CN101555241B - Ampelopsin pro-dug and preparing method and application thereof - Google Patents
Ampelopsin pro-dug and preparing method and application thereof Download PDFInfo
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- CN101555241B CN101555241B CN2009101118071A CN200910111807A CN101555241B CN 101555241 B CN101555241 B CN 101555241B CN 2009101118071 A CN2009101118071 A CN 2009101118071A CN 200910111807 A CN200910111807 A CN 200910111807A CN 101555241 B CN101555241 B CN 101555241B
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- KJXSIXMJHKAJOD-UHFFFAOYSA-N OC(C(c(cc1O)cc(O)c1O)Oc1cc(O)cc(O)c11)C1=O Chemical compound OC(C(c(cc1O)cc(O)c1O)Oc1cc(O)cc(O)c11)C1=O KJXSIXMJHKAJOD-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses an ampelopsin pro-drug and a preparing method and application thereof. The general formula (I) of the ampelopsin pro-drug is:, and compared with ampelopsin, the compound increases the water solubility obviously. In the preparing method, poisonous organic solvent is not used, all the solvents can be recycled, and other non-environmental-friendly reagents are not used. The ampelopsin pro-drug compound can be prepared into various dosage forms in pharmacy, including injection, tablets, capsules and granules, which is especially suitable for preparing powder-injection for injection.
Description
Technical field:
The present invention relates to pharmaceutical field, relate in particular to novel Ampelopsin pro-dug compound, its preparation method and be the preparation of active ingredient with this compound.
Background technology:
ZL2004 has another name called dibydro myricetrin, and this compound is to separate the leaf of the A.Meliaefolia of A. Meliaefolia to obtain the called after ZL2004 by Kotake and Kubota from Vitaceae ampelopsis fujian tea in 1940 first.That ZL2004 has been proved to be is antitumor, anti-oxidant, reducing blood-fat, anti-inflammatory, effect such as antibacterial, but because its solubleness is little, and maybe be through bacteriological action and by metabolism in enteron aisle, so the oral administration bioavailability is low.Owing to solubleness in its water is little, be unfavorable for processing the drug administration by injection form in addition.These all are to influence the obstacle that it is used clinically, do not see also that at present the monomeric related prods of ZL2004 is applied to clinical.Though bibliographical information (Ruan LP is arranged; Yu BY; Et.al.Improving the solubility ofampelopsin by solid dispersions and inclusion complexes.Journal of Pharmaceutical andBiomedical Analysis.2005; 38 (3): 457-64) adopt preparation techniques such as solid dispersions technique, cyclodextrin inclusion technique to improve the solubleness of ZL2004, but these methods exist complicated process of preparation, cost high, be difficult for shortcoming such as suitability for industrialized production.And adopt reagent such as tensio-active agent, ethanol, DMSO 99.8MIN. to increase solubleness, there is the big shortcoming of toxicity or pungency again.Therefore, this area presses for and develops effectively and the water miscible method of increase ZL2004 of low toxicity.
People such as the Qin of Lanzhou University red rock; Proposed to form a kind of new porcelain vine element unsaturated sodium salt (open CN101045721A with the Wasserstoffatoms in the unsaturated alternative ZL2004 of sodium ion; The Chinese invention patent application in open day on October 3rd, 2007); Its objective is in order significantly to lower the toxicity of ZL2004, and unexposed dissolubility data, all exist basic different with method of the present invention and purpose.
Summary of the invention:
The purpose of this invention is to provide one type of new, water-soluble high Ampelopsin pro-dug compound, this compound is applicable to the manufacturing powder injection.
Another object of the present invention provides the preparation method of this Ampelopsin pro-dug compound.
Ampelopsin pro-dug compound provided by the invention has following structure (I):
B representes basic aminoacids or glucose amine material in the formula, preferred glucose amine material, preferred meglumine.
The present invention also relates to above-claimed cpd (I) in pharmaceutically formulation, as: the Ampelopsin pro-dug of significant quantity and pharmaceutically acceptable carrier and/or vehicle, it comprises tablet, capsule, granule is especially for the powder injection of making injection.
