CN108484705B - Cinefungin analogue and preparation method thereof - Google Patents
Cinefungin analogue and preparation method thereof Download PDFInfo
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
The invention relates to a cinofenide analogue shown in a formula (I), a preparation method and medical application thereof, and an anti-flavivirus pharmaceutical composition taking the same as an effective component. More particularly, the invention relates to a class of analogs of cinofungin in which Ar represents a substituted phenyl, pyridyl, naphthyl, quinolyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, furyl or thienyl group, and W represents t-butyl, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-cyanophenyl, pyridyl, naphthyl, quinolyl, pyrazinyl, pyrimidinyl, pyrazolyl, Imidazolyl, furyl or thienyl.
Description
Technical Field
The invention belongs to the field of medical chemistry, and relates to nucleoside compounds with anti-flavivirus activity, a preparation method thereof and an anti-flavivirus pharmaceutical composition containing the nucleoside compounds.
Background
Flaviviruses are a class of arboviruses that are primarily transmitted by vectors such as mosquitoes, ticks, and the like. Among them, there are more than 70 kinds of viruses such as Zika virus, dengue virus 1-4(DENV 1-4), Yellow Fever Virus (YFV), West Roni virus (WNV), tick-borne encephalitis virus (TBEV), and Japanese Encephalitis Virus (JEV). 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. However, there is no drug for overcoming flavivirus infection in clinic, so the search for effective drugs for treating flavivirus infection is significant and urgent.
XinaifenThe net (Sinefungine, SIN) is a natural product isolated by the present company in 1973 from the fermentation broth of Streptomyces NRL 3739, and is structurally similar to the in vivo methylation donor SAM, and can be regarded as a SAM derivative in which the methylthio moiety of the methylation donor SAM is replaced by an aminomethyl group. Relevant pharmacological studies show that SIN can widely act on methyltransferases of prokaryotes and eukaryotes, is a SAM competitive inhibitor and has various biological activities such as antifungal activity, antiviral activity, antitumor activity and the like. Recently, Hongming and Ghosh have reported that SIN can act on flavivirus methyltransferase, and is effective on WNV, YFV and DENV-2. Methylation activity assay showed that SIN methylated IC to WNV and DENV-22' -O and N-7500.7-14 μm; antiviral Activity showed EC of SIN against WNV, DENV-2 and YFV5027-250 μm, see Table 1.
TABLE 1 SIN structures and their anti-flavivirus activity
The inventors designed and synthesized a series of analogs of cinafungin of formula I and evaluated their anti-zika virus activity. Finally, part of the compounds of the invention are found to have excellent anti-Zika virus activity, and compared with the natural product of cinofungin, the anti-Zika virus activity is superior. The activity of the compound on dengue fever virus and west Roy virus is being further evaluated.
Disclosure of Invention
1. The invention aims to provide a compound shown in a general formula (I),
wherein:
ar represents a substituted phenyl (not containing phenyl), pyridyl, naphthyl, quinolyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, furyl or thienyl group, and optionally, a hydrogen atom at any position of these groups may be substituted by an R group;
the R group is selected from: alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 3 carbon atoms, halogen, -CF3, -OCF3, -NO2 or-CN.
Wherein W represents methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, cyclopentyl, cyclobutyl, phenyl, pyridyl;
when the W group is a phenyl group, the hydrogen atom at any position thereof may be substituted with oxy, halogen, -CF3, -OCF3, -NO2 or-CN.
Specific compounds of the invention are:
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-fluorophenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methoxyphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-tert-butylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-trifluoromethylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (3-trifluoromethylphenyl) urea
1- (tert-butyl) -3- (3- (((((2R, 3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea
1- (cyclohexyl) -3- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-fluorophenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methoxyphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-tert-butylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-trifluoromethylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (3-trifluoromethylphenyl) urea
1- (tert-butyl) -3- (3- (((((2R, 3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea
1- (cyclohexyl) -3- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea
2. The invention further provides a preparation method of the compound shown in the formula (I), and the synthetic route is as follows:
Reagents and conditions：a)amines，Et3N，EtOH，reflux；b)DIAD，phthalimide，Ph3PTHF，rt；c)85％NH2NH2.H2O，EtOH，reflux；d)NaCNBH3，acetone，AcOH，MeOH，rt；e)Methylacrylate，MeOH，microwave，80℃；f)LiAlH4，THF，0℃；g)isocyanate，DCM；h)TFA，DCM
a compound 2 which is commercially available is taken as a starting material and undergoes nucleophilic substitution reaction with amine to prepare a compound 3; then, preparing a compound 5 through a mitsunobu reaction and a hydrazinolysis reaction; compound 6, which is obtained by reductive amination reaction of compound 5 and acetone; reacting the compound 6 with methyl acrylate under the microwave condition to obtain a compound 7; reducing the compound 7 by lithium aluminum hydride to obtain a hydroxyl compound 8; carrying out a mitsunobu reaction and a hydrazinolysis reaction on the compound 8 to obtain a compound 9; reacting the compound 9 with isocyanate to obtain a compound 10; finally, the compound 10 is hydrolyzed under the condition of trifluoroacetic acid to remove propylidene protection to obtain the target compound 1.
