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CN1097194A - Dammarane-type saponin ginseng lowhydric alcohol derivative and preparation method - Google Patents

Dammarane-type saponin ginseng lowhydric alcohol derivative and preparation method Download PDF

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CN1097194A
CN1097194A CN 93108189 CN93108189A CN1097194A CN 1097194 A CN1097194 A CN 1097194A CN 93108189 CN93108189 CN 93108189 CN 93108189 A CN93108189 A CN 93108189A CN 1097194 A CN1097194 A CN 1097194A
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panoxatriol
formula
preparation
panoxadiol
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CN1047598C (en
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魏均娴
陈业高
张红彬
赵爱华
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Guangzhou Tianzhijiao Life Technology Co., Ltd.
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UNMING MEDICAL COLLEGE
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Abstract

The present invention relates to and have dammarane and be new genseng low valence alcohol derivative of female ring structure and preparation method thereof, and this series compound is as the application of medicine.Panoxatriol glycoside of the present invention, panoxadiol potassium succinate, panoxatriol sodium succinate and panoxadiol glycoside have the stronger ability that presses down the knurl effect and kill and wound cancer cells through experiment.Respectively with 12-25mg/ml, can make pharmaceutically acceptable dosage formulation with dammarane-type saponin ginseng lowhydric alcohol derivative of the present invention.

