CN103739653A - Novel 23-oleanolic acid compound as well as preparation method and application of compound in preparation of glycosidase inhibitor medicine - Google Patents
Novel 23-oleanolic acid compound as well as preparation method and application of compound in preparation of glycosidase inhibitor medicine Download PDFInfo
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Abstract
The invention discloses a compound 2-hydroxyl-3-carbonyl-23-oleanolic acid-1,4,12-triene-28-acid as well as a preparation method and application of the compound preparation of a glycosidase inhibitor medicine. An alpha-glucosidase inhibitor with high efficiency is extracted and separated from an akebia plant, a plant material is rich in source, an extraction preparation method is easy to operate, the plant can be used for a long time without being damaged when extraction is performed by adopting a plant fruit, and thus the economic benefit can be increased, and the environment friendliness is achieved; the monomeric compound is stable and easy to store. Pharmacological experiments prove that the inhibitory activity of the compound 2-hydroxyl-3-carbonyl-23-oleanolic acid-1,4,12-triene-28-acid is stronger than that of a first-grade diabetes drug acarbose by about 16 times, and thus the compound 2-hydroxyl-3-carbonyl-23-oleanolic acid-1,4,12-triene-28-acid can be expected to be further developed into a medicine for clinically treating type 2 diabetes mellitus and is good in prospect.
Description
Technical field:
The invention belongs to Natural Medicine Chemistry field, be specifically related to a kind of new 23-and fall Oleanolic Acid compounds, be that olea-1 falls in 2-hydroxyl-3-carbonyl-23-, 4,12-triolefin-28-acid, and the preparation method of this compound and this compound or its pharmaceutically useful salt or its esterified derivative are in the application of preparing in glycosidase inhibitor.
Background technology:
Diabetes are clinical common endocrine metabolism dysfunctional disease, and the occurred frequently year by year of itself and cardiovascular disease and cancer etc. has an important dependency, is the potential important killer of human health.Along with social progress and the raising of people's living standard, the sickness rate of diabetes improves in the world, has especially the morbidity that exceedes 100,000,000 people in China, and presents the trend increasing year by year.Diabetes cause more and more great loss just to China's people ' s health and national economy.
Diabetes doctor trained in Western medicine is divided into insulin-dependent diabetes mellitus (IDDM) (or claim insulin-dependent, DM1) and type II diabetes (or old non-insulin-dependent, DM2), and wherein type II diabetes morbidity, with morbidity all far above insulin-dependent diabetes mellitus (IDDM), thereby endangers larger.Competitive alpha-glucosidase inhibitor has the glucide of postponement to be digested and assimilated, alleviates kidney burden, control blood sugar after meal and sharply raise and then can make the functions such as blood sugar concentration changed that fluctuating range reduced in a day, and they are just becoming people and are finding and can develop the medicine that is used for the treatment of type II diabetes.Having developed at present listing and positive clinic trial makes the important alpha-glucosidase inhibitor for the treatment of type II diabetes one line medication and comprises acarbose(acarbose), voglibose, miglitol and emigliate etc.
Diabetes claim again diabetes in the traditional Chinese medical science, and the single medicinal material that in Compendium of Materia Medica, record can be used for treating diabetes has nearly 200 kinds, shows that from Chinese medicine or plant origin, excavating new alpha-glucosidase inhibitor has important prospect.Existing bibliographical information discloses, and Lardizabalaceae Three Akebia Decne Species has the pharmacological functions such as anti-inflammatory, diuresis, and is rich in triterpene and falls the compounds such as triterpene, but deep not enough on the general study of pharmacologically active and composition.We find that this platymiscium tissue extract has the activity of certain inhibition alpha-glycosidase in the recent period, thereby it has important potentiality exploring to excavate aspect alpha-glucosidase inhibitor new, highly effective and safe.
