CN103819665B - Tetravalence zanamivir and preparation method thereof and application - Google Patents
Tetravalence zanamivir and preparation method thereof and application Download PDFInfo
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- CN103819665B CN103819665B CN201410068706.1A CN201410068706A CN103819665B CN 103819665 B CN103819665 B CN 103819665B CN 201410068706 A CN201410068706 A CN 201410068706A CN 103819665 B CN103819665 B CN 103819665B
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Abstract
The invention discloses a kind of tetravalence zanamivir and preparation method thereof and application.The structural formula of tetravalence zanamivir is such as formula shown in I, and in formula, m is the number between 3 ~ 12.The present invention still further provides the application of tetravalence zanamivir shown in formula I in preparation Tamiflu, and described application is embodied in following 1) or 2): 1) described Tamiflu suppresses the enzyme activity of neuraminidase; 2) described Tamiflu suppresses the growth of influenza infection cell.Tetravalence zanamivir provided by the invention may be used for the treatment of various viral influenza, and more existing zanamivir has anti-influenza virus activity more efficiently, and infected by influenza persister has efficient inhibition; And tetravalence zanamivir provided by the invention can be prepared into oral pharmaceutical.
Description
Technical field
The present invention relates to a kind of tetravalence zanamivir and preparation method thereof and application, belong to field of medicaments.
Background technology
Zanamivir, commodity are called Relenza, and be a kind of Tamiflu of having gone on the market developed by Australian Biota company, its structural formula is as follows.It is mainly by suppressing the activity of the neuraminidase of influenza surface thus stoping the influenza virus of new assembling to be discharged into Budding process enchylema from host cell content.
Zanamivir, due to water-soluble very good, enter after in human body rapidly by metabolism, excretes, so be made into nose spraying system with urine form.Because route of administration is complicated, greatly limit it and promote clinically.
Document Nature.403, the pentavalent inhibitor designed according to the space layout of five groups of drug binding sites on shiga toxin albumen homology pentamer in 2000,669-672, can form the highly stable mixture of structure with toxin, the inhibition (IC of its contratoxin
50) comparatively unit price medicine can improve 400,000 times.
Summary of the invention
The object of this invention is to provide a kind of tetravalence zanamivir and preparation method thereof and application, the more existing zanamivir of tetravalence zanamivir molecule provided by the invention has anti-influenza virus activity more efficiently, and water-solublely to make moderate progress, be expected to make oral medicine.
The structural formula of tetravalence zanamivir provided by the present invention such as formula shown in I,
In formula I, m is the number between 3 ~ 12.
Tetravalence zanamivir provided by the present invention, wherein m specifically can be 3,6 or 12.
Present invention also offers the preparation method of tetravalence zanamivir shown in formula I, comprise the steps:
(1) shown in formula II, poly ethylene glycol obtains compound shown in formula III through tosylation, azide and propargyl bromide successively;
In formula II and formula III, m is the number between 3 ~ 12;
(2) compound shown in formula III obtains compound shown in formula IV after triphenyl phosphorus reduction;
In formula IV, m is the number between 3 ~ 12;
(3) shown in formula IV, shown in compound and formula V, zanamivir intermediate obtains compound shown in formula VI through transesterification reaction;
In formula VI, m is the number between 3 ~ 12;
(4) azide Ji Wusi alkane shown in compound and formula VII shown in formula VI obtains the shown tetravalence zanamivir protected of formula VIII through cycloaddition reaction, namely obtains tetravalence zanamivir shown in formula I through deprotection reaction;
Formula VIII
In above-mentioned preparation method, m specifically can be 3,6 or 12.
In above-mentioned preparation method, in step (1), the temperature of described tosylation can be 25 ~ 35 DEG C, and the time can be 16 ~ 24 hours, and can carry out under triethylamine existent condition, as reacted 16 hours under the condition of 25 DEG C;
The temperature of described azide can be 80 DEG C, and the time can be 3 ~ 16 hours, as reacted 3 hours under the condition of 80 DEG C;
The temperature of described propargyl bromide can be 25 ~ 35 DEG C, and the time can be 1 ~ 3 hour, as reacted 3 hours under the condition of 25 DEG C.