3. The present invention also provides an anti-flavivirus composition comprising as an active ingredient a compound of formula (I) as defined above. The pharmaceutical composition contains 0.1-99.9% of the compound and 0.1-99.9% of the pharmaceutically acceptable carrier. The pharmaceutical composition is in the form of a formulation suitable for pharmaceutical use. The pharmaceutical composition of the invention can be prepared into any pharmaceutically acceptable dosage form. Preferably, the pharmaceutical preparation is a tablet, a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a capsule, a hard capsule, a soft capsule, a sustained-release capsule, or a powder.
The pharmaceutical composition of the present invention is in the form of a preparation, wherein each preparation contains 0.1-1000 mg of the compound of the present invention, and each preparation unit, such as each tablet of a tablet, each capsule, or each dose, such as 100mg per dose.
The pharmaceutical composition of the present invention may be prepared into solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, using a solid carrier. The solid carrier which may be used is preferably one or more substances selected from diluents, flavouring agents, solubilising agents, lubricants, suspending agents, binders, bulking agents and the like, or may be an encapsulating substance. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets, capsules and the like represent the most advantageous oral solid dosage forms.
It is particularly advantageous to formulate the above pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of a formulation refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect. Such dosage unit forms may be in the form of a pack, such as a tablet, capsule or powder in a small tube or vial.
Although the amount of active ingredient contained in the dosage unit form may vary, it is generally adjusted within the range of 1 to 800mg, depending on the potency of the active ingredient selected.
4. When the active compounds of formula (I) of the present invention are used to treat flavivirus infections, including Zika virus, dengue virus, and West Rony virus.
Detailed Description
In the following examples, the present invention will be explained more specifically. It is to be understood, however, that the following examples are intended to illustrate the present invention without limiting the scope of the present invention in any way.
Example 1.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4 fluorophenyl) urea 1aa
Reagents and conditions：a)amines，Et3N，EtOH，reflux；b)DIAD，phthalimide，Ph3P，THF，rt；c)85％NH2NH2.H2O，EtOH，reflux；d)NaCNBH3，acetone，AcOH，MeOH，rt；e)Methyl acrylate，MeOH，microwave，80℃；f)LiAIH4，THF，0℃；g)isocyanate，DCM；h)TFA，DCM
The route for the preparation of compound 1aa is shown in the above formula, 3-fluorobenzylamine (2.6mL, 22.79mmol) and triethylamine (4.0mL, 28.7mmol) were added to a solution of compound 2(3.0g, 9.18mmol) in ethanol (50mL) under argon, stirred at 40 ℃ for 6 hours, concentrated, and chromatographed on silica gel (petroleum ether: ethyl acetate 1: 2) to give compound 3a (3.1g, 82% yield).
To a solution of compound 3a (1g, 2.4mmol) in tetrahydrofuran (30mL) was added phthalic diamide (1.06g, 7.2mmol), triphenylphosphine (1.89g, 7.2mmol), and diisopropyl azodicarboxylate (1.4mL,7.1mmol) at room temperature, stirred overnight at the same temperature, concentrated, and chromatographed on silica gel (petroleum ether: ethyl acetate ═ 1: 1) to give crude compound 4 a. To a solution of crude 4a in ethanol (50mL) was added hydrazine hydrate (85% aqueous, 0.7mL), stirred overnight at 80 deg.C, and filtered. The filtrate was concentrated, and silica gel column chromatography (dichloromethane: methanol: ammonia 100: 10: 1.5) was performed to give compound 5a (0.8g, 80% yield in two steps).
To a solution of compound 5a (2.8g, 6.7mmol) in methanol (30mL) was added acetone (5mL), sodium cyanoborohydride (1.7g, 27.4mmol), and acetic acid (1.5mL) at room temperature, and the mixture was stirred at the same temperature for 3 hours. An aqueous solution of sodium hydroxide (1N,20mL) was added to the reaction mixture under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. Water (50mL) was added to the reaction mixture, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (dichloromethane: methanol: aqueous ammonia 200: 10: 1.5) to give compound 6a (2.88g, 93%).
To a solution of compound 6a (2.6g, 5.7mmol) in methanol (10mL) was added methyl acrylate (5mL), and the mixture was reacted at 90 ℃ for 10 hours with a microwave and concentrated. The residue was subjected to silica gel column chromatography (dichloromethane: methanol 40: 1) to give compound 7a (2.6g, 84%).