The preparation method of compound provided by the invention (I) may further comprise the steps:
1) earlier basic aminoacids or glucose amine material are added in an amount of absolute ethyl alcohol, 35～70 ℃ of reflux are stirred to whole dissolvings; Other gets ZL2004 and is dissolved in the absolute ethyl alcohol, keeps uniform temp; Basic aminoacids or glucose amine substance solution are slowly added in the ZL2004 solution, continue stirring reaction, the pressure reducing and steaming partial solvent is put low temperature place crystallization, crosses and filters bullion;
2) bullion adds agitator treating in a small amount of absolute ethyl alcohol or the ETHYLE ACETATE, removes excessive ZL2004, filters, and drying under reduced pressure or Vanadium Pentoxide in FLAKES drying or lyophilize get compound (I).
The charging capacity of ZL2004 and basic aminoacids or glucose amine material is 1～1.1: 1 in molar ratio among the above-mentioned preparation method, preferred 1.05: 1.
One of above-mentioned preparing method's characteristics: selecting water-free reagent for use is reaction solvent, preferred absolute ethyl alcohol.Because used basic aminoacids or glucose amine material solubleness in absolute ethyl alcohol are little, through the reflux dissolving, to reduce solvent load.Basic aminoacids or glucose amine substance solution are slowly added in the reaction system, avoid excessive base contact ZL2004, to keep imitating the stability of relevant group with structure.
Two of above-mentioned preparing method's characteristics: the product of acquisition is orange-yellow powder, has to draw moistly, can be dissolved in fast in the cold water during injection in preparation, processes cryodesiccated stoste, avoids heating waiting and operates the detrimentally affect to stability.
In general, nitrogenous organic base compound and ZL2004 complex forming salt can increase its solubleness in water, but different nitrogenous organic base compounds, degree effect improved after it is compound is also different.The contriver finds that through a large amount of experiment some nitrogenous organic base compound and ZL2004 can not significantly improve solubleness after compound, and the bigger pungency of existence, like benzene methanamine, quadrol etc.Thereby B of the present invention representes to choose basic aminoacids or glucose amine material, preferred glucose amine material, preferred meglumine.Compound provided by the invention has well water-soluble, is the solubility experiment data statistics contrast table of part experimental subjects under 25 ℃ with the lower section:
| Title | Solubleness in water (g/ml) |
| ZL2004 | 1/1200 |
| ZL2004 Methionin mixture | 1/40 |
| ZL2004 l-arginine mixture | 1/40 |
| ZL2004 meglumine mixture | 1/10 |
| ZL2004 N-Octylglucamine mixture | 1/15 |
Obviously, ZL2004 and glycamine compounds are significantly improved through the preceding drug compound solubleness in water that is compounded to form.
And; Compound (I) is even the aqueous solution is when being 1% (g/100ml) in concentration; The pH value of solution is 8.74, meets human injection liquid requirement pH value and is no more than 9 general requirement, like this under intravenous drip volume 100～500ml situation commonly used; 1～5g the compound (I) that once can instil, this dosage can reach the requirement of human effective dose fully.These character make compound (I) can adopt domestic method manufacturing powder injection such as freeze-drying; Face with before adding sterilized water for injection or normal saline solution dissolving posterior vein and instil; Realize directly being processed into injection, can improve bioavailability, realized clinical application.
Beneficial effect of the present invention: compound provided by the present invention (I) and preparation method thereof does not use deleterious organic solvent, and all recyclable utilization of used low toxicity or innoxious solvent does not use other to the disagreeableness reagent of environment yet.This compound yield is high, and good water solubility can be made into various formulations pharmaceutically, comprises injection, tablet, capsule, granule, is specially adapted to make powder ampoule agent for injection.
Embodiment:
Below in conjunction with the practical implementation example, further illustrate the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
The preparation of embodiment 1 compound (I)
(1) preparation of ZL2004 meglumine mixture: feed intake at 1.05: 1 by ZL2004 and meglumine mol ratio.Take by weighing meglumine 1.95g and add in the 100ml absolute ethyl alcohol, 60 ℃ of reflux are stirred to whole dissolvings; Other takes by weighing ZL2004 3.36g and is dissolved in the 10ml absolute ethyl alcohol, and heating keeps uniform temp; Above-mentioned meglumine ethanol solution is slowly added in the ZL2004 solution, and the limit edged stirs, and keeps 60 ℃ of reaction 30min, and it is muddy that pressure reducing and steaming partial solvent to solution begins to become, and puts-15 ℃ and preserve 12h, crosses and filter bullion.
