CN103992216B - Houttuynine sodium bisulfite metal complexes preparation method and application thereof - Google Patents
Houttuynine sodium bisulfite metal complexes preparation method and application thereof Download PDFInfo
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Abstract
The present invention relates to the metal complexes of a kind of houttuynine sodium bisulfite class (alkane acyl acetaldehyde homologue), its structural formula is as shown in formula I.Decanoylacetaldehyde zinc, magnesium two kinds of title complexs of the present invention's synthesis are white solid, are insoluble in water, are soluble in the organic solvents such as trichloromethane; The decanoylacetaldehyde calcium of the present invention's synthesis is micro-yellow solid, water-soluble and organic solvent hardly.Title complex has antimicrobial antiphlogistic effect, and particularly in vitro and in vivo test proves there is decorporation effect to the heavy metal such as copper, lead, and toxicity is very low, is potential metal detoxification medicine.
Description
Technical field
The present invention relates to houttuynine sodium bisulfite metal complexes preparation method and application thereof.
Background technology
The chemistry of houttuynine sodium bisulfite is called decanoylacetaldehyde, and be the main antibiotic effective ingredient of Chinese Medicinal Houttuynia Cordata Thunb, unbound state is oily liquids, is very easily polymerized inefficacy.China's synthetic in 1972 Houttuynin sodium bisulfite affixture, general Sodium Houttuyfonate by name, white crystal is China's legal medicine.The eighties China has synthesized again dodecanoyl syntheticum affixture, general Sodium New Houttuyfonate by name, and its physico-chemical property is similar to Sodium Houttuyfonate with drug effect, is also classified as China's legal medicine, all for clearing heat and detoxicating, antisepsis and anti-inflammation.The nearly several years; Chinese scholar have developed again multiple houttuynine sodium bisulfite class homologue in succession, and carried out different modification transformations to the alkane chain of alkyloyl, groundwork is the increase and decrease of alkane chain length; their physico-chemical property and pharmacologically active and Sodium Houttuyfonate basic simlarity, do not have substantial change.Scholar unanimously thinks that the active group of houttuynine sodium bisulfite is containing oxygen part, but the research of this respect is very few.(the structure activity relationship present situation of houttuynine sodium bisulfite compounds, pharmacy is in progress, and 2009,33 (6): 163-166; The progress of synthesis of houttuynine sodium bisulfite derivative, Shenyang Medical College journal, 2010,12 (4): 241-244).
Due to the metallic element medicine of environment (water, air, soil etc.), food pollution, occupational poisoning, overdose, and human metalloproteinase metabolic disturbance etc. causes body metal poisoning, particularly the environmental pollution of current China is serious, metal acute poisoning and the poisoning problem of chronic savings increasingly outstanding, caused showing great attention to of government and society.Treatment metal poisoning toxinicide just like dimercaprol dimercaptopropanol (BAL), Ethylenediaminetetraacetic Acid Calcium Salt, Trolovol, dimercaptosuccinic acid (DMSA), dimercaptopropane sulphonate (DMPS), desferrioxamine, they have good detoxification to certain or some metal, but also there are some shortcomings, as comparatively large in toxic side effect, use inconvenience, the necessary drug administration by injection had, some meetings " take away " metallic element etc. required in body in the lump.Although the organic ligand with powerful coordination is a lot, how medicine can not be become because toxicity is large or drain the reasons such as mechanism.The metal detoxification medicine of nearly several years new listing is little, and alternative kind is few clinically at present, particularly to the toxicide of chronic savings metal poisoning.
Metal antidote, with regard to chemical structure, is all generally can play the ligand (sequestrant) of coordination with metallic element.Decanoylacetaldehyde possesses this condition, but the Sodium Houttuyfonate generated after decanoylacetaldehyde and sodium bisulfite addition can not directly and metallic element play coordination, therefore just can not become metal antidote.
