CN1028998C - Sialic acid sugar radical cholesterol, process for preparing them and drug containing them for treating neuronosis - Google Patents

Sialic acid sugar radical cholesterol, process for preparing them and drug containing them for treating neuronosis Download PDF

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Publication number
CN1028998C
CN1028998C CN87106177A CN87106177A CN1028998C CN 1028998 C CN1028998 C CN 1028998C CN 87106177 A CN87106177 A CN 87106177A CN 87106177 A CN87106177 A CN 87106177A CN 1028998 C CN1028998 C CN 1028998C
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compound
cholesterol
described method
sialic acid
solution
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CN87106177A (en
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小仓治夫
古畑公夫
佐藤慎吾
伊藤正善
志鸟善保
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KANTO ISHI PHARMACEUTICAL CO Ltd
Mect Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring

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Abstract

The present invention relates to a sodium salt of sialosyl cholesterol. The present compound has an excellent high water solubility, and therefore the compound is very useful as a medicine to be used for treating various diseases derived from lesions of peripheral or central nerves.

Description

Sialic acid sugar radical cholesterol, process for preparing them and drug containing them for treating neuronosis
The invention relates to sialic acid glycosyl cholesterol, particularly about the sialic acid glycosyl cholesterol of the various diseases that causes because of peripheral nerve and central nervous system injury as treatment.
Known so far in the present technique field, sialic acid is present in many animal bodies, and is present in the cell surface of some bacteriums as the molecular complex (for example glycoprotein, glycolipid, oligose or polysaccharide) of saliva acidic groupization.
Medically, think that recently sialic acid has important effect at neural function, cancer, inflammation, immunity, virus infection, differentiation, hormone receptor and other party mask thereof.In addition, also given very big attention people to this activated especially material that is positioned at cell surface.But sialic effect is not understood fully as yet in the molecular complex of saliva acidic groupization.
In addition, sialic acid is studied by many natural organic chemistry workers, and makes the derivative of its numerous species.But, do not obtain having the derivative of remarkable physiologically active so far as yet.
In addition, make the malignant tumour of hemocytopoietic organ, various cancer and collagen disease obtain improvement in various degree, determine to prolong human life by treatment.But these improvement will increase application inevitably such as medicines such as adrenocortical hormone, immunosuppressor in the medical treatment.Thereby many undesirable side effects (for example immunological competence reduction) have been produced.
Inventor of the present invention pays particular attention to biological inherent composition-sialic acid, and chemically by sialic acid is carried out structure of modification, in fact having no side effect and can having carried out extensive studies to the immunomodulator that immunity system plays supervisory function bit.As a result, inventor of the present invention has made and can be used as the sialic acid glycosyl cholesterol for the treatment of neurological disease drug.Basis of the present invention is, checks on mouse neuroblast oncocyte (Neuro2a) culture that when sialic acid glycosyl cholesterol is added to it does the time spent, and the contriver finds that sialic acid glycosyl cholesterol can promote the growth of Neuro2a aixs cylinder.
The purpose of this invention is to provide a kind of new sialic acid glycosyl cholesterol.
Another object of the present invention provides the cholesteric novel method of preparation sialic acid glycosyl.
Another purpose of the present invention provides the medicine of new treatment sacred disease.
In addition, exist because sialic acid glycosyl cholesterol of the present invention is a form with sodium salt, therefore cholesterol of the present invention has well water-solublely, and has effectiveness more widely.