(2) refining: bullion adds agitator treating in the 10ml absolute ethyl alcohol, filter, and triplicate, drying under reduced pressure gets compound (I).Yield is 74.2%.
The preparation of embodiment 2 compounds (I)
(1) preparation of ZL2004 meglumine mixture: feed intake at 1: 1 by ZL2004 and meglumine mol ratio.Take by weighing meglumine 195mg and add in the 20ml absolute ethyl alcohol, 50 ℃ of reflux are stirred to whole dissolvings; Other takes by weighing ZL2004 320mg and is dissolved in the 5ml absolute ethyl alcohol, and heating keeps uniform temp; The meglumine ethanol solution slowly is added in the ZL2004 solution, and the limit edged stirs, and keeps 50 ℃ of reaction 20min, and it is muddy that pressure reducing and steaming partial solvent to solution begins to become, and puts-4 ℃ and preserve 12h, crosses and filter bullion.
(2) refining: bullion adds agitator treating in the 5ml absolute ethyl alcohol, filters, and triplicate places phosphorus pentoxide desiccator dry, gets compound (I).Yield is 69.5%.
The preparation of embodiment 3 compounds (I)
(1) preparation of ZL2004 meglumine mixture: feed intake at 1.03: 1 by ZL2004 and meglumine mol ratio.Take by weighing meglumine 390mg and add in the 40ml absolute ethyl alcohol, 40 ℃ of reflux are stirred to whole dissolvings; Other takes by weighing ZL2004 660mg and is dissolved in the 10ml absolute ethyl alcohol, and heating keeps uniform temp; The meglumine ethanol solution slowly is added in the ZL2004 solution, and the limit edged stirs, and keeps 40 ℃ of reaction 20min, and it is muddy that pressure reducing and steaming partial solvent to solution begins to become, and puts-4 ℃ and preserve 12h, crosses and filter bullion.
(2) refining: bullion adds agitator treating in the amount of ethyl acetate, filters, and triplicate through lyophilize, gets compound (I).Yield is 71.5%.
The chemical structure analysis of embodiment 4 Ampelopsin pro-dug compounds
ZL2004 meglumine mixture to preparation among the embodiment 1 has carried out chemical structure analysis.
[uv absorption spectrum]
Through comparative compound (I) and the ZL2004 uv absorption spectrum in ethanol respectively, the result shows that there is same absorption peak in both at the E band, promptly have same phenyl ring fine structure; At B band, both have maximum absorption band at the 292nm place, but the absorption intensity of compound (I) is compared obviously with ZL2004 and weakened; In addition, compound (I) is at R band, and promptly new maximum absorption band also appears in 325nm place, and ZL2004 does not have maximum absorption band herein, i.e. relative red shift 33nm.Explain that institute synthetic compound (I) compares with ZL2004, big structural changes does not take place, just many individual auxochromous groups make absorption peak move to the long wave direction.
In addition; Experiment is also found; In the solution system of compound (I), add 0.1N hydrochloric acid soln accent pH to acidity; Its UV spectrum changes consistent with the UV spectrum of ZL2004 again, explain that compound (I) can change ZL2004 under acidic conditions, so compound (I) is the preceding drug compound of ZL2004.
[mass spectroscopy]
The reactant corresponding molecular weight is respectively: M
1=C
7H
17NO
5=195; M
2=C
15H
12O
8=320; Compound (I) M=M then
1+ M
2-H=195+320-1=514.By mass spectroscopy, wherein two important mass spectra peak ownership resolve to: the positive ion detecting pattern corresponds to: 196 (M
1+ H)
+, 515 (M+H)
+, explain that compound (I) is to be composited by ZL2004 and the meglumine mol ratio by 1: 1.
