2bOH reaction, adds Pentafluorophenol and reacts to obtain compound F2B-1 and F2B-2；Under cryogenic, compound F2B-1 or F2B-2 are reacted with nucleosides, respectively obtain compound N2B-2 or N2B-1.
6. nucleoside phosphorylase ester compounds described in -4 according to claim 1, it is characterized in that: with pharmaceutically acceptable carrier, dilute It releases agent or excipient is prepared by mixing into pharmaceutical preparation and nanometer formulation, to be suitable for oral or parenteral；Medication Include, but are not limited in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.
7. a kind of medical composition comprising nucleoside phosphorylase ester compounds described in claim 1.
8. medical composition according to claim 7, it is characterized in that: also containing the other treatment independently selected from following drug Agent: the non-nucleosides of Ribavirin (Ribavirin), interferon, hepatitis NS3 protease inhibitors, HCV reverse transcriptase NS5B inhibits Agent, HCV reverse transcriptase NS5B nucleosidic inhibitors, NS5A inhibitor and NS5A inhibitor synergist, entry inhibitor, ring spore Plain immunosuppressor, NS4A antagonist, NS4B inhibitor, cyclophilin inhibitor.
9. a kind of nucleoside phosphorylase ester compounds described in claim 1 and its Pharmaceutical composition are preparing anti-Flaviviridae Application in drug, it is characterized in that: the flaviviridae is Hepatitis C Virus.
10. the pharmaceutical composition as described in claim 7-9, it is characterised in that: the dosage form of described pharmaceutical composition be tablet, Injection or capsule.
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Application publication date: 20190416