CN111393494A - Compound based on nucleotide structure, preparation method and application - Google Patents
Compound based on nucleotide structure, preparation method and application Download PDFInfo
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Abstract
The invention relates to a compound based on a nucleotide structure and a preparation method thereof, and also relates to application of the compound based on the nucleotide structure in inhibiting hepatitis C virus and coronavirus. The compound can effectively inhibit the hepatitis C virus, and the compound or the pharmaceutically acceptable salt or ester thereof can be used for preparing the medicine for treating the hepatitis C virus infection. Since hepatitis c virus and coronavirus use similar virus genome replication mechanisms, it can be concluded that the compound of the present invention can also inhibit coronavirus, including 2019-nCoV, SARS and MERS virus, and the compound of the present invention or its pharmaceutically acceptable salt or ester can be used for preparing medicines for treating coronavirus infection.
Description
Technical Field
The invention relates to a compound based on a nucleotide structure, a synthesis method of the compound based on the nucleotide structure, and application of the compound based on the nucleotide structure in inhibiting hepatitis C virus and coronavirus.
Background
Viral diseases are one of the biggest threats faced by human beings, and the main characteristics of the diseases are high infectivity (such as HIV, SARS and novel coronavirus 2019-nCov), changeability of the virus itself, and carcinogenicity of certain viruses (HPV, HBV and the like). Although viruses are inherently simple in structure, they have proven to be the most difficult causative agents to control. In particular, the novel coronavirus 2019-nCov has great influence on the health and economic development of the people in China, and no specific treatment medicine exists up to now.
For viral diseases, only a few drugs have been widely used clinically so far, such as Acycovir for herpes virus-related diseases, Gancilvir for cytomegalovirus-related diseases, AZT for AIDS treatment, and the like. However, these antiviral drugs have serious side effects such as severe renal cells and immune cells.
The nucleotide is a normal product and a precursor of metabolism in a human body, and the modified nucleotide obtained by modifying the nucleotide has low potential toxicity to the human body, so that the medicament developed based on the nucleotide structure is possible to become a novel safe and effective antiviral medicament.
Disclosure of Invention
The invention provides a compound based on a nucleotide structure on one hand and a synthesis method of the compound based on the nucleotide structure on the other hand, and also provides application of the compound based on the nucleotide structure in preparing a medicament for treating hepatitis C virus infection and application in preparing a medicament for treating coronavirus infection, in particular application in preparing a medicament for treating 2019-nCoV, SARS-CoV and MERS-CoV infection.
The structure of the compound based on the nucleotide structure is shown as a formula I or a pharmaceutically acceptable salt or ester of the formula I:
wherein:
R1is adenine, guanine, uracil or cytosine, and pharmaceutically acceptable variants thereof;
R2is hydrogen, methyl, halogen, hydroxyl, alkoxy, alkynyl, (C2-C8) substituted alkynyl, N3Or a dialkylamino group; further, the alkynyl group may be selected from (C2-C8) alkynyl;
R3is hydrogen, methyl, halogen, alkoxy, alkynyl, cyano, (C2-C8) substituted alkynyl, N3Or a dialkylamino group; further, the alkynyl group may be selected from (C2-C8) alkynyl;
R4and R5Independently hydrogen or methyl;
R6is hydroxy, alkoxy, dialkylamino, N3A (C1-C8) straight chain alkyl group, a (C4-C8) carbocyclylalkyl group, a (C1-C8) substituted alkyl group, a (C2-C8) alkenyl group, a (C2-C8) substituted alkenyl group, a (C2-C8) alkynyl group, a (C2-C8) substituted alkynyl group; further, the (C1-C8) straight chain alkyl group may be selected from methyl or ethyl.
In another embodiment of the compounds of formula I, the phosphate group in formula I is in the R configuration, and the chirality of the phosphate group has an effect on the bond involved in the biological activity of the compound.
In another embodiment of the compounds of formula I, the R5 group in formula I has the S configuration at the carbon atom to which it is attached and the chirality of the R5 group at the carbon atom has an effect on the biologically active bond of the compound. In another aspect of this embodiment, the phosphate group in formula I is in the R configuration.
