CN108892693B - Nucleoside compound, preparation method thereof and pharmaceutical composition for treating flavivirus infection - Google Patents

Nucleoside compound, preparation method thereof and pharmaceutical composition for treating flavivirus infection Download PDF

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CN108892693B
CN108892693B CN201810941785.0A CN201810941785A CN108892693B CN 108892693 B CN108892693 B CN 108892693B CN 201810941785 A CN201810941785 A CN 201810941785A CN 108892693 B CN108892693 B CN 108892693B
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CN108892693A (en
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刘明亮
吕凯
钟武
曹瑞源
汪阿鹏
闫赟政
陶泽宇
和青昊
王洪建
李微
耿云鹤
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention provides a nucleoside compound with a structure shown in a formula I, which has better anti-flavivirus activity. In the embodiment, vero cells are used as Zika virus vectors, and the inhibitory activity and cytotoxicity of the nucleoside compounds on Zika viruses are determined.

Description

Nucleoside compound, preparation method thereof and pharmaceutical composition for treating flavivirus infection
Technical Field
The invention relates to the technical field of medical chemistry, in particular to a nucleoside compound, a preparation method thereof and a pharmaceutical composition for treating flavivirus infection.
Background
Flaviviruses are insect-borne viruses which are mainly transmitted by vectors such as mosquitoes and ticks, and more than 70 viruses such as Zika virus, dengue virus 1-4(DENV 1-4), Yellow Fever Virus (YFV), West Roney virus (WNV), tick-borne encephalitis virus (TBEV) and Japanese Encephalitis Virus (JEV) are common. These viruses are a serious threat to human health and can cause a variety of diseases including fever, hepatitis, hemorrhagic fever, and in severe cases even death. Among them Zika virus was originally discovered and named in 1947, Zika virus caused multiple pandemics in the Central and south America since 2013; in 2015, brazil outbreaks of large-scale Zika epidemic; 2016, month 2, day 1, the world health organization announced that outbreaks and spread of Zika virus have constituted a global emergent public health event. Therefore, the research for developing effective drugs for treating flavivirus infection is of great significance and is imminent.
Nucleoside compounds have various biological activities, such as anti-tumor, anti-tuberculosis, anti-virus, etc., wherein the anti-flavivirus activity of nucleoside compounds has been widely noticed in recent years, and drugs have been clinically studied (BCX 4430). Further investigation of compounds with excellent anti-flavivirus activity remains a problem that needs to be addressed.
Disclosure of Invention
The invention aims to provide a nucleoside compound, a preparation method thereof and a pharmaceutical composition for treating flavivirus infection.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a nucleoside compound, which has a structure shown in a formula I:
Figure BDA0001769251920000011
in the formula I, Ar is R substituted or unsubstituted phenyl, R substituted or unsubstituted pyridyl, R substituted or unsubstituted naphthyl, R substituted or unsubstituted quinolyl, R substituted or unsubstituted pyrazinyl, R substituted or unsubstituted pyrimidyl, R substituted or unsubstituted pyrazolyl, R substituted or unsubstituted imidazolyl, R substituted or unsubstituted furyl or R substituted or unsubstituted thienyl;
R1and R2Independently hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, hydroxybenzyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted phenylcarbonyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstituted naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethylene, R ' substituted or unsubstituted pyrimidylmethylene, R ' substituted or unsubstituted pyrazolylmethylene, R ' substituted or unsubstituted imidazolylmethylene, R ' substituted or unsubstituted furanylmethylene, or R ' substituted or unsubstituted thienylmethylene, and R1And R2Not simultaneously being R' substituted or unsubstituted phenylcarbonyl, and R1And R2Not hydrogen at the same time;
r and R' are independently C1-C4 alkyl, C1-C3 alkoxy, halogen group, -CF3、-OCF3、-NO2or-CN.
Preferably, the alkyl group of C1-C6 includes methyl, ethyl, isopropyl, n-butyl or tert-butyl.
Preferably, the cycloalkyl group of C4-C6 includes cyclohexyl, cyclopentyl or cyclobutyl.
Preferably, the halogen group is-F, -Cl or-Br.
Preferably, the nucleoside compound comprises
Figure BDA0001769251920000021
Figure BDA0001769251920000022
Figure BDA0001769251920000031
The invention provides a preparation method of nucleoside compounds in the technical scheme, which comprises the following steps:
(1) mixing the compound 2, ethanol, triethylamine and Ar-CH2NH2Mixing, nucleophilic substitution reaction to obtainCompound 3; the compound 2 has the structure shown in formula II:
Figure BDA0001769251920000041
(2) mixing the compound 3, tetrahydrofuran, triphenylphosphine, diisopropyl azodicarboxylate and phthalimide, and carrying out a mitsunobu reaction to obtain a compound 4;
(3) mixing the compound 4, ethanol and hydrazine hydrate, and carrying out hydrazinolysis reaction to obtain a compound 5;
(41) when R in formula I1Is hydrogen, R2When the compound is C1-C6 alkyl, C4-C6 cycloalkyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstituted naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethylene, R ' substituted or unsubstituted pyrimidylmethylene, R ' substituted or unsubstituted pyrazolyl methylene, R ' substituted or unsubstituted imidazolyl methylene, R ' substituted or unsubstituted furyl methylene or R ' substituted or unsubstituted thienyl methylene, the compound 5, ethanol, sodium cyanoborohydride and R ' are mixed together3-CO-R4Mixing, adjusting the pH value of the obtained system to 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-1;
the R is3And R4Independently hydrogen, C1-C5 alkyl, R 'substituted or unsubstituted phenyl, R' substituted or unsubstituted pyridyl, R 'substituted or unsubstituted naphthyl, R' substituted or unsubstituted quinolyl, R 'substituted or unsubstituted pyrazinyl, R' substituted or unsubstituted pyrimidyl, R 'substituted or unsubstituted pyrazolyl, R' substituted or unsubstituted imidazolyl, R 'substituted or unsubstituted furyl, or R' substituted or unsubstituted thienyl, and R3And R4Not hydrogen at the same time; or R3And R4Form a C4-C6 cycloalkyl;
(42) when R in formula I1And R2Independently C1-C6 alkyl, C4-C6 cycloalkyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstitutedWhen naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethylene, R ' substituted or unsubstituted pyrimidylmethylene, R ' substituted or unsubstituted pyrazolyl methylene, R ' substituted or unsubstituted imidazolyl methylene, R ' substituted or unsubstituted furanylmethylene, or R ' substituted or unsubstituted thiophenylmethylene, compound 6-1 is reacted with methanol, sodium cyanoborohydride, and R3-CO-R4Mixing, adjusting the pH value of the obtained system to 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-2;
(43) when R in formula I1Is hydroxybenzyl or hydrogen, R2When the compound is hydroxybenzyl, mixing the compound 5, ethanol, sodium cyanoborohydride and 4-acetoxybenzaldehyde, adjusting the pH value of the obtained system to be 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-3;
(44) when R in formula I1Is hydrogen, R2When R 'is substituted or unsubstituted phenylcarbonyl, mixing the compound 5, dichloromethane, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, triethylamine and R' substituted benzoic acid or benzoic acid, and carrying out condensation reaction to obtain a compound 6-4;
(5) mixing the compound 6 with dichloromethane, trifluoroacetic acid and water, and carrying out deprotection reaction to obtain a nucleoside compound with a structure shown in a formula I; the compound 6 comprises the compound 6-1, the compound 6-2, the compound 6-3 or the compound 6-4.
Preferably, the reagent used for adjusting the pH value in the steps (41), (42) and (43) is acetic acid.
The invention provides a pharmaceutical composition for treating flavivirus infection, which comprises nucleoside compounds and a pharmaceutically acceptable carrier.
Preferably, the mass content of the nucleoside compound in the pharmaceutical composition is 0.1-99.9%.
Preferably, the flavivirus comprises Zika virus, dengue virus or West Roy virus.
The invention provides a nucleoside compound with a structure shown in a formula I, which has better anti-flavivirus activity. In the embodiment, vero cells are used as Zika virus vectors, and the inhibitory activity and cytotoxicity of the nucleoside compounds on Zika viruses are determined.