The present invention is relevant with the compound with following general expression (4) or (5):
Figure 871061775_IMG6
The invention still further relates to the method for preparing compound (4) or (5), this method comprises makes the have general expression compound of (1) and cholesterol reaction, obtain the having general expression compound of (2) or (3), then with compound (2) or (3) hydrolysis:
In addition, the present invention also is related to the medicine of the treatment sacred disease that contains compound (4) or (5).
To be described in detail the present invention below.
The method for preparing compound (4) or (5) is at first with following reaction formula general introduction.
Figure 871061775_IMG8
The compound of using among the present invention (1) is a known compound, and can buy on the market.
In above-mentioned reaction, in the presence of Ke Nixi-Nore (Koenigs-Knorr) catalyzer,, compound (1) and cholesterol were reacted about 1～7 day in about 20～25 ℃.In reaction, make the reaction of about 1～5 mole cholesterol and 1 mole compound (1).
The catalyzer that uses has mercuric bromide, mercury cyanide, silver perchlorate, silver trifluoromethanesulfonate, Silver Trifluoroacetate etc.Per 1 normal compound (1) is with about 1.0～1.2 normal catalyzer.
Adaptable solvent has acetonitrile, Nitromethane 99Min., acetone, benzene, tetrahydrofuran (THF), methylene dichloride etc. among the present invention.Wherein, the solvent of preferentially selecting for use is benzene, methylene dichloride and tetrahydrofuran (THF).In the present invention, can use siccative.As siccative, can use drierite ze or 4A molecular sieve.
The compound (2) that generates can separate and purifying by conventional method (for example column chromatography) with (3).
Then, make compound (2) and (3) hydrolysis, change their methoxycarbonyl into the sodium carboxyl, and change their ethanoyl into hydrogen.By hydrolysis, obtain compound (4) and (5).Hydrolysis is carried out with conventional method usually.For example, at about 15～25 ℃, be that the alkaline solution of 1～3N was handled compound (2) or (3) about 5～15 hours with concentration.
Compound of the present invention can be oral.But The compounds of this invention preferably through eye use, through sucking application, intramuscularly, subcutaneous injection or intravenous injection.Dose is decided according to the situation of disease and patient's body weight.But consumption is preferably 0.001～10 milligram.
By following example, at length narrate the present invention.
Example 1
5-acetylaminohydroxyphenylarsonic acid 4,7,8,9-four-O-ethanoyl-2-O ethanoyl-2-O-(5-cholestene-3-beta-yl)-3,5-dideoxy-α-D-glycerine-D-semi-lactosi-2-pyrans nonoses ketone acid methyl esters synthetic
Get 0.77 the gram (2 mmole) in advance thorough drying cholesterol, be dissolved in 10 milliliters of solvents (as anhydrous methylene chloride).After being added to 0.5 gram 4A molecular sieve (high temperature drying under vacuum in advance) in the cholesterol solution, at room temperature in argon gas stream, the mixture that generates was stirred 30 minutes～1 hour.In this mixture, add 1.02 gram (2 mmole) compounds (1), add 2～2.4 mmole silver trifluoromethanesulfonates then.In under the room temperature under the inclined-plane light action, the mixture that generates stirred spends the night, to react.
Reaction soln passes through diatomite filtration.Remove silver salt with saturated salt solution.With drying composites such as anhydrous sodium sulphate.Vacuum boils off solvent, gets white solid.
In order to separate and purifying compounds (2) and (3), white solid is carried out column chromatography (silica gel).Get 0.56 gram (productive rate 33%) compound (2) and 0.55 gram (productive rate 32%) compound (3).
The physical properties of compound (2):
Mass spectrum (EI) m/z860(M+1), 800(M-59)
Ultimate analysis, C 47H 73N
Calculated value (%): C65.63; H8.55; N1.63
Analytical value (%): C65.41; H8.61; N1.60
[α] 25 D-23.8 ° (C=1, chloroform)
Fusing point: 113～115 ℃
Membrane process
Infrared spectra ν 3250,2940,1745,1660 and 1540cm -1
Maximum
1The H nuclear magnetic resonance spectrum, CDCl 3, δ (TMS), 400MHz
0.663H，s，CH 3-18
0.9853H，s，CH 3-19
1.8833H，s，NAC
2.026，2.031，2.126.2.145.3Hx4，sx4，OAcx4