In another embodiment of the compounds of formula I, wherein R is1、R2、R3、R4、R5、R6Respectively as follows:
R1is guanine or uracil, and pharmaceutically acceptable variants thereof;
R2is halogen, alkynyl, alkoxy or hydroxy;
R3is cyano, halogen, alkynyl or alkoxy;
R4and R5Independently hydrogen or methyl;
R6is hydroxy, alkoxy, dialkylamino, N3A (C1-C8) straight-chain alkyl group, a (C6-C8) branched-chain alkyl group, a (C4) branched-chain alkyl group, a (C4-C8) carbocyclylalkyl group, a (C1-C8) substituted alkyl group, a (C2-C8) alkenyl group, a (C2-C8) substituted alkenyl group, a (C2-C8) alkynyl group and a (C2-C8) substituted alkynyl group.
In addition to the compounds of the formula IIn one embodiment, in formula I, R1、R2、R3、R4、R5、R6Respectively as follows:
R1is guanine, and pharmaceutically acceptable variants thereof;
R2is halogen, alkynyl or hydroxy;
R3independently cyano, halogen or alkynyl;
R4and R5Independently hydrogen or methyl;
R6is (C3-C6) straight-chain alkyl, isopropyl, C5 branched-chain alkyl, (C4-C8) carbocyclylalkyl, or (C3-C6) substituted alkyl.
In another embodiment of the compounds of formula I, the compounds are selected from compounds 7-1 to 7-29 of the following structures:
synthesis of a compound based on a nucleotide structure of formula I, comprising the steps of:
preparation of intermediate compound 5:
the compound 1 shown as the formula II and a compound 2 providing a R1 group are subjected to substitution reaction to generate a compound 3, the compound 3 and a substance providing a R2 group are reacted to ensure that a hydroxyl at the 2-position of a furan ring is substituted by R2 to form a compound 4, and a benzyl protecting group on the compound 4 is removed to form a compound 5.
Wherein R is1Is adenine, guanine, uracil or cytosine, and pharmaceutically acceptable variants thereof; r2Is hydrogen, methyl, halogen, hydroxyl, alkoxy, alkynyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, N3Or a dialkylamino group.
Preparation of intermediate compound 6:
the amino compound shown as the formula III reacts with dichlorophenoxy phosphate to generate an intermediate compound, and then the intermediate compound reacts with 4-nitrophenol to generate a compound 6 shown as the formula IV.
Wherein R is5Is hydrogen, methyl, ethyl, isopropyl, hydroxy, alkoxy, dialkylamino, N3、CN、NO2Sulfonyl, SR (R represents alkyl), halogen, (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, and (C2-C8) substituted alkynyl.
R6Is hydrogen, methyl, ethyl, hydroxy, alkoxy, dialkylamino, N3、CN、NO2Sulfonyl, SR (R represents alkyl), halogen, (C1-C8) straight-chain alkyl, C5 branched-chain alkyl, C7 branched-chain alkyl, C8 branched-chain alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, and (C2-C8) substituted alkynyl.
Synthesis of target compound 7:
Use of a compound based on a nucleotide structure represented by formula I above, or a pharmaceutically acceptable salt or ester thereof, for the preparation of a medicament for the treatment of hepatitis C virus infection, or for the treatment of coronavirus infection, in particular for the treatment of 2019-nCoV, SARS-CoV, MERS-CoV infection.
In another embodiment, a compound based on a nucleotide structure as shown in formula I above, or a pharmaceutically acceptable salt or ester thereof, is used in the preparation of a medicament for treating hepatitis C virus infection or coronavirusUse of a medicament for the treatment of infections, in particular 2019-nCoV, SARS-CoV, MERS-CoV infections, in which R is as defined in formula I1、R2、R3、R4、R5、R6Respectively as follows:
R1is guanine or uracil, and pharmaceutically acceptable variants thereof;
R2is halogen, alkynyl, alkoxy or hydroxy;
R3is cyano, halogen, alkynyl or alkoxy;
R4and R5Independently hydrogen or methyl;
R6is hydroxy, alkoxy, dialkylamino, N3(C1-C8) straight-chain alkyl, isopropyl, C5 branched-chain alkyl, C7 branched-chain alkyl, C8 branched-chain alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, and (C2-C8) substituted alkynyl.
