CN109651452A - With the active nucleoside phosphorylase long-chain dibasic acid esters analog of suppressing virus replication, preparation method and its medicinal usage - Google Patents

With the active nucleoside phosphorylase long-chain dibasic acid esters analog of suppressing virus replication, preparation method and its medicinal usage Download PDF

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CN109651452A
CN109651452A CN201811577369.3A CN201811577369A CN109651452A CN 109651452 A CN109651452 A CN 109651452A CN 201811577369 A CN201811577369 A CN 201811577369A CN 109651452 A CN109651452 A CN 109651452A
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nucleoside phosphorylase
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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
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • 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
    • 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
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide

Abstract

The invention discloses one group to have the active nucleoside phosphorylase long-chain dibasic acid esters analog of suppressing virus replication, preparation method and its medicinal usage.Novel nucleoside phosphoric acid long-chain dibasic acid esters analog disclosed by the invention is significantly superior to the Suo Feibuwei of clinical application in terms of anti-hepatitis activity, on chiral phosphorus atoms, long-chain alkoxy base alkyl-substituted phenyl, alkoxycarbonyloxyalkyl substituted 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 nucleoside phosphorylase long-chain dibasic acid esters analog of suppressing virus replication, preparation side Method and its medicinal usage
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to the preparation of a kind of novel nucleoside phosphorylase long-chain dibasic acid esters analog Method and its pharmaceutical composition and purposes, especially as the purposes for the treatment of hepatitis C.
Background technique
Hepatitis C Virus (HCV) is positive chain RNA virus.It is estimated that there is about 200,000,000 people's HCV infections in the world.Hepatitis C The diverse clinical manifestations of virus infection, gently to inflammation, weight to cirrhosis, liver cancer.Chronic hepatitis C can also concurrent certain livers Outer performance, including rheumatoid arthritis, drying property conjunctivokeratitis, lichen planus, glomerulonephritis, mixed type cryoglobulin Mass formed by blood stasis, B cell lymphoma and porphyria cutanea tarda etc., it may be possible to caused by the reaction of body abnormal immune.And hepatitis cirrhosis When Decompensated stage, various complication such as ascites abdominal cavity infection can occur, 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.But most scholars think that cellular immunity pathological reaction may play an important role, and find hepatitis C and hepatitis B Equally, for tissues-infiltrating cells based on CD3+, cytotoxic T cell (TC) specifically attacks the target cell of HCV infection, can cause liver Cellular damage.
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 is It is also easy to produce that mutation, toxicity is big, poor bioavailability, it is effective to a other gene type.
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 test for grinding drug combination Also good effect is shown.But since bioavilability is low in vivo by sofosbuvir, need with biggish dosage, Hepatitis patient needs to receive long-term treatment, and bring virus drug resistance and long-term safety problem can not be ignored therewith, therefore, opens The bioavilability for sending out new is high, 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；
M=0-4, n=14-16；
A=OC (O) O, OC (O) or C (O) O；
R22=H, C1- C6Alkyl.
As further preferred scheme, compound (Ia) of the present invention, salt, tautomer or free alkali, It is preferred that combination or the m=0 of m=1, n=14, the combination of n=16；It is preferred that A=OC (O) O；R22It is preferred that isopropyl, isobutyl group, new penta Base.
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)The mixing of configuration any proportion 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 method of nucleoside phosphorylase long-chain diester compound of the present invention, which is characterized in that the synthesis road of the method Line is as follows:
Here: Base, Ri, X, Y, m, n, A, R22Definition is the same as claim 1.
Under alkaline condition, with after phosphorus oxychloride reaction, addition K2 reaction adds Pentafluorophenol and reacts to obtain chemical combination K1 Object F12-1 and F12-2；Under cryogenic, compound F12-1 or F12-2 are reacted with nucleosides, respectively obtain compound N12-2 or N12-1.
Nucleoside phosphorylase long-chain diester compound of the present invention, with pharmaceutically acceptable carrier, diluent or figuration Agent is prepared by mixing into pharmaceutical preparation and nanometer formulation, to be suitable for oral or parenteral；Medication includes, but unlimited In in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.
