CN109503688A - With the active nucleoside phosphorylase long-chain ester analogs of suppressing virus replication, preparation method and its medicinal usage - Google Patents
With the active nucleoside phosphorylase long-chain ester analogs of suppressing virus replication, preparation method and its medicinal usage Download PDFInfo
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- 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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- 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
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- 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
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- 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
Abstract
The invention discloses one group to have the active nucleoside phosphorylase long-chain ester analogs of suppressing virus replication, preparation method and its medicinal usage.Novel nucleoside phosphoric acid long-chain ester 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, long-chain alkoxy base alkyl-substituted phenyl, hydroxy substituted amino acid, cytotoxicity is significantly reduced in surveyed cell line, antiviral activity is improved, there is extraordinary potential applicability in clinical practice.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to the preparation side of a kind of novel nucleoside phosphorylase long-chain ester analogs
Method and its pharmaceutical composition and purposes, especially as the purposes for the treatment of hepatitis C.
Background technique
The patient that Hepatitis C Virus (HCV) has 3-4 million newly-increased every year, the World Health Organization estimate global
The infected 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 infection is gently to inflammation, weight to cirrhosis, liver cancer.
Initially the method for the treatment of HCV infection is interferon and interferon and ribavirin combination therapy, only 50% is controlled
Treatment person has a reaction to this method, and interferon has an apparent side effect, for example, flu-like symptoms, weight lower and
Fatigue and weak, and interferon and ribavirin combination therapy then generate sizable side effect, including haemolysis, anemia and tired
Deng.
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.
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.Egg of the Telaprevir as the first generation
White enzyme inhibitor has logged out market.The second generation of high activity and wide spectrum and third generation protease inhibitors is mainly used as and other
One of the component of drug combination of hepatitis drug.
The hepatitis C drug Suo Feibuwei (trade name: Sovaldi, common name: Sofosbuvir) of lucky Leadd B.V
Acquisition U.S. Food and Drug Administration on December 6 (FDA) approval in 2013 is used for chronic hepatitis C (HepatitisC)
The treatment of adult patient.Suo Feibuwei is the first granted drug that can be used for the full oral treatment regimes of hepatitis C, for spy
When determining the treatment of genotype (2 types, 3 types) chronic hepatitis C, the demand to conventional injection interfering effects of drug plain (IFN) can be eliminated.
But since bioavilability is low in vivo by sofosbuvir, need with biggish dosage, hepatitis patient need
Receive long-term treatment, bring virus drug resistance and long-term safety problem can not be ignored therewith, therefore, develop new biology
The HCV infection therapeutic agent that availability is high and longer half-life period, drug effect are high is still clinical urgent need.
Summary of the invention:
The purpose of the present invention is the structures to nucleoside phosphorylase long-chain ester analogs to be further transformed, and is had
The active novel nucleoside phosphate analogs of more high bioavilability, more hypotoxicity and more highly resistance HCV virus, deeply to grind from now on
Study carefully and lays the foundation with the antiviral application of exploitation the compounds of this invention.
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;
Rb=R0, R1, R4;
Here, R0=H, C1- C6Alkyl;R1=CH2(CH2)mCH2OCH2(CH2)nCH3;
R4=aryl.
As further preferred scheme, compound (Ia) of the present invention, salt, tautomer or free alkali,
It is preferred that R0=H;It is preferred that combination or the m=0 of m=1, n=14, the combination of n=16;It is preferred that R4=phenyl.
As further preferred scheme, compound of the present invention, salt, tautomer or free alkali, phosphorus original
Son 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:
Nucleoside phosphorylase long-chain ester compounds of the present invention, synthetic route are as follows:
Here: Base, Ri, X, Y, m, n, RbDefinition is the same as claim 1.
Under alkaline condition, R is added with after phosphorus oxychloride reaction in K1bOH reaction, adds Pentafluorophenol reaction
Close object F1B-1 and F1B-2;Under cryogenic, F1B-2 and F1B-1 are reacted with nucleosides, respectively obtain compound N 1B-1
Or N1B-2.
Nucleoside phosphorylase long-chain ester compounds of the present invention, with pharmaceutically acceptable carrier, diluent or excipient
It is prepared by mixing into pharmaceutical preparation and nanometer formulation, to be suitable for oral or parenteral;Medication includes, but are not limited to
In intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.