Lithium aluminum hydride (3.3mL,1N tetrahydrofuran solution) was added to a tetrahydrofuran solution of compound 7a (900mg, 1.6mmol) under ice-cooling, and the mixture was stirred at the same temperature for 3 hours, and diethyl ether (20mL), water (120. mu.L) and an aqueous solution of sodium hydroxide (15%, 120. mu.L) were added to the reaction mixture and stirred for 5 minutes. Water (360. mu.L) was added to the reaction mixture, the mixture was stirred at room temperature for 15 minutes, and anhydrous magnesium sulfate was added to the reaction mixture, followed by filtration. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol ═ 30: 1) to give compound 8a (550mg, yield 64%).
To a solution of compound 8a (2g, 3.9mmol) in tetrahydrofuran was added phthalic diamide (1.06g, 7.2mmol), triphenylphosphine (1.89g, 7.2mmol), and diisopropyl azodicarboxylate (1.4mL,7.1mmol) at room temperature, stirred overnight at the same temperature, concentrated, and chromatographed on silica gel (petroleum ether: ethyl acetate: 1) to give a crude intermediate. To a solution of the above intermediate in ethanol (50mL) was added hydrazine hydrate (85% aqueous solution, 0.7mL), stirred overnight at 80 deg.C, and filtered. The filtrate was concentrated, and silica gel column chromatography (dichloromethane: methanol: ammonia 100: 10: 1.5) was performed to give compound 9a (1.4g, yield in two steps 70%).
To a solution of compound 9a (130mg,0.25mmol) in acetonitrile (5mL) was added p-fluorophenyl isocyanate (44. mu.L) at room temperature, and the mixture was stirred at the same temperature for 1 hour and concentrated. The residue was subjected to silica gel column chromatography (dichloromethane: methanol 20: 1) to give compound 10aa (98mg, yield 59%).
To a solution of compound 10aa (90mg) in dichloromethane (5mL) under ice bath were added water (0.5mL) and trifluoroacetic acid (0.5mL), and the mixture was stirred at the same temperature for 1 hour and concentrated. Preparative thin layer chromatography (dichloromethane: methanol: ammonia 100: 5: 0.5) afforded the title compound 1aa (69mg, yield 82%),1H NMR(500MHz,MeOD)8.28(s,1H),8.24(s,1H),7.35-7.29(m,3H),7.22(d,J＝7.5Hz,1H),7.15(d,J＝9.8Hz,1H),7.01-6.95(m,3H),6.02(d,J＝4.0Hz,1H),4.88(brs,2H),4.77(brs,1H),4.37-4.35(m,1H),4.25-4.22(m,1H),3.28-3.21(m,3H),3.08-2.76(m,4H),1.76-1.73(m,2H),1.15(s,3H),1.10(s,3H)；13C NMR(400MHz,MeOD)162.1(d,J＝244.5Hz),158.6(d,J＝240.1Hz),156.9,154.5,152.4,141.9,139.7,135.5,129.7(d,J＝8.3Hz),129.3,122.7(d,J＝2.8Hz),120.6(d,J＝7.7Hz),119.6,114.7(d,J＝22.6Hz),113.6(d,J＝20.6Hz),113.3(d,J＝20.3Hz),89.2,82.7,73.2,72.1,52.1,48.1,43.0,37.7,27.3,16.5,16.0.
example 2.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methylphenyl) urea 1ab
To a solution of compound 9a (100mg,0.19mmol) in acetonitrile (5mL) was added p-methylphenyl isocyanate (44. mu.L) at room temperature, and the mixture was stirred at the same temperature for 1 hour and concentrated. The residue was subjected to silica gel column chromatography (dichloromethane: methanol 20: 1) to give compound 10ab (60mg, yield 48%).
To a solution of compound 10ab (50mg) in dichloromethane (5mL) under ice-cooling, water (0.5mL) and trifluoroacetic acid (0.5mL) were added, and the mixture was stirred at the same temperature for 1 hour and concentrated. Preparative thin layer chromatography (dichloromethane: methanol: ammonia 100: 5: 0.5) gave the title compound 1aa (35mg, yield 74%),1H NMR(500MHz,MeOD)8.28(s,1H),8.20(s,1H),7.36-7.30(m,1H),7.22-7.18(m,3H),7.13(d,J＝9.8Hz,1H),7.04(d,J＝7.6Hz,1H),6.96(t,J＝7.5Hz,1H),6.02(d,J＝4.0Hz,1H),4.88(brs,2H),4.77(brs,1H),4.41-4.38(m,1H),4.30-4.25(m,1H),3.44-3.41(m,1H),3.26-3.20(m,4H),2.92-2.90(m,2H),2.72(s,3H),1.82-1.78(m,2H),1.22(s,3H),1.17(s,3H)；13C NMR(400MHz,MeOD)162.1(d,J＝244.5Hz),157.3,154.6,152.4,141.9,139.8,136.5,131.7,129.8(d,J＝8.3Hz),128.7,122.7(d,J＝2.8Hz),119.7,113.6(d,J＝22.1Hz),113.3(d,J＝21.9Hz),89.7,81.5,73.1,72.0,52.0,48.3,43.0,37.2,19.3,16.1,15.7.