The molecular structure that the present invention is based on decanoylacetaldehyde (comprising alkane acyl acetaldehyde homologue) contains beta-dicarbonyl functional group, its keto-acid and enol form can tautomerisms, there are two ligating atoms, be one good in oxygen ligand, metal complexes can be generated with some metal ion.Accordingly, we have developed decanoylacetaldehyde metal complexes, about this type of research has no bibliographical information.Although the decanoylacetaldehyde zinc (magnesium, calcium) of the present invention's synthesis is inherently title complex, but the stability of the title complex that their stability generates far below some harmful metal ion and decanoylacetaldehyde, due to the difference of this stability, when some harmful metal elements runs into decanoylacetaldehyde zinc, just may capture zinc displacement and generate more stable new decanoylacetaldehyde metal complexes.Here it is, and decanoylacetaldehyde zinc (magnesium, calcium) may become the chemical fundamentals of potential metal antidote.Bibliographical information zinc has lead-eliminating effect (trace elements and health is studied, 2011,28 (4)), and clinical treatment liver acne shape nuclear degeneration patient also gives zinc sulfate.Therefore also there is the decorporation effect strengthened poisonous metal from the zinc that decanoylacetaldehyde zinc cements out by poisonous metal.
In a word, the present invention has synthesized decanoylacetaldehyde zinc, magnesium, calcium three kinds of title complexs.Decanoylacetaldehyde zinc, magnesium complex are white solid, are insoluble in water, are soluble in the organic solvents such as trichloromethane; Decanoylacetaldehyde calcium is micro-yellow solid, hardly water-soluble and organic solvent.Title complex has antimicrobial antiphlogistic effect, and particularly in vitro and in vivo test proves there is decorporation effect to the heavy metal such as copper, lead, and toxicity is very low, is potential metal detoxification medicine.
Summary of the invention
The present invention is intended to overcome the deficiencies in the prior art, provides a kind of houttuynine sodium bisulfite metal complexes and its preparation method and application.
In order to achieve the above object, technical scheme provided by the invention is:
Described houttuynine sodium bisulfite metal complexes has the structure shown in formula I.
Wherein, R is CH
3(CH
2)
3-15-
M is Zn
2+, Mg
2+or Ca
2+.
The preparation method of above-mentioned houttuynine sodium bisulfite metal complexes comprises the steps:
(1) with deionized water solving zinc salt, magnesium salts or calcium salt, then the ammonia solution dripping 1-5mol/L dissolves completely to the precipitation generated, and must contain zinc, magnesium or calcium ion mass percentage content is the ammonia solution of 0.1-1%;
(2) with concentration of volume percent be 10-100% dissolve with ethanol solution Sodium Houttuyfonate, obtain the houttuynine sodium bisulfite sodium ethoxide solution that Sodium Houttuyfonate mass percentage content is 0.5-5%;
(3) houttuynine sodium bisulfite sodium ethoxide solution is added in ammonia solution, the volume ratio of houttuynine sodium bisulfite sodium ethoxide solution and ammonia solution is 1:0.2-1:1, add water stirring, generation is precipitated, filter, wash with water and be precipitated to filtrate in neutral, drain precipitation, obtain filter cake, by filter cake in 40-105 DEG C of dryings, cool recrystallizations with after the reflux such as ethanol, water, methyl alcohol, acetone or chloroform in-20-10 DEG C, drain precipitation, obtain filter cake, by filter cake in 40-105 DEG C of dryings, obtain compound shown in formula I.
Upper houttuynine sodium bisulfite metal complexes can be applicable to prepare metal decorporation medicine, and medicine can be prepared into any formulation be suitable for clinically.
Below in conjunction with principle, the invention will be further described:
One, preparation method and chemical structure characterize
Decanoylacetaldehyde is produced in Sodium Houttuyfonate hydrolysis immediately in basic solution, forms the tautomer of aldehyde ketone formula and enol form simultaneously, and with metal ion generation sequestering action, generate corresponding inner complex, principal reaction is as follows:
R＝CH
3(CH
2)
3～15-
M＝Zn
2+,Mg
2+,Ca
2+
Preparation method:
Get zinc sulfate (or other zinc salts) to be dissolved in water, drip 1-5mol/L ammonia solution to the resolution of precipitate generated, filter, obtain clear and bright liquid (be the ammonia solution of 0.1-1% containing zine ion mass percentage content); Separately get Sodium Houttuyfonate, add the warm dissolving of 55% ethanol; By Sodium Houttuyfonate ethanol slowly gradation join (volume ratio of houttuynine sodium bisulfite sodium ethoxide solution and ammonia solution is 1:0.2-1:1) in ammonia zinc solution, limit edged stirs, and thin up, namely adularescent precipitation generates, and filters, and washes with water and is precipitated to filtrate in neutral, drain precipitation, obtain filter cake, by filter cake in 60 DEG C of dryings, cool recrystallizations with after alcohol heating reflux in-20-10 DEG C, drain precipitation, obtain filter cake, by filter cake in 60 DEG C of dryings, obtain houttuynine sodium bisulfite Zn complex.