The present invention provides a kind of medical compositions of nucleoside phosphorylase long-chain ester compounds comprising compound (Ia).
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 ester compounds and its Pharmaceutical composition of the present invention are preparing anti-Flaviviridae
Application in drug, the flaviviridae are 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
(S) -3- (hexadecane epoxide) propyl pentafluorophenyl group phosphate (FP011-1) and (R) -3- (hexadecane oxygen
Base) propyl pentafluorophenyl group phosphate (FP011-2) 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 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, after reaction overnight, is cooled to 0 DEG C, by Pentafluorophenol (5.4g, 29.4mmol) and triethylamine
The acetonitrile solution 60mL liquid of (7.3 grams, 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 8.5g 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 FP011-2 (3.4g), mother liquor with silica gel post separation (50% ethyl acetate/oneself
Alkane) FP011-1 (2.5g) and FP011-2 (0.4g), FP011-2 and FP011-1 purity are all larger than 99%.
FP011-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.08-1.39 (26H, m, 13
×CH2), 1.45-1.61 (2H, m, CH2), 1.81-1.95 (2H, m, CH2), 3.30-3.50 (4H, m, 2 × OCH2),
3.85-4.00 (2H, m, OCH2)。
31P NMR (162MHz, CDCl3) δ -1.66.
FP011-2:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.11-1.42 (26H, m, 13
×CH2), 1.47-1.64 (2H, m, CH2), 1.84-1.99 (2H, m, CH2), 3.33-3.53 (4H, m, 2 × OCH2),
3.87-4.04 (2H, m, OCH2)。
31P NMR (162MHz, CDCl3) δ -1.92.
Embodiment 2
(S) -2- (octadecane epoxide) ethyl pentafluorophenyl group phosphate (FP012-1) and (R) -2- (octadecane oxygen
Base) ethyl pentafluorophenyl group phosphate (FP012-2) synthesis.
FP012-1 and FP012-2 is synthesized in the similar method of embodiment 1
FP012-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.07-1.41 (30H, m, 15
×CH2), 1.46-1.62 (2H, m, CH2), 3.32-3.48 (4H, m, 2 × OCH2), 3.85-3.99 (2H, m, OCH2)。
31P NMR (162MHz, CDCl3) δ -1.77.
FP012-2:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.09-1.44 (30H, m, 15
×CH2), 1.49-1.66 (2H, m, CH2), 3.35-3.50 (4H, m, 2 × OCH2), 3.87-4.04 (2H, m, OCH2)。
31P NMR (162MHz, CDCl3) δ -2.06.
Embodiment 3
The synthesis of two (3- (hexadecane epoxide) propyl) pentafluorophenyl group phosphates (FP11).
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 (19.6g, 65.2mmol) and triethylamine (6.6g, 9.06ml, 65.2mmol) 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 (7.3 grams, 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 100 milliliters of methylene chloride and 100 milliliters of water, separates organic phase, subtracts after being dried with anhydrous sodium sulfate
Pressure concentration, residue obtain 13.1g white solid, 10% tertiary fourth of solid with silica gel post separation (0-30% ethyl acetate/hexane)
Ylmethyl ether/hexane recrystallization, obtains white solid FP11 (5.2g), and mother liquor is with silica gel post separation (50% ethyl acetate/hexane)
FP11 (4.1g) again, FP11 purity are greater than 99%.
FP11:1H NMR (400MHz, CDCl3) δ (ppm): 0.89 (6H, dt, 2 × CH3), 1.08-1.40 (52H, m, 26
×CH2), 1.45-1.63 (4H, m, 2 × CH2), 1.81-1.97 (4H, m, 2 × CH2), 3.30-3.53 (8H, m, 4 ×
OCH2), 3.85-4.03 (4H, m, 2 × OCH2)。
Embodiment 4
(R) -3- (hexadecane epoxide) propyl pentafluorophenyl group phenyl phosphate ester (FP14-1) and (S) -3- (hexadecane
Oxygroup) propyl pentafluorophenyl group phenyl phosphate ester (FP14-2) synthesis.