Detailed Description
The invention provides a nucleoside compound, which has a structure shown in a formula I:
Figure BDA0001769251920000051
in the formula I, Ar is R substituted or unsubstituted phenyl, R substituted or unsubstituted pyridyl, R substituted or unsubstituted naphthyl, R substituted or unsubstituted quinolyl, R substituted or unsubstituted pyrazinyl, R substituted or unsubstituted pyrimidyl, R substituted or unsubstituted pyrazolyl, R substituted or unsubstituted imidazolyl, R substituted or unsubstituted furyl or R substituted or unsubstituted thienyl;
R1and R2Independently hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, hydroxybenzyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted phenylcarbonyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstituted naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethylene, R ' substituted or unsubstituted pyrimidylmethylene, R ' substituted or unsubstituted pyrazolylmethylene, R ' substituted or unsubstituted imidazolylmethylene, R ' substituted or unsubstituted furanylmethylene, or R ' substituted or unsubstituted thienylmethylene, and R1And R2Not simultaneously being R' substituted or unsubstituted phenylcarbonyl, and R1And R2Not hydrogen at the same time;
r and R' are independently C1-C4 alkyl, C1-C3 alkoxy, halogen group, -CF3、-OCF3、-NO2or-CN.
In the present invention, the position of the Ar substituted by R is not particularly limited, and any hydrogen atom-containing position of phenyl, pyridyl, naphthyl, quinolyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, furyl or thienyl may be substituted by R.
In the invention, R is C1-C4 alkyl, C1-C3 alkoxy, halogen group, -CF3、-OCF3、-NO2or-CN, preferably a halogen group, more preferably-F, -Cl or-Br, most preferably-Cl.
In the present invention, Ar is preferably a halogen-substituted phenyl group, more preferably a chlorine-substituted phenyl group, and most preferably 3-chlorophenyl group.
In the present invention, the alkyl group having 1 to 6 preferably includes a methyl group, an ethyl group, an isopropyl group, a n-butyl group or a tert-butyl group.
In the present invention, the cycloalkyl group having 4 to 6 preferably includes cyclohexyl, cyclopentyl or cyclobutyl.
The invention relates to said R1And R2The position of R 'substitution is not particularly limited, and any hydrogen atom-containing position of phenyl, pyridyl, naphthyl, quinolyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, furyl or thienyl may be substituted with R'.
In the present invention, said R1And R2Independently hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, hydroxybenzyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted phenylcarbonyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstituted naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethylene, R ' substituted or unsubstituted pyrimidylmethylene, R ' substituted or unsubstituted pyrazolylmethylene, R ' substituted or unsubstituted imidazolylmethylene, R ' substituted or unsubstituted furanylmethylene, or R ' substituted or unsubstituted thienylmethylene, and R1And R2Not hydrogen at the same time; preferably independently hydrogen, methyl, ethyl, isopropyl, cyclohexyl, cyclopentyl, cyclobutyl, benzyl, halo-substituted benzyl, trifluoromethylbenzyl, nitrobenzyl, methoxybenzyl, trifluoromethoxybenzyl, hydroxybenzyl, naphthylmethylene, pyridylmethylene, thienylmethylene or haloAn aryl substituted by phenyl carbonyl.
In the present invention, the nucleoside compound preferably comprises
Figure BDA0001769251920000061
Figure BDA0001769251920000062
Figure BDA0001769251920000071
Figure BDA0001769251920000081
The invention provides a preparation method of nucleoside compounds in the technical scheme, which comprises the following steps:
(1) mixing the compound 2, ethanol, triethylamine and Ar-CH2NH2Mixing, and carrying out nucleophilic substitution reaction to obtain a compound 3; the compound 2 has the structure shown in formula II:
Figure BDA0001769251920000082
(2) mixing the compound 3, tetrahydrofuran, triphenylphosphine, diisopropyl azodicarboxylate and phthalimide, and carrying out a mitsunobu reaction to obtain a compound 4;
(3) mixing the compound 4, ethanol and hydrazine hydrate, and carrying out hydrazinolysis reaction to obtain a compound 5;
(41) when R in formula I1Is hydrogen, R2Is C1-C6 alkyl, C4-C6 cycloalkyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstituted naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethylene, R ' substituted or unsubstituted pyrimidylmethylene, R ' substituted or unsubstituted pyrazolyl methylene, R ' substituted or unsubstituted imidazolyl methylene, R ' substituted or unsubstitutedWhen the compound is unsubstituted furyl methylene or R' is substituted or unsubstituted thienyl methylene, the compound 5, ethanol, sodium cyanoborohydride and R3-CO-R4Mixing, adjusting the pH value of the obtained system to 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-1;
the R is3And R4Independently hydrogen, C1-C5 alkyl, R 'substituted or unsubstituted phenyl, R' substituted or unsubstituted pyridyl, R 'substituted or unsubstituted naphthyl, R' substituted or unsubstituted quinolyl, R 'substituted or unsubstituted pyrazinyl, R' substituted or unsubstituted pyrimidyl, R 'substituted or unsubstituted pyrazolyl, R' substituted or unsubstituted imidazolyl, R 'substituted or unsubstituted furyl, or R' substituted or unsubstituted thienyl, and R3And R4Not hydrogen at the same time; or R3And R4Forming C4-C6 cyclane;
(42) when R in formula I1And R2Independently C1-C6 alkyl, C4-C6 cycloalkyl, R 'substituted or unsubstituted benzyl, R' substituted or unsubstituted pyridylmethylene, R 'substituted or unsubstituted naphthylmethylene, R' substituted or unsubstituted quinolylmethylene, R 'substituted or unsubstituted pyrazinylmethylene, R' substituted or unsubstituted pyrimidylmethylene, R 'substituted or unsubstituted pyrazolyl methylene, R' substituted or unsubstituted imidazolyl methylene, R 'substituted or unsubstituted furanylmethylene, or R' substituted or unsubstituted thienylmethylene, Compound 6-1 with methanol, sodium cyanoborohydride, and R3-CO-R4Mixing, adjusting the pH value of the obtained system to 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-2;
(43) when R in formula I1Is hydroxybenzyl or hydrogen, R2When the compound is hydroxybenzyl, mixing the compound 5, ethanol, sodium cyanoborohydride and 4-acetoxybenzaldehyde, adjusting the pH value of the obtained system to be 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-3;
(44) when R in formula I1Is hydrogen, R2When R' is substituted or unsubstituted phenylcarbonyl, the compound 5, dichloromethane, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1-hydroxyMixing benzotriazole, triethylamine and R' substituted benzoic acid or benzoic acid, and carrying out condensation reaction to obtain a compound 6-4;
(5) mixing the compound 6 with dichloromethane, trifluoroacetic acid and water, and carrying out deprotection reaction to obtain a nucleoside compound with a structure shown in a formula I; the compound 6 comprises the compound 6-1, the compound 6-2, the compound 6-3 or the compound 6-4.
The invention comprises the following steps of mixing a compound 2, ethanol, triethylamine and Ar-CH2NH2Mixing, and carrying out nucleophilic substitution reaction to obtain a compound 3; the compound 2 has the structure shown in formula II:
Figure BDA0001769251920000091
in the present invention, the compound 2, triethylamine and Ar-CH2NH2The ratio of the amount of substance(s) to the volume of ethanol is preferably 1 mmol: (1.8-2.2) mmol: (1.8-2.2) mmol: (4-6) mL, more preferably 1 mmol: 2 mmol: 2 mmol: (5-5.5) mL.
In the present invention, the compound 2 and Ar-CH2NH2Is a reactant, the ethanol is a reaction solvent, and the triethylamine is an acid-binding agent.
In the invention, the temperature of the nucleophilic substitution reaction is preferably 35-45 ℃, and more preferably 40 ℃; the time is preferably 4.5 to 5.5 hours, and more preferably 4 hours. In the present invention, the nucleophilic substitution reaction is preferably performed under stirring conditions; the stirring rate is not particularly limited in the present invention, and a stirring rate known to those skilled in the art may be used.
After the nucleophilic substitution reaction is completed, the present invention preferably concentrates the resulting system, and separates and purifies the residue with a silica gel column to obtain compound 3. In the present invention, the eluent used for the separation and purification of the silica gel column is preferably Dichloromethane (DCM), methanol (MeOH) and ammonia (NH)3·H2O), the volume ratio of dichloromethane, methanol and ammonia is preferably 200:10: 0.1; the mass concentration of the ammonia water is preferably 25-28%.
After the compound 3 is obtained, the compound 3, tetrahydrofuran, triphenylphosphine, diisopropyl azodicarboxylate and phthalimide are mixed for mitsunobu reaction to obtain a compound 4. In the present invention, the volume ratio of the amount of the substance of the compound 3, phthalimide, triphenylphosphine, and diisopropyl azodicarboxylate to tetrahydrofuran is preferably 1.2 mmol: (1.6-2.0) mmol: (2.2-2.6) mmol: (2.2-2.6) mmol: (8-12) mL, more preferably 1.2 mmol: 1.8 mmol: 2.4 mmol: 2.4 mmol: 10 mL.