The preparation method of magnesium complex is similar, gets magnesium salts preparation.
The preparation method of calcium chelate gets calcium carbonate saturated solution and Sodium Houttuyfonate ethanol to react and generate houttuynine sodium bisulfite calcium composition.
Physico-chemical property and chemical structure:
Houttuynine sodium bisulfite zinc, magnesium, calcium chelate are white solid powder, are insoluble in water, and zinc, magnesium compound have lipotropy, and calcium cpd solvability is very poor.
Quality determination proves, houttuynine sodium bisulfite zinc (magnesium, calcium) is that molecular composition is compared for 2 of 2:1 symmetrical six-membered cyclic inner complexs, and molecular formula is respectively C
24h
42o
4zn, molecular weight are 459.9; C
24h
42o
4mg, molecular weight are 418.8; C
24h
42o
4ca, molecular weight are 434.4; Structural formula is as shown in general formula.
Two, acute toxicity test in mice
It is 3.1g/kg (2.7---3.6g/kg) that mld is measured in mouse stomach administration.
Three, metal decorporation test
3.1, chemical experiment method
Houttuynine sodium bisulfite zinc respectively with Pb
2+, Cu
2+reaction, measure with atomic absorption graphite tube spectrometry, test-results shows, Pb
2+reaction rate of displacement be 38%, Cu
2+reaction rate of displacement up to 99%.
3.2, animal decorporation test
Make high lead poisoning model to rat plumbic acetate solution of feeding continuously, then give gavage and give houttuynine sodium bisulfite zinc, test-results shows, houttuynine sodium bisulfite zinc significantly can reduce lead content in the brain of Lead-poisoning Rats, bone, liver and blood, increases lead content in urine simultaneously.
Embodiment
Embodiment 1
One, preparation method
Houttuynine sodium bisulfite Zn complex:
Get zinc sulfate (ZnSO47H2O) (or other zinc salts) 5g (amount ratio mol ratio is excessive), add deionized water (lower same) 300mL and make dissolving, drip 4mol/L ammonia solution to dissolve completely to the precipitation generated, filter to obtain clear and bright filtrate; Separately get Sodium Houttuyfonate 10g and add 55% ethanol 500mL warm dissolving in water-bath, filter, by filtrate slowly gradation join in above-mentioned obtained zinc ammonia solution, limit edged stirs, and finishes the 500mL that adds water again, stirs, precipitation is fully generated, filter, precipitation washes with water, to filtrate in neutral, drain, 60 DEG C of dryings, alcohol reflux dissolves, in 0-10 DEG C of refrigerator, place the recrystallization that spends the night.
Houttuynine sodium bisulfite magnesium inner complex:
Get magnesium sulfate (MgSO47H2O) (or other magnesium salts) to operate by chelates of zinc preparation method.
Houttuynine sodium bisulfite calcium chelate:
Get calcium carbonate (CaCO3) to add water and make saturated solution, get saturated solution 500mL and to add water 500mL dilution, filter for subsequent use.Separately get Sodium Houttuyfonate 10g and add 55% ethanol 500mL warm dissolving in water-bath, filter, by filtrate slowly gradation join in above-mentioned obtained calcium carbonate saturated solution, fully stir, by sedimentation and filtration, wash with water to neutrality, drain, 60 DEG C of dryings.