In above-mentioned preparation method, in step (2), the temperature of described triphenyl phosphorus reduction can be 40 ~ 50 DEG C, and the time can be 3 ~ 12 hours, as reacted 3 hours under the condition of 45 DEG C;
Shown in triphenyl phosphorus and formula III, the mol ratio of compound can be 1 ~ 2:1, as 1.2:1.
In above-mentioned preparation method, in step (3), described transesterification reaction is carried out under DMAP existent condition;
Shown in described DMAP and described formula V, the mol ratio of zanamivir intermediate can be 1:10 ~ 20, as 1:20;
The temperature of described transesterification reaction can be 25 ~ 35 DEG C, and the time can be 2 ~ 12 hours, as reacted 2 hours under the condition of 25 DEG C.
In above-mentioned preparation method, in step (4), described cycloaddition reaction is carried out under copper sulfate and sodium ascorbate existent condition;
Described cycloaddition reaction need be carried out under an inert atmosphere;
The temperature of described cycloaddition reaction can be 40 ~ 60 DEG C, and the time can be 1 ~ 10 hour, as reacted 1 hour under the condition of 45 DEG C.
The present invention still further provides the application of tetravalence zanamivir shown in formula I in preparation Tamiflu.
Described application is embodied in following 1) or 2):
1) described Tamiflu suppresses the enzyme activity of neuraminidase;
2) described Tamiflu suppresses the growth of influenza infection cell.
Present invention also offers any one application following of tetravalence zanamivir shown in formula I:
1) preparation has the product of the enzyme activity function suppressing neuraminidase;
2) preparation has the product of the growth function suppressing influenza infection cell.
A kind of Tamiflu provided by the invention, its activeconstituents is tetravalence zanamivir shown in formula I.
Tool of the present invention has the following advantages:
Tetravalence zanamivir provided by the invention may be used for the treatment of various viral influenza, and more existing zanamivir has anti-influenza virus activity more efficiently, and infected by influenza persister has efficient inhibition; And tetravalence zanamivir provided by the invention can be prepared into oral pharmaceutical.
Accompanying drawing explanation
Fig. 1 be the body weight of embodiment 4 small mouse after influenza virus infection over time.
Fig. 2 be the survival rate of embodiment 4 small mouse after influenza virus infection over time.
Embodiment
The experimental technique used in following embodiment if no special instructions, is ordinary method.
Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
Zanamivir intermediate shown in the formula V used in following embodiment prepares according to the method recorded in such as Publication about Document: One-Bead – One-Inhibitor – One-Substrate Screening of Neuraminidase Activity.Chem.Bio.Chem.2005,6,1857 – 1865.
Embodiment 1, preparation tetravalence zanamivir
(1) three polyoxyethylene glycol (m=3) 2.8g is dissolved in tetrahydrofuran (THF), after adding the triethylamine stirring 30min of 1.4mL, adds Tosyl chloride solid 1.9g, filter after reacting 16h under room temperature and be spin-dried for.With 100 ~ 200 order silica gel column chromatographies, gradient elution obtains single tolysulfonyl polyethylene glycol 2.52g, and yield is 58%.
The reaction equation of this step is as follows:
(2) the single tolysulfonyl polyethylene glycol 2.52g upper step prepared is dissolved in acetonitrile; add sodiumazide solid 0.57g; filter after being spin-dried for after reacting 3h at 80 DEG C; add a small amount of ethyl acetate again; filtration is spin-dried for obtain colourless transparent liquid list azide polyoxyethylene glycol 1.53g, and yield is 86.5%.
The reaction equation of this step is as follows:
(3) the single azide polyoxyethylene glycol 1.13g upper step obtained is dissolved in tetrahydrofuran (THF), adds Sodium Borohydride powder 355mg, drips 0.44mL propargyl bromide liquid after stirring at room temperature 30min, and room temperature continues reaction 3h.Add a small amount of methyl alcohol termination reaction, filtration is spin-dried for.With 100 ~ 200 order silica gel column chromatographies, gradient elution obtains azide propargyl bromide polyethylene glycol 0.53g light yellow transparent liquid, and yield is 41.5%.