[ultimate analysis]
The chemical molecular formula C of compound of the present invention (I)
22H
28NO
13, results of elemental analyses is following:
C％ H％ N％
Analytical value 51.42 5.44 2.76
Calculated value 51.36 5.45 2.72
Analysis differs in 0.5% with calculated value, and description architecture is correct.
The mensuration of compound (I) pH value of water solution of embodiment 5 different concns
Get compound (I) 0.5g and be dissolved in the solution that is made into 1% concentration in the 50ml water, recording the pH value is 8.74; With 10 times of this solution dilutions, promptly concentration is about 0.1%, records dilution back pH value of solution for value 8.05, all meets the injection requirement.
The quality controlling means of embodiment 6 compounds (I)
ZL2004 meglumine mixture with preparation among the embodiment 1 is an example, has carried out the research of quality controlling means.
[ultraviolet determination]
Precision takes by weighing compound (I) 20mg in the 25ml volumetric flask, adds 50% ethanolic soln, after the ultra-sonic oscillation dissolving; Get 0.2ml in the 10ml volumetric flask, add 0.1N hydrochloric acid soln dilution constant volume, after shaking up; By ultraviolet spectrophotometry, measure absorbance at the 292nm place.Other the learn from else's experience ZL2004 reference substance of 105 ℃ of dry constant weights is an amount of, handles with aforementioned method, is made into certain density solution, measures with method, calculates, and the result multiply by 1.606, promptly gets.
[high-efficient liquid phase technique mensuration]
Chromatographic condition and system suitability test: chromatographic column is C
18Stainless steel column; Moving phase is methyl alcohol: water: phosphoric acid (65: 35: 0.2); Flow velocity 0.7ml/min; The detection wavelength is 292nm; Sample size is 20 μ l; Column temperature is a room temperature.Theoretical plate number is calculated by ZL2004 should be not less than 3000.
Assay method: precision takes by weighing compound (I) 20mg in the 25ml volumetric flask, adds 50% ethanolic soln, after the ultra-sonic oscillation dissolving; Get 0.2ml in the 10ml volumetric flask, add 0.1N hydrochloric acid soln dilution constant volume, after shaking up; The supersound process 10min degassing; 0.45 the filtering with microporous membrane of micron is measured 20 μ l sample introductions, the record peak area.Other the learn from else's experience ZL2004 reference substance of 105 ℃ of dry constant weights is an amount of, handles with aforementioned method, is made into certain density solution, measures with method, and with calculated by peak area, the result multiply by 1.606, promptly gets by external standard method.
Embodiment 7 compounds (I) security is investigated
ZL2004 meglumine mixture with preparation among the embodiment 1 is an example, has carried out the security investigation.
[blood vessel irritation test]
Get 4 of healthy male rabbit, body weight 2～2.3Kg is divided into two groups; Every rabbit auris dextra is the administration group; Give the physiological salt soln of ZL2004 meglumine mixture of the present invention, left ear is a physiology saline control group, the saline water of capacity such as every rabbit right ear vein injection.Once a day, continuous three days, observe animal ear vascular stimulation reaction symptom then, and get sample and carry out histopathologic examination.
Test-results: administration group, saline water control group rabbit ear blood vessel all do not have hyperemia; Reaction symptoms such as tubercle, oedema and tissue degeneratiaon or necrosis; The also no abnormal change of pathological examination shows that trial-product does not have obvious blood vessel irritation, meets the specified requirement of drug administration by injection.
[hypersensitive test]
Get 12 of healthy guinea pigs, the male and female dual-purpose, female no pregnant, health, body weight 220～250g.By aseptic technique; The abdominal injection need testing solution 0.5ml (physiological salt soln of 1% ZL2004 meglumine mixture next day that every animal of administration group being equal; In the ZL2004 meglumine), totally 3 times, abdominal injection 1% Protalbinic acid 0.5ml is totally 3 times next day of every animal of positive controls; First group of wherein administration group intravenous injection trial-product 2ml on the 14th after first administration attacks; Second group in attacking with method in 21st after the first administration: first group of positive controls intravenous injection on the 14th 1% BSA 2ml after first administration attacks; After first administration, attacked in 21st, observe the symptoms of allergic of attacking the back animal for second group with method.