The medical composition of nucleoside phosphorylase long-chain diester compound 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 long-chain diester compound and its Pharmaceutical composition of the present invention are preparing anti-Flaviviridae Drug 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)-((3- (hexadecane epoxide) propoxyl group) (phenyl-pentafluoride oxygroup) phosphoryl oxygroup) methyl carbonic acid isopropyl ester (FP1120-1) and (S)-((3- (hexadecane epoxide) propoxyl group) (phenyl-pentafluoride oxygroup) phosphoryl oxygroup) methyl carbonic acid isopropyl The synthesis of ester (FP1120-2).
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 K11 (9.8g, 32.6mmol) and triethylamine (3.3 grams, 4.53ml, 32.6mmol) is slowly added dropwise, drips It adds complete, is slowly increased to room temperature, reaction is overnight.Above-mentioned mixed liquor is cooled to 0 DEG C, is added K20 (3.94g, 29.4mmol), it is cold But -70 DEG C are arrived, the acetonitrile solution 60mL of triethylamine (7.3 grams, 10ml, 72mmol) is added dropwise, finishes, is warming up to 0 DEG C, reaction 3 is small When, the acetonitrile solution 60mL liquid of Pentafluorophenol (5.4g, 29.4mmol) and triethylamine (7.3 grams, 10ml, 72mmol) is added dropwise Into above-mentioned solution, is stirred 1 hour at 0 DEG C, be warmed to room temperature, after being stirred overnight, 100 milliliters of methylene chloride and 100 milliliters are added Water separates organic phase, with anhydrous sodium sulfate it is dry after be concentrated under reduced pressure, residue with silica gel post separation (0-30% ethyl acetate/ Hexane) 10.8g white solid is obtained, solid is recrystallized with 10% t-butyl methyl ether/hexane, obtains white solid FP1120-2 (4.3g), mother liquor obtain FP1120-1 (3.1g) and FP1120-2 (0.4g) with silica gel post separation (50% ethyl acetate/hexane), FP1120-2 and FP1120-1 purity is all larger than 99%.
FP1120-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.07-1.37 (32H, m, 13×CH2and2×CH3), 1.44-1.59 (2H, m, CH2), 1.80-1.93 (2H, m, CH2), 3.29-3.48 (4H, m, 2 ×OCH2), 3.84-3.98 (2H, m, OCH2), 4.85-4.97 (1H, m, COOCH), 5.53-5.70 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -1.68.
FP1120-2:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.09-1.39 (32H, m, 13×CH2and2×CH3), 1.46-1.62 (2H, m, CH2), 1.83-1.96 (2H, m, CH2), 3.32-3.51 (4H, m, 2 ×OCH2), 3.86-4.00 (2H, m, OCH2), 4.88-5.01 (1H, m, COOCH), 5.56-5.72 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -1.94.
Embodiment 2
(R)-((3- (hexadecane epoxide) propoxyl group) (phenyl-pentafluoride oxygroup) phosphoryl oxygroup) methyl carbonic acid isobutyl ester (FP1122-1) and (S)-((3- (hexadecane epoxide) propoxyl group) (phenyl-pentafluoride oxygroup) phosphoryl oxygroup) methyl carbonic acid isobutyl The synthesis of ester (FP1122-2).
FP1122-1 and FP1122-2 is synthesized in the similar method of embodiment 1
P1122-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (9H, t, 3 × CH3), 1.07-1.37 (26H, M, 13 × CH2), 1.44-1.59 (2H, m, CH2), 1.80-2.08 (3H, m, CH2AndCH), 3.29-3.48 (4H, m, 2 × OCH2), 3.84-4.08 (4H, m, OCH2andCOOCH2), 5.53-5.70 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -1.82.
P1122-2:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (9H, t, 3 × CH3), 1.09-1.40 (26H, M, 13 × CH2), 1.47-1.60 (2H, m, CH2), 1.83-2.09 (3H, m, CH2AndCH), 3.33-3.49 (4H, m, 2 × OCH2), 3.86-4.12 (4H, m, OCH2andCOOCH2), 5.55-5.73 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -2.12.