example 3.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methoxyphenyl) urea 1ac
The preparation method is the same as example 2, 4-methoxyphenyl isocyanate is used to replace 4-methylphenyl isocyanate, the yield is 84%,1H NMR(500MHz,CDCl3)8.30(s,1H),7.92(s,1H),7.66(s,1H),7.29-7.24(m,1H),7.21(d,J＝8.5Hz,2H),7.14(d,J＝7.5Hz,1H),7.09(d,J＝9.5Hz,1H),6.95(t,J＝7.5Hz,1H),6.75(d,J＝8.5Hz,2H),6.66(brs,1H),6.31(brs,1H),5.95(d,J＝3.3Hz,1H),4.84(brs,2H),4.65(brs,1H),4.51(brs,1H),4.32(brs,1H),3.72(s,3H),3.24-3.17(m,3H),2.97-2.83(m,2H),2.67(brs,2H),1.69-1.65(m,2H),1.07(d,J＝5.6Hz,3H),0.98(d,J＝5.6Hz,3H)；13C NMR(400MHz,CDCl3)162.1(d,J＝244.5Hz),157.4,155.8,154.6,152.9,148.4,141.2,139.0,131.8,130.1(d,J＝8.3Hz),123.1,122.3,120.1,114.4(d,J＝22.3Hz),114.3,114.1(d,J＝22.0Hz),89.8,82.0,74.1,72.5,51.9,48.4,43.8,38.1,29.7,26.8,17.9,16.2.
example 4.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-tert-butylphenyl) urea 1ad
The preparation method is the same as example 2, 4-tert-butylphenyl isocyanate is used instead of 4-methylphenyl isocyanate, the yield is 80%,1H NMR(500MHz,CDCl3)8.32(s,1H),7.94(s,1H),7.71(s,1H),7.29-7.24(m,5H),7.14(d,J＝7.5Hz,1H),7.09(d,J＝9.5Hz,1H),6.96(t,J＝7.5Hz,1H),6.66(brs,1H),6.36(brs,1H),5.95(d,J＝3.3Hz,1H),4.85(brs,2H),4.66(brs,1H),4.54(brs,1H),4.35(brs,1H),3.27(brs,2H),3.14-3.10(m,1H),2.97-2.83(m,2H),2.67(brs,2H),1.71-1.68(m,2H),1.27(s,9H),1.07(d,J＝5.6Hz,3H),0.98(d,J＝5.6Hz,3H)；13C NMR(400MHz,CDCl3)162.1(d,J＝244.5Hz),156.9,154.6,152.9,145.8,141.9,139.0,136.3,130.1(d,J＝8.3Hz),125.8,123.1(d,J＝2.8Hz),120.1,119.5,114.5(d,J＝21.6Hz),114.2(d,J＝20.8Hz),89.8,82.3,74.2,72.6,52.0,50.7,48.5,43.8,38.2,31.3,29.7,26.8,18.2,16.1.
example 5.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-trifluoromethylphenyl) urea 1ae
The preparation method is the same as example 2, 4-trifluoromethyl phenyl isocyanate is used for replacing 4-methyl phenyl isocyanate, and the yield is high80％，1H NMR(500MHz,CDCl3)8.29(s,1H),8.19(brs,1H),7.92(s,1H),7.45(d,J＝8.1Hz,2H),7.40(d,J＝8.1Hz,2H),7.29-7.24(m,1H),7.14(d,J＝7.5Hz,1H),7.09(d,J＝9.5Hz,1H),6.96(t,J＝7.5Hz,1H),6.69(brs,2H),5.97(d,J＝3.3Hz,1H),4.83(brs,2H),4.64(brs,1H),4.49(brs,1H),4.35-4.32(m,1H),3.27(brs,2H),3.14-3.10(m,1H),2.97-2.83(m,2H),2.67(brs,2H),1.71-1.68(m,2H),1.07(d,J＝5.6Hz,3H),0.98(d,J＝5.6Hz,3H)；13C NMR(400MHz,CDCl3)162.1(d,J＝244.5Hz),156.1,154.6,152.9,148.2,142.6,140.9(d,J＝6.9Hz),138.6,130.1(d,J＝8.2Hz),126.0(d,J＝3.5Hz),124.2(q,J＝272Hz),123.5(q,J＝32.7Hz),123.0(d,J＝2.8Hz),120.04,114.5,114.2,89.8,82.3,74.3,72.8,52.0,51.343.8,38.4,31.9,26.3,18.1,16.0.