Two, molecular structure confirmation and physico-chemical property
2.1 houttuynine sodium bisulfite zinc
2.1.1 essential information
Product designation: HZ
Structural formula:
Molecular formula: C
24h
42o
4zn
Molecular weight: 459.96
2.1.2. proterties: this product is white or off-white powder, slightly fishy smell.Easily molten in chloroform, soluble,very slightly in the hydrochloric acid of methyl alcohol, acetone, ether, sherwood oil, 1mol/L and the sodium hydroxide solution of 1mol/L; Almost insoluble in water.
2.1.3. fusing point: 122 ~ 127 DEG C.
2.1.4. ultra-violet absorption spectrum
In the interscan of 200-400nm scope, it is 281nm that the ethanolic soln of HZ records maximum absorption wavelength.
2.1.5. nuclear magnetic resonance spectrum (see table 1 and 2)
Table 1HZ hydrogen spectrum measurement result
Table 2HZ carbon spectrum measurement result
| Chemical shift (ppm) | Ownership | Remarks |
| 13.92 | C 13 | CH 3 |
| 22.07 | C | CH 2 |
| 25.92 | C | CH 2 |
| 28.69 | C | CH 2 |
| 28.78 | C | CH 2 |
| 28.92 | C | CH 2 |
| 31.28 | C | CH 2 |
| 39.52 | C | CH 2 |
| 40.58 | C 4 | CH 2 |
| 100.27 | C 2 | CH |
| 181.00 | C 1 | CH |
| 197.16 | C 3 | C＝O |
1in H-NMR spectrum, desolventize outside peak and have 5 groups of peaks, its integration ratio (by low field to High-Field) is 1:2:2:14:3, and this product is complex compound, and structure has symmetry, shows to have 42 protons.The proton number of this product is 42, and the proton number provided with spectrum conforms to.
13in C-NMR spectrum, desolventize outside peak and have 12 to compose peak, owing to being complex compound, structure has symmetry, conforms to 24 carbonatomss contained in this product molecule.
2.1.6. mass spectrum
[M-H] of this product
+the mass-to-charge ratio at peak is 459.1, shows that the molecular weight of this product is 459, conforms to the molecular weight of HZ.Houttuynine sodium bisulfite magnesium: NMR is similar to houttuynine sodium bisulfite zinc, MS [M+H]
+the mass-to-charge ratio at peak is molecular formula C
24h
42o
4mg, 418.9.
Houttuynine sodium bisulfite calcium: water insoluble and common organic solvents, NMR cannot measure.MS [M+H]
+the mass-to-charge ratio at peak is 435.5, molecular formula C
24h
42o
4ca, 434.4.
2.2 houttuynine sodium bisulfite calcium
2.2.1. essential information
Product designation: HC
Structural formula:
Molecular formula: C
24h
42o
4ca
Molecular weight: 434.4
2.2.2. proterties: this product is micro-yellow powder, slightly fishy smell.Soluble,very slightly in the hydrochloric acid of methyl alcohol, acetone, chloroform, ether, sherwood oil, 1mol/L and the sodium hydroxide solution of 1mol/L; Almost insoluble in water.
2.2.3. fusing point: be greater than 250 DEG C, cannot measure.
2.2.4. nuclear magnetic resonance spectrum
Because solubleness is minimum, do not find the deuterated reagent that polarity is minimum in laboratory, and all do not obtain desirable nuclear-magnetism spectrum with deuterochloroform and deuterated DMS, being that solubleness is too little in existing deuterated solvent causes the reason that signal is too low.
2.2.5. mass spectrum
[M+H] of this product
+the mass-to-charge ratio at peak is 435.5, shows that the molecular weight of this product is 434, conforms to the molecular weight of HZ-Ca.
Three, HZ and Pb
2+vitro reactions test
Vitro Experimental Results: HZ in vitro with Pb
2+there is displacement to a certain degree.
1. measure Pb by graphite furnace atomic absorption spectrometry
2+with Pb in solution before and after HZ reaction
2+concentration, result records its maximum reactivity and is about 36%.
2. use ultraviolet absorption spectroscopy to measure HZ with Pb
2+before and after reaction, in solution, HZ is in the absorbancy of maximum absorption wave strong point, and result records its maximum reactivity and is about 38%.
