CN100390183C - Antiviral medicine with rare earth of heteropoly compound - Google Patents
Antiviral medicine with rare earth of heteropoly compound Download PDFInfo
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- CN100390183C CN100390183C CNB2006100166591A CN200610016659A CN100390183C CN 100390183 C CN100390183 C CN 100390183C CN B2006100166591 A CNB2006100166591 A CN B2006100166591A CN 200610016659 A CN200610016659 A CN 200610016659A CN 100390183 C CN100390183 C CN 100390183C
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Abstract
The present invention relates to antiviral medicine with the rare earth of heteropoly compound with functions of hepatitis virus and respirovirus resistance, which is composed of the following general formula of Ap (H2O)q Ay Lnz (H2O) jClXW<12-m> Tim O <40>. n Og, wherein A is cations of K and Na or an aminoacid cation. X is Si, Ge, P or Se. Ln is La, Ce, Pr, Nd, Pr, Sm, Eu, Gd, Tb or Dy. Og is hydroxylamine or hydrazine. P is equal to 4 to 9.5; q is equal to zero to four; y is equal to zero to five; z is equal to 0.5 to 1; i is equal to one to eight; m is equal to one to three; n is equal to one to five. The rare earth of heteropoly compound of the present invention has strong inhibiting effect on hepatitis b viruses, influenza viruses, avian viruses and low toxicity.
Description
Technical field
The invention belongs to the research of chemical synthetic drug hepatitis virus resisting and Respirovirus, specially refer to the research of rare earth of heteropoly compound class chemical synthetic drug anti-hepatitis B virus, influenza virus and avian influenza virus.
Background technology
Virus is one of important pathogenic agent that causes the human infectious disease.In the mankind's transmissible disease, the disease that is caused by virus accounts for 3/4.The disease that is caused by virus has characteristics such as strong, popular wide, the sickness rate height of infectivity.For example now serious threat human health by H5N1 virus causes, its mortality ratio is higher infecting both domestic animals and human disease bird flu; The hepatitis B whole world the infected who is caused by hepatitis B virus surpasses 2,000,000,000 people, and wherein China accounts for 1/3.Studies show that hepatitis B patient develops into the probability of liver cirrhosis and hepatocellular carcinoma than the high 200-250 of normal people times, the infected of 25%-40% so and fatal.In addition, also have some common transmittable diseases that caused by virus, as the acquired immune deficiency syndrome (AIDS) that is caused by HIV virus, the influenza that is caused by influenza virus etc. all belongs to by what virus caused human health is produced the disease of serious harm.Also there is not effective way aspect the human up to now disease that causes by virus in treatment.Antiviral commonly used clinically at present, the nucleoside analogs that belong to more, there is shortcoming such as easily produce resistance, the antivirus action spectrum is narrower, majority has toxic side effect, price is higher and administration time is long in this analogue, to making its widespread use be subjected to very big restriction.Therefore develop high-efficiency low-toxicity, antivirus action wide spectrum, cheap antiviral and become the Chinese scholars problem demanding prompt solution.
The antiviral research of heteropoly compound started from the seventies, found heteropolyanion [SiW first from 1971
12O
40]
4-Had since the leukosis virus of the inhibition activity, find that in succession some heteropoly compound has stronger restraining effect to multiple viruses such as syncytial virus, Measles virus, mumps viruses.The antiviral research of heteropoly compound in recent years mainly concentrates in the research of multiple RNA viruses such as anti HIV-1 virus, influenza virus.Domestic and international research shows that heteropoly compound has the characteristics of good inhibitory effect to multiple RNA viruses and retrovirus.
Summary of the invention
The object of the present invention is to provide a kind of hepatitis virus resisting and respiratory tract disease cytotoxic activity higher, toxicity is lower, and is cheap, the antiviral medicine with rare earth of heteropoly compound that the antivirus action spectrum is wider.