Summary of the invention:
First object of the present invention is to provide a kind ofly to be had alpha-glucosidase and suppresses active 23-and fall triterpenes new compound 2-hydroxyl-3-carbonyl-23-and fall olea-Isosorbide-5-Nitrae, 12-triolefin-28-acid.
Olea-Isosorbide-5-Nitrae falls in 2-hydroxyl-3-carbonyl-23-of the present invention, 12-triolefin-28-acid, and its structural formula is as shown in formula I:
Second object of the present invention is to provide a kind of compound 2-hydroxyl-3-carbonyl-23-and falls olea-1, 4, the preparation method of 12-triolefin-28-acid, it is characterized in that, olea-1 falls in compound 2-hydroxyl-3-carbonyl-23-, 4, 12-triolefin-28-acid is from akebi (Akebia quinata (Thumb.) Decne.), threeleaf akebia (Akebiatrifolia (Thumb.) Koidz), long order akebi (Akebia longeracemosaMatsumura), the stem of Caulis Akebiae (Akebiatrifolia (Thumb.) Koidz.Var.australis (Diels) Rehd) or long calyx threeleaf akebia (Akebiatrifolia (Thumb.) Koidz..subsp.LongisepalaH.N.Qin), in leaf or fruit, preparation separation obtains.Concrete material can be dry product or fresh goods, the fruit dry product of preferred plant.
Concrete steps are preferably:
A, prepare total medicinal extract: by stem, leaf or the fruit material disintegrating of the akebi gathering, threeleaf akebia, long order akebi, Caulis Akebiae or long calyx threeleaf akebia, then with aqueous ethanolic solution or aqueous acetone solution lixiviate, after the concentrated removal of extracting solution organic solvent, obtain total medicinal extract crude extract, total medicinal extract crude extract is suspended in water, with sherwood oil or ethyl acetate extraction, extract obtains total medicinal extract after concentrated;
B, separation and purification: total medicinal extract is through purification on normal-phase silica gel column chromatography, take sherwood oil/acetone as eluent, successively from volume ratio 100:0, 20:1, 10:1, 8:1, 5:1, 3:1, 2:1, 1:1, 0:100 gradient elution, collect the cut that sherwood oil/acetone 5:1 elutes, again through purification on normal-phase silica gel column chromatography, with sherwood oil/acetone successively from volume ratio 100:0, 10:1, 8:1, 6:1, 4:1, 2:1, 0:100 is eluent gradient wash-out, collect the cut of sherwood oil/acetone 6:1 wash-out, again through the separation and purification of SephadexLH-20 gel column with acetone wash-out, elutriant carries out recrystallization, obtain the pure compound 2-hydroxyl-3-carbonyl-23-shown in formula I and fall olea-1, 4, 12-triolefin-28-acid.
Described aqueous ethanolic solution or aqueous acetone solution are preferably volume fraction and are more than or equal to 70% aqueous ethanolic solution or aqueous acetone solution.
Olea-Isosorbide-5-Nitrae falls in new compound 2-hydroxyl-3-carbonyl-23-of the present invention, and 12-triolefin-28-acid confirms through external pharmacological evaluation, and it has potent restraining effect to alpha-glucosidase, and it suppresses active (IC
50=24.8 ± 0.28 μ M) even than positive control acarbose (IC
50=408.78 ± 5.67 μ M) also strong.Therefore this new compound is the alpha-glucosidase inhibitor stronger than acarbose, can develop the medicine for the preparation of prevention and treatment type II diabetes, and application potential quality is extensive.
The 3rd object of the present invention is to provide 2-hydroxyl-3-carbonyl-23-and falls olea-Isosorbide-5-Nitrae, and 12-triolefin-28-acid, its pharmaceutically useful salt or its esterified derivative are in the application of preparing in alpha-glucosidase inhibitor medicament.
The 4th object of the present invention is to provide a kind of alpha-glucosidase inhibitor medicament, it is characterized in that, olea-Isosorbide-5-Nitrae falls in the compound 2-hydroxyl-3-carbonyl-23-that contains significant quantity, 12-triolefin-28-acid or its pharmacologically acceptable salt or its esterified derivative, and pharmaceutically commonly use auxiliary material or carrier.
