CN101041684A - Celastrine grape aminomethane salt and preparation method thereof - Google Patents
Celastrine grape aminomethane salt and preparation method thereof Download PDFInfo
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- CN101041684A CN101041684A CNA200710039694XA CN200710039694A CN101041684A CN 101041684 A CN101041684 A CN 101041684A CN A200710039694X A CNA200710039694X A CN A200710039694XA CN 200710039694 A CN200710039694 A CN 200710039694A CN 101041684 A CN101041684 A CN 101041684A
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- celastrin
- meglumine
- celastrine
- grape
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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Abstract
The invention discloses a celastrine glucomethylamine salt compound and preparing method with the molar rate of acid group and alkaline group at 1: 1 through ionic bond, which possesses certainly structure to be recycled by low-poison or non-poison solvent, wherein the agent pattern contains injecting agent, pill, capsule, particle and solution.
Description
Technical field
The present invention relates to Celastrine grape aminomethane salt and preparation method thereof.
Background technology
Celastrin (Celastrol) has another name called Tripterine, is the anticancer active constituent that is present in Celastraceae plant trypterygine, the Stem of Oriental Bittersweet etc.Document 1:Pristimerin.Spectroscopic properties ofthe dienone-phenol-type rearrangement products and other derivatives[KojiNakanishi, Yoshikazu Takahashi, et al.J.Org.Chem., 1965 (30), 1729] mention in, early than nineteen sixty, found that promptly this compounds has anti-tumor activity, nearest document 2:Celastrol, a Triterpene Extracted from the Chinese Thunder of God Vine Is aPotent Proteasome Inhibitor and Suppresses Human Prostate Cancer Growthin Nude Mice[Huanjie Yang, Di Chen, et al.Cancer Research, 2006 (66), 4758] confirm: celastrin is by arrestin enzyme body activity and then bring out cancer cell-apoptosis, be effective protein proteins enzyme body inhibitor, celastrin has significantly suppressed the nude mice hyperplasia of prostate cancer on one's body.Therefore, aspect the prevention and treatment of cancer, celastrin is the neutral protease body inhibitor with huge potentiality to be exploited.
Document 1 studies show that the Alpha-hydroxy methyl quinone structure in the celastrin molecular structure is very sensitive to acid, can comprise multiple variations such as open loop, rearrangement through acid treatment, during the administration of prompting oral administration, tart hydrochloric acid in gastric juice can destroy the part celastrin, causes drug effect to reduce.Therefore drug administration by injection is a suitable method, as the abdominal injection administrated method of document 2, has verified the antitumor efficacy of celastrin, does not see obvious toxic and side effects simultaneously.
The molecular structure of celastrin belongs to triterpenes, is fat-soluble component, can not dissolve in water, and being difficult to prepare with water is the injection of solvent.Document 2 adopts following combination as solvent: 10% dimethyl sulfoxide (DMSO), 3: 1 mixture of 70%Cremophor and ethanol, 20% phosphate buffered saline buffer.This solvent can not be used for human body, only can be used among the zooscopy.
Preparing water miscible salt is a kind of ordinary method that increases organic acid solubleness in water, but the hydroxyl of the carbonyl α position in the celastrin structure, result of study as document 1 shows, be in the conjugated system, has slightly acidic as phenolic hydroxyl group, easily oxidation, the contact soda acid all can produce complicated rearrangement reaction.Just common acid-base neutralisation reaction can't make the salt of celastrin.At present there is not success to make the report of any associated salts of celastrin as yet.
Usually be used for salify with organic bases such as arginine, Methionin, meglumine, can obtain better water solubility.Such as in a large number about having increased water miscible bibliographical information behind the silymarin salify.The phenolic hydroxyl group that utilization flies in the Ji guest molecule has certain acidity, and the salt made from the meglumine reaction finally enters clinical practice.Such reaction method will be avoided for celastrin just.Also having certain methods in addition is to add above-mentioned organic amine as solubilizing agent in the formulation preparation process, make with water is the injection liquid or the powder injection of solvent, such method also is inappropriate for celastrin, will influence stability of formulation because excessive alkali exists.