The reaction equation of this step is as follows:
(4) upper step products obtained therefrom 0.53g is dissolved in tetrahydrofuran (THF): in water (5:1, volume ratio) solution, the mol ratio adding triphenylphosphine 0.95g(and upper step products obtained therefrom is 1.2:1), the solid being spin-dried for orange after reacting 3h at 45 DEG C.
The reaction equation of this step is as follows:
(5) the safran solid of upper step gained is directly dissolved in pyridine, add zanamivir intermediate 1.15g, the mol ratio added again in the middle of DMAP10mg(itself and zanamivir is 1:20), 2h is reacted under room temperature, with 100 ~ 200 order silica gel column chromatographies after concentrated, obtain the zanamivir molecule 0.86g that poly ethylene glycol connects after gradient elution, productive rate is 61%.
The reaction equation of this step is as follows:
(6) the zanamivir molecule that the poly ethylene glycol upper step obtained connects adds tetrahydrofuran (THF): in water (1:1, volume ratio) solution, add the azide Ji Wusi alkane of 0.5 times of equivalent, drip 2 1M CuSO
4after solution, add the sodium ascorbate solid of 10mg, the lower 45 DEG C of reaction 1h of nitrogen protection.Reacting liquid filtering is spin-dried for, and with 100 ~ 200 order silica gel column chromatographies, gradient elution obtains protected tetravalence zanamivir molecule.Products therefrom is dissolved in methyl alcohol, add 1 milliliter of 1M sodium hydrate methanol solution, stirring at room temperature 3h, add in H+ ion exchange resin and 10min, DCM/TFA(1:1 is added after filtration is spin-dried for) solution 5mL, room temperature reaction 3h, 30 DEG C concentrated after, add a small amount of water filtration freeze-drying and obtain tetravalence zanamivir molecule.
The reaction equation of this step is as follows:
Tetravalence zanamivir molecule marker prepared by the present embodiment is tetra-PEG3-zanamivir, and structural characterization data are as follows:
1H-NMR(400MHz,D
2O)8.16（1H,s）,5.86(1H,s),4.86(1H,dd),4.60(2H,s),4.56(2H,s),4.47(1H,dd),4.35(1H,dd),4.05(1H,t),3.93-3.90(1H,m),3.63-3.56(10H,m),3.48(2H,s),3.40-3.38(1H,m),3.19-3.10(2H,m),1.87(3H,s)；
MS ESI（m/z）:[M+2H]
2+，calcd.for C
93H
150N
32O
44,1209.52363;found 1209.52099。
From above-mentioned data, compound structure prepared by the present embodiment is correct.
Prepare tetravalence zanamivir when m is respectively 6 and 12 according to the step in embodiment 1, and be labeled as tetra-PEG6-zanamivir and tetra-PEG12-zanamivir respectively.
The structural characterization data of tetra-PEG6-zanamivir are as follows:
1H-NMR(400MHz,D
2O)8.17（1H,s）,5.94(1H,s),4.88(1H,dd),4.61(2H,s),4.57(2H,s),4.50(1H,dd),4.36(1H,dd),4.06(1H,t),3.95-3.90(1H,m),3.65-3.48(24H,m),3.43-3.39(1H,m),3.26-3.10(2H,m),1.88(3H,s)；
MS ESI（m/z）:[M+H]
+calcd.for C
117H
196N
32O
56,2945.34734;found 2945.35760。
From above-mentioned data, compound structure prepared by the present embodiment is correct.
The structural characterization data of tetra-PEG12-zanamivir are as follows:
1H-NMR(400MHz,D
2O)8.16（1H,s）,5.86(1H,s),4.86(1H,dd),4.60(2H,s),4.56(2H,s),4.47(1H,dd),4.35(1H,dd),4.05(1H,t),3.93-3.90(1H,m),3.63-3.56(48H,m),3.40-3.38(1H,m),3.19-3.10(2H,m),1.87(3H,s)；
MS ESI（m/z）:[M+2H]
2+calcd.for C
165H
294N
32O
80,2001.99550;found 2001.99083。
From above-mentioned data, compound structure prepared by the present embodiment is correct.