2.5961H，dd，J＝5.2，12.8Hz，2 1Heq
3.6501H，m，H-3
3.7903Hs，COOMe
4.02-4.09 2H，m，H-4′，H-5′
4.166 1H，dd，J＝5.8，12.5Hz，Ha-8′
4.3471H，dd，J＝2.5，12.8Hz，Hb-8′
4.854 1H，ddd，J＝5.2，9.8，12.0Hz，H-3′
5.205 1H，d，J＝10.1Hz，NH
5.33-5.37 2H，m，H-6′，7′
The physical properties of compound (3):
Mass spectrum (EI) m/z860(M+1), 800(M-59)
Ultimate analysis, C 47H 73O 13N
Calculated value (%): C65.63; H8.55; N1.63
Analytical value (%): C65.89; H8.58; N1.66
[α] 25 D-40.2 ° (C=1, chloroform)
Fusing point: 138～140 ℃
Membrane process
Infrared spectra ν 3420,3250,2930,1740, and 1660 and 1540cm -1
Maximum
1The H nuclear magnetic resonance spectrum, CDCl 3, δ (TMS), 400MHz
0.6703H，s，CH 3-18
0.9993H，s，CH 3-19
1.871 3H，s，NAC
2.021，2.021，2.077，2.130.3Hx4，sx4，OAcx4
2.525 1H，dd，J＝4.9，13.1Hz，Heq-2′
3.572 1H，m，H-3
3.798 3Hs，COOCH
4.04-4.13 2H，m，H-4′，5′
4.146 1H，dd，J＝7.6，12.5Hz，Ha-8′
4.888 1H，dd，J＝1.8，12.5Hz，Hb-8′
5.07 1H，tt，J＝2.0，8.2Hz，H-7′
5.22-5.27 1H，m，H-3′
5.34-5.38 2H，m，NH，H-6′
Example 2
5-acetylaminohydroxyphenylarsonic acid 2-O-(5-cholestene-3-beta-yl)-3,5-dideoxy-α-D-glycerine-D-semi-lactosi-2-pyrans nonoses ketone acid synthetic
The compound (2) that example 1 is obtained is dissolved in 2 ml methanol.In this solution, add 3 milliliters of 1N aqueous sodium hydroxide solutions, under room temperature, stir then and spend the night.In the solution that generates, add after 2 ml waters solution strong acid ion exchange resin Dowex50(H +) neutralization, removing by filter a spot of precipitation, filtrate vacuum-drying gets 31.4 milligrams of (productive rate 79.7%) compounds (4) (being white powder).
With above-mentioned identical method, can obtain 30.0 milligrams of (productive rate 76.1%) compounds (5) from compound (3).
The physical properties of compound (4):
Membrane process
Infrared spectra ν 2750,1570cm -1
Maximum
1The H nuclear magnetic resonance spectrum, CDCl 3, δ (TMS), 90MHz
0.71（3H，s，CH 3-18）
0.84 and 0.91(6H, CH 3-26 and CH 3-27)
0.95（3H，d，J＝4.5Hz，CH 3-21）
1.00（3H，s，CH 3-19）
2.01（3H，S，NAc）
2.43(1H, dd, J=4.5 and 12.6Hz, 3-Heq)
[α] 25 D-12.58 ° (C=0.41, methyl alcohol)
The physical properties of compound (5):
KBr
Infrared spectra ν 2870,1620 and 1550cm -1
Maximum
1The H nuclear magnetic resonance spectrum, CD 3OP, δ (TMS), 90MHz
0.71（3H，s，CH 3-18）
0.86 and 0.92(6H, CH 3-26 and CH 3-27)
0.95（3H，d，J＝4.5Hz，CH 3-21）
1.00（3H，S，CH 3-19）
2.00（3H，S，NAc）
2.39(1H, dd, J=4.5 and 12.6Hz, 3-Heq)
[α] 20 D-31.77 ° (C=0.78, methyl alcohol)
Example 3
Get 50 milligrams of compounds (2) [be 5-acetylaminohydroxyphenylarsonic acid 4,7,8,9-four-O-ethanoyl-2-O(5-cholestene-3-beta-yl)-3,5-dideoxy-α-D-glycerine-D-semi-lactosi-2-pyrans nonoses ketone acid methyl esters], be dissolved in 100 ml methanol.Stir on one side, to this solution in splash into about 20 milliliter 2N aqueous sodium hydroxide solutions on one side, obtain about 0.2N sodium hydroxide/methanol solution, under room temperature, stir then and spend the night, make the compound saponification.
Then, while stir adding strong acid ion exchange resin Dowex(H in the solution that generates +).After the pH of solution value transfers to acidity (about pH4), remove resin.Solution is dry in a vacuum, gets 5-acetylaminohydroxyphenylarsonic acid 2-O-ethanoyl-(5-cholestene-3-beta-yl) 3, and 5-dideoxy-α-D-glycerine-D-semi-lactosi-2-pyrans nonoses ketone acid is white powder.This white powder is dissolved in the 0.02N aqueous sodium hydroxide solution.The solution that generates is carried out chromatography by Dianon HP20 resin column, wash resin with water.After with 75% methanol aqueous solution wash-out, steam methyl alcohol, carry out lyophilize, get 37 milligrams of (productive rate 91%) 5-acetylaminohydroxyphenylarsonic acid 2-O-(5-cholestene-3-yls)-3,5-dideoxy-α-D-glycerine-D-semi-lactosi-2-pyrans nonoses ketone acid sodium [compound (4)] is white powder.The physical properties of compound (4) is described with example 2.
Example 4
Get 50 milligrams of compounds (2), be dissolved in 100 ml methanol, in this solution, add 20 milliliters of 2N aqueous sodium hydroxide solutions.Under room temperature, the solution stirring that generates is spent the night, make its saponification.In this solution, add strong acid ion exchange resin Dowex50W(H +) and stir the mixture after, make the pH value of mixture be controlled at 7～8.In order to remove resin,, use methanol wash again with the mixture suction filtration.Filtrate and methanol wash merge, and boil off methyl alcohol.Filter and collect the white insoluble matter of separating out, and lyophilize, 39 milligrams of (productive rate 96%) white powders [compound (4)] got.