Note: reactivity=[(C
strength of solution before reaction-C
strength of solution after reaction)/C
strength of solution before reaction] * 100%
Below HZ and Pb
2+and Cu
2+vitro reactions test specific experiment and result
4.1. ultraviolet absorption spectroscopy is used to measure HZ and Pb
2+the absorbancy of HZ in solution before and after vitro reactions
4.1.1 experiment purpose
Prove HZ energy and Pb by experiment
2+reaction.
4.1.2 experimental principle
Ultraviolet absorption spectroscopy is used to measure HZ with Pb
2+in the solution of reaction front and back, HZ is in the absorbancy of maximum absorption wave strong point, if the absorbancy of HZ lower than the absorbancy of HZ in solution before reaction, then can prove HZ energy and Pb in the rear solution of reaction
2+reaction.
4.1.3 experimental technique and result
4.1.3.1 the preparation of solution
4.1.3.1.1 lead nitrate (Pb (NO
3)
2) solution
4.1.3.1.1.1 lead nitrate solution A accurately takes lead nitrate 41.72mg in 25mL volumetric flask, is dissolved in water and is settled to scale, and lead nitrate concentration is 1.667mg/mL.
4.1.3.1.1.2 under lead nitrate solution B gets 3.1.1.1 item, solution 15mL is in 25mL volumetric flask, is dissolved in water and is settled to scale, and lead nitrate concentration is 1.0002mg/mL.
4.1.3.1.1.3 under lead nitrate solution C gets 3.1.1.1 item, solution 2mL is in 10mL volumetric flask, is dissolved in water and is settled to scale, and lead nitrate concentration is 0.3334mg/mL.
4.1.3.1.2HZ solution
Accurately take HZ31.32mg in 50mL volumetric flask, add dissolve with ethanol and be settled to scale, its concentration is 0.6264mg/mL.
4.1.3.1.3 reaction
After preparing solution by table 3, in 37 DEG C of heating in water bath 2h, jolting in every 15 minutes once.
Table 3
4.1.3.2 the mensuration of solution
Each solution after reaction is transferred in 10mL measuring bottle, adds water and be settled to scale, after jolting, cross 0.45 μm of filter membrane, blank is done with water, the above-mentioned reaction solution of sequentially determining (210nm-350nm), has maximum absorption at 281nm place, each solution in this place's absorbancy as table 4:
Table 4
4.1.4 experiment conclusion
By this experiment, after can finding out reaction, in solution, the concentration of HZ, lower than the concentration of reacting HZ in front solution, proves HZ energy and Pb
2+reaction, and the concentration of lead is higher, in reaction solution, remaining HZ concentration is lower, and highest response rate is about 38%.
4.2. graphite furnace atomic absorption spectrometry measures Pb
2+and Cu
2+pb in solution before and after reacting with HZ
2+and Cu
2+concentration
4.2.1 experiment purpose
Prove Pb by experiment
2+, Cu
2+the Zn in HZ can be replaced
2+.
4.2.2 experimental principle
Graphite oven atomic absorption is used to measure Pb respectively
2+and Cu
2+with Pb in solution before and after HZ reaction
2+and Cu
2+concentration, if Pb in solution after reaction
2+, Cu
2+concentration lower than Pb in solution before reaction
2+, Cu
2+concentration, then can prove Pb
2+, Cu
2+the Zn in HZ can be replaced
2+.
4.2.3 experimental technique
4.2.3.1 the preparation of solution
4.2.3.1.1 lead nitrate (Pb (NO
3)
2) solution
Accurately take lead nitrate 0.0151g in 100mL volumetric flask, be dissolved in water and be settled to scale, its concentration is 0.151mg/mL.
4.2.3.1.2 cupric nitrate (Cu (NO
3)
2.3H
2o) solution
Accurately take cupric nitrate 0.0518g in 50mL volumetric flask, be dissolved in water and be settled to scale, cupric nitrate concentration is 1.036mg/mL.
4.2.3.1.3HZ solution
Accurately take HZ0.0501g in 25mL volumetric flask, add dissolve with ethanol and be settled to scale, its concentration is 2.004mg/mL.