Stem, leaf or the fruit that the 5th object of the present invention is to provide akebi, threeleaf akebia, long order akebi, Caulis Akebiae or long calyx threeleaf akebia falls olea-Isosorbide-5-Nitrae, the application in 12-triolefin-28-acid preparing compound 2-hydroxyl-3-carbonyl-23-.
Olea-1 falls in new compound 2-hydroxyl-3-carbonyl-23-of the present invention, 4,12-triolefin-28-acid or its pharmaceutically useful salt or esterified derivative, its substantive inhibition glycosidase activity composition is all that olea-1 falls in compound 2-hydroxyl-3-carbonyl-23-, 4,12-triolefin-28-acid molecule.Olea-1 falls in described 2-hydroxyl-3-carbonyl-23-, 4, the pharmaceutically useful salt of 12-triolefin-28-acid, its essence that suppresses alpha-glycosidase is in people's digestive tube, under the physiological conditions such as hydrochloric acid in gastric juice, can be converted into bioactive molecule 2-hydroxyl-3-carbonyl-23-to fall olea-1,4,12-triolefin-28-acid and working.Olea-1 falls in described compound 2-hydroxyl-3-carbonyl-23-, 4, the esterified derivative of 12-triolefin-28-acid refers to that olea-1 falls in compound 2-hydroxyl-3-carbonyl-23-, 4, 2-position hydroxyl in 12-triolefin-28-acid molecule is by the derivative compound of the 28-position carboxyl in esterifying organic acid or molecule and alcohol compound esterification, described esterified derivative can be partial esterification or the full esterification of one or two group in 2-position hydroxyl and 28-position carboxyl functional group, these fall olea-1 based on 2-hydroxyl-3-carbonyl-23-, 4, the esterified derivative of 12-triolefin-28-acid molecule skeleton, it can be converted into easily bioactive molecule 2-hydroxyl-3-carbonyl-23-and fall olea-1 in people's digestive tube under the physiological conditions such as hydrochloric acid in gastric juice or intestines alkali, 4, 12-triolefin-28-acid, its essence is also that olea-1 falls in compound 2-hydroxyl-3-carbonyl-23-, 4, 12-triolefin-28-acid plays alpha-glucoside inhibiting activity, thereby belong to strict protection scope of the present invention.Wherein organic acid and the Organic Alcohol of esterification can be any forms of related esters bond energy hydrolysis under physiology acid-base condition respectively with 2-position hydroxyl and 28-position carboxyl respectively, preferably can strengthen the C1 of whole macromolecule water-solubility characteristic to small molecular organic acid and the alcohol of C4, and contain the C6 of phenyl ring to organic acid or the Organic Alcohol of the various small moleculars of C10.
Olea-1 falls in new compound 2-hydroxyl-3-carbonyl-23-of the present invention, 4, the acid of 12-triolefin-28-or its pharmaceutically useful salt or esterified derivative can with pharmaceutically conventional auxiliary material or pharmaceutical carrier are combined, prepare and there is 2-hydroxyl-3-carbonyl-23-and fall olea-1,4,12-triolefin-28-acid suppresses alpha-glycosidase activity, can be used for medicine or the pharmaceutical composition of prevention and treatment type II diabetes.This medicine or pharmaceutical composition can adopt the formulations such as wettable powder, tablet, granule, capsule, oral liquid, dripping pill, injection, aerosol; Also can adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
The present invention adopts the Three Akebia Decne Species extensively distributing from China and extracts and separate potent alpha-glucosidase inhibitor, material source is abundant, preparation process is easy, easy handling, and can also make plant itself be utilized for a long time without destruction when adopting fruit to extract, can also be environmentally friendly when obtaining better economic benefit, and this monomeric compound is stable, easy to store.Olea-1 falls in this compound 2-hydroxyl-3-carbonyl-23-, 4, the alpha-glucoside inhibiting activity of 12-triolefin-28-acid is even higher than clinical application acarbose, the alpha-glucosidase inhibitor class medicine that is further development of most probably effective, safe new prevention and treatment type II diabetes, market-oriented prospect is better.