Example 6.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (3-trifluoromethylphenyl) urea 1af
The preparation method is the same as example 2, 3-trifluoromethyl phenyl isocyanate is used to replace 4-methyl phenyl isocyanate, the yield is 80 percent,1H NMR(500MHz,CDCl3)8.29(s,1H),7.96(s,1H),7.78(s,1H),7.51(d,J＝7.8Hz,1H),7.29-7.24(m,1H),7.17-7.14(m,2H),7.09(d,J＝9.5Hz,1H),6.96(t,J＝7.5Hz,1H),6.75(brs,1H),6.50(brs,1H),5.99(d,J＝3.3Hz,1H),4.83(brs,2H),4.65(brs,2H),4.51(brs,1H),4.35-4.32(m,1H),3.32-2.87(m,7H),1.87(brs,2H),1.19(d,J＝5.6Hz,3H),1.07(d,J＝5.6Hz,3H)；13C NMR(400MHz,CDCl3)162.1(d,J＝244.5Hz),156.1,154.6,152.9,141.0,140.0,139.2,131.0(q,J＝32.5Hz),130.2(d,J＝8.4Hz),129.2,123.2(q,J＝272.1Hz),123.1,121.6,118.6,115.0,114.5(d,J＝21.7Hz),114.3(d,J＝21.5Hz),90.2,82.3,74.1,72.5,52.0,48.9,37.6,29.7,26.0,17.7,15.9.
example 7.1- (tert-butyl) -3- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea 1ag
The preparation method is the same as example 2, tert-butyl isocyanate is used to replace 4-methylphenyl isocyanate, the yield is 80%,1H NMR(500MHz,CDCl3)8.37(s,1H),7.97(s,1H),7.29-7.24(m,1H),7.14(d,J＝7.5Hz,1H),7.09(d,J＝9.5Hz,1H),6.96(t,J＝7.5Hz,1H),6.52(brs,1H),5.99(d,J＝3.3Hz,1H),4.89(brs,2H),4.74(brs,1H),4.60(brs,1H),4.35-4.32(m,1H),3.27(brs,2H),3.14-3.10(m,1H),3.04(brs,1H),2.86(brs,1H),2.72(brs,2H),1.75-1.72(m,2H),1.32(s,9H),1.16(d,J＝5.6Hz,3H),1.03(d,J＝5.6Hz,3H)；13C NMR(400MHz,CDCl3)162.1(d,J＝244.5Hz),158.8,154.6,152.9,148.6,141.2(d,J＝6.9Hz),139.2,130.2,(d,J＝8.2Hz),123.0(d,J＝2.8Hz),120.3,114.5(d,J＝21.7Hz),114.3(d,J＝21.8Hz),90.0,82.6,74.0,72.3,51.8,50.3,48.6,43.8,38.6,29.7,26.7,18.6,15.8.
example 8.1- (cyclohexyl) -3- (3- (((((2R, 3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea 1ah
The preparation method is the same as example 2, cyclohexyl isocyanate is used to replace 4-methylphenyl isocyanate, the yield is 80 percent,1H NMR(500MHz,MeOD)8.31(s,1H),8.25(s,1H),7.40-7.34(m,1H),7.20(d,J＝7.5Hz,1H),7.15(d,J＝9.5Hz,1H),7.00(t,J＝7.5Hz,1H),6.04(d,J＝4.0Hz,1H),4.88(brs,2H),4.79(brs,1H),4.37(brs,1H),0.98(brs,1H),3.46-3.43(m,1H),3.24-2.72(m,7H),1.85-1.61(m,8H),1.23-1.10(m,10H)；13C NMR(400MHz,CDCl3)162.1(d,J＝244.5Hz),159.1,154.6,152.5,142.0,139.8,129.7(d,J＝8.2Hz),129.3,122.7(d,J＝2.8Hz),119.7,113.5(d,J＝22.2Hz),113.3(d,J＝22.4Hz),89.2,82.7,73.1,72.0,52.0,48.5,37.5,33.2,26.6,25.4,25.2,16.7,15.8.