Test-results: administration does not all have symptoms of allergic such as perpendicular hair, expiratory dyspnea, spasm, shock and death for animal after injection; And the positive control treated animal all has in various degree perpendicular hair, grabs allergic symptoms such as nose, spasm after injection; Show and supply the no obvious supersensitivity of reagent article, requirement up to specification.
The safety testing result shows that compound (I) can reach the requirement of drug administration by injection.
The preparation of embodiment 8 powder injection
Get compound (I) 1g, N.F,USP MANNITOL 1g with the dissolving of 50ml water for injection, through 0.22 micron filtering with microporous membrane, is sub-packed in the vial of 7ml capacity, and the 2ml/ bottle was put freeze drier dry 24 hours, added the sealing of plug and aluminium lid, promptly got.Dried orange red packaged thing adds sterilized water for injection 5ml, and jolting is all dissolved for 5 seconds.This solution is with the dilution of 100ml water for injection, and dilution back pH value of solution value is 8.34, is fit to intravenous drip.
Claims (6)
1. the Ampelopsin pro-dug of formula (I):
B representes glucose amine material in the formula.
2. according to the Ampelopsin pro-dug of claim 1, it is characterized in that described B is a meglumine.
3. the preparation method of the described Ampelopsin pro-dug of claim 1 may further comprise the steps:
1) earlier glucose amine material is added in the absolute ethyl alcohol, 35～70 ℃ of reflux are stirred to whole dissolvings; Other gets ZL2004 and is dissolved in the absolute ethyl alcohol, keeps uniform temp; Glucose amine substance solution is slowly added in the ZL2004 solution, continue stirring reaction, the pressure reducing and steaming partial solvent is put low temperature place crystallization, crosses and filters bullion;
2) bullion adds agitator treating in a small amount of absolute ethyl alcohol or the ETHYLE ACETATE, removes excessive ZL2004, filters, and drying under reduced pressure or Vanadium Pentoxide in FLAKES drying or lyophilize get compound (I).
4. the preparation method of Ampelopsin pro-dug according to claim 3, it is characterized in that: the charging capacity of ZL2004 and glucose amine material is 1～1.1: 1 in molar ratio.
5. the preparation method of Ampelopsin pro-dug according to claim 4, it is characterized in that: the charging capacity of ZL2004 and glucose amine material is 1.05: 1 in molar ratio.
6. according to the preparation method of claim 3 or 4 or 5 described Ampelopsin pro-dugs, it is characterized in that: glucose amine material is a meglumine.
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| CN2009101118071A CN101555241B (en) | 2009-05-20 | 2009-05-20 | Ampelopsin pro-dug and preparing method and application thereof |
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| CN101555241B true CN101555241B (en) | 2012-05-02 |
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| CN107286220B (en) * | 2017-07-02 | 2020-10-23 | 石家庄学院 | 1,2, 4-triazole coupled dihydromyricetin derivative and preparation method and application thereof |
| CN108042661B (en) * | 2017-12-16 | 2021-01-19 | 江西天元药业有限公司 | White tea extract rich in dihydromyricetin and application thereof in preparing medical health products |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1288747A (en) * | 1999-09-16 | 2001-03-28 | 宋新荣 | Composite medicine containing dihydromyricetrin |
| CN101045721A (en) * | 2006-03-31 | 2007-10-03 | 兰州大学 | Preparation of porcelain vine element unsaturated sodium salt and its application |
| CN101513400A (en) * | 2008-02-22 | 2009-08-26 | 兰州大学 | Ampelopsin and basic amino acid solubilizing system |
-
2009
- 2009-05-20 CN CN2009101118071A patent/CN101555241B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1288747A (en) * | 1999-09-16 | 2001-03-28 | 宋新荣 | Composite medicine containing dihydromyricetrin |
| CN101045721A (en) * | 2006-03-31 | 2007-10-03 | 兰州大学 | Preparation of porcelain vine element unsaturated sodium salt and its application |
| CN101513400A (en) * | 2008-02-22 | 2009-08-26 | 兰州大学 | Ampelopsin and basic amino acid solubilizing system |
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