Embodiment 2, tetravalence zanamivir are to the enzyme of NA neuraminidase inhibition test alive
By tetra-PEG3-zanamivir, tetra-PEG6-zanamivir, tetra-PEG12-zanamivir and zanamivir(zanamivir) be all mixed with 50 μMs, 5 μMs, 500 μMs, the PBS solution of 50nM, 5nM, 0.5nM, 0.1nM.The damping fluid first adding the inhibitor solution of the above-mentioned configuration of 10 μ L and the Tris PH=8.0 of 10uL NA neuraminidase in 96well standard opaque plate hatches 30min altogether in 37 DEG C of incubators, then add 167 μMs of 4-MUNANA fluorescent substrate solution of 30 μ L, immediately 96 orifice plates are put into microplate reader and measure 355-460nM fluorescent value 30min.With GraphPad Prism software processes the data obtained, calculate IC50, as shown in data in table 1.
Table 1 tetravalence zanamivir molecule and zanamivir are lived to the enzyme of NA neuraminidase and are suppressed result
As can be seen from the above table, three kinds of tetravalence zanamivir molecules tetra-PEG3-zanamivir, tetra-PEG6-zanamivir and tetra-PEG12-zanamivir provided by the invention all have inhibition to various NA, particularly still have good inhibition to the NA of resistance to zanamivir.
Embodiment 3, tetravalence zanamivir infected by influenza infect the inhibition test of mdck cell
By tetra-PEG3-zanamivir, tetra-PEG6-zanamivir, tetra-PEG12-zanamivir and zanamivir all prepares the PBS solution of 500nM, 250nM, 125nM, 62.5nM, 31.25nM, 2nM, 1nM, 0.5nM, 0.125nM and 0.0625nM.Cell culture processes cultivates mdck cell (Beijing Jia Xinsheng Science and Technology Ltd.) routinely.Trysinization mdck cell, divides equally with 96 orifice plates, 100 μ L/ holes, and ensures that cell count is (2 ~ 8) × 10
5/ hole; CO
2cell culture incubator cultivates 24h.By inhibitor DMEM solution 56 DEG C of water-bath deactivation 30min of different concns, after 2 doubling dilutions, with equivalent, mix containing the influenza virus (plasma-free DMEM medium dilutes) of 100TCID50 after, hatch 1h for 37 DEG C.Cell culture medium in reject 96 orifice plate, adds serum-virus mixture 100 μ L/ hole, is placed in CO
2in cell culture incubator, absorption 2h.Reject supernatant, washes 2 times with aseptic PBS, and after blotting the debris in each hole, the DMEM(added containing 2 μ g/ml pancreatin contains 1 ~ 2% serum), be placed in CO
2cell culture incubator cultivates 5d.4th day, observation of cell pathology CPE under opticmicroscope, record pathology number of perforations.Arrange the virus control containing 100 TCID50, blanc cell contrasts, serum control simultaneously.Calculate NAT, calculate EC according to utilization Reed-Muench method
50, result is as shown in table 2.
The suppression result that table 2 tetravalence zanamivir molecule and zanamivir infected by influenza infect
As can be seen from the above table, three kinds of tetravalence zanamivir molecules provided by the invention have good HIV suppression effect equally at cell levels, also have good inhibition, may be used for the treatment of various influenza infection to the virus of zanamivir resistance.
The mouse medicine-feeding test of embodiment 4, tetravalence zanamivir
At random 20 8 weeks large BALB/c mouse are divided into four groups, often group 5 (A. Tamiflus; B. zanamivir; C.Tetra-PEG12-zanamivir; D. physiological saline), at infection TCID
50after the PR8H1N1 influenza virus 24h of=50, be administered once 50 μ L(A, B groups by 20mg/kg/7d dosage gastric infusion every 12h, C group presses 50mg/kg/7d dosage gastric infusion, and D group is control group administered physiological saline).Successive administration 5 days, every day records Mouse Weight, continues 14 days.Interpretation as depicted in figs. 1 and 2.