In another embodiment, the use of a compound based on a nucleotide structure as shown in formula I above, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for the treatment of hepatitis C virus infection or coronavirus infection, in particular 2019-nCoV, SARS-CoV, MERS-CoV infection, wherein R is in formula I1、R2、R3、R4、R5、R6Respectively as follows:
R1is guanine, and pharmaceutically acceptable variants thereof;
R2is halogen, alkynyl or hydroxy;
R3is cyano, halogen or alkynyl;
R4and R5Independently hydrogen or methyl;
R6is (C3-C6) straight-chain alkyl, isopropyl, C5 branched-chain alkyl, (C4-C8) carbocyclylalkyl, or (C3-C6) substituted alkyl.
In another embodiment, the use of a compound based on a nucleotide structure as shown in formula I above, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of hepatitis C virus infection or coronavirus infection, in particular 2019-nCoV, SARS-CoV, MERS-CoV infection, said compound being selected from compounds 7-1 to 7-29 of the following structures:
compared with the prior art, the invention has the beneficial effects that:
the invention provides a compound based on a nucleotide structure and a preparation method thereof, wherein the compound is shown as the formula I. The compound can effectively inhibit the hepatitis C virus, and the compound or the pharmaceutically acceptable salt or ester thereof can be used for preparing the medicine for treating the hepatitis C virus infection.
Nucleotide analogs have a blocked phosphate group that allows entry into infected eukaryotic cells, are prodrugs, are converted to the active triphosphate form by cellular enzymes, the activated drug binds to the active site of RdRp and is then incorporated into RNA, and due to the modification at position 2, inhibits further extension of the RNA strand and terminates RNA replication, which competes with the native ribonucleotide as an RNA polymerase inhibitor. Since hepatitis c virus and coronavirus use similar virus genome replication mechanisms, it can be concluded that the compound of the present invention can also inhibit coronavirus, including 2019-nCoV, SARS and MERS virus, and the compound of the present invention or its pharmaceutically acceptable salt or ester can be used for preparing medicines for treating coronavirus infection.
Drawings
FIG. 1 is a synthetic route to compounds 7-29;
FIG. 2 is a synthetic route for compound 7-1.
Detailed Description
In order to more fully understand the technical contents of the present invention, the technical solutions of the present invention will be further described and illustrated with reference to the following specific embodiments.
Examples
The structure of the compound based on the nucleotide structure is shown as a formula I, wherein:
wherein:
R1is adenine, guanine, uracil or cytosine, and pharmaceutically acceptable variants thereof;
R2is hydrogen, methyl, halogen, hydroxyl, alkoxy, alkynyl, (C2-C8) substituted alkynyl, N3Or a dialkylamino group; further, the alkynyl group may be selected from (C2-C8) alkynyl;
R3is hydrogen, methyl, halogen, alkoxy, alkynyl, cyano, (C2-C8) substituted alkynyl, N3Or a dialkylamino group; further, the alkynyl group may be selected from (C2-C8) alkynyl;
R4and R5Independently hydrogen or methyl;
R6is isopropyl, hydroxy, alkoxy, dialkylamino, N3(C1-C8) straight-chain alkyl, C5 branched-chain alkyl, C7 branched-chain alkyl, C8 branched-chain alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, and (C2-C8) substituted alkynyl; further, the (C1-C8) alkyl group may be selected from methyl or ethyl.
In another embodiment of the compounds of formula I, the phosphate group in formula I is in the R configuration.
In another embodiment of the compounds of formula I, the R5 group in formula I has the S configuration at the carbon atom to which it is attached.
The compound shown in the formula I can be synthesized by firstly synthesizing an intermediate compound 5 and an intermediate compound 6, and then condensing the compound 5 and the compound 6 to form a target compound 7.
Preparation of intermediate compound 5:
the compound 1 shown as the formula II and a compound 2 providing a R1 group are subjected to substitution reaction to generate a compound 3, the compound 3 and a substance providing a R2 group are reacted to ensure that a hydroxyl at the 2-position of a furan ring is substituted by R2 to form a compound 4, and a benzyl protecting group on the compound 4 is removed to form a compound 5.
Wherein R is1Is adenine, guanine, uracil or cytosine, and pharmaceutically acceptable variants thereof; r2Is hydrogen, methyl, halogen, hydroxyl, alkoxy, alkynyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, N3Or a dialkylamino group.
Preparation of intermediate compound 6:
the amino compound shown as the formula III reacts with dichlorophenoxy phosphate to generate an intermediate compound, and then the intermediate compound reacts with 4-nitrophenol to generate a compound 6 shown as the formula IV.