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 K11 (9.8g, 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 11.2g 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 FP14-2 (4.5g), mother liquor silica gel post separation
(50% ethyl acetate/hexane) obtains FP14-1 (3.3g) and FP14-2 (0.5g), FP14-2 and FP14-1 purity are all larger than
99%.
FP14-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.08-1.39 (26H, m, 13
×CH2), 1.45-1.61 (2H, m, CH2), 1.81-1.95 (2H, m, CH2), 3.31-3.49 (4H, m, 2 × OCH2),
3.85-4.03 (2H, m, OCH2), 7.22-7.31 (2H, m, the H on phenyl ring ortho position), 7.31-7.41 (3H, m, it is right between phenyl ring
H on position).
31P NMR (162MHz, CDCl3) δ -2.03.
FP14-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.89 (3H, t, CH3), 1.10-1.42 (26H, m, 13
×CH2), 1.48-1.62 (2H, m, CH2), 1.83-1.99 (2H, m, CH2), 3.33-3.53 (4H, m, 2 × OCH2),
3.88-4.04 (2H, m, OCH2), 7.25-7.36 (2H, m, the H on phenyl ring ortho position), 7.38-7.46 (3H, m, it is right between phenyl ring
H on position).
31P NMR (162MHz, CDCl3) δ -2.36.
Embodiment 5
(S)-[(3- (hexadecane epoxide) propyl) (((2R, 3R, 4R, 5R) -5- (2,4 (1H, 3H)-pyrimidines two
Ketone -1- base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methyl)] phosphate (SOF011-1)
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 FP011-2 (874.5mg, 1.6mmol) in 5mL THF is then added dropwise in 30min at 0 DEG C.By gained
To clarifying reaction solution be warmed to room temperature, stirring 20 hours after, be added saturation NH4Cl (15mL) is stirred 5 minutes, by mixture
It is diluted with ethyl acetate (200mL), separates organic phase, aqueous layer with ethyl acetate (30mL) is extracted twice.Combined organic layer is used
Water (30mL), saturation NaHCO3The washing of (2x30mL), salt water (30mL), and through Na2SO4Decompression boils off solvent, residue after drying
It purifies, obtains white solid product SOF011-1 (305.3mg) via silica gel column chromatography (methylene chloride of 0-10% methanol), receive
Rate 49%).
SOF011-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.08-1.39 (29H, m,
13×CH2andCH3), 1.45-1.61 (2H, m, CH2), 1.81-1.95 (2H, m, CH2), 3.30-3.50 (4H, m, 2 ×
OCH2), 3.85-3.99 (2H, m, OCH2), 4.08-4.19 (1H, m, the H on saccharide ring 3 '-position), 4.27 (1H, brs, saccharide rings
OH on 3 '-positions), 4.34-4.41 (1H, m, the H on saccharide ring 4 '-position), 4.46-4.52 (2H, m, on saccharide ring 5 '-position
H), 5.58-5.72 (1H, d, the H on pyrimidine ring 5), 6.18 (1H, s, the H on saccharide ring 1 '-position), 7.21-7.51 (1H,
D, the H on pyrimidine ring 6), 9.74 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.25;
ESI+MS:(M+H)+623.4。
Embodiment 6
(R)-[(3- (hexadecane epoxide) propyl) (((2R, 3R, 4R, 5R) -5- (2,4 (1H, 3H)-pyrimidines two
Ketone -1- base) the fluoro- 3- hydroxy-4-methyl tetrahydrofuran -2- base of -4-) methyl)] phosphate (SOF011-2)
Synthesis
SOF011-2 is synthesized in the similar method of embodiment 5.
SOF011-1:1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.10-1.41 (29H, m,
13×CH2andCH3), 1.48-1.64 (2H, m, CH2), 1.84-1.97 (2H, m, CH2), 3.33-3.51 (4H, m, 2 ×
OCH2), 3.87-4.03 (2H, m, OCH2), 4.11-4.20 (1H, m, the H on saccharide ring 3 '-position), 4.27 (1H, brs, saccharide rings
OH on 3 '-positions), 4.37-4.46 (1H, m, the H on saccharide ring 4 '-position), 4.49-4.54 (2H, m, on saccharide ring 5 '-position
H), 5.59-5.73 (1H, d, the H on pyrimidine ring 5), 6.18 (1H, s, the H on saccharide ring 1 '-position), 7.22-7.53 (1H,
D, the H on pyrimidine ring 6), 9.74 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.56;
ESI+MS:(M+H)+623.4。
Embodiment 7
(S)-[(2- (octadecane epoxide) ethyl) (((2S, 3S, 5R) -5- (5- methyl -2,4 (1H, 3H)-phonetic
Pyridine diketone -1- base) -3- nitrine tetrahydrofuran -2- base) methyl)] synthesis of phosphate (AZT012-1).