example 9.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-fluorophenyl) urea 1ba
Reagents and conditions：a)amines，Et3N，EtOH，reflux；b)DIAD，phthalimide，Ph3P，THF，rt；c)85％NH2NH2.H2O，EtOH，reflux；d)NaCNBH3，acetone，AcOH，MeOH，rt；e)Methyl acrylate，MeOH，microwave，80℃；f)LiAIH4，THF，0℃；g)isocyanate，DcM；h)TFA，DcM
As described above for the concrete procedure with reference to example 1, 3-chlorobenzylamine was used in place of 3-fluorobenzylamine to obtain compound 1ba,1H NMR(500MHz，DMSO-d6)8.47(brs，1H)，8.43(s，1H)，8.22(s，1H)，7.39-7.35(m，3H)，7.33-7.25(m，3H)，7.06-7.01(m，2H)，6.13(brs，1H)，5.88(d，J＝6.9Hz，1H)，5.44(d，J＝7.4Hz，1H)，5.18(d，J＝5.8Hz，1H)，4.76-4.70(m，3H)，4.15(brs，1H)，3.93(brs，1H)，3.08-3.06(m，2H)，2.98-2.92(m，1H)，2.86-2.78(m，1H)，2.46-2.40(m，2H)，1.54-1.50(m，2H)，0.97(d，J＝6.3Hz，1H)，0.88(d，J＝6.3Hz，1H)；13C NMR(400MHz，DMSO-d6)157.2(d，J＝237.5Hz)，155.7，154.7，152.9，148.3，143.2，140.6，137.4，133.3，130.5，127.3，127.0，126.2，119.6(d，J＝7.4Hz)，115.6，115.3，87.8，84.3，72.8，72.1，50.2，50.7，48.1，42.8，37.8，29.4，19.4，17.1.
example 10.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methylphenyl) urea 1bb
The preparation method is shown in the formula,concrete procedure referring to example 2, compound 1bb was prepared using 9b instead of 9a,1H NMR(500MHz，MeOD)8.30(s，1H)，8.18(s，1H)，7.41(s，1H)，7.33-7.28(m，3H)，7.20(d，J＝8.8Hz，2H)，7.05(d，J＝8.8Hz，2H)，6.01(d，J＝4.0Hz，1H)，4.79(brs，2H)，4.78-4.76(m，1H)，4.49(brs，1H)，4.40(brs，1H)，3.38-3.35(m，3H)，3.28-3.17(m，4H)，2.28(s，3H)，1.92(brs，2H)，1.29(s，3H)，0.94(s，3H)；13C NMR(400MHz，MeOD)157.4，152.5，141.5，140.0，136.4，133.9，131.9，129.5，129.3，128.8，128.4，126.9，126.7，125.3，119.2，90.2，80.2，72.9，72.1，51.9，48.6，42.9，26.6，22.2，19.3.
EXAMPLE 11.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methoxyphenyl) urea 1bc
The preparation method is the same as example 10, 4-methoxyphenyl isocyanate is used to replace 4-methylphenyl isocyanate, the yield is 70%,1H NMR(500MHz，MeOD)8.29(s，1H)，8.22(s，1H)，7.41(s，1H)，7.33-7.28(m，3H)，7.20(d，J＝8.8Hz，2H)，6.84(d，J＝8.8Hz，2H)，6.02(d，J＝4.0Hz，1H)，4.79(brs，2H)，4.78-4.76(m，1H)，4.49(brs，1H)，4.34(brs，1H)，3.79(s，3H)，3.38-3.35(m，3H)，3.28-3.17(m，4H)，1.84(brs，2H)，1.29(s，3H)，0.94(s，3H)；13C NMR(400MHz，MeOD)157.7，155.7，152.5，141.5，139.9，133.9，131.8，129.5，129.3，126.9，126.7，125.3，121.4，113.6，89.9，73.0，72.1，54.4，51.9，48.5，42.9，31.6，26.6，25.4，22.3.
example 12.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-tert-butylphenyl) urea 1bd
The preparation method is the same as example 10, 4-tert-butylphenyl isocyanate is used instead of 4-methylphenyl isocyanate, the yield is 88%,1H NMR(500MHz,MeOD)8.27(s,1H),8.25(s,1H),7.41(s,1H),7.32-7.22(m,7H),6.02(d,J＝4.0Hz,1H),4.8(brs,2H),4.79-4.76(m,1H),4.35-4.32(m,1H),4.22-4.18(m,1H),3.29-3.20(m,2H),3.09(brs,1H),2.96(d,J＝12.9Hz,1H),2.79(brs,1H),2.62(brs,2H),1.70-1.68(m,2H),1.07(d,J＝5.7Hz,3H),1.02(d,J＝5.7Hz,3H)；13C NMR(400MHz,MeOD)157.0,152.4,144.9,141.4,139.6,136.6,133.9,129.5,126.9,126.7,125.3,125.1,125.0,118.8,89.0,83.2,73.2,72.0,52.1,50.6,42.9,39.0,33.5,30.4,27.8,17.0,16.2.