In the invention, the compound 3 and phthalimide are reactants, tetrahydrofuran is a reaction solvent, and triphenylphosphine and diisopropyl azodicarboxylate are reagents required by a mitsunobu reaction.
In the invention, the temperature of the mitsunobu reaction is preferably 15-40 ℃, and more preferably 20-30 ℃; in the embodiments of the present invention, the mitsunobu reaction is performed specifically at room temperature, i.e., without additional heating or cooling. In the invention, the time of the mitsunobu reaction is preferably 2.5-3.5 h, and more preferably 3 h. In the present invention, the mitsunobu reaction is preferably carried out under stirring conditions; the stirring rate is not particularly limited in the present invention, and a stirring rate known to those skilled in the art may be used.
After the completion of the mitsunobu reaction, the present invention preferably concentrates the resulting system and separates and purifies the residue by means of a silica gel column to obtain compound 4. In the present invention, the eluent used for the separation and purification of the silica gel column is preferably dichloromethane, methanol and ammonia water, and the volume ratio of the dichloromethane to the methanol to the ammonia water is preferably 200:10: 0.1; the mass concentration of the ammonia water is preferably 25-28%.
After the compound 4 is obtained, the compound 4, ethanol and hydrazine hydrate are mixed for hydrazinolysis reaction to obtain a compound 5. In the present invention, the hydrazine in the hydrazine hydrate is preferably contained in an amount of 65% by mass.
In the invention, the compound 4 and hydrazine hydrate are reactants, and the ethanol is a reaction solvent.
In the present invention, the temperature of the hydrazinolysis reaction is preferably the temperature of ethanol reflux; the time of the hydrazinolysis reaction is preferably 1.5-2.5 h, and more preferably 2 h.
After the completion of the hydrazinolysis reaction, the present invention preferably cools the resulting system to room temperature and then filters, concentrates the resulting filtrate, and separates and purifies the residue by a silica gel column to obtain compound 5. In the present invention, the eluent used for the separation and purification of the silica gel column is preferably dichloromethane, methanol and ammonia water, and the volume ratio of the dichloromethane to the methanol to the ammonia water is preferably 100:10: 0.2; the mass concentration of the ammonia water is preferably 25-28%.
After the compound 5 is obtained, different reaction raw materials and preparation methods are selected according to the specific structure of the nucleoside compound with the structure shown in the formula I.
When R in formula I1Is hydrogen, R2When the alkyl group is C1-C6, the cycloalkyl group is C4-C6, R 'substituted or unsubstituted benzyl, R' substituted or unsubstituted pyridylmethylene, R 'substituted or unsubstituted naphthylmethylene, R' substituted or unsubstituted quinolylmethylene, R 'substituted or unsubstituted pyrazinylmethylene, R' substituted or unsubstituted pyrimidylmethylene, R 'substituted or unsubstituted pyrazolyl methylene, R' substituted or unsubstituted imidazolyl methylene, R 'substituted or unsubstituted furyl methylene or R' substituted or unsubstituted thienyl methylene, the invention combines the compounds 5, ethanol, sodium cyanoborohydride and R3-CO-R4Mixing, adjusting the pH value of the obtained system to 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-1;
the R is3And R4Independently hydrogen, C1-C5 alkyl, R 'substituted or unsubstituted phenyl, R' substituted or unsubstituted pyridyl, R 'substituted or unsubstituted naphthyl, R' substituted or unsubstituted quinolyl, R 'substituted or unsubstituted pyrazinyl, R' substituted or unsubstituted pyrimidyl, R 'substituted or unsubstituted pyrazolyl, R' substituted or unsubstituted imidazolyl, R 'substituted or unsubstituted furyl, or R' substituted or unsubstituted thienyl, and R3And R4Not hydrogen at the same time; or R3And R4Forming C4-C6 cyclane.
In the present invention, said R3-CO-R4Preferably formaldehyde, acetone, acetaldehyde, cyclobutanone, cyclopentanone, cyclohexanone, benzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde, 4-trifluoromethylbenzaldehyde, 4-nitrobenzaldehyde, 4-methoxybenzaldehyde, 4-trifluoromethoxybenzaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, 4-pyridineformaldehyde, thiophene-2-formaldehyde or 3-fluorobenzaldehyde. For convenience of operation, in the examples of the present invention, paraformaldehyde is specifically used.
In the present invention, the amounts of compound 5 and sodium cyanoborohydride are combined with ethanol and R3-CO-R4Is preferably 2.4 mmol: (9-10) mmol: (28-32) mL: (0.4 to 0.6) mL, more preferably 2.4 mmol: 9.6 mmol: 30mL of: 0.5 mL. In the present invention, the compound 5 and R3-CO-R4The method is characterized in that the method is a reactant, ethanol is a reaction solvent, and sodium cyanoborohydride is a reducing reagent.
In the present invention, the reagent used for adjusting the pH is preferably acetic acid; the amount of acetic acid used is not particularly limited, and the pH of the reaction system can be adjusted to 6.5 to 7.5. In the present invention, the pH of the reaction system is preferably 7.
In the invention, the temperature of the reductive amination reaction is preferably 15-40 ℃, and more preferably 20-30 ℃; in the examples of the present invention, the reductive amination reaction is carried out in particular at room temperature, i.e. without additional heating or cooling. In the invention, the time of the reductive amination reaction is preferably 3.5-4.5 h, and more preferably 4 h; the invention preferably detects the reaction progress through a thin layer to ensure the reaction is complete. In the present invention, the reductive amination reaction is preferably carried out under stirring conditions; the stirring rate is not particularly limited in the present invention, and a stirring rate known to those skilled in the art may be used.
After the reductive amination reaction is finished, the obtained system is preferably quenched at 0 ℃ by adopting 1mol/L NaOH solution, and H is added2Diluting with O, extracting with DCM, washing the organic phase with saturated saline, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate, and passing the residue through silica gelSeparating and purifying the column to obtain the compound 6-1. In the present invention, the eluent used for the separation and purification of the silica gel column is preferably dichloromethane, methanol and ammonia water, and the volume ratio of the dichloromethane to the methanol to the ammonia water is preferably 100:10: 1; the mass concentration of the ammonia water is preferably 25-28%.
When R in formula I1And R2Independently C1-C6 alkyl, C4-C6 cycloalkyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstituted naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethylene, R ' substituted or unsubstituted pyrimidylmethylene, R ' substituted or unsubstituted pyrazolyl methylene, R ' substituted or unsubstituted imidazolyl methylene, R ' substituted or unsubstituted furanylmethylene, or R ' substituted or unsubstituted thiophenylmethylene, this invention is directed to the reaction of Compound 6-1 with methanol, sodium cyanoborohydride, and R ' substituted or unsubstituted thiophenylmethylene3-CO-R4And mixing, adjusting the pH value of the obtained system to 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-2. In the present invention, the ratio of the reaction raw materials and the reaction parameters in the preparation of the compound 6-2 are preferably the same as those in the preparation of the compound 6-1, and will not be described herein again.
When R in formula I1Is hydroxybenzyl or hydrogen, R2In the case of hydroxybenzyl, the compound 5, ethanol, sodium cyanoborohydride and 4-acetoxybenzaldehyde are mixed, the pH value of the obtained system is adjusted to 6.5-7.5, and then reductive amination reaction is carried out to obtain a compound 6-3. In the present invention, the ratio of the reaction raw materials and the reaction parameters in the preparation of the compound 6-3 are preferably the same as those in the preparation of the compound 6-1, and will not be described herein again.
When R in formula I1Is hydrogen, R2When R 'is substituted or unsubstituted phenylcarbonyl, the compound 5, dichloromethane, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, triethylamine and R' substituted benzoic acid or benzoic acid are mixed for condensation reaction to obtain a compound 6-4. In the present invention, the compound 5, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazoleAnd the ratio of the amount of R' substituted benzoic acid or benzoic acid to the volume of dichloromethane and triethylamine is preferably 0.46 mmol: (0.55-0.65) mmol: (0.55-0.65) mmol: (0.55-0.65) mmol: (4.8-5.2) mL: (0.08 to 0.12) mL, more preferably 0.46 mmol: 0.6 mmol: 0.6 mmol: 0.6 mmol: 5mL of: 0.1 mL.