AZT012-1 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.07-1.41 (30H, m, 15 × CH2),
1.46-1.62 (2H, m, CH2), 1.89-1.99 (3H, d, the CH on pyrimidine ring 53), 2.29-2.53 (3H, m, saccharide ring
The H on 3 '-position of Hand saccharide ring on 2 '-positions), 3.32-3.48 (5H, m, 2 × OCH2H on 4 '-position of and saccharide ring),
3.85-4.01 (4H, m, OCH2H on 5 '-position of and saccharide ring), 6.15 (1H, t, the H on saccharide ring 1 '-position), 7.25 (1H, s,
H on pyrimidine ring 6), 9.25 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.46;
ESI+MS:(M+H)+644.7。
Embodiment 8
(R)-[(2- (octadecane epoxide) ethyl) (((2S, 3S, 5R) -5- (5- methyl -2,4 (1H, 3H)-phonetic
Pyridine diketone -1- base) -3- nitrine tetrahydrofuran -2- base) methyl)] synthesis of phosphate (AZT012-2).
AZT012-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.09-1.44 (30H, m, 15 × CH2),
1.49-1.64 (2H, m, CH2), 1.91-2.00 (3H, d, the CH on pyrimidine ring 53), 2.31-2.54 (3H, m, saccharide ring
The H on 3 '-position of Hand saccharide ring on 2 '-positions), 3.34-3.50 (5H, m, 2 × OCH2H on 4 '-position of and saccharide ring),
3.87-4.03 (4H, m, OCH2H on 5 '-position of and saccharide ring), 6.15 (1H, t, the H on saccharide ring 1 '-position), 7.25 (1H, s,
H on pyrimidine ring 6), 9.25 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.76;
ESI+MS:(M+H)+644.7。
Embodiment 9
[(((2R, 5S) -5- (fluoro- -2 (1H)-pyrimidone -1- base of 4- amino of 5-) -1,3- oxygen thia ring
Pentane -2- base) methoxyl group) (two (3- (hexadecane epoxide) propyl))] and phosphate (FTC11) synthesis.
FTC11 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (6H, dt, 2 × CH3), 1.08-1.38 (52H, m, 26 ×
CH2), 1.45-1.60 (4H, m, 2 × CH2), 1.81-1.94 (4H, m, 2 × CH2), 3.30-3.49 (10H, m, 4 ×
OCH2H on 2 '-position of and saccharide ring), 3.85-3.99 (4H, m, 2 × OCH2), 4.25-4.46 (1H, m, on saccharide ring 4 '-position
H), 5.28-5.41 (2H, m, the H on saccharide ring 5 '-position), 5.57-5.69 (1H, m, the H on saccharide ring 1 '-position), 5.80-
6.20 (2H, dbrs, the NH on pyrimidine ring 42), 7.91 (1H, s, the H on pyrimidine ring 6).
ESI+MS:(M+H)+893.2。
Embodiment 10
(S)-[(((2R, 5S) -5- (4- amino -2 (1H)-pyrimidone -1- base) -1,3- oxygen sulphur Polymorphs
Alkane -2- base) methyl) (3- (hexadecane epoxide) propyl) (phenyl)] and phosphate (3TC14-1) synthesis.