Description

Dammarane-type saponin ginseng lowhydric alcohol derivative and preparation method
The present invention relates to and have dammarane and be new genseng low valence alcohol derivative of female ring structure and preparation method thereof, and this series compound is as the application of medicine.
Arasaponin has multiple important physiologically active, as to cardiovascular disease effect metabolism, increase immunization etc., but effect is strong inadequately.Can not be applicable to production again and separate the monomeric technology of various saponins.Use total saponin because the saponin monomer of forming is inconsistent, the remorse instability of polysaccharid glucoside is led and is caused the curative effect instability.So separate in the pseudo-ginseng derivative of two kinds of main sapogenin panoxadiols and the semi-synthetic stable in properties of panoxatriol, to strengthen its effect, stablize its curative effect, be applicable to and produce and clinical application, necessary.
The purpose of this invention is to provide a series of preparation methods with the low compound of antitumour activity and toxicity, compound and as the application of medicine.
Dammarane-type saponin ginseng lowhydric alcohol derivative of the present invention has the general formula of formula I, and the formula I is:
Figure 931081890_IMG3
In the formula I, R=H, COCH 2CH 2COOK, COCH 2CH 2COONa,
Figure 931081890_IMG4
(abbreviation II), R '=II, H, OCOCH 2CH 2COONa.When R=H, R '=II, the represented compound of formula I is the panoxatriol glycoside, molecular formula C 36H 62O 9, white crystal.Work as R=COCH 2CH 2During COOK, R '=H, the represented compound of formula I is the panoxadiol potassium succinate, molecular formula C 34H 55O 6K, white crystal, variable color more than 360 ℃.Work as R=COCH 2CH 2During COONa, R '=OCOCH 2COONa, the represented compound of formula I is the panoxatriol sodium succinate, molecular formula C 38H 58O 10Na 2, white crystal, variable color more than 300 ℃.When the R=II, R '=H, the represented compound of formula I is the panoxadiol glycoside, molecular formula C 36H 62O 8, white crystal, fusing point 223-226 ℃.
Panoxatriol glycoside C 36H 62O 9The preparation method be: get panoxatriol 4-5g, dry ether 90-190ml, ethylene dichloride 85-120ml mixes, heating for dissolving adds acetyl bromide for glucose 6-12g, refluxes and stirs 4-10 hour, adding silver carbonate 4-7.9g backflow again stirred 4-10 hour, filter, filtrate is reclaimed solvent, and resistates is dissolved in methyl alcohol, filter, filtrate adds distilled water to the solution muddiness, adds the 6-12ml triethylamine again, stirring at room 8-14 hour, reclaim solvent to doing, by silica gel column chromatography,, get product with chloroform-methanol flushing in 9: 1.
Panoxadiol potassium succinate C 34H 55O 6The preparation method of K: a: with panoxadiol, succinyl oxide, pyridine is pressed 1-3: 5-6: the mixed of 15-20, heated and stirred refluxes, and room temperature is put cold, in the impouring cold water, have the precipitation separate out, filter the pale precipitation thing, throw out is dissolved in the ethanol, heating for dissolving adds activated carbon decolorizing, filtration under diminished pressure, reclaim ethanol, put coldly, an adularescent bunch shape crystallization is separated out, filter is done, and gets the panoxadiol succsinic acid; B, panoxadiol succsinic acid add stirring and dissolving in the acetone, drip the KOH ethanol solution, stir until precipitation fully, leave standstill, filter, and the throw out washing with acetone, filtration under diminished pressure gets product.
Panoxatriol sodium succinate C 38H 58O 10Na 2The preparation method be: a, panoxatriol, succinyl oxide, pyridine are pressed 1-2.5: the mixed of 3-6: 9-12, in 134-135 ℃ oil bath backflow 3-5 hour, then with in the reaction mixture impouring water, leave standstill, filter, drying, get pale solid, this solid is dissolved in the ethanol, with activated carbon decolorizing, filter, in the filtrate impouring water, leave standstill the leaching precipitate, make panoxatriol 3, the 6-disuccinic acid.
B, with panoxatriol-3, the 6-disuccinic acid is dissolved in the acetone, stir splash into the NaOH methanol solution to precipitation fully, filter, use washing with acetone, drying gets finished product.
Panoxatriol grape glucoside sugar of the present invention, panoxadiol potassium succinate, panoxatriol sodium succinate and panoxadiol glycoside (be called for short B ' 3) be through experiment, has the stronger ability that presses down the knurl effect and kill and wound cancer cells.The human cancer cell vitro culture fragmentation test data of above-claimed cpd see Table 1, the result shows that above-claimed cpd has the effect that kills and wounds lung adenocarcinoma cell, and significant concn-effect dependence is arranged, ultimate density is 100 μ g/ml when above, and kill rate can surpass 50%.3 pairs of Lewis lung cancer tumor-inhibiting actions of B ' are as shown in table 2, and the result shows that successive administration 7 days has tangible tumor-inhibiting action to Lewis liver cancer, and 50mg/kg group tumour inhibiting rate is 53.3%, reaches the rules requirement.Under equal conditions compare its tumor-inhibiting action and be lower than cis-platinum slightly with cis-platinum.3 couples of H of B ' 22Liver ascites lengthen the life the effect as shown in table 3, the result shows, 7 days H of successive administration 22Liver cancer has the effect of obviously lengthening the life, and the 50mg/kg group can lengthen the life 155.3%, reaches the rules requirement, under equal conditions compares with cis-platinum, and its antitumor action and chemotherapeutic are suitable.3 pairs of mouse Emhorns of B ' EAS tumor-inhibiting action is as shown in table 4, and the result shows that successive administration 7 days has tangible tumor-inhibiting action to Emhorn EAS, and its action intensity and cis-platinum are suitable.
Dammarane-type saponin ginseng lowhydric alcohol derivative of the present invention can be made pharmaceutically acceptable dosage formulation respectively with 12-25mg/ml.