Accompanying drawing explanation:
Fig. 1 is that olea-Isosorbide-5-Nitrae falls in compound 2-hydroxyl-3-carbonyl-23-, 12-triolefin-28-acid
1hNMR collection of illustrative plates;
Fig. 2 is that olea-Isosorbide-5-Nitrae falls in compound 2-hydroxyl-3-carbonyl-23-, 12-triolefin-28-acid
13cNMR collection of illustrative plates;
Fig. 3 is that olea-Isosorbide-5-Nitrae falls in compound 2-hydroxyl-3-carbonyl-23-, the HMBC collection of illustrative plates of 12-triolefin-28-acid.
Embodiment:
Following examples are to further illustrate of the present invention, rather than limitation of the present invention, and the simple modifications that essence according to the present invention is carried out the present invention all belongs to the scope of protection of present invention.
Embodiment 1: in Trilobed Caulis Akebiae fruit, olea-Isosorbide-5-Nitrae falls in 2-hydroxyl-3-carbonyl-23-, the preparation of 12-triolefin-28-acid
1.1 instruments and reagent
Concentrating under reduced pressure adopts the Tokyo N-1000 of physics and chemistry company Rotary Evaporators, the circulating cooling tank of CCA-1110 and SB-1000 electric-heated thermostatic water bath; HPLC adopts the Japanese Shimadzu LC-20AT of company type liquid chromatograph, SPD-M20A detector and Shim-PackPRC-ODS chromatographic column (particle diameter 5 μ m, aperture 12nm, 250mm × 20mm); Electrospray ionization mass spectrum (ESIMS) adopts the MDSSCIEXAPI2000LC/MS/MS of Applied biosystems instrument, take methyl alcohol as solvent direct injection, measures;
1hNMR spectrum and
13cNMR spectrum adopts BrukerDRX-400 nuclear magnetic resonance analyser, and fixed take tetramethylsilane as interior mapping.Coloration method adopts 10% ethanol solution of sulfuric acid or sulfuric acid Vanillin to process post-heating colour developing or iodine vapor colour developing.
1.2 plant origins and evaluation
For the fruit sample that extracts vegetable material threeleaf akebia (Akebiatrifolia (Thumb.) Koidz.), in September, 2009, pick up from Hunan Province domestic, by South China Botanical Garden Chinese Academy of Sciences, Xing Fuwu researcher identifies.
1.3 extract with separation
Sample (Trilobed Caulis Akebiae fruit, 2.0 kilograms of dry weights) is pulverized rear with extracting three times under volume fraction 95% aqueous ethanolic solution room temperature, and merging filtrate concentrating under reduced pressure is removed organic solvent, obtains total medicinal extract crude extract.Total medicinal extract crude extract is suspended in 500ml water, then uses isopyknic petroleum ether extraction, extraction liquid obtains the total medicinal extract of sherwood oil (32g) through concentrating under reduced pressure.Total sherwood oil medicinal extract is dissolved by the chloroform/methanol (100mL) of 1:1, add purification on normal-phase silica gel (80-100 order) to mix sample with weight ratio 1:1.5 and volatilize, dry column-packing (200-300 order, 800 grams), dry method loading, uses sherwood oil/acetone=100:0 successively, 20:1,10:1,8:1,5:1,3:1,2:1,1:1,0:100v/v is eluent gradient wash-out, according to thin layer plate, detects, and each stream part is collected 9 component E1 – E9 from small to large successively according to the difference of polarity, the cut that E5(sherwood oil/acetone 5:1 is eluted) again through purification on normal-phase silica gel column chromatography (200-300 order, 50g gram) separation and purification, with sherwood oil/acetone=100:0,10:1,8:1,6:1,4:1,2:1,0:100v/v is eluent gradient wash-out (each gradient elution 300ml, every 15ml is collected as a component), according to positive thin layer plate, detect and collect and the appropriate elutriant that merges, obtain 7 component E5-1-E5-7, E5-4(sherwood oil/acetone 6:1 wash-out part) through SephadexLH-20 gel column (acetone) separation and purification, use acetone wash-out, according to thin layer plate, detect, collect elutriant, obtain 7 component E5-4-1-E5-4-7, this component of component E5-4-7(is carried out positive TLC detection take chloroform/methanol 9:0.25 as developping agent, and spray heating colour developing with 10% sulfuric acid-ethanol, principal constituent presents the mauve spot of Rf=0.8) take methyl alcohol as solvent, carry out again repeatedly recrystallization, obtain colourless (white) powdered compounds 1(2-hydroxyl-3-carbonyl-23-and fall olea-1, 4, 12-triolefin-28-acid) (8mg).