Wherein R is5Is hydrogen, methyl, ethyl, isopropyl, hydroxy, alkoxy, dialkylamino, N3、CN、NO2Sulfonyl, SR (R represents alkyl), halogen, (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkyneA group (C2-C8) substituted alkynyl.
R6Is hydrogen, methyl, ethyl, hydroxy, alkoxy, dialkylamino, N3、CN、NO2Sulfonyl, SR (R represents alkyl), halogen, (C1-C8) straight-chain alkyl, C5 branched-chain alkyl, C7 branched-chain alkyl, C8 branched-chain alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, and (C2-C8) substituted alkynyl.
Synthesis of target compound 7:
The synthesis of the compounds of the present invention is described below by taking compounds 7-29 as examples.
Compounds 7-29:
2,3-dimethylbutyl((R)-(((2R,3S,4R,5S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-5-yl)-5-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
structures of compounds 7-29:
the synthetic route of the compounds 7-29 is shown in figure 1, and the specific synthetic process is as follows:
synthesis of Compound 3:
weighing compound 2(23.6g,23.9mmol,1equiv) and TMSCl (6.07M L, 23.9mmol,2.00equiv), under argon protection, adding tetrahydrofuran dropwise at room temperature and stirring for 10min, cooling the solution to 0 ℃, adding a tetrahydrofuran solution of PhMgCl (23.9M L, 47.8mmol,2.00equiv) slowly, adding a tetrahydrofuran solution of iPrMgCl (25.1M L, 25.1mmol, 1.00equiv) slowly, keeping the reaction temperature below 5 ℃ for 15min, cooling the mixture to-20 ℃, adding compound 1(1,7.8g,23.9mmol,1.00equiv slowly, keeping the reaction temperature about-20 ℃, after reacting for 1 h, heating the reaction mixture to 0 ℃, quenching the reaction with methanol, adding acetic acid (20M L) and water (20M L), concentrating under reduced pressure, concentrating the concentrate with ethyl acetate (250M) and concentrating the ethyl acetate (250M) under reduced pressure, distilling off-white sodium bicarbonate solution to obtain crude sodium bicarbonate, and extracting the ethyl acetate (250-10M) with sodium bicarbonate, concentrating the ethyl acetate (250-10M) to obtain sodium bicarbonate solution, and concentrating the crude sodium bicarbonate.
Synthesis of Compound 4:
compound 3(2.19g,5mmol) and DAST (793 μ L, 6mmol) were weighed out under nitrogen and tetrahydrofuran (15m L) was added dropwise under ice water bath the reaction mixture was heated to room temperature and stirred for 30 min, then cooled to-30 ℃ and quenched with methanol (5m L) the residue was dissolved in DCM (50m L), washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, concentrated under reduced pressure and eluted with a gradient of 0-20% ethyl acetate and hexane to give compound 4.
Synthesis of Compound 5:
weighing boron trichloride (1M,35.0M L, 35.0mmol,3.80equiv) and compound 4(4.0g, 9.10mmol,1equiv), and adding argon for protection, slowly adding dichloromethane (50M L) dropwise at-78 ℃, stirring for 2h at-40 ℃, cooling the reaction mixture to-78 ℃, adding a methanol solution (20M L) of triethylamine (13M L) dropwise, heating the reaction mixture to room temperature, carrying out reduced pressure rotary evaporation to obtain a solid residue, mixing the solid residue with hexane (50M L), washing for 3 times, suspending the remaining solid residue in methanol (50M L), heating to 45 ℃, adding water (50M L), concentrating the obtained mixture at 45 ℃ under reduced pressure to about 35 ml of water, cooling to room temperature, collecting white solid particles by vacuum filtration, and drying at 70 ℃ in a vacuum drying oven overnight.
Synthesis of Compound 6:
(S) -2, 3-dimethylbutyl 2-aminopropionic acid hydrochloride (8,26.0g,124mmol,1.10equiv) was added dichloromethane (200m L) and cooled to-78 deg.C, dichlorophenoxyphosphate (18.5m L, 124mmol,1.10equiv) was added, then triethylamine (17.2m L, 124mmol,1.10equiv) was slowly added, the reaction was stirred at room temperature for 3h, ice water was cooled, 4-nitrophenol (15.5g,112mmol,1equiv) was added, then triethylamine (17.2m L, 124mmol,1.10equiv) was slowly added and stirring was continued at room temperature for 3h, the crude product was concentrated and eluted by gradient elution with 0-30% ethyl acetate and hexane on silica gel.