example 13.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-trifluoromethylphenyl) urea 1be
The preparation method is the same as example 10, 4-trifluoromethyl phenyl isocyanate is used to replace 4-methyl phenyl isocyanate, the yield is 88 percent,1H NMR(500MHz,MeOD)8.25(s,2H),7.52-7.48(m,4H),7.41(s,1H),7.33-7.27(m,3H),6.02(d,J＝4.0Hz,1H),4.88(brs,2H),4.79-4.76(m,1H),4.35-4.32(m,1H),4.22-4.18(m,1H),3.30-3.20(m,2H),3.09(brs,1H),2.96(d,J＝12.9Hz,1H),2.79(brs,1H),2.62(brs,2H),1.70-1.68(m,2H),1.08(d,J＝5.7Hz,3H),1.04(d,J＝5.7Hz,3H)；13C NMR(400MHz,MeOD)156.1,154.5,152.4,148.5,143.3,141.4,139.5,133.9,129.5,126.9,126.7,125.4(q,J＝3.8Hz),125.3,124.5(q,J＝273Hz),12.9(q,J＝32.3Hz),119.6,117.5,89.0,83.1,73.2,72.1,52.2,50.6,42.9,38.0,27.5,16.8,16.2.
example 14.1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (3-trifluoromethylphenyl) urea 1bf
The preparation method is the same as example 10, 3-trifluoromethyl phenyl isocyanate is used to replace 4-methyl phenyl isocyanate, the yield is 86 percent,1H NMR(500MHz,MeOD)8.27(s,1H),8.25(s,1H),7.48(d,J＝2.9Hz,1H),7.42(s,1H),7.38(t,J＝7.8Hz,1H),7.33-7.30(m,2H),7.28(brs,1H),7.21(d,J＝7.3Hz,1H),6.02(d,J＝4.0Hz,1H),4.88(brs,2H),4.79-4.76(m,1H),4.35-4.32(m,1H),4.22-4.18(m,1H),3.30-3.20(m,2H),3.13(brs,1H),2.96(d,J＝12.9Hz,1H),2.84(brs,1H),2.66(brs,2H),1.74-1.70(m,2H),1.10(d,J＝5.7Hz,3H),1.05(d,J＝5.7Hz,3H)；13C NMR(400MHz,MeOD)156.3,154.5,152.4,141.4,140.5,139.6,133.9,130.5(q,J＝31.8Hz),129.5,128.9,126.9,126.7,125.3,124.2(q,J＝274.3Hz),121.3,119.6,117.3(q,J＝3.5Hz),114.5(q,J＝3.9Hz),89.0,83.0,73.2,72.1,52.2,50.7,42.9,37.9,27.5,16.8,16.1.
example 15.1- (tert-butyl) -3- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea 1bg
The preparation method is the same as that of example 10, tert-butyl isocyanate is used to replace 4-methylphenyl isocyanate, the yield is 84%,1H NMR(500MHz,MeOD)8.31(s,1H),8.28(s,1H),7.43(s,1H),7.35-7.30(m,2H),7.28-7.25(m,1H),6.04(d,J＝4.0Hz,1H),4.88(brs,2H),4.81-4.80(m,1H),4.38-4.35(m,1H),4.22-4.18(m,1H),3.30-3.20(m,1H),3.13(t,J＝6.1Hz,1H),3.10-2.98(m,2H),2.72(brs,1H),1.69(brs,2H),1.29(s,9H),1.14(d,J＝5.7Hz,3H),1.08(d,J＝5.7Hz,3H)；)；13C NMR(400MHz,MeOD)159.1,154.5,152.4,141.5,139.1,133.9,129.5,127.0,126.7,125.3,119.7,89.2,82.5,73.1,72.0,52.0,49.3,42.9,37.2,28.3,27.6,16.7,15.8.
example 16.1- (cyclohexyl) -3- (3- (((((2R, 3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea 1bh
The preparation method is the same as example 10, cyclohexyl isocyanate is used to replace 4-methylphenyl isocyanate, the yield is 82 percent,1H NMR(500MHz,MeOD)8.31(s,1H),8.28(s,1H),7.43(s,1H),7.35-7.30(m,2H),7.28-7.25(m,1H),6.04(d,J＝4.0Hz,1H),4.88(brs,2H),4.81-4.80(m,1H),4.38-4.35(m,1H),4.22-4.18(m,1H),3.30-3.20(m,1H),3.16(t,J＝6.1Hz,1H),3.10-2.98(m,2H),2.69(brs,1H),1.86(brs,2H),1.70-1.60(m,6H),1.21-1.07(m,10H)；13C NMR(400MHz,MeOD)159.1,154.5,152.4,148.6,141.5,139.8,133.9,129.5,126.9,126.7,125.3,119.7,89.1,82.8,73.1,72.0,52.0,49.8,43.0,37.5,33.2,25.2,24.6,16.7,15.9.
biological example 1
In vitro anti-Zika virus Activity assay
The cytotoxicity of the target compound against the inhibitor of Zika virus was measured using vero cells as the Zika virus vector, and compared with the natural product, i.e., cinafenin, the results are shown in Table 1.