Summary of the invention
The purpose of this invention is to provide and have definite molecular structure, good stability and water miscible Celastrine grape aminomethane salt compound, this Celastrine grape aminomethane salt compound is used to make powder injection.
Another object of the present invention provides the preparation method of this Celastrine grape aminomethane salt compound.
What the present invention disclosed is that a kind of acid group and alkali root passed through ionic linkage chemical combination in 1: 1 in molar ratio, has the compound of the meglumine salt of definite structure.This compound adopts a kind ofly optionally to be had only in the celastrin molecule carboxyl to participate in salifiable special methods to make.
Celastrine grape aminomethane salt compound provided by the invention has following structure (I):
The present invention also relates to above-claimed cpd (I) in pharmaceutically formulation, comprise tablet, capsule, granule and solution are especially for making powder ampoule agent for injection.
The preparation method of compound provided by the invention (I) may further comprise the steps:
A) earlier celastrin is dissolved in dehydrated alcohol or the Virahol, holding temperature adds the meglumine solid at 15～35 ℃ under stirring gradually, stirring reaction to meglumine all dissolves, and continue to stir 2～3 hours, reaction solution gets crude product in 30～40 ℃ of following pressure reducing and steaming solvents;
B) add ethyl acetate or washing with acetone in the crude product and remove a small amount of excessive celastrin, filter, solid is with ethyl acetate or washing with acetone 1～2 time, drying under reduced pressure, compound (I).
Celastrin and meglumine charging capacity are 1～1.1: 1 in molar ratio among the above-mentioned preparation method, preferred 1.05: 1; Meglumine adds in the reaction solution with pressed powder.
One of above-mentioned preparation method's characteristics: utilize the slightly soluble character of meglumine in dehydrated alcohol or Virahol, under the condition of gentleness, add in the reaction system with solid, the base of dissolving part is reacted with excessive acidic group all the time, has avoided excessive base contact celastrin.This has just realized optionally and the celastrin carboxyl reaction, and can not influence the hydroxyl on the conjugated system, has finally obtained compound (I), keeps the stability of the group relevant with the structure effect.
Two of above-mentioned preparation method's characteristics: the product of acquisition is fluffy amorphous powder, can be dissolved in fast in the cold water during injection in preparation, makes cryodesiccated stoste, avoids heating waiting the detrimentally affect of operating stability.
The compound (I) that the present invention discloses water-soluble better, under the room temperature, the solubleness in deionized water and physiological saline is greater than 50mg/ml.Its aqueous solution also has suitable stability, such as 10mg/ml concentration solution, places 4 hours for 25 ℃, and HPLC detected peaks area is stable.Compound (1) aqueous solution is in concentration during smaller or equal to 0.5mg/ml, the pH value of solution is smaller or equal to 8.65, meet human injection liquid requirement pH value and be no more than 9 general requirement, like this under instillation volume 100～500ml situation commonly used, 50～250mg the compound (I) that once can instil, this dosage have surpassed the human effective dose of the effective concentration conversion of press document 2 record animals.Even the concentration of 10mg/ml, the pH value of solution value also is no more than 9.46, and animal can tolerate.These character make compound (I) can adopt freeze-drying or solvent crystal manufactured powder injection, face with before adding injection water or normal saline solution or glucose injection dissolving posterior vein and instil.So just reach the purpose that directly is processed into injection, can improve bioavailability, improve drug effect, realized clinical antineoplastic application.Each unit formulation of powder injection contains compound (I) 1～250mg.
Beneficial effect of the present invention:
Bright compounds that provide of we (I) and preparation method thereof do 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 can be made into various formulations pharmaceutically, comprises injection, tablet, and capsule, granule and solution are especially for making powder ampoule agent for injection.
Embodiment
The preparation of embodiment 1 compound (I)
After getting 99.2mg celastrin usefulness 4ml anhydrous alcohol solution, to wherein adding meglumine 41.0mg, room temperature stirred 2.5 hours for 21 ℃, meglumine all dissolves, and continue to stir 2 hours again, is evaporated under 40 ℃ dried, with the solid crushing, porphyrize adds acetone 3ml, stirred for several minute, suction filtration, solids washed with acetone twice gets the reddish-brown powder, 40 ℃ of drying under reduced pressure get product compound (I) 98.2mg.Recovery rate: 70.1%.