Embodiment:
1, the preparation of panoxatriol glycoside: panoxatriol 4.2 grams, acetyl bromide are for glucose 7.2 grams, 190 milliliters of ether (drying), 85 milliliters of ethylene dichloride, silver carbonate 7.9 grams
The preparation method:
Panoxatriol, dry ether, the dissolving of ethylene dichloride mixture heating up, add acetyl bromide for glucose, reflux and stirred 10 hours, add the silver carbonate backflow and stirred 10 hours, filter, reclaim solvent, resistates 20ml dissolve with methanol, the filtering insolubles, filtrate adds water to muddiness (adding the about 10-15ml of entry), adding the 12ml triethylamine stirred 12 hours, reclaim solvent to doing, be adsorbed on the 5 gram 160-200 order silica gel by 85 gram silica gel wet method upper props, with chloroform flushing in 9: 1,50 milliliters every part, 10-19 part is collected the panoxatriol glycoside.Weigh 0.94 gram.
2, the preparation of panoxatriol sodium succinate
(A) panoxatriol-3, the preparation of 6-disuccinic acid:
4.76 gram panoxatriol and 20 gram succinyl oxides are dissolved in the 50ml pyridine, reflux 3.5 hours in 134-135 ℃ oil bath, then with standing over night in the reaction mixture impouring 800ml water, filter, drying obtains 6.57 gram pale solids.This is dissolved among the 200ml95% ethanol,, filters with activated carbon decolorizing, in the filtrate impouring 800ml water (alcohol 1: water 4-5), standing over night is filtered, vacuum-drying in the vitriol oil vacuum drier, white solid 5.46 grams, productive rate 80.8%.
(B) preparation of panoxatriol sodium succinate:
3.0 the panoxatriol-3.6-disuccinic acid that restrains is dissolved in the 600ml propyl alcohol, under constantly stirring, splashes into the NaOH methanol solution of 10ml1N, drips to precipitating fully, continues to stir 1 hour, filters, vacuum-drying gets the 3.13g white solid.
3, the preparation of panoxadiol potassium succinate:
Panoxadiol 3 gram, succinyl oxide 6 grams, 15 milliliters of pyridines, in the 100ml triangular pyramidal bottle of packing into, stirring and refluxing in the water-bath react 2 hours, put coldly, in 300 milliliters of cold water of impouring, had precipitation to separate out, and decompress filter must white depositions.TLC reaction is a bit, and above-mentioned reactant is dissolved in 200ml(95%) in the ethanol, heating for dissolving, gac suitably decolours, and decompress filter reclaims ethanol to about 30ml, puts a cold adularescent bunch shape needle and separates out, and suction filtration, drying must the 3g products, productive rate 100%.
TLC condition: developping agent CHC13-MeOH(9: 1) developer 15% ethanol solution of sulfuric acid, 105 ℃ of heating.Thin layer plate silica gel G plate.
8 gram panoxadiol succsinic acids place the 500ml Erlenmeyer flask, add 400ml acetone, fully stir, slowly splash into 0.5mlKOH ethanol liquid, 30ml continues to stir 20 minutes altogether, leave standstill a moment, treat precipitation fully, filtration under diminished pressure, throw out washing with acetone 3 times, each 10ml, precipitation seasoning, porphyrize, weigh white powder 7.5gm, yield 94%.
4, the preparation of panoxadiol glycoside (B ' 3)
(A) preparation of Bromotetraacetylgluc,se:
In the three-necked bottle of 500ml, load onto stirring, add diacetyl oxide and a little vitriol oil, under the stirring state, gradation adds glucose, controlled temperature 60-80 ℃, add the back and continue to stir 30 fens, frozen water is cooled to below 30 ℃, and gradation adds red phosphorus, add the back and continue to stir 30 minutes, slowly drip Br below 30 ℃ 2, after adding, the bottle stopper plug is good, puts refrigerator overnight.Add gauge water, with chloroform extraction, the chloroform layer washing adds CaC 12Drying is filtered, and filtrate decompression is regained chloroform, recrystallization in the resistates dehydrated alcohol, vacuum-drying.
(B) acetylize B ' 3 preparations:
Panoxadiol, acetylize bromo glucose, anhydrous diethyl ether; dichloroethane solution is heated to 40 ℃ in the water-bath, add silver carbonate; lucifuge stirred 8 hours; filter, reclaim the solvent residues thing and add 20ml methyl alcohol, remove by filter insolubles; evaporate to dryness methyl alcohol; last silicagel column with 8: 2 wash-outs of sherwood oil-acetone, gets acetylize B ' 3.Yield about 25%.
(3) preparation of B ' 3
Acetylize B ' 3 adds dissolve with methanol, drips to add water to little muddyly, adds triethylamine; stirring at room 10 hours; solvent evaporated, crystallization in the ethanol, thin layer is checked B ' 3 and panoxadiol; crystallization is dissolved in methyl alcohol; by silica gel column chromatography, 8: 2 wash-out panoxadiols of sherwood oil-acetone, again with chloroform-methanol wash at 9: 1 B ' 3; crystallization in vinyl acetic monomer, yield about 10%.
Table 1.
Medicine name The living cells mean Kill rate 7. The nuclear fission phase
A blank contrast 170.8 0 4.9
Fluorouracil 100ug 10ug 1ug 102.3 134.3 147.7 40.1 21.4 13.6 0.1 0.3 0.4
Panoxadiol 100ug Potassium Suceinate 10ug 1ug 18.6 92.8 185.3 89.2 45.7 0 0 0.6 4.5
Panaxatriol 100ug glycoside 10ug 1ug 70.4 136.7 182.6 58.8 20.0 0 1.1 4.5 5.2
Panoxadiol 100ug glycoside 10ug 1ug 0.1 109.7 176.0 100.0 35.8 0 0 1.7 5.6
Table 2.
The group mouse count heavy (mg) tumour inhibiting rate P of dosage knurl value (mg/kg * d) (* ± SD) %
Normal mice group 9 N.S * 7 1703.0 ± 1078--control group 9 20%DMSO * 7 159.5 ± 731--synthetic B ' 39 50 * 7 915.9 ± 702 53.3＜0.01 7 100 * 7 986 ± 467 49.7＜0.01 CDDP 10 3 * 4 653.2 ± 326.5 66.7＜0.001
Table 3.
The group mouse count dosage work deposit fate life prolong the P value (mg/kg * d) (* ± SD) %
Normal mice group 10 N.S * 7 16.1 ± 3.0--control group 10 20%DMSO * 7 15.9 ± 1.0--synthetic B ' 3 10 50 * 7 40.6 ± 9.6 155.3＜0.001 10 100 * 7 32.4 ± 12.2 103.8＜0.001 CDDP 10 3 * 4 40.5 ± 7.7 154.7＜0.001
Table 4.
The group mouse count heavy (mg) tumour inhibiting rate P of dosage knurl value (mg/kg * d) (* ± SD) %
Normal mice group 10 N.S * 7 1.48 ± 0.50--control group 9 20%DMSO * 7 1.40 ± 0.38--synthetic B ' 39 25 * 7 0.52 ± 0.16 62.9＜0.001 10 50 * 7 0.51 ± 0.19 63.6＜0.001 CDDP 93 * 4 0.47 ± 0.22 66.4＜0.001