Olea-Isosorbide-5-Nitrae falls in 1.4 compound 1(2-hydroxyl-3-carbonyl-23-, 12-triolefin-28-acid) Structural Identification
Institute's compound that obtains 1 is white amorphous powder, and molecular formula is C
29h
40o
4;
uV (MeOH) λ
maxnm (log ε): 203 (4.13), 262 (3.8); HRESIMS (pos.) m/z475.2816 (calcd.forC
29h
40naO
4, 475.2819); ESIMS (pos.) m/z475[M+Na]+, 491[M+K]+, (neg.) m/z451[M-H] –, 487[M+Cl]
–;
1h-NMR and
13c-NMR data are as shown in table 1:
Table 1. obtains compound 2-hydroxyl-3-carbonyl-23-and falls olea-Isosorbide-5-Nitrae, the NMR data (inCD of 12-triolefin-28-acid
3oD)
According to the comprehensive analysis of the wave spectrum related datas such as above ultraviolet, mass spectrum and a peacekeeping two-dimensional nucleus magnetic, the chemical structure that analytic derivation goes out this new compound 1 is that olea-Isosorbide-5-Nitrae falls in 2-hydroxyl-3-carbonyl-23-, 12-triolefin-28-acid, and its structure is as shown in formula I.
Embodiment 2: in threeleaf akebia cauline leaf, olea-Isosorbide-5-Nitrae falls in 2-hydroxyl-3-carbonyl-23-, the preparation of 12-triolefin-28-acid
2.1 instruments and reagent: with embodiment 1
2.2 plant origins and evaluation: with embodiment 1
2.3 extract with separation
Sample (threeleaf akebia cauline leaf, 2.0 kilograms of dry weights) is pulverized rear with extracting three times under volume fraction 95% aqueous ethanolic solution room temperature, and merging filtrate concentrating under reduced pressure is removed organic solvent, obtains total medicinal extract crude extract.Total medicinal extract crude extract is suspended in 500ml water, then uses isopyknic petroleum ether extraction, extraction liquid obtains the total medicinal extract of sherwood oil (24g) through concentrating under reduced pressure.Total sherwood oil medicinal extract is dissolved by the chloroform/methanol (100mL) of volume ratio 1:1, add purification on normal-phase silica gel (80-100 order) to mix sample with weight ratio 1:1.5 and volatilize, dry column-packing (200-300 order, 800 grams), dry method loading, uses sherwood oil/acetone=100:0 successively, 20:1,10:1,8:1,5:1,3:1,2:1,1:1,0:100v/v is eluent gradient wash-out, according to thin layer plate, detects, and each stream part is collected 9 component F1 – F9 from small to large successively according to the difference of polarity, the cut that F5(sherwood oil/acetone 5:1 is eluted) again through purification on normal-phase silica gel column chromatography (200-300 order, 50g gram) separation and purification, with sherwood oil/acetone=100:0,10:1,8:1,6:1,4:1,2:1,0:100v/v is eluent gradient wash-out (each gradient elution 300ml, every 15ml is collected as a component), according to positive thin layer plate, detect and collect and the appropriate elutriant that merges, obtain 7 component F5-1-F5-7, F5-4(sherwood oil/acetone 6:1 wash-out part) through SephadexLH-20 gel column (acetone) separation and purification, use acetone wash-out, according to thin layer plate, detect, collect elutriant, obtain 7 component F5-4-1-F5-4-7, this component of component F5-4-7(is carried out positive TLC detection take chloroform/methanol 9:0.25 as developping agent, and spray heating colour developing with 10% sulfuric acid-ethanol, principal constituent presents the mauve spot of Rf=0.8) take methyl alcohol as solvent, carry out again repeatedly recrystallization, obtain colourless (white) powdered compounds 2-hydroxyl-3-carbonyl-23-and fall olea-1, 4, 12-triolefin-28-acid (5mg).