The physical properties of compound (4)
Mass spectrum (FD) m/z722(M +Na), 700(M+1), 386,336 and 314
Ultimate analysis, C 38H 62O 9NNa2H 2O
Calculated value (%): C61.96; H8.42; N1.90
Analytical value (%): C61.92; H8.71; N2.04
[α] 24 D+ 2.2 ° (C=1.0, methyl alcohol)
KBr
Infrared spectra ν 3250,2940 and 1605cm -1
Maximum
1The H nuclear magnetic resonance spectrum, CP 3OP, δ (TMS), 400MHz
0.704（3H，S，CH 3-18）
0.870 and 0.885(3H * 2, d, J=1.7Hz, CH 3-26 and CH 3-27)
0.936（3H，d，J＝6.5Hz，CH 3-21）
0.992（3H，S，CH-19）
2.010（3H，S，NAc）
2.839(1H, dd, J=4.2 and 12.0Hz, 2 '-Heq)
5.332（1H，d，J＝5.5Hz，6-H）
13The C nuclear magnetic resonance spectrum, CD 3OP, δ (TMS), 100MHz
175.91（NAc）
175.26（1′-COONa）
142.87（C-5）
122.59（C-6）
102.57（C-1′）
70.50（C-3）
41.00（C-2）
Example 5
Repeat the method for example 3; but using compound (3) [is 5-acetylaminohydroxyphenylarsonic acid 4; 7; 8; 9-four-O-ethanoyl-2-O(5-cholestene-3-beta-yl)-3; 5-dideoxy-β-D-glycerine-D-semi-lactosi-2-pyrans nonoses ketone acid methyl esters] replace compound (2), 36 milligrams of (productive rate 88%) compounds (5) [be 5-acetate amino-2-O-(5-cholestene-3-beta-yl) 3,5-dideoxy-β-D-glycerine-D-semi-lactosi-2-pyrans nonoses ketone acid sodium].The physical properties of compound (5) is described identical with example 2.
Example 6
Repeat the method for example 4, replace compound (2), obtain compound (5) (40 milligrams, productive rate 98%) but use compound (3).
The physical properties of compound (5):
Mass spectrum (FD) m/z722(M +Na), 700(M+1) with 386
Ultimate analysis, C 38H 62O 9NNaH 2O
Calculated value (%): C63.52; H8.91; N1.95
Analytical value (%): C63.81; H9.25; N2.13
[α] 24 D-10.6 ° (C=1.0 methyl alcohol)
KBr
Infrared spectra ν 3270,2950 and 1608cm -1
Maximum
1H nuclear magnetic resonance spectrum CD 3OD, δ (TMS), 400MHz
0.700（3H，S，CH 3-18）
0.861 and 0.880(3H * 2, d, J=1.5Hz, CH 3-26 and CH 3-27)
0.928（3H，d，J＝6.5Hz，CH 3-21）
0.991（3H，S，CH 3-19）
1.972（3H，S，NAc）
2.482(1H, dd, J=4.5 and 13.0Hz, 2 '-Heq)
5.282（1H，d，J＝5.3Hz，6-H）
13The H nuclear magnetic resonance spectrum, CD 3OD, δ (TMS), 100MHz
176.95（NAc）
174.51（1′-COONa）
143.08（C-5）
122.46（C-6）
101.37（C-1′）
72.37（C-3）
43.82（C-2′）
Example 7
Get 50 milligrams of compounds (2), be dissolved in 100 milliliters of anhydrous methanols.The sodium methoxide solution that adds 0.02 milligram 28% in this solution is then with the solution that generates in stirring at room about 1 hour, to carry out the deacetylation reaction.In the solution that generates, add strong acid ion exchange resin Dower x50Wx8(H +), and stir and neutralize.For removing resin,, and use methanol wash with the solution suction filtration.Filtrate and methanol wash liquid merge, and add 20 milliliters of 2N calcium hydroxide aqueous solutions to this solution then, in stirred overnight at room temperature, make and carry out saponification.In saponified solution, add weak-type ion exchange resin AmberliteIRC-50(H +).The solution stirring that generates is also controlled its pH 5～7.For removing resin, then use methanol wash with the solution suction filtration.Filtrate and methanol wash liquid merge, and vacuum-drying removes methyl alcohol so that steam.The white insoluble matter that the filter collection is separated out on a small quantity, and lyophilize get 38 milligrams of (productive rate 93%) compounds (4), are white powder.Its physical properties is described with example 2.
Example 8
Repeat the method for example 7, replace compound (2), get 35 milligrams of (productive rate 86%) compounds (5) but use compound (3).Its physical properties is described with example 2.
Example 9
Injection composition
2.5 milligrams of The compounds of this invention are housed in ampoule, and 0.25 milligram of SODIUM PHOSPHATE, MONOBASIC dihydrate, 3 milligrams of Sodium phosphate dibasic dodecahydrates and distilled water for injection obtain total amount and are 1 milliliter injection composition.
Example 10
Before application, make its dissolved injection composition