Embodiment 3
(R)-((3- (hexadecane epoxide) propoxyl group) (phenyl-pentafluoride oxygroup) phosphoryl oxygroup) methyl carbonic acid peopentyl ester (FP1123-1) and (S)-((3- (hexadecane epoxide) propoxyl group) (phenyl-pentafluoride oxygroup) phosphoryl oxygroup) methyl carbonic acid new penta The synthesis of ester (FP1123-2).
FP1123-1 and FP1123-2 is synthesized in the similar method of embodiment 1.
FP1123-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (12H, t, 4 × CH3), 1.07-1.37 (32H, m, 13 × CH2), 1.44-1.59 (2H, m, CH2), 1.80-1.93 (2H, m, CH2), 3.29-3.48 (4H, m, 2 × OCH2), 3.84-4.04 (4H, m, OCH2andCOOCH2), 5.53-5.70 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -2.06.
FP1123-2:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (12H, t, 4 × CH3), 1.11-1.40 (32H, m, 13 × CH2), 1.47-1.63 (2H, m, CH2), 1.84-1.96 (2H, m, CH2), 3.32-3.51 (4H, m, 2 × OCH2), 3.88-4.07 (4H, m, OCH2andCOOCH2), 5.56-5.73 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -2.35.
Embodiment 4
(R)-((2- (octadecane epoxide) ethyoxyl) (phenyl-pentafluoride oxygroup) phosphoryl oxygroup) methyl carbonic acid isopropyl ester (FP1220-1) and (S)-((2- (octadecane epoxide) ethyoxyl) (phenyl-pentafluoride oxygroup) phosphoryl oxygroup) methyl carbonic acid isopropyl The synthesis of ester (FP1220-2).
FP1220-1 and FP1220-2 is synthesized in the similar method of embodiment 1
FP1220-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.06-1.39 (36H, m, 15×CH2and2×CH3), 1.45-1.60 (2H, m, CH2), 3.31-3.46 (4H, m, 2 × OCH2), 3.84-3.98 (2H, M, OCH2), 4.86-4.95 (1H, m, COOCH), 5.55-5.68 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -2.11.
FP1220-2:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.08-1.40 (36H, m, 15×CH2and2×CH3), 1.49-1.64 (2H, m, CH2), 3.34-3.50 (4H, m, 2 × OCH2), 3.88-4.02 (2H, M, OCH2), 4.87-4.98 (1H, m, COOCH), 5.57-5.70 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -2.43.
Embodiment 5
(S)-[(3- (hexadecane epoxide) propyl) ((isopropoxy carbonyl oxygroup) methyl) (((2R, 3R, 4R, 5R)- 5- (2,4 (1H, 3H)-hybar X -1- base) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) first Base)] synthesis of phosphotriester (SOF1120-1).
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 FP1120-2 (1.06g, 1.6mmol) in 5mLTHF is then added dropwise in 30min at 0 DEG C.It will be acquired Clarifying reaction solution be warmed to room temperature, stirring 20 hours after, be added saturation NH4Cl (15mL) is stirred 5 minutes, mixture is used Ethyl acetate (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 warp after drying It is purified by silica gel column chromatography (methylene chloride of 0-10% methanol), obtains white solid product SOF1120-1 (362mg), yield 49%).
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.07-1.37 (35H, m, 13 × CH2and3 ×CH3), 1.44-1.59 (2H, m, CH2), 1.80-1.93 (2H, m, CH2), 3.29-3.48 (4H, m, 2 × OCH2), 3.84-3.98 (2H, m, OCH2), 4.07-4.12 (1H, m, the H on saccharide ring 3 '-position), 4.27 (1H, brs, saccharide ring 3 '-positions On OH), 4.33-4.39 (1H, m, the H on saccharide ring 4 '-position), 4.45-4.50 (2H, m, the H on saccharide ring 5 '-position), 4.85-4.97 (1H, m, COOCH), 5.53-5.70 (3H, m, OCH2H on Oand pyrimidine ring 5), 6.17 (1H, d, pyrimidines H on 6, ring), 7.14-7.22 (1H, m, the H on saccharide ring 1 '-position), 9.73 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ6.37；
ESI+MS:(M+H)+739.8。
Embodiment 6
R)-[(3- (hexadecane epoxide) propyl) ((isopropoxy carbonyl oxygroup) methyl) (((2R, 3R, 4R, 5R)- 5- (2,4 (1H, 3H)-hybar X -1- base) fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) first Base)] synthesis of phosphotriester (SOF1120-2).