Embodiment 3:
Take stem, leaf or the fruit of akebi, long order akebi, Caulis Akebiae or long calyx threeleaf akebia as sample, according to the extraction described in embodiment 1 and separation method final purification, obtain the pure compound 2,3 of formula I, olea-12-alkene-28-acid falls in 20-trihydroxy--29-.
Olea-Isosorbide-5-Nitrae falls in embodiment 4:2-hydroxyl-3-carbonyl-23-, and the alpha-glucoside inhibiting activity of 12-triolefin-28-acid detects
4.1 instruments and reagent
Laboratory apparatus: microplate reader Genoismicroplatereader(TecanGENios, Swizerland)
Reagent and compound sample: alpha-glucosidase is purchased from SigmaChemicalCo.(Sigma-Aldrich, St.Louis, USA); 4-nitrophenol-alpha-D-glucose pyrans glycosides (PNPG) is purchased from TokyoChemicalIndustryCo., Ltd. (Japan); Acarbose (Acarbose), purchased from TokyoChemicalIndustryCo., Ltd. (Japan); Olea-Isosorbide-5-Nitrae falls in 2-hydroxyl-3-carbonyl-23-, and 12-triolefin-28-acid is prepared by above experimental example
4.2 testing method:
A) compounding pharmaceutical solution: olea-1 is fallen in 2-hydroxyl-3-carbonyl-23-, 4,12-triolefin-28-acid and acarbose are respectively by dimethyl sulfoxide (DMSO) (DMSO) preparation 10mg/ml solution, and prepare the phosphoric acid buffer (ultrapure water preparation) of 67mmol, PNPG substrate solution (5mM, phosphoric acid buffer preparation), and the NaCO of 0.2M
3solution (phosphoric acid buffer preparation).
B) adopt colorimetry, by 96 porocyte culture plates, with regard to compound 2-hydroxyl-3-carbonyl-23-, fall olea-Isosorbide-5-Nitrae, 12-triolefin-28-acid is measured the half-inhibition concentration of alpha-glucosidase.First the alpha-glucosidase of 20 μ L (0.8U) is joined in sample well, then will test sample solution phosphoric acid buffer dilutes by a certain percentage, every hole adds sample solution 120 μ L, (olea-1 falls in 2-hydroxyl-3-carbonyl-23-to make to test sample, 4,12-triolefin-28-acid or acarbose) ultimate density be: 500 μ g/mL, 250 μ g/mL, 125 μ g/mL, 62.5 μ g/mL, 31.25 μ g/mL, 15.625 μ g/mL, finally add reaction substrate 4-nitrophenol-α-D-glucopyranoside 20 μ L (5mM) again.After 37 ℃ of water-bath 15min, in each sample well, add the NaCO of 80 μ L
3(0.2M) termination reaction, in the place's colorimetric estimation of 405nm wavelength.The phosphoric acid buffer of same volume replaces enzyme solution.Compound inhibiting rate is calculated for blank and contrast OD value by sample OD value, and calculation formula is as follows: inhibiting rate (%)=(OD
control– OD
neg)-(OD
test– OD
test control)/(OD
control– OD
neg) × 100%.Wherein olea-Isosorbide-5-Nitrae falls in test compounds 2-hydroxyl-3-carbonyl-23-, the half-inhibition concentration (IC of 12-triolefin-28-acid to alpha-glucosidase
50) by dose effect curve, obtained.