In the present invention, the R' substituted benzoic acid is preferably p-fluorobenzoic acid.
In the invention, the compound 5 and R' substituted benzoic acid or benzoic acid are reactants, the dichloromethane is a reaction solvent, and the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole and triethylamine are reagents required by a condensation reaction.
In the invention, the condensation reaction temperature is preferably 15-40 ℃, and more preferably 20-30 ℃; in the examples of the present invention, the condensation reaction is carried out in particular at room temperature, i.e. without additional heating or cooling. In the invention, the time of the condensation reaction is preferably 4.5-5.5 h, and more preferably 5 h. In the present invention, the condensation reaction is preferably carried out under stirring conditions; the stirring rate is not particularly limited in the present invention, and a stirring rate known to those skilled in the art may be used.
After the condensation reaction is completed, the present invention preferably concentrates the obtained system, and separates and purifies the residue with a silica gel column to obtain compound 6-4. In the present invention, the eluent used for the separation and purification of the silica gel column is preferably dichloromethane, methanol and ammonia water, and the volume ratio of the dichloromethane to the methanol to the ammonia water is preferably 100:10: 1; the mass concentration of the ammonia water is preferably 25-28%.
Mixing a compound 6 with dichloromethane, trifluoroacetic acid and water, and carrying out deprotection reaction to obtain a nucleoside compound with a structure shown in a formula I; the compound 6 comprises the compound 6-1, the compound 6-2, the compound 6-3 or the compound 6-4. In the present invention, the ratio of the mass of the compound 6 to the volume of dichloromethane, trifluoroacetic acid and water is preferably 50 mg: (4.5-5.5) mL: (1.8-2.2) mL: (0.08-0.12) mL, more preferably 50 mg: 5mL of: 2mL of: 0.1 mL.
In the present invention, the compound 6 is a reactant, the dichloromethane is a reaction solvent, the trifluoroacetic acid provides an acidic environment to remove protecting groups, and the water is used for hydrolysis.
In the invention, the temperature of the deprotection reaction is preferably 15-40 ℃, and more preferably 20-30 ℃; in the examples of the present invention, the condensation reaction is carried out in particular at room temperature, i.e. without additional heating or cooling. In the invention, the time for the deprotection reaction is preferably 50-70 min, and more preferably 60 min; the invention preferably detects the reaction progress through a thin layer to ensure the reaction is complete. In the present invention, the deprotection reaction is preferably carried out under stirring conditions; the stirring rate is not particularly limited in the present invention, and a stirring rate known to those skilled in the art may be used.
After the deprotection reaction is completed, the obtained system is preferably concentrated, and the residue is subjected to preparative thin chromatography to obtain the nucleoside compound with the structure shown in the formula I. In the present invention, the eluent used for the preparative thin layer chromatography is preferably dichloromethane, methanol and ammonia water, and the volume ratio of dichloromethane, methanol and ammonia water is preferably 700:100: 1; the mass concentration of the ammonia water is preferably 25-28%.
The invention provides a pharmaceutical composition for treating flavivirus infection, which comprises nucleoside compounds and a pharmaceutically acceptable carrier. In the invention, the mass content of the nucleoside compound in the pharmaceutical composition is preferably 0.1-99.9%, more preferably 1-90%, even more preferably 10-70%, and most preferably 30-50%.
In the present invention, the flavivirus preferably comprises Zika virus, dengue virus or West Roni virus, more preferably Zika virus.
The type of the pharmaceutically acceptable carrier in the present invention is not particularly limited, and any carrier known to those skilled in the art, such as magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, or cocoa butter, may be used.
The dosage form of the drug for treating flavivirus infection prepared by the drug composition is not particularly limited, and can be prepared by adopting dosage forms well known to those skilled in the art, such as tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules or powder.
The preparation method of the drug for treating flavivirus infection is not particularly limited, and the preparation method well known to those skilled in the art can be adopted according to different formulations.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- (isopropylamino) methyl) tetrahydrofuran-3, 4-diol (1a) the reaction scheme is as follows:
Figure BDA0001769251920000141
et was added to a solution of Compound 2(3g,9.2mmol) in ethanol (50mL) at room temperature3N (2.6mL,18.4mmol) and 3-chlorobenzylamine (2.1mL,18.4mmol), and the resulting mixture was stirred at 40 ℃ for 5 h; concentrated and the residue was purified by column chromatography over silica gel (DCM: MeOH: NH, vol.) (B/S)3·H2O200: 10:0.1) to give compound 3(3.13g, 82%) as a colorless oil, [ α ]]20 D＝-59.03(c 0.93,MeOH)；1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.79(s,1H),7.39(s,1H),7.30-7.28(m,3H),6.59(brs,1H),5.89(s,1H),5.24(t,J＝5.1Hz,1H),5.14(d,J＝5.5Hz,1H),4.89(brs,2H),4.58(s,1H),4.00(d,J＝12.6Hz,1H),3.84(d,J＝12.6Hz,1H),1.68(s,3H),1.42(s,3H)；LRMS(ESI):m/z＝454[M+Na]+。
To a solution of compound 3(1g,2.4mmol) in tetrahydrofuran (20mL) was added triphenylphosphine (1.26g,4.8mmol), diisopropyl azodicarboxylate (DIAD,0.94mL,4.8mmol) and phthalimide (0.53g,3.6mmol) at room temperature and stirred at the same temperature for 3 h; concentrated and the residue was purified by column chromatography over silica gel (DCM: MeOH: NH, vol.) (B/S)3·H2O200: 10:0.1) to give compound 4 as a brown oil, which was used directly in the next reaction.
Adding hydrazine hydrate (1mL) into an absolute ethyl alcohol (50mL) solution of the compound 4 at room temperature, and carrying out reflux reaction for 2 h; the resulting system was cooled to room temperature and filtered, the resulting filtrate was concentrated, and the residue was purified by silica gel column separation (DCM: MeOH: NH, in volume ratio)3·H2O100: 10:0.2) to give compound 5(680mg, 68%) as an oil, [ α ]]20 D＝-23.43(c 1.05,MeOH)；1HNMR(500MHz,CDCl3)δ8.44(s,1H),7.88(s,1H),7.40(s,1H),7.35-7.30(m,3H),6.34(brs,1H),6.06(d,J＝2.6Hz,1H),5.48-5.46(m,1H),5.16-5.14(m,1H),4.91(brs,2H),4.30(brs,1H),3.10-2.99(m,1H),1.64(s,3H),1.43(s,3H)；LRMS(ESI):m/z＝431[M+H]+.
Adding acetone (0.5mL) and sodium cyanoborohydride (0.6g,9.6mmol) into an ethanol (30mL) solution of the compound 5(1g,2.4mmol) at room temperature, adjusting the pH value of the obtained system to 7 by adopting acetic acid, stirring at the same temperature for 4 hours, and detecting the reaction to be complete by a thin layer; quenching with 1mol/L NaOH solution (10mL) at 0 deg.C, and adding H2Diluting with O (50mL), extracting with DCM (30 mL. times.3), washing the organic phase with saturated brine, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate, and separating and purifying the residue with silica gel column (by volume, DCM: MeOH: NH)3·H2O100: 10:1) to give compound 6a as an oil (850mg, 78%).
Trifluoroacetic acid (2mL) and water (0.1mL) were added to a solution of compound 6a (50mg) in dichloromethane (5mL) at room temperature, and the mixture was stirred at the same temperature for 1h, and the reaction was checked to completion by thin layer chromatography; concentrated and the residue chromatographed by preparative thin chromatography (DCM: MeOH: NH, vol.3·H2O700: 100:1) to give compound 1a (35mg, 78%), [ α ″]20 D＝-4.13(c 0.99,MeOH)；1H NMR(500MHz,MeOD)δ8.30(s,1H),8.26(s,1H),7.42(s,1H),7.33-7.26(m,3H),6.01(d,J＝3.8Hz,1H),4.85-4.83(m,2H),4.35(dd,J＝4.2,4.7Hz,1H),4.18-4.16(m,1H),3.20-3.04(m,3H),1.19-1.17(m,6H)；13C NMR(500MHz,MeOD)δ154.6,152.5,141.5,140.4,133.9,129.6,129.4,126.9,126.7,125.4,120.0,89.7,82.6,73.1,72.0,49.2,48.2,20.15,20.10；LRMS(ESI):m/z＝433[M+H]+。
Example 2
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((isopropyl (methyl) amino) methyl) tetrahydrofuran-3, 4-diol (1b) the reaction scheme is as follows:
Figure BDA0001769251920000151
compound 6a was prepared according to the procedure of example 1.