Synthesis of Compounds 7-29:
compound 6(1.79g,3.98mmol,1.20equiv) and compound 5(2.59g,3.32mmol, 1equiv), magnesium chloride (316mg,3.32mmol,1.00equiv), acetonitrile (16m L) was added at room temperature, heated to 50 ℃ after reaction for 10 minutes, N-diisopropylethylamine (1.45m L, 8.30mmol,2.50equiv) was added dropwise after 20 minutes, the reaction mixture was cooled to room temperature and then quenched with ethyl acetate (100m L), the organic layer acid solution (40m L) was washed with 5% citric acid water, the saturated ammonium chloride solution (40m L), the 5% aqueous potassium carbonate solution (2 × 40m L), the brine (40m L), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was eluted with a gradient of 0 to 100% ethyl acetate and hexane by silica gel chromatography.
Compound 7-1:
isobutyl-((R)-(((2R,3R,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-3,5-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)glycinate
structure of Compound 7-1:
FIG. 2 shows an example of compound 7-1, which illustrates the synthesis of the compound of the present invention.
The compounds of formula I of the present invention also include:
compound 7-2:
2-methylbutyl((R)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compound 7-3:
propyl((S)-(((2R,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-chloro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-4:
2-methylbutyl((S)-(((2R,3R,4R,5R)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-5:
ethyl((R)-(((2R,3S,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-ethynyl-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-6:
butyl((R)-(((2R,3S,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-ethynyl-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-7:
propyl((R)-(((2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-ethynyl-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-8:
propyl((R)-(((2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-ethynyl-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-9:
2-methylpentyl((R)-(((2R,3S,4R,5S)-5-(4-amino-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-ethynyl-5-fluoro-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-10:
2-methylpentyl((R)-(((2R,3S,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-cyano-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-11:
2-methylpentyl((R)-(((2R,3S,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-cyano-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-12:
2-ethylpentyl((R)-(((2R,3S,4R,5R)-4-cyano-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-13:
propyl((R)-(((2R,3S,4R,5R)-4-cyano-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-14:
2-methylpentyl((R)-(((2R,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-chloro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-15:
2-propylpentyl((R)-(((2R,3R,4R,5R)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-16:
butyl((R)-(((2R,3S,4R,5R)-4-cyano-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,5-dihydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-17:
propyl((R)-(((2R,3S,4R,5S)-5-(4-amino-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-ethynyl-5-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-18:
2-cyclohexylethyl((R)-(((2R,3S,4R,5S)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-19:
2-methylbutyl((R)-(((2R,3S,4R,5S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-5-yl)-5-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-20:
2,3-dimethylbutyl((R)-(((2R,3S,4R,5S)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-21:
2-methylbutyl((R)-(((2R,3S,4S,5S)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-5-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-22:
2,3-dimethylbutyl((R)-(((2R,3S,4R,5S)-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)-5-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-23:
2-methylbutyl((R)-(((2R,3S,4R,5S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-5-yl)-5-chloro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-24:
2,3-dimethylbutyl((R)-(((2R,3R,4R,5S)-5-(2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)-4-chloro-3-hydroxy-5-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-25:
2-methylpentyl((R)-(((2R,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-hydroxy-4-methoxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-26:
3-ethylpentyl((R)-(((2R,3R,4R,5S)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-fluoro-3-hydroxy-4-methoxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
compounds 7-27:
2-methylbutyl((R)-(((2R,3R,4R,5R)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-5-yl)-5-chloro-3-hydroxy-4-methoxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
compounds 7-28:
2-methylbutyl((R)-(((2R,3S,4R,5R)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-5-yl)-4-cyano-3,5-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate
experiment on inhibitory Effect of the Compound of the present invention on hepatitis C Virus
(I) hepatitis C Virus inhibitory Effect of different concentrations
Inoculating Vero cells in logarithmic growth phase to a 96-well plate, and inoculating the Vero cells at 37 ℃ and CO2Culturing in incubator to form monolayer, discarding culture solution, washing with PBS twice, adding 100ul virus solution of 100TCID50, and culturing at 37 deg.C with 5% CO2After incubation for 1.5h in the incubator, the infection solution was discarded, PBS was washed three times, and a blank DMEM culture solution and a 7-29DMEM cell maintenance solution containing compounds of 10nM, 33nM and 100nM were added, respectively, to continue the culture. After about 48 hours, when the viral control wells showed about 90% cellular CPE, the supernatant from the cell culture plates was removed, washed twice with PBS, and stained by adding 20-25ul of a soluble tetrazolium-based dye MTS (3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (-4-sulfophenyl) -2H-tetrazolium to each well and 5% CO at 37 deg.C2Incubate for 4-6 hours, read at 460nm/650 nm. MTS is metabolized by the mitochondrial enzymes that metabolize active cells to produce a soluble formazan product, allowing rapid quantitative analysis of cell survival and compound toxicity.