As can be seen from the above results, tetra-PEG12-zanamivir provided by the invention serves the effect of protection in mouse experiment by the mode of oral administration, therefore compound of the present invention has the potentiality being developed as oral Tamiflu.
Claims (10)
1. tetravalence zanamivir shown in formula I,
In formula I, m is the number between 3 ~ 12.
2. the preparation method of tetravalence zanamivir shown in formula I described in claim 1, comprises the steps:
(1) shown in formula II, poly ethylene glycol obtains compound shown in formula III through tosylation, azide and propargyl bromide successively;
In formula II and formula III, m is the number between 3 ~ 12;
(2) compound shown in formula III obtains compound shown in formula IV after triphenyl phosphorus reduction;
In formula IV, m is the number between 3 ~ 12;
(3) shown in formula IV, shown in compound and formula V, zanamivir intermediate obtains compound shown in formula VI through transesterification reaction;
In formula VI, m is the number between 3 ~ 12;
(4) azide Ji Wusi alkane shown in compound and formula VII shown in formula VI obtains the shown tetravalence zanamivir protected of formula VIII through cycloaddition reaction, namely obtains tetravalence zanamivir shown in formula I through deprotection reaction;
3. preparation method according to claim 2, is characterized in that: in step (1), and the temperature of described tosylation is 25 ~ 35 DEG C, and the time is 16 ~ 24 hours;
The temperature of described azide is 80 DEG C, and the time is 3 ~ 16 hours;
The temperature of described propargyl bromide is 25 ~ 35 DEG C, and the time is 1 ~ 3 hour.
4. the preparation method according to Claims 2 or 3, is characterized in that: in step (2), and the temperature of described triphenyl phosphorus reduction is 40 ~ 50 DEG C, and the time is 3 ~ 12 hours;
The mol ratio of compound shown in triphenyl phosphorus and formula III is 1 ~ 2:1.
5. the preparation method according to Claims 2 or 3, is characterized in that: in step (3), described transesterification reaction is carried out under DMAP existent condition;
The mol ratio of zanamivir intermediate shown in described DMAP and described formula V is 1:10 ~ 20;
The temperature of described transesterification reaction is 25 ~ 35 DEG C, and the time is 2 ~ 12 hours.
6. the preparation method according to Claims 2 or 3, is characterized in that: in step (4), and described cycloaddition reaction is carried out under copper sulfate and sodium ascorbate existent condition;
Described cycloaddition reaction is carried out under an inert atmosphere;
The temperature of described cycloaddition reaction is 40 ~ 60 DEG C, and the time is 1 ~ 10 hour.
7. the application of tetravalence zanamivir shown in formula I described in claim 1 in preparation Tamiflu.
8. application according to claim 7, is characterized in that: described application shows as following 1) or 2):
1) described Tamiflu suppresses the enzyme activity of neuraminidase;
2) described Tamiflu suppresses the growth of influenza infection cell.
9. any one application following of tetravalence zanamivir shown in formula I described in claim 1:
1) preparation has the product of the enzyme activity function suppressing neuraminidase;
2) preparation has the product of the growth function suppressing influenza infection cell.
10. a Tamiflu, its activeconstituents is tetravalence zanamivir shown in formula described in claim 1 I.
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| CN111233962B (en) * | 2020-03-12 | 2021-06-04 | 中国科学院微生物研究所 | Influenza virus neuraminidase inhibitor and preparation method and application thereof |
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| US20040058853A1 (en) * | 2000-09-08 | 2004-03-25 | Wen-Yang Wu | Multivalent neuraminidase inhibitor conjugates |
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| Title |
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| Synthesis and 5-lipoxygenase inhibitory activity of new cinnamoyl and caffeoylclusters;Jeremie Doiron et al;《Bioorganic & Medicinal Chemistry Letters》;20091231;第1118-1121页 * |
| Synthesis of C-4 and C-7 triazole analogs of zanamivir as multivalent sialic acid containing scaffolds;Yan Lu et al;《Carbohydrate Research》;20071231;第1636-1650页 * |
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