SOF1120-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.11-1.40 (35H, m, 13 × CH2and3 ×CH3), 1.47-1.63 (2H, m, CH2), 1.82-1.96 (2H, m, CH2), 3.33-3.51 (4H, m, 2 × OCH2), 3.87-4.02 (2H, m, OCH2), 4.09-4.16 (1H, m, the H on saccharide ring 3 '-position), 4.28 (1H, brs, saccharide ring 3 '-positions On OH), 4.36-4.41 (1H, m, the H on saccharide ring 4 '-position), 4.48-4.53 (2H, m, the H on saccharide ring 5 '-position), 4.88-4.99 (1H, m, COOCH), 5.56-5.73 (3H, m, OCH2H on Oand pyrimidine ring 5), 6.18 (1H, d, pyrimidines H on 6, ring), 7.16-7.21 (1H, m, the H on saccharide ring 1 '-position), 9.74 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ6.66；
ESI+MS:(M+H)+739.8。
Embodiment 7
(S)-[(3- (hexadecane epoxide) propyl) ((isobutoxy carbonyl oxygroup) methyl) (((2R, 5S) -5- (5- Fluoro- -2 (1H)-pyrimidone -1- base of 4- amino) -1,3- oxathiolane -2- base) methyl)] phosphate (FTC1122-1) synthesis.
FTC1122-1 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (9H, t, 3 × CH3), 1.07-1.37 (26H, m, 13 × CH2), 1.44-1.59 (2H, m, CH2), 1.80-2.08 (3H, m, CH2AndCH), 3.04-3.48 (6H, m, 2 × OCH2and H on saccharide ring 2 '-position), 3.84-4.08 (4H, m, OCH2andCOOCH2), 4.24-4.43 (1H, m, on saccharide ring 4 '-position H), 5.27-5.40 (2H, m, the H on saccharide ring 5 '-position), 5.53-5.70 (3H, m, OCH2H on 1 '-position of Oand saccharide ring), 5.79-6.18 (2H, dbrs, the NH on pyrimidine ring 42), 7.90-8.14 (1H, s, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ6.92；
ESI+MS:(M+H)+740.8。
Embodiment 8
(R)-[(3- (hexadecane epoxide) propyl) ((isobutoxy carbonyl oxygroup) methyl) (((2R, 5S) -5- (5- Fluoro- -2 (1H)-pyrimidone -1- base of 4- amino) -1,3- oxathiolane -2- base) methyl)] phosphate (FTC1122-2) synthesis.
FTC1122-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (9H, t, 3 × CH3), 1.112-1.40 (26H, m, 13 × CH2), 1.47-1.63 (2H, m, CH2), 1.84-2.13 (3H, m, CH2AndCH), 3.08-3.53 (6H, m, 2 × OCH2and H on saccharide ring 2 '-position), 3.88-4.12 (4H, m, OCH2andCOOCH2), 4.27-4.42 (1H, m, on saccharide ring 4 '-position H), 5.30-5.44 (2H, m, the H on saccharide ring 5 '-position), 5.57-5.75 (3H, m, OCH2H on 1 '-position of Oand saccharide ring), 5.83-6.21 (2H, dbrs, the NH on pyrimidine ring 42), 7.93-8.17 (1H, s, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ7.24；
ESI+MS:(M+H)+740.8。
Embodiment 9
(S)-[(3- (hexadecane epoxide) propyl) ((neopentyl oxygen carbonyl oxygroup) methyl) (((2R, 5S) -5- (4- Amino -2 (1H)-pyrimidone -1- base) -1,3- oxathiolane -2- base) methyl)] phosphate (3TC1123- 1) synthesis.