At room temperature, adding polyformaldehyde (15mg,0.5mmol) and sodium cyanoborohydride (131mg,2.1mmol) into a methanol (10mL) solution of a compound 6a (200mg,0.42mmol), adjusting the pH value of the obtained system to 7 by adopting acetic acid, stirring at the same temperature for 4 hours, and detecting the reaction completion by a thin layer; quenching with 1mol/L NaOH solution (2mL) at 0 deg.C, adding H2Diluting with O (10mL), extracting with DCM (10 mL. times.3), washing the organic phase with saturated brine, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate, and separating and purifying the residue with silica gel column (by volume, DCM: MeOH: NH)3·H2O100: 10:1) to give compound 6b as an oil.
Trifluoroacetic acid (2mL) and water (0.1mL) were added to a solution of compound 6b (50mg) in dichloromethane (5mL) at room temperature, and the mixture was stirred at the same temperature for 1h, and the reaction was checked to be complete by a thin layer; concentrated and the residue chromatographed by preparative thin chromatography (DCM: MeOH: NH, vol.3·H2O700: 100:1) to give compound 1b (40mg, 89%) as an oil, [ α ]]20 D＝-2.90(c 1.07,MeOH)；1H NMR(500MHz,CDCl3)δ8.27(s,1H),7.94(s,1H),7.40(s,1H),7.33-7.26(m,3H),5.91(d,J＝3.8Hz,1H),4.89(brs,2H),4.70-4.68(m,1H),4.54-4.50(m,1H),4.34-4.32(m,1H),3.04-3.01(m,2H),2.49-2.46(m,1H),1.92-1.62(m,6H),1.15-1.01(m,3H)；LRMS(ESI):m/z＝447[M+H]+。
Example 3
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- (ethylamino) methyl) tetrahydrofuran-3, 4-diol (1c) the reaction scheme is as follows:
Figure BDA0001769251920000161
compound 5 was prepared according to the procedure of example 1.
Adding acetaldehyde (0.1mL) and sodium cyanoborohydride (144mg,2.3mmol) into an ethanol (10mL) solution of the compound 5(200mg,0.46mmol) at room temperature, adjusting the pH value of the obtained system to 7 by using acetic acid, stirring at the same temperature for 4 hours, and detecting the reaction completion by a thin layer; quenching with 1mol/L NaOH solution (3mL) at 0 deg.C, and adding H2Diluting with O (20mL), extracting with DCM (15 mL. times.3), washing the organic phase with saturated brine, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate, and separating and purifying the residue with silica gel column (by volume, DCM: MeOH: NH)3·H2O100: 10:1) to give compound 6c (63mg, 30%) and compound 6d (130mg, 58%) as an oil.
Trifluoroacetic acid (2mL) and water (0.1mL) were added to a solution of compound 6c (50mg) in dichloromethane (5mL) at room temperature, and the mixture was stirred at the same temperature for 1h, and the reaction was checked to completion by thin layer chromatography; concentrated and the residue chromatographed by preparative thin chromatography (DCM: MeOH: NH, vol.3·H2O700: 100:1) to give compound 1c (36mg, 80%) as an oil, [ α ]]20 D＝-10.10(c 1.03,MeOH)；1H NMR(500MHz,CDCl3)δ8.28(s,1H),7.96(s,1H),7.41(s,1H),6.25(s,1H),5.91(s,1H),4.90(brs,2H),4.68(s,1H),4.50(s,1H),4.37(s,1H),3.00(brs,2H),2.75-2.71(m,2H),1.14-1.12(m,3H)；LRMS(ESI):m/z＝419[M+H]+。
Example 4
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- (diethylamino) methyl) tetrahydrofuran-3, 4-diol (1d), see example 3 for a reaction scheme:
Figure BDA0001769251920000171
trifluoroacetic acid (2mL) and water (0.1mL) were added to a solution of compound 6d (50mg) in dichloromethane (5mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour, and the reaction was checked to be complete by a thin layer; concentrated and the residue chromatographed by preparative thin chromatography (DCM: MeOH: NH, vol.3·H2O700: 100:1) to obtain compound 1d (30mg, 65%) as a white solid at mp 111-113 ℃ [ α ]]20 D＝2.57(c 1.01,MeOH)；1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.96(s,1H),7.41(s,1H),6.25(s,1H),5.97(s,1H),4.90(brs,2H),4.62-4.60(m,1H),4.58-4.56(m,1H),4.37-4.35(m,1H),2.96(brs,2H),2.81-2.75(m,4H),1.46(t,J＝6.9Hz,6H)；LRMS(ESI):m/z＝447[M+ H]+。
Example 5
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- (cyclobutylamino) methyl) tetrahydrofuran-3, 4-diol (1e) the reaction scheme is as follows:
Figure BDA0001769251920000172
at room temperature, cyclobutanone (0.1mL) and sodium cyanoborohydride (144mg,2.3mmol) are added into an ethanol (10mL) solution of the compound 5(200mg,0.46mmol), the pH value of the obtained system is adjusted to 7 by adopting acetic acid, the mixture is stirred at the same temperature for 4 hours, and the thin layer detection reaction is complete; quenching with 1mol/L NaOH solution (3mL) at 0 deg.C, and adding H2Diluting with O (20mL), extracting with DCM (15 mL. times.3), washing the organic phase with saturated brine, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate, and separating and purifying the residue with silica gel column (by volume, DCM: MeOH: NH)3·H2O100: 10:1) to give compound 6e (63mg, 30%) as an oil.
Trifluoroacetic acid (2mL) and water (0.1mL) were added to a solution of compound 6e (50mg) in dichloromethane (5mL) at room temperature, and the mixture was stirred at the same temperature for 1h, and the reaction was checked to be complete by a thin layer; concentrated and the residue chromatographed by preparative thin chromatography (DCM: MeOH: NH, vol.3·H2O700: 100:1) to yieldWhite solid compound 1e (33mg, 71%), mp 95-97 deg.C, [ α ]]20 D＝-12.23(c 1.48,MeOH)；1H NMR(500MHz,CDCl3)δ8.22(s,1H),7.94(s,1H),7.41(s,1H),6.42(s,1H),5.88(d,J＝5.4Hz,1H),4.89(brs,2H),4.74-4.73(m,1H),4.48-4.46(m,1H),4.37-4.35(m,1H),3.29-3.25(m,1H),2.89(s,2H),2.21-2.17(m,2H),1.73-1.71(m,4H)；13C NMR(500MHz,CDCl3)δ152.48,139.19,134.59,129.97,127.17,127.68,125.72,90.33,84.40,74.25,72.13,53.94,50.83,48.27,30.27,14.67；LRMS(ESI):m/z＝445[M+H]+。
Example 6
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- (cyclopentylamino) methyl) tetrahydrofuran-3, 4-diol (1 f):
Figure BDA0001769251920000181