0.5 milligram of The compounds of this invention is mixed with 1 ml physiological saline, make injection composition, carry out lyophilize, the phial of packing into then.In order to make this injection composition dissolving, can in phial, add 1 milliliter of distilled water for injection.
Example 11
Be applied to the composition of eye
Pack in phial 1 milligram of The compounds of this invention, 52.5 milligrams of boric acid, 14.5 milligrams of boraxs, an amount of benzalkonium chloride (benzalkonium chloride) and eyes use solubilization solution, obtains total amount and be 5 milliliters of compositions that can be applicable to.
Example 12
Composition for inhalation
In agate brain mortar The compounds of this invention is ground well, the diameter that makes fine powder is 1～20 micron.In this fine powder, add lactose, grind and mix.In this mixture, add lactose more bit by bit.Carefully grind and mix, get a powder, wherein The compounds of this invention is diluted 20 to 40 times.Press general method, during 20～40 milligrams of medicinal powder are incapsulated or good with the cartridge bag paper bag.Capsule is used for the powdery aerosol, and the pulvis of cartridge bag paper pack is used for the liquid aerosol.
The confirmation The compounds of this invention has the test of promotion axon growth effect and states as follows on the way.
Experiment 1
To the outgrowth influence of neuroblast oncocyte (Neuro2a strain)
Neuro2a is suspended in EagleShi substratum and the 10% N of tire serum (FCS) improved by 90%DulbeccoShi is formed and contain on the substratum of 100 units per ml penicillin Gs and 100 mcg/ml Vetstreps, place then in the carbonic acid gas brooder that contains air and 5% carbonic acid gas in 37 ℃ of cultivations.Used culture dish is that diameter is 60 millimeters a polystyrene ware.In each culture dish, implant 1～2 * 10 neuroblast oncocytes and cultivated 48 hours.From the cell culture of gained, remove the culture that contains ox tire serum (FCS).(this culture contains 100% minimum necessary substratum to the culture that does not contain FCS, the degree of depth of antibiotic is then identical with the substratum of removing before the FCS) add following test sample respectively and continue and cultivate: compound (4) (table 1), compound (5) (table 2); Gal(β 1-3) GlaNAC(β 1-4)＜NAC Neu-(α 2-3)＞Gal(β 1-4) Glc(β 1-1)-ceramide (following represent) (table 3) with GM; With＜NACNeu(α 2-8) NAC Neu(α 2-3)＞Gal(β 1-3) GalNAC(β 1-4)-＜NAC Neu-(α 2-8) NAC Neu-(α 2-3)＞-Gal(β 1-4) Glc(β 1-1)-ceramide (below use GQ 1bExpression) (table 4), the heat that adds of test sample sees Table 1～table 4 respectively.Heat above-mentioned medicine 24 and after 48 hours, measure the quantity that viable cell increases in the culture, the quantity of aixs cylinder increase and the length that aixs cylinder increases.The test of each concentration is with three culture dish.The result adds standard error (SE) expression with mean value.
The result:
At compound (4), GM 1And GQ 1bAfter being added on the culture 48 hours, their minimum significant depth was respectively 10 nanogram(ng)s, 10 mcg/ml and 10 mcg/ml.Consider the molecular weight of said medicine, the activity of compound (4) is 420 times of GM, is GQ 1b270 times.Adding compound (5) 48 hours afterwards, its minimum effective concentration is 100 millimicro grams per milliliters, and the activity of compound (5) is GM 142 times, be GQ 1b27 times.
In addition, when cultivation is carried out 24 hours, GM 1And GQ 1bNot effect.But the test-results of compound (4) and (5) shows that when cultivation was carried out 24 hours, the concentration of compound (4) and (5) was 10 millimicro grams per milliliters, and they still have effect.The above results clearly illustrates that compound (4) and (5) have good effect for the aixs cylinder hyperplasia.
Acute toxicity test:
The compound vein is injected the ddy male mice in 45 ages in week to carry out acute toxicity test.The result shows, the LD of compound (4) and (5) 50Be respectively 93 milligrams/kilogram and 291 milligrams/kilogram.
Practical use:
Sialic acid glycosyl cholesterol of the present invention is useful, particularly can be used as the medicine for the treatment of sacred disease.
Figure 871061775_IMG10
Figure 871061775_IMG11
Figure 871061775_IMG12