The inventor is on the basis to the antiviral research work of heteropoly compound, characteristics and pathogenesis according to hepatitis B virus, influenza virus and avian influenza virus, utilize heteropoly compound that RNA viruses and retrovirus are had better inhibiting characteristic, discover that rare earth of heteropoly compound all has stronger restraining effect and toxicity lower to hepatitis B virus, influenza virus and avian influenza virus.
Antiviral of the present invention is with general formula A
p(H
2O)
q[A
yLn
z(H
2O)
jClXW
12-mTi
mO
40] the represented rare earth of heteropoly compound of nOg, wherein A is K, Na positively charged ion or amino acid positively charged ion; X is Si, Ge, P or Se; Ln is La, Ce, Pr, Nd, Pr, Sm, Eu, Gd, Tb or Dy in the lanthanon; Og is azanol or hydrazine; Usually p=4-95 under, q=0-4, y=0-5, z=0.5-1, j=1-8, m=1-3, n=1-5.
In the soluble in water or polar organic solvent of this compound, the aqueous solution of antiviral of the present invention is stable in pH=2～8 an o'clock chemical property, and the ph stability of its aqueous solution is according to potentiometric determination.
The preparation method of antiviral medicine with rare earth of heteropoly compound is with Disodium tungstate (Na2WO4) dihydrate 1.82mol; Water glass or SODIUM PHOSPHATE, MONOBASIC or sodium germanate or Sodium Selenite 0.86mol are dissolved in the distilled water of 2000g, drip to contain TiCl
40.32mol after, return and to heat up in a steamer, filter, in filtrate, add 8.1mol basic metal sodium salt or sylvite or amino acid salts and get throw out, throw out obtains the solid of certain mass with 500g hot water recrystallization.A
fXW
12-mTi
mO
40BH
2O, wherein A is K, Na positively charged ion or amino acid positively charged ion; X is Si, Ge, P or Se in the periodictable, f=6～10, m=1～3, b=3～5.The A of certain mass
fXW
12-mTi
mO
40BH
2O is dissolved in 500g water, adds a certain amount of reductive agent and stirs, and adds a certain amount of rare earth chloride again, and stirring is after 3～5 hours down at 90～95 ℃, and filtration is placed, and separates out solid A after several days
p(H
2O)
q[A
yLn
z(H
2O)
jClXW
12-mTi
mO
40] nOg.
Adopt cytopathy political reform, mtt assay, PCR fluorescent quantitation to detect respectively and methods such as virus antigen detection kit are carried out inside and outside toxicity and antiviral activity screening to the compound of above-mentioned preparation.Adopt the interior acute toxicity test method of mtt assay and mouse body to detect the inside and outside toxicity of test-compound respectively.Experimental result shows: rare earth of heteropoly compound of the present invention all has lower than strong restraining effect and toxicity to hepatitis B virus, influenza virus and avian viruses.
Be aided with pharmaceutically acceptable carrier or auxiliary material is applied to treat in the preparation of hepatitis B, influenza, bird flu medicine with rare earth of heteropoly compound of the present invention.
Description of drawings
Fig. 1 is that test-compound the 3rd day is to HBeAg excretory restraining effect;
Fig. 2 is that test-compound the 5th day is to HBeAg excretory restraining effect;
Fig. 3 is that test-compound the 7th day is to HBeAg excretory restraining effect;
Fig. 4 is that test-compound the 9th day is to HBeAg excretory restraining effect;
Fig. 5 is that test-compound effect different time is to HBeAg excretory restraining effect;
Fig. 6 is that test-compound the 3rd day is to HBsAg excretory restraining effect;
Fig. 7 is that test-compound the 5th day is to HBsAg excretory restraining effect;
Fig. 8 is that test-compound the 7th day is to HBsAg excretory restraining effect;
Fig. 9 is that test-compound the 9th day is to HBsAg excretory restraining effect;
Figure 10 is that test-compound effect 2.2.15 cell different time is to HBsAg excretory restraining effect.