Analytical results:
1HNMR (DMSO-d6,300M), δ 7.080 (2H, d, J=7.1Hz, H-6), 6.392 (1H, s, H-1), 6.356 (1H, d, J=7.1Hz, H-7), 3.3～3.7 (6H, multiplet, CH that links to each other with oxygen on the meglumine and CH
2), 2.620 (2H, d, J=4.4 ,-CH
2-N), 2.293 (3H, s, CH
3-N), 2.087 (3H, s, CH
3-23), 1.382 (3H, s, CH
3-25), 1.222 (3H, s, CH
3-26), 1.080 (3H, s, CH
3-30), 1.063 (3H, s, CH
3-28), 0.644 (3H, s, CH
3-27).
Meglumine and sour salify can be positively charged on the nitrogen-atoms, to the CH that links to each other
2And CH
3The effect of deshielding of middle hydrogen atom will strengthen, and corresponding hydrogen spectrum signal can be mobile to low.In the hydrogen spectrum of Celastrine grape aminomethane salt, the CH that links to each other with N
2And CH
3Comparing in signal and the meglumine hydrogen spectrum, respectively to low field displacement 0.074 and 0.034ppm, show the certain and celastrin salify of meglumine, be not simple solublization.
The hydrogen spectrum of meglumine:
1HNMR (DMSO-d6,300M), δ 4.680,4.429,4.278 (each1H, brs, OH), 3.30～3.70 (multiplet, CH that links to each other with oxygen and CH
2), 2.546 (2H, d, J=4.1 ,-CH
2-N), 2.259 (3H, s, CH
3-N).
The preparation of embodiment 2 compounds (I)
Get the 101.2mg celastrin with the dissolving of 3ml Virahol after, stir down to wherein adding meglumine 41.8mg, be warming up to 30 ℃, treat that meglumine all dissolved the back restir 2 hours.Be evaporated to driedly under 35 ℃,, add ethyl acetate 3ml solid crushing, porphyrize, stirred for several minute, suction filtration, solid ethyl acetate washed twice, the reddish-brown powder, 35 ℃ of drying under reduced pressure must product compound (I) 96mg.Recovery rate: 67.1%.
The preparation of embodiment 3 compounds (I)
After getting 10.15g celastrin usefulness 200ml anhydrous alcohol solution, to wherein adding meglumine 4.188g, room temperature stirs down for 18 ℃, and meglumine all dissolved the back restir 3 hours.Be evaporated to driedly under 30 ℃,, add ethyl acetate 300ml and make dissolving, stirred 10 minutes residue crushing, porphyrize, suction filtration, solid ethyl acetate washed twice, the reddish-brown powder, 35 ℃ of drying under reduced pressure must product compound (I) 10.61g.Recovery rate: 74.0%.
The preparation of embodiment 4 compounds (I)
Get the 100.5mg celastrin with the dissolving of 3ml Virahol after, stir down to wherein adding meglumine 43.5mg, be warming up to 30 ℃, treat that meglumine all dissolved the back restir 2 hours.Be evaporated to driedly under 35 ℃, with solid crushing, porphyrize, add ethyl acetate 3ml, stirred for several minute is filtered, solid ethyl acetate washed twice, the reddish-brown powder, 35 ℃ of drying under reduced pressure get product compound (I) 102mg.Recovery rate: 70.8%.
The preparation of embodiment 5 compounds (I)
After getting 100.3mg celastrin usefulness 3ml anhydrous alcohol solution, to wherein adding meglumine 39.5mg, 20 ℃ are stirred down, and meglumine all dissolved the back restir 3 hours.Be evaporated to driedly under 30 ℃, with residue crushing, porphyrize, add ethyl acetate 3ml and make dissolving, stirred 10 minutes, filter, solid ethyl acetate washed twice gets the reddish-brown powder, and 35 ℃ of drying under reduced pressure get product compound (I) 92.3mg.Recovery rate: 66.0%.
Embodiment 6 solution stability testings
Experiment condition: chromatographic column is enlightening horse C18 5 μ 250 * 4.6mm, and Waters 3487 detectors detect wavelength 425nm, and moving phase is methyl alcohol by volume: 0.1% acetic acid (93: 7), flow velocity 1ml/min.