4.2.3.1.4 reaction solution
4.2.3.1.4.1 accurately pipette lead nitrate solution 1mL+ ethanol 1mL to mix, cross 0.45 μm of filter membrane, as unreacted solution.Separately accurately pipette lead nitrate solution 1mL+HZ solution 1mL to mix, prepare 5 parts of solution altogether, after 37 DEG C of water-baths heat 1h, 2h, 3h, 4h, 5h respectively, take off clear liquid and cross 0.45 μm of filter membrane, as solution after reaction.
4.2.3.1.4.2 accurately pipette copper nitrate solution 1mL+ ethanol 1mL to mix, cross 0.45 μm of filter membrane, as unreacted solution.Separately accurately pipette copper nitrate solution 1mL+HZ solution 1mL to mix, prepare 5 parts of solution altogether, after 37 DEG C of water-baths heat 1h, 2h, 3h, 4h, 5h respectively, take off clear liquid and cross 0.45 μm of filter membrane, as solution after reaction.
4.2.3.1.5 plumbous standardized solution
Accurately pipette plumbous standardized solution (1000 μ g/mL) 20 μ L, be settled to 2.0mL (10 μ g/mL) with ultrapure water, more therefrom get 10 μ L, be settled to 2.0mL (50ng/mL) with ultrapure water.
4.2.3.1.6 copper standardized solution
Accurately pipette copper standardized solution (1000 μ g/mL) 20 μ L, be settled to 2.0mL (10 μ g/mL) with ultrapure water, more therefrom get 10 μ L, be settled to 2.0mL (50ng/mL) with ultrapure water.
4.2.3.2 the mensuration of solution
Graphite furnace atomic absorption spectrophotometer is adjusted to optimum regime, using the lead mark liquid of 50ng/mL and copper mark liquid as mother liquor, after automatic preparation typical curve, measures the absorbancy (if reaction solution concentration is too high, sample introduction after dilution) of each reaction solution.
4.2.4 experimental result
4.2.4.1 lead nitrate and HZ reaction result
4.2.4.1.1 typical curve
Record absorbancy under each concentration as table 5:
Table 5
| Concentration | 0 | 10 | 20 | 30 | 40 | 50 |
| (ng/mL) | ||||||
| Absorbancy | 0.0033 | 0.0501 | 0.1011 | 0.1457 | 0.1875 | 0.2355 |
Its curvilinear equation is: Abs=0.00462 × C+0.00499; R=0.9996.
4.2.4.1.2 the mensuration (table 6) of reaction soln
Table 6
4.2.4.2 cupric nitrate and HZ reaction result
4.2.4.2.1 typical curve
Record absorbancy under each concentration as table 7:
Table 7
Its curvilinear equation is: Abs=0.00565 × C+0.01291; R=0.9995.
4.2.4.2.2 the mensuration (table 8) of reaction soln
Table 8
4.2.5 experiment conclusion
By this experiment, Pb in the rear solution of reaction can be found out
2+, Cu
2+concentration lower than Pb in solution before reaction
2+, Cu
2+concentration, prove Pb
2+and Cu
2+the Zn in HZ can be replaced
2+.
Five. decanoylacetaldehyde zinc acute toxicity test in mice
This research of this experimental study adopts ICR mouse stomach to give the decanoylacetaldehyde zinc of various dose, the degree understanding toxic reaction from the acute toxicity tests of mouse and the organ related to.
5.1. experiment material
5.1.1 trial-product
Decanoylacetaldehyde zinc is tested Science and Technology Ltd. by Hunan Pu Ruima new drug and is provided, and center code name: HZ is white powder, content: 99%, specification: 70g/ bag, lot number: 20120815, valid until in August, 2013.Preparation employing 0.5% Xylo-Mucine is mixed with suspension.
5.1.2 laboratory animal
ICR mouse 60, SPF level, male and female half and half, body weight 18 ~ 22g, above animal is all purchased from Hunan Si Laike Jing Da laboratory animal company limited, laboratory animal production licence number: SCXK (Hunan) 2011-0003, Quality of Experimental Animals conformity certification number: NO.4304702700; Raise at Drug Safety Evaluation Center of Hunan Province's barrier environment, laboratory animal occupancy permit number: SYXK (Hunan) 2010-0008.