Embodiment
The present invention is further elaborated by the following examples.
Embodiment 1
The preparation of antiviral medicine with rare earth of heteropoly compound: be with Disodium tungstate (Na2WO4) dihydrate 1.82mol, SODIUM PHOSPHATE, MONOBASIC 0.86mol is dissolved in the distilled water of 2000 grams, drips to contain TiCl
40.32mol after, return and heated up in a steamer 1 hour, filter, the hydrochloride that adds the 50.2g glycine in filtrate gets white depositions, get the 66g white depositions and be dissolved in 400g water, add the 10g oxammonium hydrochloride, stir, add the 110g Cerium II Chloride, 90～95 ℃ were stirred 3～5 hours down, separate out solid after several days
(HGly)
5[Ce(H
2O)
8ClPTi
2W
10O
40]·NH
2OH
Embodiment 2
The preparation of antiviral medicine with rare earth of heteropoly compound: be with Disodium tungstate (Na2WO4) dihydrate 1.82mol, SODIUM PHOSPHATE, MONOBASIC 0.86mol is dissolved in the 2000g distilled water, drips titanium tetrachloride 0.32mol, backflow l hour, filter, the hydrochloride that adds the 50.2g glycine in filtrate gets white depositions, gets the 66g white depositions and is dissolved in 400g water, adds the 10g hydrazine, stir, add the 11.0g Neodymium trichloride, 90-95 ℃ was stirred 3-5 hour, and separated out solid (HGly) after several days
5[Nd (H
2O)
8ClPTi
2W
10O
40] NH
2OH.
The preparation of antiviral medicine with rare earth of heteropoly compound: be with Disodium tungstate (Na2WO4) dihydrate 1.82mol, SODIUM PHOSPHATE, MONOBASIC 0.86mol is dissolved in the 2000g distilled water, drips titanium tetrachloride 0.32mol, refluxes 1 hour, filter, in filtrate, add the 600g solid sodium chloride and get white depositions, get the 66g white depositions and be dissolved in 400g water, add the 10g hydrazine, stir, add the 11.0g Cerium II Chloride, 90-95 ℃ was stirred 3-5 hour, and separated out solid after several days
Na
4(H
2O)
4{Na
3.5Ce
0.5(H
2O)
8ClPTi
2W
10O
40}·NH
2NH
2。
Embodiment 4
The preparation of antiviral medicine with rare earth of heteropoly compound: be with Disodium tungstate (Na2WO4) dihydrate 1.82mol, SODIUM PHOSPHATE, MONOBASIC 0.86mol is dissolved in the 2000g distilled water, drips titanium tetrachloride 0.32mol, refluxes 1 hour, filter, in filtrate, add the 600g solid sodium chloride and get white depositions, get 66 gram white depositions and be dissolved in 400g water, add 10 gram hydrazines, stir, add the 11.0g samarium trichloride, 90-95 ℃ was stirred 3-5 hour, and separated out solid after several days
Na
4(H
2O)
4{Na
3.5Sm
0.5(H
2O)
8ClPTi
2W
10O
40}·NH
2NH
2。
The acute toxicity of The compounds of this invention detects
Choose body weight 18～22g mouse, be divided into 5 groups at random, 10 every group, male and female half and half, routine feeding 3～5 days, healthy person is used for experiment.Fasting 12h before the experiment, 3h feeding after the administration.Negative control group: oral normal saline; Experimental group: totally 6 dosage groups are respectively 406.23,641.85,1014.12,1602.31,2531.65, the 4000mg/kg body weight.Press the 0.2ml/10g body weight, gastric infusion of per os, the poisoning manifestations of observing mouse after the administration is observed 14d continuously, the record death toll, experimental result sees Table 1.Calculate mld LD50 with the improvement karber's method, be subjected to the toxic grade of reagent thing according to WHO toxicity grading standard evaluation.