the preparation method is the same as example 5, except that cyclopentanone is used instead of cyclobutanone to obtain white solid compound 1f with yield of 67%, mp 88-90 ℃ [ α ]]20 D＝-6.27(c 1.18,MeOH)；1H NMR(500MHz,CDCl3)δ8.15(s,1H),7.89(s,1H),7.40(s,1H),7.32-7.30(m,3H),6.46(s,1H),5.88(d,J＝5.4Hz,1H),4.88(brs,2H),4.79-4.77(m,1H),4.54(s,1H),4.36-4.34(m,1H),3.10-2.95(m,3H),1.84-1.80(m,2H),1.64-1.60(m,2H),1.52-1.50(m,2H),1.30-1.28(m,2H)；13C NMR(500MHz,CDCl3)δ152.65,140.45,139.24,134.58,129.98,127.72,127.69,125.74,90.39,84.09,74.34,71.87,60.09,49.76,32.33,24.05,24.03；LRMS(ESI):m/z＝459[M+H]+。
Example 7
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- (cyclohexylamino) methyl) tetrahydrofuran-3, 4-diol (1 g):
Figure BDA0001769251920000182
the preparation process is the same as example 5, except that cyclohexanone is used instead of cyclobutanKetone to obtain 1g of a white solid compound in a yield of 67%, mp 102-104 ℃ [ α ]]20 D＝-7.76(c 0.98,MeOH)；1H NMR(500MHz,CDCl3)δ8.37(s,1H),7.99(s,1H),7.40(s,1H),7.32-7.30(m,3H),6.46(s,1H),5.98(d,J＝5.4Hz,1H),4.88(brs,2H),4.63-4.61(m,1H),4.46(s,1H),4.36-4.34(m,1H),3.03-3.00(m,1H),2.84(s,2H),1.29-1.26(m,4H),1.11-1.06(m,6H)；13C NMR(500MHz,CDCl3)δ154.63,152.72,140.45,139.14,134.57,129.97,127.70,127.68,125.71,120.54,90.32,84.27,74.42,72.03,57.36,50.78,48.17,32.78,32.52,24.91,24.87；LRMS(ESI):m/z＝473[M+H]+。
Example 8
Preparation of (2R,3S,4R,5R) -2- ((benzylamine) methyl) -5- (6- (3-chlorobenzylamine) -9H-purin-9-yl) tetrahydrofuran-3, 4-diol (1H):
Figure BDA0001769251920000191
the preparation method is the same as example 5, except that benzaldehyde is used instead of cyclobutanone to obtain oily compound for 1h, the yield is 67%, [ α ]]20 D＝-15.15(c 0.99,MeOH)；1H NMR(500MHz,CDCl3)δ8.15(s,1H),7.87(s,1H),7.40(s,1H),7.34-7.27(m,8H),6.42(s,1H),5.86(d,J＝5.4Hz,1H),4.85(brs,2H),4.72-4.69(m,1H),4.44-4.41(m,1H),4.37-4.34(m,1H),3.84(s,2H),3.01-2.89(m,2H)；13CNMR(500MHz,CDCl3)δ154.64,152.82,140.50,138.92,138.74,134.48,129.90,128.55,128.20,127.66,127.59,127.37,125.70,90.17,84.20,74.43,71.92,53.88,50.46,27.21；LRMS(ESI):m/z＝479[M+H]+。
Example 9
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-fluorobenzylamino) methyl) tetrahydrofuran-3, 4-diol (1i):
Figure BDA0001769251920000192
the preparation process is as in example 5, except that 4-fluorobenzaldehyde is usedReplacing cyclobutanone to obtain a white solid compound 1i, mp 89-91 ℃ [ α ]]20 D＝-12.54(c 1.22,MeOH)，1HNMR(500MHz,MeOD)δ8.05(s,1H),7.76(s,1H),7.25(s,1H),7.16-1.14(m,5H),6.89(t,J＝8.5Hz,2H),6.20(brs,1H),5.73(d,J＝5.8Hz,1H),4.73(brs,2H),4.57(t,J＝5.4Hz,1H),4.31(brs,1H),4.26(brs,1H),3.68(s,2H),2.85(dd,J＝12.5,3.8Hz,1H),2.75(dd,J＝12.5,4.5Hz)；13C NMR(500MHz,CDCl3)δ162.10(d,J＝242.5Hz),154.30,152.65,140.37,138.70,134.59,129.98,129.66(d,J＝7.9Hz),127.75,125.73,125.73,115.38,115.24,90.35,85.43,75.03,72.66,53.12,50.53,29.70；LRMS(ESI):m/z＝499[M+H]+。
Example 10
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-chlorobenzylamino) methyl) tetrahydrofuran-3, 4-diol (1j):
Figure BDA0001769251920000201
the preparation method is the same as example 5, except that 4-chlorobenzaldehyde is used instead of cyclobutanone to obtain oily compound 1j with the yield of 70% [ α ]]20 D＝-13.62(c 1.52,MeOH)，1H NMR(500MHz,MeOD)δ8.21(s,1H),8.12(s,1H),7.43(s,1H),7.34-7.29(m,3H),7.21(d,J＝7.5Hz,2H),7.14(d,J＝7.5Hz,2H),4.88(brs,1H),4.34(brs,1H),4.26(brs,1H),3.83(s,2H),3.02(s,2H),2.34(s,2H)；13CNMR(500MHz,CDCl3)δ153.47,151.47,139.41,137.11,135.54,133.52,132.21,131.77,128.91,126.66,126.61,126.58,125.99,125.06,124.69,89.24,83.50,74.18,72.21,58.51,54.37,28.75.LRMS(ESI):m/z＝515[M+H]+。
Example 11
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-bromobenzylamino) methyl) tetrahydrofuran-3, 4-diol (1k):
Figure BDA0001769251920000202
the preparation method is the same as that in the example5, the difference lies in that 4-bromobenzaldehyde is used to replace cyclobutanone to obtain a white solid compound 1k with a yield of 60 percent and a temperature of mp 84-86 ℃ [ α ]]20 D＝-25.84(c 0.98,MeOH)，1H NMR(500MHz,CDCl3)δ8.21(brs,1H),7.89(brs,1H),7.45(d,J＝8.0Hz,2H),7.39(s,1H),7.28(brs,3H),7.20(d,J＝7.93Hz,1H),6.42(brs,1H),5.87(d,J＝5.8Hz,1H),4.87(brs,2H),4.72(t,J＝5.5Hz,1H),4.43(s,1H),4.38(s,1H),3.80(s,2H),2.97(dd,J＝12.5,4.0Hz,1H),2.87(dd,J＝12.5,4.8Hz,1H)；13C NMR(500MHz,CDCl3)δ154.62,152.71,140.39,138.84,138.42,134.56,131.57,129.97,129.78,127.73,127.70,125.74,121.01,90.19,85.24,74.69,72.53,53.15,50.53,29.71。LRMS(ESI):m/z＝560[M+H]+。
Example 12
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-trifluoromethylbenzylamino) methyl) tetrahydrofuran-3, 4-diol (1l):
Figure BDA0001769251920000203
the preparation method is the same as example 5, except that 4-trifluoromethylbenzaldehyde is used instead of cyclobutanone to obtain 1l of white solid compound with the yield of 55%, mp 80-82 ℃ [ α ]]20 D＝-17.73(c 1.25,MeOH)；1H NMR(500MHz,CDCl3)δ8.26(s,1H),7.94(s,1H),7.62(d,J＝7.8Hz,2H),7.47(d,J＝7.8Hz,2H),7.41(s,1H),7.30-7.28(m,3H),6.23(brs,1H),5.90(d,J＝5.8Hz,1H),4.90(brs,1H),4.59(brs,1H),4.47-4.44(m,2H),3.95(s,2H),3.03-2.93(m,2H)；LRMS(ESI):m/z＝549[M+H]+。
Example 13
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-nitrobenzylamino) methyl) tetrahydrofuran-3, 4-diol (1m):
Figure BDA0001769251920000211
the preparation process is as in example 5, except that 4-nitro group is usedBenzaldehyde replaces cyclobutanone to obtain a white solid compound with the yield of 1m, the yield of 65 percent, the temperature of mp 84-86 ℃, and the temperature of α ℃]20 D＝-24.08(c1.07,MeOH)，1H NMR(500MHz,MeOD)δ8.20(s,1H),8.19(d,J＝8.6Hz,2H),7.89(s,1H),7.52(d,J＝8.6Hz,2H),7.40(s,1H),7.31-7.29(m,3H),6.42(brs,1H),5.87(d,J＝5.8Hz,1H),4.87(brs,2H),4.79-4.76(m,1H),4.47(brs,1H),4.42(brs,1H),3.87(d,J＝7.2Hz,2H),3.03(dd,J＝12.6,3.5Hz,1H),2.90(dd,J＝12.6,4.7Hz,1H)；13C NMR(500MHz,CDCl3)δ154.65,152.67,147.47,147.14,138.87,134.57,129.99,128.56,127.76,127.67,125.75,123.68,90.24,85.43,74.61,72.56,53.08,50.76,29.33.LRMS(ESI):m/z＝526[M+H]+。
Example 14
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-methoxybenzylamino) methyl) tetrahydrofuran-3, 4-diol (1n):
Figure BDA0001769251920000212