4.3 experimental datas are referring to table 2:
The a-Glucosidase inhibitor activity of 12-triolefin-28-acid is fallen olea-Isosorbide-5-Nitrae, in table 2.2-hydroxyl-3-carbonyl-23-
4.4 experiment conclusion:
A-glucuroide is the index tested enzyme of a-glycosidase inhibitor screening, and the medicine of many treatment diabetes develops into ofhypoglycemic medicine just based on having the competitive inhibition of a-glucuroide.This experimental result shows, olea-1 falls in new compound 2-hydroxyl-3-carbonyl-23-that we excavate out, 4,12-triolefin-28-acid has the effect of potent inhibition a-glucuroide, it suppresses activity is even that a line hypoglycemic medication acarbose approximately surpasses by force 16 times than positive reference substance, thereby there is stronger exploitation potential quality, and being expected to further develop the medication that becomes new prevention and treatment type II diabetes, application potential quality is extensive.
Claims (9)
1. olea-Isosorbide-5-Nitrae falls in compound 2-hydroxyl-3-carbonyl-23-, 12-triolefin-28-acid, its pharmaceutically useful salt or its esterified derivative, and its structural formula is as shown in formula I:
2. olea-1 falls in 2-hydroxyl-3-carbonyl-23-according to claim 1,4, the esterified derivative of 12-triolefin-28-acid, it is characterized in that, olea-Isosorbide-5-Nitrae falls in described 2-hydroxyl-3-carbonyl-23-, and the esterified derivative of 12-triolefin-28-acid is that olea-1 falls in 2-hydroxyl-3-carbonyl-23-, the derivative that one or two in 2-position hydroxyl and the 28-position carboxyl functional group of 4,12-triolefin-28-acid obtains with organic acid or Organic Alcohol esterification respectively.
3. olea-1 falls in 2-hydroxyl-3-carbonyl-23-according to claim 2,4, the esterified derivative of 12-triolefin-28-acid, it is characterized in that, described organic acid be C1 to the organic acid of C4 or containing the C6 of phenyl ring the organic acid to C10, described Organic Alcohol is that C1 is to the Organic Alcohol of C4 or contain the C6 of phenyl ring to the Organic Alcohol of C10.
4. olea-1 falls in compound 2-hydroxyl-3-carbonyl-23-claimed in claim 1, 4, the preparation method of 12-triolefin-28-acid, it is characterized in that, olea-1 falls in compound 2-hydroxyl-3-carbonyl-23-, 4, 12-triolefin-28-acid is from akebi (Akebia quinata (Thumb.) Decne.), threeleaf akebia (Akebiatrifolia (Thumb.) Koidz), long order akebi (Akebia longeracemosaMatsumura), the stem of Caulis Akebiae (Akebiatrifolia (Thumb.) Koidz.Var.australis (Diels) Rehd) or long calyx threeleaf akebia (Akebiatrifolia (Thumb.) Koidz..subsp.LongisepalaH.N.Qin), in leaf or fruit, preparation separation obtains.