3TC14-1 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.08-1.39 (26H, m, 13 × CH2),
1.45-1.61 (2H, m, CH2), 1.81-1.95 (2H, m, CH2), 3.05-3.51 (6H, m, the Hand2 on saccharide ring 2 '-position
×OCH2), 3.85-4.00 (2H, m, OCH2), 4.25-4.47 (1H, m, the H on saccharide ring 4 '-position), 5.28-5.42 (3H,
M, the H on Hand pyrimidine ring 5 on saccharide ring 5 '-position), 5.62 (1H, s, the H on saccharide ring 1 '-position), 5.80-6.21 (2H,
Dbrs, the NH on pyrimidine ring 42), 7.22-7.29 (2H, m, the H on phenyl ring ortho position), 7.31-7.39 (3H, m, between phenyl ring
H in contraposition), 8.31-8.72 (1H, d, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ3.92;
ESI+MS:(M+H)+668.8。
Embodiment 11
(R)-[(((2R, 5S) -5- (4- amino -2 (1H)-pyrimidone -1- base) -1,3- oxygen sulphur Polymorphs
Alkane -2- base) methyl) (3- (hexadecane epoxide) propyl) (phenyl)] and phosphate (3TC14-2) synthesis.
3TC14-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.88 (3H, t, CH3), 1.11-1.41 (26H, m, 13 × CH2),
1.48-1.63 (2H, m, CH2), 1.84-1.98 (2H, m, CH2), 3.09-3.51 (6H, m, the Hand2 on saccharide ring 2 '-position
×OCH2), 3.88-4.03 (2H, m, OCH2), 4.27-4.49 (1H, m, the H on saccharide ring 4 '-position), 5.30-5.45 (3H,
M, the H on Hand pyrimidine ring 5 on saccharide ring 5 '-position), 5.63 (1H, s, the H on saccharide ring 1 '-position), 5.82-6.24 (2H,
Dbrs, the NH on pyrimidine ring 42), 7.24-7.31 (2H, m, the H on phenyl ring ortho position), 7.32-7.42H, m are right between phenyl ring
H on position), 8.33-8.73 (1H, d, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ4.22;
ESI+MS:(M+H)+668.8。
Embodiment 12
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;
Rb=R0, R1, R4;
Here, R0=H, C1- C6Alkyl;R1=CH2(CH2)mCH2OCH2(CH2)nCH3;
R4=aryl.
2. compound (Ia) as described in claim 1, salt, tautomer or free alkali, which is characterized in that preferred R0=
H;It is preferred that combination or the m=0 of m=1, n=14, the combination of n=16;It is preferred that R4=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 long-chain ester compounds described in claim 1-4, which is characterized in that the side
The synthetic route of method is as follows:
Here: Base, Ri, X, Y, m, n, RbDefinition is the same as claim 1;
Under alkaline condition, R is added with after phosphorus oxychloride reaction in K1bOH reaction, adds Pentafluorophenol and reacts to obtain compound
F1B-1 and F1B-2;Under cryogenic, F1B-2 and F1B-1 are reacted with nucleosides, respectively obtain compound N 1B-1 or
N1B-2.
6. nucleoside phosphorylase long-chain ester compounds described in -4 according to claim 1, it is characterized in that: with pharmaceutically acceptable load
Body, diluent or excipient are prepared by mixing into pharmaceutical preparation and nanometer formulation, to be suitable for oral or parenteral;Administration
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 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 long-chain ester compounds described in claim 1 and its Pharmaceutical composition are preparing anti-flavivirus section disease
Application in the drug of poison, 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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CN102137676A (en) * | 2007-12-27 | 2011-07-27 | 伊皮芬尼生物科学公司 | Antiviral compounds |
TW201542581A (en) * | 2013-09-11 | 2015-11-16 | Univ Emory | Nucleotide and nucleoside therapeutic compositions and uses related thereto |
CN108276463A (en) * | 2017-01-06 | 2018-07-13 | 米文君 | A new class of compound and application thereof |
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2018
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Publication number | Priority date | Publication date | Assignee | Title |
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CN102137676A (en) * | 2007-12-27 | 2011-07-27 | 伊皮芬尼生物科学公司 | Antiviral compounds |
TW201542581A (en) * | 2013-09-11 | 2015-11-16 | Univ Emory | Nucleotide and nucleoside therapeutic compositions and uses related thereto |
CN108276463A (en) * | 2017-01-06 | 2018-07-13 | 米文君 | A new class of compound and application thereof |
Non-Patent Citations (2)
Title |
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STEVEN D. DONG,ET AL.: "Synthesis and evaluation of a new phosphorylated ribavirin prodrug", 《ANTIVIRAL RESEARCH》 * |
寿雪枫等: "抗丙型肝炎药物索磷布韦的设计合成研究进展", 《国际药学研究杂志》 * |
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