Table 1
Embodiment 6
The compounds of this invention detects the toxicity of 2.2.15 cell
Get the 2.2.15 cell that is in exponential phase of growth, transferring cell concn with the IMDM nutrient solution that contains 10% foetal calf serum is 5 * 10
4/ ml adds 200 μ l single cell suspensions in 96 well culture plates, in 37 ℃, and 5% CO
2Overnight incubation under the condition.Supernatant is abandoned in suction, and the every hole of experimental group adds the nutrient solution 200 μ l that contain the different concns compound, and maximum concentration is 2000 μ g/ml, and minimum concentration is 125 μ g/ml, doubling dilution.The every hole of negative control group adds the IMDM nutrient solution 200 μ l that contain 10% foetal calf serum, in 37 ℃, and 5% CO
2Cultivate 48h under the condition.The every hole of 4h added MTT liquid (5mg/ml) 20 μ l before experiment finished, and cultivated 4h again, abandoned supernatant, and every hole adds 150 μ l DMSO, vibrated 5 minutes, measured the OD value with microplate reader under the 490nm wavelength.Each concentration three multiple hole.Experimental result is as shown in table 2, calculates the half-inhibition concentration EC of each compound to the 2.2.15 cell respectively
50
Table 2
Embodiment 7
The compounds of this invention detects the restraining effect of HBeAg, HBsAg
Get the 2.2.15 cell that is in logarithmic phase, transferring cell concn with the IMDM nutrient solution that contains 10% foetal calf serum is 5 * 10
4/ ml, every hole adds single cell suspension in 24 well culture plates, in 37 ℃, 5% CO
2Cultivate under the condition, cell grows to the every hole of experimental group when converging and adds the cell culture fluid that contains the different concns test-compound, and maximum concentration is 360 μ g/ml, and doubling dilution, minimum concentration are 28 μ g/ml.The every hole of negative control group adds the IMDM nutrient solution that contains 10% foetal calf serum, and the every hole of positive controls adds the nutrient solution that contains different concns Lamivudine, continues to cultivate.Collect supernatant liquor, replenish isopyknic cell culture fluid that contains the different concns test-compound simultaneously.After collecting supernatant liquor on the 9th day after the dosing, collect the 2.2.15 cell, PBS is suspended in the Eppendorf pipe, adds DEPC-H
2O ,-70 ℃ frozen.Get the supernatant liquor that different time is collected, with the restraining effect of hepatitis B virus e (s) antigen diagnose reagent kit detection compound pair cell secretion HBeAg, HBsAg.
Test-compound sees Table 3 and accompanying drawing 1-5 to the restraining effect of HBeAg, as can be seen from the table along with the increase of test-compound concentration, test-compound strengthens HBeAg excretory restraining effect, test-compound is the highest at the 5th day to HBeAg excretory inhibiting rate, drug level is that 22.5 μ g/ml inhibiting rates reach 50.27%, and drug level is that 360 μ g/ml inhibiting rates reach 9947%.
Table 3
Test-compound sees Table 4 and accompanying drawing 6-10 to the restraining effect of HBsAg.
As can be seen from the table, increase along with test-compound concentration, test-compound strengthens HBsAg excretory restraining effect, when the secretory volume of drug effect HBsAg in the time of the 9th day all has been subjected to obvious suppression, wherein test-compound concentration is that 56 μ g/ml reach 52.12% to HBsAg secretory volume inhibiting rate.
Table 4
Embodiment 8
The PCR fluorescent quantitation detects the restraining effect of The compounds of this invention to 2.2.15 extracellular HBV DNA
With certain density test-compound effect 2.2.15 cell, HBV DNA in the supernatant liquor of collecting with different time uses HBV DNA in Roche hepatitis B virus (HBV) nucleic acid amplification (PCR) the fluorescence quantitative detection kit quantitative analysis supernatant liquor.The results are shown in Table 5, be subjected to the reagent thing that supernatant HBV DNA is all had restraining effect as can be seen from the table.