Claims (7)

1, preparation has the cholesteric method of sialic acid glycosyl of following general expression (B);
Wherein Ac is an ethanoyl, R 3And R 4In one be-COONa that another has following general expression:
This method comprises makes the have following formula compound of (1) and cholesterol at Ke Nixi-Nore
Catalyzer reacts under existing,
Figure 871061775_IMG3
Obtain the having following formula compound of (A) is hydrolyzed compound (A) then,
R wherein 1And R 2In one be-COOCH 3, another is the group with following formula,
2, the described method of claim 1, wherein this Ke Nixi-Nore catalyzer system is selected from mercuric bromide, mercury cyanide, silver perchlorate, silver trifluoromethanesulfonate and Silver Trifluoroacetate.
3, the described method of claim 2, wherein between compound (1) and the cholesterol be reflected at about 20～25 ℃, under normal pressure, carried out 1～7 day.
4, the described method of claim 1, wherein said cholesteric consumption are 1 mole compound (1) with 1～5 mole of cholesterol.
5, the described method of claim 2, wherein said Ke Nixi-Nore catalyst consumption are 1 equivalent compound (1) with 1.0～1.2 equivalent catalyzer.
6, the described method of claim 1, wherein used solvent can be selected from benzene, methylene dichloride and tetrahydrofuran (THF).
7, the described method of claim 1 wherein for making compound (A) hydrolysis, is handled its alkaline solution with 1～3N 5～15 hours in 15～25 ℃.
CN87106177A 1986-09-04 1987-09-03 Sialic acid sugar radical cholesterol, process for preparing them and drug containing them for treating neuronosis Expired - Fee Related CN1028998C (en)

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JP61208380A JPH07116216B2 (en) 1986-09-04 1986-09-04 Method for producing sialosil cholesterol
JP208380/86 1986-09-04

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CN1064048C (en) * 1996-08-29 2001-04-04 中国科学院昆明植物研究所 Five compounds of Qingyang ginseng glucoside and its preparation method and application

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CN87106177A (en) 1988-04-20
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ES2007358A6 (en) 1989-06-16
KR880003968A (en) 1988-06-01
KR890004136B1 (en) 1989-10-21

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