(II) hepatitis C Virus inhibitory Effect of different Compounds
Inoculating Vero cells in logarithmic growth phase into 96-well plate, culturing at 37 deg.C in CO2 incubator to obtain monolayer, discarding culture medium, washing with PBS twice, adding 100ul of 100TCID50 virus solution, and culturing at 37 deg.C in 5% CO2After incubation for 1.5h in the incubator, the infection solution was discarded, washed three times with PBS, and added with a blank DMEM culture solution and a DMEM cell maintenance solution of 33nM different compounds (compounds 7-1 to 7-29), respectively, to continue the culture. After about 48 hours, when the viral control wells showed about 90% cellular CPE, the supernatant from the cell culture plates was removed, washed twice with PBS, and stained by adding 20-25ul of a soluble tetrazolium-based dye MTS (3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (-4-sulfophenyl) -2H-tetrazolium to each well and 5% CO at 37 deg.C2Incubate for 4-6 hours, read at 460nm/650 nm. MTS is metabolized by the mitochondrial enzymes that metabolize active cells to produce a soluble formazan product, allowing rapid quantitative analysis of cell survival and compound toxicity.
The inhibition experiment of the hepatitis C virus shows that the compound can effectively inhibit the hepatitis C virus, and the compound or the pharmaceutically acceptable salt or ester thereof can be used for preparing the medicine for treating the hepatitis C virus infection.
Nucleotide analogs have a blocked phosphate group that allows entry into infected eukaryotic cells, are prodrugs, are converted to the active triphosphate form by cellular enzymes, the activated drug binds to the active site of RdRp and is then incorporated into RNA, inhibits further extension of the RNA strand and terminates RNA replication due to the modification at the 2' position, which competes with the native ribonucleotide as an RNA polymerase inhibitor. Since hepatitis c virus and coronavirus use similar virus genome replication mechanisms, it can be concluded that the compound of the present invention can also inhibit coronavirus, including 2019-nCoV, SARS and MERS virus, and the compound of the present invention or its pharmaceutically acceptable salt or ester can be used for preparing medicines for treating coronavirus infection.
The technical contents of the present invention are further illustrated by the examples, so as to facilitate the understanding of the reader, but the embodiments of the present invention are not limited thereto, and any technical extension or re-creation based on the present invention is protected by the present invention.
Claims (10)
1. A compound based on a nucleotide structure, wherein the structure of the compound is shown as formula I or a pharmaceutically acceptable salt or ester of formula I:
wherein:
R1is adenine, guanine, uracil or cytosine, and pharmaceutically acceptable variants thereof;
R2is hydrogen, methyl, halogen, hydroxyl, alkoxy, alkynyl, (C2-C8) substituted alkynyl, N3Or a dialkylamino group; further, the alkynyl group may be selected from (C2-C8) alkynyl;
R3is hydrogen, methyl, halogen, alkoxy, alkynyl, cyano, (C2-C8) substituted alkynyl, N3Or a dialkylamino group; further, the alkynyl group may be selected from (C2-C8) alkynyl;
R4and R5Independently hydrogen or methyl;
R6is hydroxy, alkoxy, dialkylamino, N3(C1-C8) straight-chain alkyl, C5 branched-chain alkyl, C7 branched-chain alkyl, C8 branched-chain alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, and (C2-C8) substituted alkynyl; further, the (C1-C8) alkyl group may be selected from methyl or ethyl.
2. The compound of claim 1, wherein the phosphate group in formula I is in the R configuration.
3. A compound according to claim 1 or 2, wherein R in formula I5The radical has the S configuration at the carbon atom to which it is attached.