Table 5
Southern blot method detects the restraining effect of The compounds of this invention to HBV DNA in the 2.2.15 cell.
With certain density test-compound effect 2.2.15 cell, the 9th day collecting cell extracts genomic dna, adopts Southern blot method to detect the restraining effect of HBV DNA in the test-compound pair cell.The experimental result demonstration is strengthened by the restraining effect of HBV DNA in the reagent thing pair cell along with test-compound concentration increases, trace obviously shoals.
Test-compound is to the research of HBV DNA knock-on in the 2.2.15 cell
Get be in logarithmic phase the 2.2.15 cell inoculation in 24 well culture plates, cell grows to when converging the every hole of experimental group and adds and contain different pharmaceutical concentration nutrient solution, maximum concentration is 360 μ g/ml, doubling dilution, minimum concentration are 2.8 μ g/ml.The every hole of negative control group adds the IMDM nutrient solution, and positive controls adds and contains different concns Lamivudine nutrient solution.Collect supernatant liquor, replenish isopyknic nutrient solution that contains different pharmaceutical simultaneously.Remove the dosing nutrient solution in dosing suction in the 6th day, add the nutrient solution that does not contain test-compound and continue to cultivate.Use HBV dna content in the cell conditioned medium liquid after Roche hepatitis B virus (HBV) nucleic acid amplification (PCR) fluorescence quantitative detection kit is measured pharmaceutically-active cell and drug withdrawal respectively, found that the content of HBV DNA does not have obvious rebound phenomenon after the drug withdrawal, and in the pharmaceutically-active cell conditioned medium liquid between the HBV dna content comparative statistics difference do not have significance.
The compounds of this invention detects dog kidney (MDCK) cytotoxicity
Mdck cell is made suspension and transferred concentration to 2 * 10 with 2%FCS-IMDM
5Individual/ml, be inoculated in 96 well culture plates by 200 μ l/ holes, put into 37 ℃, 5% CO
2Cultivate 24h in the incubator.Treat to discard original fluid after cell covers with individual layer.Experiment is divided into normal cell control group and experimental group, and every kind of compound is established 11 concentration groups, and each group is all established four multiple holes, 200 μ l/ holes.Culture plate is moved into 37 ℃, 5% CO
2Cultivate the form and the variation of observation of cell under the every day inverted microscope, record cytopathy (CPE) degree in the incubator of saturated humidity condition.
Tetramethyl-azo azoles indigo plant (MTT) staining is measured compound pair cell toxicity, add 5mg/ml MTT solution 10 μ L to each hole, after equal conditions continues down to cultivate 4h, the careful suction abandoned supernatant liquor in the hole, adds DMSO100 μ L/ hole, concussion 10min, in microplate reader, wavelength 570nm place measures each hole OD value, presses the median toxic concentration (TC of Reed-Muench method computerized compound to mdck cell
50).The results are shown in Table 6.More than operation is all carried out under aseptic condition.
Table 6
Embodiment 12
The compounds of this invention resisiting influenza virus H1N1 is active to be detected
96 well culture plates that will grow up to the individual layer mdck cell, except that control group, all the other are each winding kind 100TCID all
50H1N1,100 μ l/ holes, 37 ℃, 5% CO
2Behind the absorption 2h, discard viral liquid in the incubator of saturated humidity condition.The normal control group not infective virus, do not add compound; The virus control group, infective virus does not add compound: positive controls amantadine group; Tried the thing experimental group, added each compound TC
0Below the soup of 9 different concns.Each group is all established four multiple holes, 200 μ l/ holes.37 ℃, 5% CO
2Cultivate in the incubator of saturated humidity condition, observe continuously.Adopt the MTT staining, measure each hole OD value at wavelength 570nm place.More than operation is all carried out under aseptic condition.The record result also calculates each compound suppresses pathological changes caused by virus under different concns percentage, presses the half-inhibition concentration (IC that Reed-Muench method computerized compound suppresses virus
50).The results are shown in Table 7.