the preparation method was the same as example 5 except that 4-methoxybenzaldehyde was used instead of cyclobutanone to obtain the oily compound 1n in 65% yield [ α ]]20 D＝-15.95(c 1.11,MeOH)，1HNMR(500MHz,CDCl3)δ8.13(s,1H),7.90(s,1H),7.40(s,1H),7.29-7.25(m,5H),6.87(d,J＝7.8Hz,2H),6.42(brs,1H),5.90(d,J＝5.8Hz,1H),4.87(brs,1H),4.67(brs,1H),4.50(brs,1H),4.38(brs,1H),3.87-3.80(m,5H),3.00(br,2H)；13C NMR(500MHz,CDCl3)δ159.05,152.71,140.46,138.95,134.54,129.95,129.61,127.71,127.69,125.74,114.01,90.30,84.44,74.79,72.17,55.29,53.09,50.10,29.71；LRMS(ESI):m/z＝511[M+H]+。
Example 15
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-trifluoromethoxybenzylamino) methyl) tetrahydrofuran-3, 4-diol (1o):
Figure BDA0001769251920000221
the preparation method was the same as example 5 except that 4-trifluoromethoxybenzaldehyde was used instead of cyclobutanone to obtain 1o, an oily compound in 50% yield [ α ]]20 D＝-14.41(c 1.45,MeOH)，1H NMR(500MHz,MeOD)δ8.24(s,1H),8.15(s,1H),7.45(d,J＝8.2Hz,2H),7.42(s,1H),7.33-7.23(m,5H),5.99(d,J＝5.3Hz,1H),4.84(brs,3H),4.38-4.36(m,1H),4.28-4.26(m,1H),3.90(s,2H),3.02(s,2H)；13C NMR(500MHz,CDCl3)δ154.23,152.67,148.41,140.38,138.88,134.55,129.96,129.50,127.72,127.69,125.74,121.30,119.60,90.23,84.99,74.70,72.40,52.94,50.46,29.79；LRMS(ESI):m/z＝565[M+H]+。
Example 16
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-hydroxybenzylamino) methyl) tetrahydrofuran-3, 4-diol (1p):
Figure BDA0001769251920000222
the preparation method is the same as example 5, except that 4-acetoxybenzaldehyde is used instead of cyclobutanone to obtain white solid compound 1p with yield of 50%, mp 84-85 deg.C, [ α ]]20 D＝-5.71(c 1.53,MeOH)，1H NMR(500MHz,MeOD)δ8.21(s,1H),8.13(s,1H),7.41(s,1H),7.34-7.28(m,5H),6.84(d,J＝7.9Hz,2H),6.04(d,J＝4.7Hz,1H),4.84-4.82(m,3H),4.47-4.43(m,1H),4.40-4.38(m,1H),4.25-4.16(m,2H),3.64-3.60(m,1H),3.47-3.38(m,1H)；13C NMR(500MHz,MeOD)δ158.67,152.54,140.58,133.96,131.28,129.64,126.97,126.82,125.43,121.09,115.56,90.61,79.98,73.08,71.90,50.83,48.45,29.42；LRMS(ESI):m/z＝497[M+H]+。
Example 17
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- (((naphthyridin-1-methyl) amino) methyl) tetrahydrofuran-3, 4-diol (1q):
Figure BDA0001769251920000231
the preparation method is the same as example 5, except that 1-naphthaldehyde is used to replace cyclobutanone to obtain a white solid compound 1q, the yield is 64%, mp 94-95 ℃, [ α ℃]20 D＝-19.44(c 1.25,MeOH)，1H NMR(500MHz,CDCl3)δ8.02-7.99(m,2H),7.77(m,3H),7.49(d,J＝6.8Hz,1H),4.46-7.37(m,4H),7.28-7.25(m,3H),6.45(brs,1H),5.86(d,J＝5.8Hz,1H),4.81(brs,1H),4.63(s,1H),4.46(brs,1H),4.37(s,1H),4.31(s,2H),3.10(s,2H)；LRMS(ESI):m/z＝531[M+H]+。
Example 18
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- (((naphthyridin-2-methyl) amino) methyl) tetrahydrofuran-3, 4-diol (1R):
Figure BDA0001769251920000232
the preparation method is the same as example 5, except that 2-naphthaldehyde is used to replace cyclobutanone to obtain a white solid compound 1r with a yield of 45 percent, mp 77-78 ℃, [ α ℃]20 D＝-28.68(c 1.52,MeOH)，1H NMR(500MHz,CDCl3)δ8.20(s,1H),7.88(s,1H),7.82-7.78(m,3H),7.71(s,1H),7.47-7.45(m,2H),7.42(d,J＝8.3Hz,1H),7.37(s,1H),7.24(brs,3H),6.52(s,1H),5.87(d,J＝5.5Hz,1H),4.82(brs,1H),4.71-4.69(m,1H),4.42(brs,1H),4.36(brs,1H),3.98(brs,2H),3.00-2.98(m,1H),2.92-2.89(m,1H)；13C NMR(500MHz,CDCl3)δ154.56,152.77,140.45,138.85,137.07,134.51,133.33,132.67,129.93,128.21,127.66,126.55,126.30,126.12,125.69,120.16,90.05,85.16,74.64,72.53,53.99,50.67,29.71.LRMS(ESI):m/z＝531[M+H]+。
Example 19
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((pyridin-4-ylmethyl) amino) methyl) tetrahydrofuran-3, 4-diol (1S):
Figure BDA0001769251920000241
the preparation method is carried out at the same timeExample 5, except that 4-pyridylaldehyde was used in place of cyclobutanone to obtain a white solid compound in a yield of 73% at mp 89-91 ℃ [ α ]]20 D＝-17.00(c 1.31,MeOH)，1HNMR(500MHz,CDCl3)δ8.47(d,J＝4.8Hz,2H),8.15(s,1H),7.90(s,1H),7.39(s,1H),7.30-7.28(m,5H),6.35(brs,1H),5.90(d,J＝6.1Hz,1H),4.90-4.87(m,3H),4.51(brs,1H),4.41(brs,1H),3.93-3.83(m,2H),3.04(dd,J＝12.6,3.0Hz,1H),2.89(dd,J＝12.6,4.2Hz,1H)；13C NMR(500MHz,CDCl3)δ154.60,152.67,149.45,139.28,134.57,129.98,127.73,127.69,125.72,123.04,90.23,85.27,74.05,72.38,52.47,50.76,29.71；LRMS(ESI):m/z＝482[M+H]+。
Example 20
Preparation of (2R,3R,4S,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((thien-2-ylmethyl) amino) methyl) tetrahydrofuran-3, 4-diol (1t):
Figure BDA0001769251920000242
the preparation method is the same as example 5, except that thiophene-2-formaldehyde is used to replace cyclobutanone to obtain a white solid compound 1t with a yield of 65%, mp 81-82 ℃ [ α ]]20 D＝-12.47(c 1.24,MeOH)，1H NMR(500MHz,CDCl3)δ8.14(s,1H),7.88(s,1H),7.39(s,1H),7.27(s,2H),7.21(d,J＝4.5Hz,1H),6.95-6.94(m,1H),6.53(brs,1H),5.89(d,J＝5.6Hz,1H),4.86(brs,1H),4.75-4.73(m,1H),4.45(brs,1H),4.36(brs,1H),4.04(s,2H),3.03(dd,J＝12.6,3.4Hz,1H),2.94(dd,J＝12.6,4.3Hz,1H)；13C NMR(500MHz,CDCl3)δ154.57,152.75,142.80,140.46,138.96,134.52,129.95,127.68,126.75,125.73,125.47,124.87,120.18,90.06,84.92,74.55,72.36,50.19,48.36,29.71；LRMS(ESI):m/z＝487[M+H]+。
Example 21
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((3-fluorobenzylamino) methyl) tetrahydrofuran-3, 4-diol (1u):
Figure BDA0001769251920000251
the preparation method was the same as example 5, except that 3-fluorobenzaldehyde was used instead of cyclobutanone to obtain 1u as an oily compound in 52% yield [ α ]]20 D＝-16.57(c 2.5,DCM)，1H NMR(500MHz,MeoD)δ8.22(s,1H),8.13(s,1H),7.42(s,1H)7.30(brs,4H)7.15(m,2H)7.00(t,J＝5.0Hz,1H)5.98(d,1H)4.84(brs,1H)4.43(s,1H)4.27(s,1H)3.89(s,2H)3.35(s,2H)3.02(dd,2H).LRMS(ESI):m/z＝499[M+H]+。
Example 22
Preparation of N- (((2R,3S,4R,5R) -5- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -3, 4-dihydrotetrahydrofuran-2-yl) methyl-4-fluorobenzamide (1v), the reaction scheme is as follows:
Figure BDA0001769251920000252
to a solution of compound 5(200mg,0.46mmol) in dichloromethane (5mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC,93mg,0.6mmol), 1-hydroxybenzotriazole (HOBt,92mg,0.6mmol), triethylamine (0.1mL), and p-fluorobenzoic acid (84mg,0.6mmol) at room temperature, and stirred at the same temperature for 5 h; concentrated and the residue chromatographed over silica gel (by volume, DCM: MeOH: NH)3·H2O100: 10:1) to give compound 6v (130mg, 50%) as an oil.