4. A process for the preparation of a compound as claimed in claim 1, wherein intermediate compound 5 and intermediate compound 6 are synthesized, and then compound 5 and compound 6 are condensed to form target compound 7;
synthesis of the intermediate compound 5:
carrying out substitution reaction on a compound 1 shown as a formula II and a compound 2 providing a R1 group to generate a compound 3, reacting the compound 3 with a substance providing a R2 group to enable a hydroxyl at the 2-position of a furan ring to be substituted by R2 to form a compound 4, and removing a benzyl protecting group on the compound 4 to form a compound 5;
wherein R is1Is adenine, guanine, uracil or cytosine, and pharmaceutically acceptable variants thereof; r2Is hydrogen, methyl, halogen, hydroxyl, alkoxy, alkynyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, N3Or a dialkylamino group;
synthesis of the intermediate compound 6:
reacting an amino compound shown as a formula III with dichlorophenoxy phosphate to generate an intermediate compound, and then reacting the intermediate compound with 4-nitrophenol to generate a compound 6 shown as a formula IV;
wherein R is5Is hydrogen, methyl, ethyl, isopropyl, hydroxy, alkoxy, dialkylamino, N3、CN、NO2Sulfonyl, SR (R represents alkyl), halogen, (C1-C8) alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl;
R6is hydrogen, methyl, ethyl, hydroxy, alkoxy, dialkylamino, N3、CN、NO2Sulfonyl, SR (R represents alkyl), halogen, (C1-C8) straight-chain alkyl, C5 branched-chain alkyl, C7 branched-chain alkyl, C8 branched-chain alkyl, (C4-C8) carbocyclylalkyl, (C1-C8) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, and (C2-C8) substituted alkynyl.
5. Use of a compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for the treatment of a coronavirus infection.
6. The use of claim 5, the coronavirus comprising 2019-nCoV, SARS-CoV, MERS-CoV.
7. The use according to claim 5, in formula I,
R1is guanine or uracil, and pharmaceutically acceptable variants thereof;
R2is halogen, alkynyl, alkoxy or hydroxy;
R3is cyano, halogen, alkynyl or alkoxy;
R4and R5Independently hydrogen or methyl;
R6is hydroxy, alkoxy, dialkylamino, N3A (C1-C8) straight-chain alkyl group, a C5 branched-chain alkyl group, a C7 branched-chain alkyl group, a C8 branched-chain alkyl group, a (C4-C8) carbocyclylalkyl group, a (C1-C8) substituted alkyl group, a (C2-C8) alkenyl group, a (C2-C8) substituted alkenyl group, a (C2-C8) alkynyl group, and a (C2-C8) substituted alkynyl group.
8. The use according to claim 5, said compound being selected from at least one of the compounds represented by the following structures:
9. use of a compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for treating a hepatitis c virus infection.
10. The use according to claim 9, said compound being selected from at least one of the compounds represented by the following structures:
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| CN202110176199.3A CN112920243B (en) | 2020-04-17 | 2021-02-07 | Application of nucleotide compounds in inhibiting new coronavirus and influenza virus |
| CN202110177417.5A CN112724186B (en) | 2020-04-17 | 2021-02-07 | Nucleotide compound for inhibiting virus |
| CN202110176029.5A CN112759622B (en) | 2020-04-17 | 2021-02-07 | Nucleotide compound without causing bradycardia |
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| CN112920243A (en) * | 2020-04-17 | 2021-06-08 | 广东帕派恩生物科技有限公司 | Application of nucleotide compounds in inhibiting new coronavirus and influenza virus |
| CN112940053A (en) * | 2021-02-26 | 2021-06-11 | 江苏阿尔法药业股份有限公司 | Preparation method of anti-HCV (hepatitis C Virus) medicine |
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| CN111875638A (en) * | 2020-07-16 | 2020-11-03 | 江苏省原子医学研究所 | Preparation method of Reidesciclovir derivative, Reidesciclovir derivative and application thereof |
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| CN116120383A (en) * | 2023-02-02 | 2023-05-16 | 广东帕派恩生物科技有限公司 | Compound for inhibiting RNA virus and preparation method thereof |
| CN116217621A (en) * | 2023-04-26 | 2023-06-06 | 北京沐华生物科技有限责任公司 | Nucleoside double-prodrug, synthesis method and application |
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| CN112920243B (en) | 2022-03-11 |
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| CN112759622B (en) | 2022-01-07 |
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