Claims (9)

1, a kind of dammarane-type saponin ginseng lowhydric alcohol derivative, the general formula with formula I, the formula I is:
Figure 931081890_IMG1
It is characterized in that in the formula I R=H, COCH 2CH 2COOK, COCH 2CH 2COONa,
Figure 931081890_IMG2
(abbreviation II), R '=II, H, OCOCH 2CH 2COONa.
2, according to the described derivative of claim 1, it is characterized in that when R=H, R '=II, the represented compound of formula I is the panoxatriol glycoside, molecular formula C 36H 62O 9, white crystal.
3, according to the described derivative of claim 1, it is characterized in that working as R=COCH 2CH 2During COOK, R '=H, the represented compound of formula I is the panoxadiol potassium succinate, molecular formula C 34H 55O 6K, white crystal, variable color more than 360 ℃.
4, according to the described derivative of claim 1, it is characterized in that working as R=COCH 2CH 2During COONa, R '=OCOCH 2COONa, the represented compound of formula I is the panoxatriol sodium succinate, molecular formula C 38H 58O 10Na 2, white crystal, variable color more than 300 ℃.
5, according to the described derivative of claim 1, it is characterized in that when the R=II, R '=H, the represented compound of formula I is the panoxadiol glycoside, molecular formula C 36H 62O 8, white crystal, fusing point 223-226 ℃.
6,, it is characterized in that described panoxatriol glycoside C according to the preparation method of the described derivative of claim 2 36H 62O 9The preparation method be: get panoxatriol 4-5g, dry ether 90-190ml, ethylene dichloride 85-120ml mixes, heating for dissolving adds acetyl bromide for glucose 6-12g, refluxes and stirs 4-10 hour, adding silver carbonate 4-7.9g backflow again stirred 4-10 hour, filter, filtrate is reclaimed solvent, and resistates is dissolved in methyl alcohol, filter, filtrate adds distilled water to the solution muddiness, adds the 6-12ml triethylamine again, stirring at room 8-14 hour, reclaim solvent to doing, by silica gel column chromatography,, get product with chloroform-methanol flushing in 9: 1.
7,, it is characterized in that panoxadiol potassium succinate C according to the preparation method of the described derivative of claim 3 34H 55O 6The preparation method of K: a: with panoxadiol, succinyl oxide, pyridine is pressed 1-3: 5-6: the mixed of 15-20, heated and stirred refluxes, and room temperature is put cold, in the impouring cold water, have the precipitation separate out, filter the pale precipitation thing, throw out is dissolved in the ethanol, heating for dissolving adds activated carbon decolorizing, filtration under diminished pressure, reclaim ethanol, put coldly, an adularescent bunch shape crystallization is separated out, filter is done, and gets the panoxadiol succsinic acid; B, panoxadiol succsinic acid add stirring and dissolving in the acetone, drip the KOH ethanol solution, stir until precipitation fully, leave standstill, filter, and the throw out washing with acetone, filtration under diminished pressure gets product.
8,, it is characterized in that panoxatriol sodium succinate C according to the preparation method of the described derivative of claim 4 38H 58O 10Na 2The preparation method be: a, panoxatriol, succinyl oxide, pyridine are pressed 1-2.5: the mixed of 3-6: 9-12, in 134-135 ℃ oil bath backflow 3-5 hour, then with in the reaction mixture impouring water, leave standstill, filter, drying, get pale solid, this solid is dissolved in the ethanol, with activated carbon decolorizing, filter, in the filtrate impouring water, leave standstill the leaching precipitate, make panoxatriol 3, the 6-disuccinic acid; B, with panoxatriol-3, the 6-disuccinic acid is dissolved in the acetone, stir splash into the NaOH methanol solution to precipitation fully, filter, use washing with acetone, drying gets finished product.
9,, it is characterized in that with described derivative making pharmaceutically acceptable dosage formulation respectively with 12-25mg/ml according to of the application of the described derivative of claim 1 as medicine.
CN93108189A 1993-07-06 1993-07-06 Dammarane-type saponin ginseng lowhydric alcohol derivative and preparation method Expired - Fee Related CN1047598C (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002003996A1 (en) * 2000-07-12 2002-01-17 RAJKUMAR, Sujatha Use of dammarane-type tritepenoid saporins
CN100381458C (en) * 2003-11-24 2008-04-16 山东绿叶天然药物研究开发有限公司 Protopanoxadiol lower alcohol derivatives and process for preparing same
CN103059088A (en) * 2013-01-16 2013-04-24 烟台大学 Dammarane saponin derivatives with novel structure as well as preparation method and anti-microbial application thereof
CN104434939A (en) * 2014-11-14 2015-03-25 深圳大学 Antitumor medicament composition of panax notoginseng saponins R7 and oridonin with capabilities of reducing toxicity and enhancing efficacy and application of antitumor medicament composition
CN105985398A (en) * 2015-02-10 2016-10-05 北京佗林医药科技有限公司 Tetracyclic triterpenoid compound and its use in medicines