Trifluoroacetic acid (2mL) and water (0.1mL) were added to a solution of compound 6v (50mg) in dichloromethane (5mL) at room temperature, and the mixture was stirred at the same temperature for 1h, and the reaction was checked to be complete by a thin layer; concentrated and the residue chromatographed by preparative thin chromatography (DCM: MeOH: NH, vol.3·H2O700: 100:1) to obtain 1v (23mg, 50%) as a white solid compound, mp 118-119 ℃ [ α ]]20 D＝-51.43(c0.56,DMF)，1H NMR(500MHz,CDCl3)δ8.26(s,1H),8.00(s,1H),7.90-7.87(m,2H),7.42(s,1H),7.34-7.20(m,3H),7.22-7.18(m,2H),5.98(d,J＝5.3Hz,1H),4.83(brs,3H),4.42(brs,1H),4.33-4.31(m,1H),3.87(dd,J＝14.2,4.6Hz,1H),3.70(dd,J＝14.2,3.7Hz,1H).LRMS(ESI):m/z＝513[M+H]+。
Example 23
Preparation of (2R,3S,4R,5R) -2- (6- (3-chlorobenzylamine) -9H-purin-9-yl) -5- ((4-fluorobenzylamino) methyl) tetrahydrofuran-3, 4-diol (1w) the reaction scheme is as follows:
Figure BDA0001769251920000261
intermediate compound 6i was prepared according to the procedure of example 9.
The preparation method was the same as example 2, except that the compound 6i was used in place of the compound 6a to obtain 1w as a white solid in a yield of 65%, mp 79-81 ℃ [ α ]]20 D＝-20.74(c 1.26,MeOH)，1H NMR(500MHz,MeOD)δ8.24(s,1H),8.16(s,1H),7.41(s,1H),7.34-7.30(m,4H),7.27-7.25(m,1H),6.98(t,J＝8.8Hz,2H),4.69(brs,2H),4.28-4.24(m,2H),3.60W(s,2H),2.82-2.78(m,2H),2.30(s,3H)；LRMS(ESI):m/z＝513[M+H]+。
Example 24
In vitro anti-zika virus activity tests were performed on the target compounds 1a to 1w prepared in examples 1 to 23, specifically, using vero cells as zika virus vectors, the inhibitory activity and cytotoxicity of the target compounds against zika virus were measured, and the results were compared with cinofenin and NITD008, and are shown in table 1.
TABLE 1 data of in vitro Activity test of target Compounds 1a to 1w against Zika Virus
Figure BDA0001769251920000262
Figure BDA0001769251920000271
As can be seen from Table 1, the compound provided by the invention has better anti-Zika virus activity, and is worthy of being further developed and prepared into a medicament for treating flavivirus infection.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A nucleoside compound has a structure shown in formula I:
Figure FDA0002343967240000011
in the formula I, Ar is halogen substituted phenyl;
R1and R2Independently hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, hydroxybenzyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted phenylcarbonyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstituted naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethylene, R ' substituted or unsubstituted pyrimidylmethylene, R ' substituted or unsubstituted pyrazolylmethylene, R ' substituted or unsubstituted imidazolylmethylene, R ' substituted or unsubstituted furanylmethylene, or R ' substituted or unsubstituted thienylmethylene, and R1And R2Not simultaneously being R' substituted or unsubstituted phenylcarbonyl, and R1And R2Not hydrogen at the same time;
r' is independently C1-C4 alkyl, C1-C3 alkoxy, halogen group, -CF3、-OCF3、-NO2or-CN.
2. The nucleoside compound according to claim 1, wherein the alkyl group having 1-6 is methyl, ethyl, isopropyl, n-butyl or tert-butyl.
3. The nucleoside compound according to claim 1, wherein the cycloalkyl group having 4-6 is cyclohexyl, cyclopentyl or cyclobutyl.
4. The nucleoside compound according to claim 1, wherein the halogen group is-F, -Cl or-Br.
5. The nucleoside compound according to any one of claims 1 to 4, wherein the nucleoside compound is
Figure FDA0002343967240000012
Figure FDA0002343967240000013
Figure FDA0002343967240000021
6. A process for preparing nucleosides as claimed in any one of claims 1 to 5, comprising the steps of:
(1) mixing the compound 2, ethanol, triethylamine and Ar-CH2NH2Mixing, and carrying out nucleophilic substitution reaction to obtain a compound 3; the compound 2 has the structure shown in formula II:
Figure FDA0002343967240000032
(2) mixing the compound 3, tetrahydrofuran, triphenylphosphine, diisopropyl azodicarboxylate and phthalimide, and carrying out a mitsunobu reaction to obtain a compound 4;
(3) mixing the compound 4, ethanol and hydrazine hydrate, and carrying out hydrazinolysis reaction to obtain a compound 5;
(41) when R in formula I1Is hydrogen, R2Is C1-C6 alkyl, C4-C6 cycloalkyl, R ' substituted or unsubstituted benzyl, R ' substituted or unsubstituted pyridylmethylene, R ' substituted or unsubstituted naphthylmethylene, R ' substituted or unsubstituted quinolylmethylene, R ' substituted or unsubstituted pyrazinylmethyleneWhen substituted pyrimidinylmethylene, R 'substituted or unsubstituted pyrazolylmethylene, R' substituted or unsubstituted imidazolylmethylene, R 'substituted or unsubstituted furanylmethylene, or R' substituted or unsubstituted thiophenylmethylene, the compound 5, ethanol, sodium cyanoborohydride, and R3-CO-R4Mixing, adjusting the pH value of the obtained system to 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-1;
the R is3And R4Independently hydrogen, C1-C5 alkyl, R 'substituted or unsubstituted phenyl, R' substituted or unsubstituted pyridyl, R 'substituted or unsubstituted naphthyl, R' substituted or unsubstituted quinolyl, R 'substituted or unsubstituted pyrazinyl, R' substituted or unsubstituted pyrimidyl, R 'substituted or unsubstituted pyrazolyl, R' substituted or unsubstituted imidazolyl, R 'substituted or unsubstituted furyl, or R' substituted or unsubstituted thienyl, and R3And R4Not hydrogen at the same time; or R3And R4Form a C4-C6 cycloalkyl;
(42) when R in formula I1And R2Independently C1-C6 alkyl, C4-C6 cycloalkyl, R 'substituted or unsubstituted benzyl, R' substituted or unsubstituted pyridylmethylene, R 'substituted or unsubstituted naphthylmethylene, R' substituted or unsubstituted quinolylmethylene, R 'substituted or unsubstituted pyrazinylmethylene, R' substituted or unsubstituted pyrimidylmethylene, R 'substituted or unsubstituted pyrazolyl methylene, R' substituted or unsubstituted imidazolyl methylene, R 'substituted or unsubstituted furanylmethylene, or R' substituted or unsubstituted thienylmethylene, Compound 6-1 with methanol, sodium cyanoborohydride, and R3-CO-R4Mixing, adjusting the pH value of the obtained system to 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-2;
(43) when R in formula I1Is hydroxybenzyl or hydrogen, R2When the compound is hydroxybenzyl, mixing the compound 5, ethanol, sodium cyanoborohydride and 4-acetoxybenzaldehyde, adjusting the pH value of the obtained system to be 6.5-7.5, and then carrying out reductive amination reaction to obtain a compound 6-3;
(44) when R in formula I1Is hydrogen, R2Is R' substituted orWhen the phenylcarbonyl is not substituted, mixing the compound 5, dichloromethane, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, triethylamine and R' substituted benzoic acid or benzoic acid, and carrying out condensation reaction to obtain a compound 6-4;
(5) mixing the compound 6 with dichloromethane, trifluoroacetic acid and water, and carrying out deprotection reaction to obtain a nucleoside compound with a structure shown in a formula I; the compound 6 comprises the compound 6-1, the compound 6-2, the compound 6-3 or the compound 6-4.
7. The method according to claim 6, wherein the reagent used for adjusting the pH in the steps (41), (42) and (43) is acetic acid.
8. A pharmaceutical composition for treating a flavivirus infection comprising a nucleoside compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition as claimed in claim 8, wherein the nucleoside compound is contained in the pharmaceutical composition in an amount of 0.1 to 99.9% by mass.
10. The pharmaceutical composition of claim 8 or 9, wherein the flavivirus is Zika virus, dengue virus or West Roni virus.
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