Experimental technique: (I) uses dissolved in distilled water with compound, is settled to 5ml, and ultimate density is 10mg/ml, shakes up.25 ℃ of lucifuges of room temperature are placed, and pipette 0.1ml respectively at 0 hour and 4 hours precisions, are settled to 5ml with the 40%v/v methanol aqueous solution, promptly get sample solution.The rapid injecting chromatograph 20 μ l of sample solution compare each time point chromatographic peak area, and the result does not see considerable change, shows that this solution has suitable stability, enough satisfy the stability of the course of processing requirement of configuration powder ampoule agent for injection.
Experimental data: peak area 5099933 in 0 hour; Peak area 4936492 in 4 hours.
The mensuration of compound (I) pH value of water solution of embodiment 7 different concns
Compound (I) 9.9mg is dissolved in the 2ml water, dissolving, and the pH value is 9.46; With 10 times of this solution dilutions, promptly concentration is about 0.5mg/ml, records dilution back pH value of solution and is value 8.65; Again this solution is continued 10 times of dilutions, promptly concentration is about 0.05mg/ml, and recording dilution back pH value of solution value is 7.29.
Embodiment 8 preparation powder injection
Get compound (I) 1g, N.F,USP MANNITOL 1g uses 50ml, is dissolved in water, and through the filtering with microporous membrane of 0.25 micron pore size, 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.The packaged thing of dried scarlet adds injection water 5ml, jolting, all dissolvings in 5 seconds.This solution dilutes with 100ml water for injection, and dilution back pH value of solution value is 8.54, is fit to intravenous drip.
Claims (6)
1. water-soluble Celastrine grape aminomethane salt compound that structural formula is following
2. the preparation method of Celastrine grape aminomethane salt compound as claimed in claim 1 may further comprise the steps:
A. earlier celastrin is dissolved in dehydrated alcohol or the Virahol, holding temperature adds the meglumine solid at 15～35 ℃ under stirring gradually, stirring reaction to meglumine all dissolves, and continue to stir 2～3 hours, reaction solution gets crude product in 30～40 ℃ of following pressure reducing and steaming solvents;
B. crude product adds ethyl acetate or washing with acetone is removed a small amount of excessive celastrin, filters, and solid is with ethyl acetate or washing with acetone 1～2 time, drying under reduced pressure, compound (I).
3. the preparation method of Celastrine grape aminomethane salt compound according to claim 2 is characterized in that, celastrin and meglumine charging capacity are 1～1.1: 1 in molar ratio.
4. the preparation method of Celastrine grape aminomethane salt compound according to claim 3 is characterized in that, celastrin and meglumine charging capacity are 1.05: 1 in molar ratio.
5. celastrin according to claim 1 and meglumine compound is characterized in that, formulation is a powder injection.
6. celastrin according to claim 5 and meglumine compound is characterized in that, each unit formulation content of its powder injection is 1～250mg.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200710039694XA CN100439389C (en) | 2007-04-20 | 2007-04-20 | Celastrine grape aminomethane salt and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200710039694XA CN100439389C (en) | 2007-04-20 | 2007-04-20 | Celastrine grape aminomethane salt and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101041684A true CN101041684A (en) | 2007-09-26 |
| CN100439389C CN100439389C (en) | 2008-12-03 |
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| CN100490833C (en) * | 2006-09-06 | 2009-05-27 | 天津医科大学 | Method of supercritical CO2 for extracting terpenoid of effective component of triperygium wilfordii, and composition |
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Owner name: SHANGHAI HUATUO MEDICINE SCI-TECH DEVELOPMENT CO., Free format text: FORMER NAME: SHANGHAI HUATUO MEDICAL SCIENCE CO., LTD. |
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Address after: 200093 No. 90, Shulan Road, Shanghai, Yangpu District Patentee after: Shanghai Huatuo Medicine Sci-Tech Development Co., Ltd. Address before: 200093 No. 90, Shulan Road, Shanghai, Yangpu District Patentee before: Shanghai Huatuo Medical Science Co., Ltd. |
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Granted publication date: 20081203 Termination date: 20210420 |