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL128376C (en) * 1964-04-23
GB1553222A (en) * 1975-05-07 1979-09-26 Steele Chemical Co Ltd 14 - hydroxy 3- eoxycardenolides
DE3026783C2 (en) * 1980-07-11 1982-07-29 Schering Ag, 1000 Berlin Und 4619 Bergkamen Process for the preparation of 5β-hydroxy- δ → 6 → steroids

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002003996A1 (en) * 2000-07-12 2002-01-17 RAJKUMAR, Sujatha Use of dammarane-type tritepenoid saporins
CN100381458C (en) * 2003-11-24 2008-04-16 山东绿叶天然药物研究开发有限公司 Protopanoxadiol lower alcohol derivatives and process for preparing same
CN103059088A (en) * 2013-01-16 2013-04-24 烟台大学 Dammarane saponin derivatives with novel structure as well as preparation method and anti-microbial application thereof
CN103059088B (en) * 2013-01-16 2017-02-08 烟台大学 Dammarane saponin derivatives with novel structure as well as preparation method and anti-microbial application thereof
CN104434939A (en) * 2014-11-14 2015-03-25 深圳大学 Antitumor medicament composition of panax notoginseng saponins R7 and oridonin with capabilities of reducing toxicity and enhancing efficacy and application of antitumor medicament composition
CN104434939B (en) * 2014-11-14 2017-05-03 深圳大学 Antitumor medicament composition of panax notoginseng saponins R7 and oridonin with capabilities of reducing toxicity and enhancing efficacy and application of antitumor medicament composition
CN105985398A (en) * 2015-02-10 2016-10-05 北京佗林医药科技有限公司 Tetracyclic triterpenoid compound and its use in medicines

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