5. preparation method according to claim 4, is characterized in that, concrete steps are:
A, prepare total medicinal extract: by stem, leaf or the fruit material disintegrating of the akebi gathering, threeleaf akebia, long order akebi, Caulis Akebiae or long calyx threeleaf akebia, then with aqueous ethanolic solution or aqueous acetone solution lixiviate, after the concentrated removal of extracting solution organic solvent, obtain total medicinal extract crude extract, total medicinal extract crude extract is suspended in water, with sherwood oil or ethyl acetate extraction, extract obtains total medicinal extract after concentrated;
B, separation and purification: total medicinal extract is through purification on normal-phase silica gel column chromatography, take sherwood oil/acetone as eluent, successively from volume ratio 100:0, 20:1, 10:1, 8:1, 5:1, 3:1, 2:1, 1:1, 0:100 gradient elution, collect the cut that sherwood oil/acetone 5:1 elutes, again through purification on normal-phase silica gel column chromatography, with sherwood oil/acetone successively from volume ratio 100:0, 10:1, 8:1, 6:1, 4:1, 2:1, 0:100 is eluent gradient wash-out, collect the cut of sherwood oil/acetone 6:1 wash-out, again through the separation and purification of SephadexLH-20 gel column with acetone wash-out, elutriant carries out recrystallization, obtain compound 2-hydroxyl-3-carbonyl-23-and fall olea-1, 4, 12-triolefin-28-acid.
6. preparation method according to claim 5, is characterized in that, described aqueous ethanolic solution or aqueous acetone solution are that volume fraction is more than or equal to 70% aqueous ethanolic solution or aqueous acetone solution.
7. olea-Isosorbide-5-Nitrae falls in 2-hydroxyl-3-carbonyl-23-claimed in claim 1, and 12-triolefin-28-acid, its pharmaceutically useful salt or its esterified derivative are in the application of preparing in alpha-glucosidase inhibitor medicament.
8. an alpha-glucosidase inhibitor medicament, it is characterized in that, olea-Isosorbide-5-Nitrae falls in the compound 2-hydroxyl-3-carbonyl-23-claimed in claim 1 that contains significant quantity, 12-triolefin-28-acid or its pharmacologically acceptable salt or its esterified derivative, and pharmaceutically commonly use auxiliary material or carrier.
9. stem, leaf or the fruit of akebi, threeleaf akebia, long order akebi, Caulis Akebiae or long calyx threeleaf akebia fall olea-Isosorbide-5-Nitrae, the application in 12-triolefin-28-acid at preparation compound 2-hydroxyl-3-carbonyl-23-claimed in claim 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104306379A (en) * | 2014-10-09 | 2015-01-28 | 李健 | Externally applied pharmaceutical preparation for treating skin superficial fungal infections |
| CN112028963A (en) * | 2020-09-09 | 2020-12-04 | 广东省林业科学研究院 | 23-norursane triterpenoid, preparation method thereof and application thereof in preparing glycosidase inhibitor medicine |
| CN112121053A (en) * | 2020-09-09 | 2020-12-25 | 华南农业大学 | Application of akebia trifoliata triterpenoid in preparation of glycosidase inhibitor drugs |
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| US8129429B2 (en) * | 2008-01-11 | 2012-03-06 | Reata Pharmaceuticals, Inc. | Synthetic triterpenoids and methods of use in the treatment of disease |
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| US8129429B2 (en) * | 2008-01-11 | 2012-03-06 | Reata Pharmaceuticals, Inc. | Synthetic triterpenoids and methods of use in the treatment of disease |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104306379A (en) * | 2014-10-09 | 2015-01-28 | 李健 | Externally applied pharmaceutical preparation for treating skin superficial fungal infections |
| CN112028963A (en) * | 2020-09-09 | 2020-12-04 | 广东省林业科学研究院 | 23-norursane triterpenoid, preparation method thereof and application thereof in preparing glycosidase inhibitor medicine |
| CN112121053A (en) * | 2020-09-09 | 2020-12-25 | 华南农业大学 | Application of akebia trifoliata triterpenoid in preparation of glycosidase inhibitor drugs |
| CN112121053B (en) * | 2020-09-09 | 2024-03-19 | 华南农业大学 | Application of akebia trifoliate triterpene-reducing compound in preparation of glycosidase inhibitor drugs |
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| Publication number | Publication date |
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| CN103739653B (en) | 2016-08-31 |
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