3TC1123-1 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (12H, t, 4 × CH3), 1.07-1.38 (26H, m, 13 × CH2), 1.44-1.59 (2H, m, CH2), 1.80-1.93 (2H, m, CH2), 3.04-3.49 (6H, m, on saccharide ring 2 '-position Hand2×OCH2), 3.84-4.04 (4H, m, OCH2and COOCH2), 4.24-4.45 (1H, m, the H on saccharide ring 4 '-position), 5.27-5.40 (3H, m, the H on saccharide ring 5 '-position and pyrimidine ring 5), 5.53-5.70 (3H, m, OCH2Oand saccharide ring 1 '- H on position), 5.79-6.19 (2H, dbrs, the NH on pyrimidine ring 42), 8.30-8.70 (1H, d, on pyrimidine ring 6 H)。
31P NMR (162MHz, CDCl3)δ8.19；
ESI+MS:(M+H)+736.9。
Embodiment 10
(R)-[(3- (hexadecane epoxide) propyl) ((neopentyl oxygen carbonyl oxygroup) methyl) (((2R, 5S) -5- (4- Amino -2 (1H)-pyrimidone -1- base) -1,3- oxathiolane -2- base) methyl)] phosphate (3TC1123- 2) synthesis.
3TC1123-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (12H, t, 4 × CH3), 1.10-1.41 (26H, m, 13 × CH2), 1.47-1.63 (2H, m, CH2), 1.82-1.97 (2H, m, CH2), 3.07-3.53 (6H, m, on saccharide ring 2 '-position Hand2×OCH2), 3.87-4.08 (4H, m, OCH2and COOCH2), 4.22-4.49 (1H, m, the H on saccharide ring 4 '-position), 5.29-5.43 (3H, m, the H on saccharide ring 5 '-position and pyrimidine ring 5), 5.56-5.73 (3H, m, OCH2O and saccharide ring H on 1 '-position), 5.82-6.23 (2H, dbrs, the NH on pyrimidine ring 42), 8.33-8.74 (1H, d, on pyrimidine ring 6 H).
31P NMR (162MHz, CDCl3)δ8.47；
ESI+MS:(M+H)+736.9。
Embodiment 11
(S)-[(2- (octadecane epoxide) ethyl) ((isopropoxy carbonyl oxygroup) methyl) (((2S, 3S, 5R) -5- (5- methyl -2,4 (1H, 3H)-hybar X -1- base) -3- nitrine tetrahydrofuran -2- base) methyl)] phosphotriester (AZT1220-1) synthesis.
AZT1220-1 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.06-1.39 (36H, m, 15 × CH2and2 ×CH3), 1.45-1.60 (2H, m, CH2), 1.95 (4H, s, the CH on pyrimidine ring 53H on 3 '-position of and saccharide ring), 2.28-2.51 (2H, m, the H on saccharide ring 2 '-position), 3.31-3.46 (4H, m, 2 × OCH2), 3.84-3.98 (2H, m, OCH2), 4.04-4.21 (1H, m, the H on saccharide ring 4 '-position), 4.25-4.42 (2H, m, the H on saccharide ring 5 '-position), 4.86-4.95 (1H, m, COOCH), 5.55-5.68 (2H, m, OCH2O), 6.15 (1H, t, the H on saccharide ring 1 '-position, 7.25 (1H, s, the H on pyrimidine ring 6), 9.24 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ7.52；
ESI+MS:(M+H)+760.9。
Embodiment 12
(R)-[(2- (octadecane epoxide) ethyl) ((isopropoxy carbonyl oxygroup) methyl) (((2S, 3S, 5R) -5- (5- methyl -2,4 (1H, 3H)-hybar X -1- base) -3- nitrine tetrahydrofuran -2- base) methyl)] phosphate (AZT1220-2) synthesis.