5.2. test method (table 9)
ICR mouse 60, male and female half and half, body weight 18 ~ 22g, is divided into 6 groups at random, is respectively negative control group, HZ5g/kg, 3.7g/kg, 2.8g/kg, 2.1g/kg, 1.5g/kg group, often organizes 10.Before experiment, fasting 16 hours, then gives the HZ liquid of 0.5%CMC-Na and various dose, the same day 1 time respectively by 40ml/kg volume gavage.Administration same day, especially after administration on the same day, in 0 ~ 4 hour, closely examine the poisoning manifestations recording each treated animal and feature, toxic reaction appearance and time of recovery and death condition etc., observe 2 every day, morning and afternoon is each once, respectively at before administration administration on the same day and administration animal was weighed in the 4th day, the 7th day, the 10th day and the 14th day, the change of record the weight of animals, xicity related reaction and death condition.
Table 9 its mouse oral gavages HZ acute toxicity test dose design
5.2.1 statistical method:
Statistical analysis selects SPSS16.0, and measurement data all adopts mean ± standard deviation
represent, compare between two groups variance neat time adopt t inspection, P≤0.05 indicates statistical significance, and P≤0.01 represents that the difference checked is very significant.
5.3. results and analysis
5.3.1 animal dead situation: ICR mouse by 40mL/kg respectively gavage give the HZ of 5.0g/kg, 3.7g/kg, 2.8g/kg, 2.1g/kg, 1.5g/kg, each dosage treated animal mortality ratio is respectively 100%, 70%, 40%, 0%, 0%.
6.3.2 on the impact of general activity situation: after gastric infusion terminates in 0 ~ 4 hour, negative control group mouse autonomic activities reduces, no abnormality seen, Continuous Observation 14 days, no abnormality seen; HZ5 dosage group mouse upon administration about 30min starts, and all appearance activity reduces, the symptom such as to roll up, and wherein 5.0g/kg treated animal is all dead, and 3.7g/kg treated animal (3F02-3F04,3M06-3M9) is dead; 2.8g/kg treated animal (4F02,4F04,4F05,4M01) is dead; 2.1g/kg, 1.5g/kg treated animal has no dead.The symptoms such as dead mouse front all visible movement imbalance, tic, righting reflex loss, dead mouse is dissected main organs and shows no obvious abnormalities change, Continuous Observation 14 days after administration, each group mouse no abnormality seen.
5.3.3 on the impact of body weight
Administration the 4th day, the 7th day, the 10th day and the 14th day, HZ various dose administration group Mouse Weight compares with negative control group and has no notable difference, and prompting HZ various dose increases Mouse Weight and has no significant effect, and the results are shown in Table 10.
5.3.4 gross anatomy check result
2% vetanarcol anesthesia is adopted to put to death all experimental animals after off-test; Gross anatomy inspection is carried out to animal, the position, size, color and luster, adhesion etc. of visual inspection internal organs, and check organ surface and tangent plane quality, have no the abnormal change such as hydrops and tumour.
Table 10HZ is on the impact of Mouse Weight
5.4. conclusion
Its mouse oral gavages and gives 5.0g/kg, 3.7g/kg, 2.8g/kg, 2.1g/kg, 1.5g/kg, administration volume 40ml/kg, the same day 1 time, LD50=3.1g/kg, 95% fiducial interval: 2.7 ~ 3.6g/kg..
Six, decanoylacetaldehyde zinc animal lead discharging test
This experimental observation decanoylacetaldehyde zinc, to content plumbous in Lead-poisoning Rats model brain, bone, liver, blood lead, urine, ight soil, the lead-eliminating effect of research decanoylacetaldehyde zinc.
6.1. experiment material
6.1.1 medicine
Decanoylacetaldehyde zinc is tested Science and Technology Ltd. by Hunan Pu Ruima new drug and is provided, and be white powder, content: 99.0%, specification: 70g/ bag, lot number: 20120815, valid until in August, 2014.Preparation employing 0.5% Xylo-Mucine is mixed with suspension.