Table 7
Embodiment 13
The The compounds of this invention anti virus H 5 N 1 of bird flu is active to be detected
96 well culture plates that will grow up to the individual layer mdck cell, except that control group, all the other are each winding kind 50TCID all
50H5N1,100 μ l/ holes, 37 ℃, 5% CO
2Behind the absorption 2h, discard viral liquid in the incubator of saturated humidity condition.The normal control group not infective virus, do not add compound; The virus control group, infective virus does not add compound; Positive controls reaches non-group; Tried the thing experimental group, added each compound TC
0Below the soup of 9 different concns.Each group is all established four multiple holes, 200 μ l/ holes.37 ℃, 5% CO
2Cultivate in the incubator of saturated humidity condition, observe continuously.Adopt the MTT staining, measure each hole OD value at wavelength 480nm place.More than operation is all carried out under aseptic condition.The record result also calculates each compound suppresses pathological changes caused by virus under different concns percentage, presses the half-inhibition concentration (IC that Reed-Muench method computerized compound suppresses virus
50).The results are shown in Table 8.
Table 8
Embodiment 14
The preparation of The compounds of this invention treatment hepatitis B oral pharmaceutical
Effective dose in the foregoing description is put into mixing tank stirred 15 minutes, slowly add honey, sucrose, citric acid, Magnesium Stearate while stirring, add an amount of distilled water after mixing, make solution behind the mixing, dry filter is made tablet.
Effective dose in the foregoing description is put into mixing tank stirred 15 minutes, slowly add starch, pure water while stirring, high-speed stirring 15 minutes, wet grain is crossed 16 mesh sieves, puts 60 ℃ of whole grains of drying in the baking box, adds Magnesium Stearate, be mixed, the capsule of packing into No. 0 of sterilizing is made capsule.
Embodiment 15
The preparation of The compounds of this invention treatment hepatitis B injectable drug
Get effective dose in the foregoing description with filtering with microporous membrane, be sub-packed in the peace bottle with the amount of every bottle of 2.0ml, intensification gradually through-70 ℃ of precoolings after obtains preparing the dried frozen aquatic products of compound.
Claims (4)
1. the rare earth of heteropoly compound with antivirus action is characterized in that described rare earth of heteropoly compound is made of following general formula: A
p(H
2O)
q[A
yLn
z(H
2O)
jClXW
12-mTi
mO
40] nOg,
Wherein: A is K, Na positively charged ion or amino acid positively charged ion; X is Si, Ge, P or Se; Ln is La, Ce, Pr, Nd, Pr, Sm, Eu, Gd, Tb or Dy in the lanthanon; Og is azanol or hydrazine; P=4-9.5, q=0-4, y=0-5, z=0.5-1, j=1-8, m=1-3, n=1-5.
2. the application of the described rare earth of heteropoly compound of claim 1 in preparation treatment hepatitis B medicament.
3. the application of the described rare earth of heteropoly compound of claim 1 in preparation treatment bird flu medicine.
4. the application of the described rare earth of heteropoly compound of claim 1 in preparation treatment influenza medicine.
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| CN101161248B (en) * | 2007-11-06 | 2011-05-04 | 辽宁大学 | Novel anti-hepatitis B virus medicine preparing method |
| CN104445417B (en) * | 2014-11-17 | 2017-03-15 | 西安石油大学 | A kind of synthetic method of annular arsenous tungsten heteropoly compound |
Citations (1)
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|---|---|---|---|---|
| CN1669655A (en) * | 2004-12-30 | 2005-09-21 | 中国科学院成都有机化学有限公司 | Heterocompound catalyst for synthesizing diphenyl carbonate by ester exchange |
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| CN1669655A (en) * | 2004-12-30 | 2005-09-21 | 中国科学院成都有机化学有限公司 | Heterocompound catalyst for synthesizing diphenyl carbonate by ester exchange |
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