TABLE 1 in vitro Activity of the example Compounds against Zika Virus
Composition examples
EXAMPLE 1 coated tablet
Tablet core prescription:
mixing the above materials, granulating, sieving, grading, drying, and tabletting to obtain 100 tablet cores.
The prescription of the coating liquid is as follows: opadry (Opadry)5g, 80% ethanol in appropriate amount.
EXAMPLE 2 capsules
Prescription:
the preparation method comprises the following steps:
taking the formula amount of raw and auxiliary materials, respectively sieving, adding 5% of polyvinylpyrrolidone alcohol solution and tween 80 to prepare soft materials, granulating by using a 20-mesh sieve, airing at room temperature of 15 ℃, adding sodium dodecyl sulfate, uniformly mixing, filling 0.27g/S into a No. 0 gastric soluble capsule, sampling and testing, wherein the dissolution limit is 80% and the content is 90-110% of the marked amount.
Example 3 granules
Taking 100g of the compound in the embodiment 4, adding a proper amount of dextrin and steviosin, carrying out dry granulation, finishing granules, and subpackaging to obtain the compound.
EXAMPLE 4 injection
150g of the compound of example 4 was dissolved in water, and sodium chloride and ethyl p-hydroxybenzoate were dissolved in hot water, followed by mixing and adjusting the pH to 5-7. Diluting the injection water to 1000ml, filtering with hollow fiber membrane, bottling, and sterilizing.
EXAMPLE 5 lyophilized powder for injection
Dissolving 150g of the compound in example 4 in water, adding 500g of mannitol for dissolving in hot water, mixing, diluting with water for injection to 5000ml, filtering with a hollow fiber membrane, filling, sterilizing, and lyophilizing to obtain lyophilized powder for injection.
EXAMPLE 6 dropping pills
Taking 20g of the compound in the embodiment 4 as a raw material medicine for standby; weighing 200g of dripping pill matrix, heating to 80 deg.C for melting, and stirring; adding the raw materials into the adjuvant matrix while stirring, stirring for 30min to make it uniform, and keeping the temperature of the liquid medicine not lower than 60 deg.C; injecting the prepared medicinal liquid into a dripping pill machine, and dripping into dripping pills.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (6)
1. A compound of the formula (I),
formula (I)
Wherein:
ar represents a substituted phenyl group, the hydrogen atom of any position of which may be substituted by an R group;
the R group is halogen;
w is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl.
2. A compound of formula (I) according to claim 1, wherein:
ar represents: 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl.
3. The compound of formula (I) according to claim 1, selected from the following compounds:
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-fluorophenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methoxyphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-tert-butylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-trifluoromethylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (3-trifluoromethylphenyl) urea
1- (tert-butyl) -3- (3- (((((2R, 3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea
1- (cyclohexyl) -3- (3- ((((2R,3S,4R,5R) -5- (6- ((3-fluorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-fluorophenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-methoxyphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-tert-butylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (4-trifluoromethylphenyl) urea
1- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) -3- (3-trifluoromethylphenyl) urea
1- (tert-butyl) -3- (3- (((((2R, 3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea
1- (cyclohexyl) -3- (3- ((((2R,3S,4R,5R) -5- (6- ((3-chlorobenzyl) amino) -9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methylene) (isopropyl) amino) propyl) urea.
4. Use of a compound of claim 1 for the preparation of a medicament for the treatment of a flavivirus infection.
5. The use according to claim 4, wherein said flavivirus comprises Zika virus.
6. A pharmaceutical composition comprising a compound of claim 1.
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| WO2003026675A1 (en) * | 2001-09-28 | 2003-04-03 | Idenix (Cayman) Limited | Methods and compositions for treating flaviviruses and pestiviruses using 4'-modified nucleoside |
| CN1653077A (en) * | 2002-05-06 | 2005-08-10 | 健亚生物科技公司 | Nucleoside derivatives for treating hepatitis C virus infection |
| CN103339139A (en) * | 2010-12-03 | 2013-10-02 | Epizyme股份有限公司 | 7-deazapurine modulators of histone methyltransferase, and methods of use thereof |
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| WO2003026675A1 (en) * | 2001-09-28 | 2003-04-03 | Idenix (Cayman) Limited | Methods and compositions for treating flaviviruses and pestiviruses using 4'-modified nucleoside |
| CN1653077A (en) * | 2002-05-06 | 2005-08-10 | 健亚生物科技公司 | Nucleoside derivatives for treating hepatitis C virus infection |
| CN103339139A (en) * | 2010-12-03 | 2013-10-02 | Epizyme股份有限公司 | 7-deazapurine modulators of histone methyltransferase, and methods of use thereof |
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