6.1.2 laboratory animal
6.1.2.1SD rat, 70, SPF level, male, body weight 120 ~ 150g, rat animal conformity certification number: NO.4304701195.Be purchased from Hunan Si Laike Jing Da laboratory animal company limited, laboratory animal production licence number: SCXK (Hunan) 2011-0003; Raise at Drug Safety Evaluation Center of Hunan Province's barrier environment, laboratory animal occupancy permit number: SYXK (Hunan) 2010-0008.
6.1.3 main agents: vetanarcol (lot number: P3761, AMRESCO product); Plumbic acetate (lot number: T20120312, Chemical Reagent Co., Ltd., Sinopharm Group).
6.1.4 key instrument:
AUY220 type analysis balance (this center numbering 085, Japanese Shimadzu Corporation); AgilentDUOAA series Atomic Absorption Spectroscopy AAS (this center numbering 095, Agilent company).
6.2. test method
Select SD rat 60, male, body weight 180 ~ 220g, the drinking-water containing 2% plumbic acetate is adopted to feed continuously 30 days, choose the rat 40 of blood lead content≤450ug/L, be divided into model group at random, solvent control group, HZ low dose group (200mg/kg), high dose group (400mg/kg), often organize 10, every day gastric infusion 1 time, successive administration 30 days, separately get 10 rats as Normal group, take a blood sample after last administration, 24h ight soil and urine is collected with metabolic cage, then 2% Nembutal sodium solution anesthetized rat is used, solution takes brain, bone, the tissues such as liver.Graphite furnace atomic absorption spectrometry is adopted to measure content plumbous in rat brain, bone, liver, blood, urine, ight soil.
6.3. experimental result
As shown in table 1, table 2: in model control group brain, bone, liver, blood, lead concentration compared with normal control group significantly raises (P<0.01), successive administration 30 days, HZ high dosage (200mg/kg) significantly can reduce lead content (P<0.05) in Lead-poisoning Rats brain, bone, liver, ight soil, blood, significantly can increase excretion (P<0.01) plumbous in urine.The results are shown in subordinate list 11, table 12.
Table 11HZ, HZ-01 are on the impact of rat blood lead
Note: compare with Normal group
△p<0.05,
△ △p<0.01, compares * P<0.05 with model control group, * * P<0.01.
Table 12HZ, HZ-01 are on the impact of Rat Skeletal, liver, brain, ight soil, urine lead content
Note: compare with Normal group
△p<0.05,
△ △p<0.01, compares * P<0.05 with model control group, * * P<0.01.
Claims (3)
1. a houttuynine sodium bisulfite metal complexes, is characterized in that, described houttuynine sodium bisulfite metal complexes has the structure shown in formula I:
Wherein, R is CH
3(CH
2)
3-15-
M is Zn
2+, Mg
2+or Ca
2+.
2. the preparation method of houttuynine sodium bisulfite metal complexes as claimed in claim 1, is characterized in that, comprise the steps:
(1) with deionized water solving zinc salt, magnesium salts or calcium salt, then the ammonia solution dripping 1-5mol/L dissolves completely to the precipitation generated, and must contain zinc, magnesium or calcium ion mass percentage content is the ammonia solution of 0.1-1%;
(2) with concentration of volume percent be 10-100% dissolve with ethanol solution Sodium Houttuyfonate, obtain the houttuynine sodium bisulfite sodium ethoxide solution that Sodium Houttuyfonate mass percentage content is 0.5-5%;
(3) houttuynine sodium bisulfite sodium ethoxide solution is added in ammonia solution, the volume ratio of houttuynine sodium bisulfite sodium ethoxide solution and ammonia solution is 1:0.2-1:1, add water stirring, generation is precipitated, filter, wash with water and be precipitated to filtrate in neutral, drain precipitation, obtain filter cake, by filter cake in 40-105 DEG C of dryings, cool recrystallizations with after ethanol, water, methyl alcohol, acetone or chloroform reflux in-20-10 DEG C, drain precipitation, obtain filter cake, by filter cake in 40-105 DEG C of dryings, obtain compound shown in formula I.
3. houttuynine sodium bisulfite metal complexes is preparing the application in metal decorporation medicine as claimed in claim 1.
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