AZT1220-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.09-1.42 (36H, m, 15 × CH2and2 ×CH3), 1.48-1.63 (2H, m, CH2), 1.96 (4H, s, the CH on pyrimidine ring 53H on 3 '-position of and saccharide ring), 2.30-2.51 (2H, m, the H on saccharide ring 2 '-position), 3.34-3.48 (4H, m, 2 × OCH2), 3.88-4.00 (2H, m, OCH2), 4.07-4.24 (1H, m, the H on saccharide ring 4 '-position), 4.29-4.44 (2H, m, the H on saccharide ring 5 '-position), 4.89-4.98 (1H, m, COOCH), 5.58-5.71 (2H, m, OCH2O), 6.16 (1H, t, the H on saccharide ring 1 '-position, 7.25 (1H, s, the H on pyrimidine ring 6), 9.26 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ7.81；
ESI+MS:(M+H)+760.9。
Embodiment 13
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, 2mM GlutaMAX, 1%MEM nonessential amino acid, 100IU/mL penicillin, 100 The Dulbecco of μ 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 the medicine that 50 μ L are added in duplicate into plate Object dilution is to start drug-treated.The range of drug final concentration is 100nM-0.0000512n Μ.Then by cell 37 DEG C/5%CO2Lower incubation.Or compound is tested with two kinds of concentration (10nM and 100nM).In all cases, Huh-7 (its Not with HCV replicon) it is used as negative control.After being incubated for 72 hours, Fluc is passed through for 5 '-by quantization Fluorine luciferin list oxygen synthesizes the photon that oxygroup fluorine luciferin (oxyfIuoroluciferin) is emitted, to measure HCV duplication Inhibition.For this purpose, removing culture medium from plate by tapping, 50 microlitres of ONE-glo luciferase assay kits are added 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).Pass through Microsoft Excel and XLfit4.1 The dose-effect curve for the gained best fit equation formula that software is found out calculates EC50Value.
For Cytotoxic evaluation, Zluc cell is handled with above compound, is deposited using CellTiter-Blue cell Vitality test method (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.Respectively with the excitation and launch wavelength of 560 and 590nm, remember in Victor3V1420 multiple labeling The fluorescence of detection plate, finds out CC using Microsoft Excel and XLfit4.1 software in number device (Perkin Elmer)50Value.
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；
M=0-4, n=14-16；
A=OC (O) O, OC (O) or C (O) O；
R22=H, C1- C6Alkyl.
2. compound (Ia) as described in claim 1, salt, tautomer or free alkali, which is characterized in that preferred m= 1, n=14 combination or m=0, the combination of n=16；It is preferred that A=OC (O) O；R22It is preferred that isopropyl, isobutyl group, neopentyl.
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 long-chain diester compound described in claim 1-4, which is characterized in that described Below the synthetic route of method:
Here: Base, Ri, X, Y, m, n, A, R22Definition is the same as claim 1；
Under alkaline condition, with after phosphorus oxychloride reaction, addition K2 reaction adds Pentafluorophenol and reacts to obtain compound K1 F12-1 and F12-2；Under cryogenic, compound F12-1 or F12-2 are reacted with nucleosides, respectively obtain compound N12-2 or N12-1.
6. nucleoside phosphorylase long-chain diester compound described in -4 according to claim 1, it is characterized in that: with pharmaceutically acceptable Carrier, diluent or excipient are prepared by mixing into pharmaceutical preparation and nanometer formulation, to be suitable for oral or parenteral；It gives Prescription method includes, but are not limited in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.
7. a kind of medical composition comprising nucleoside phosphorylase long-chain diester compound 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 long-chain diester compound described in claim 1 and its Pharmaceutical composition are preparing anti-flavivirus section Application in the drug of virus, 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.
CN201811577369.3A 2018-12-21 2018-12-21 With the active nucleoside phosphorylase long-chain dibasic acid esters analog of suppressing virus replication, preparation method and its medicinal usage Pending CN109651452A (en)

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* Cited by examiner, † Cited by third party
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CN112142810A (en) * 2020-09-29 2020-12-29 佛山科学技术学院 Nucleotide double-phosphoramidate compound, pharmaceutical composition thereof, preparation method and application thereof
CN112194694A (en) * 2020-09-29 2021-01-08 佛山科学技术学院 Urodylate phenylpropionate phosphoramidate compound, pharmaceutical composition thereof, and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112142810A (en) * 2020-09-29 2020-12-29 佛山科学技术学院 Nucleotide double-phosphoramidate compound, pharmaceutical composition thereof, preparation method and application thereof
CN112194694A (en) * 2020-09-29 2021-01-08 佛山科学技术学院 Urodylate phenylpropionate phosphoramidate compound, pharmaceutical composition thereof, and preparation method and application thereof
CN112194694B (en) * 2020-09-29 2022-03-25 佛山科学技术学院 Urodylate phenylpropionate phosphoramidate compound, pharmaceutical composition thereof, and preparation method and application thereof

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