CN101857590A - Chromone ketoside compounds and purification method and application thereof - Google Patents
Chromone ketoside compounds and purification method and application thereof Download PDFInfo
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Abstract
The invention relates to chromone ketoside compounds which have beta-secretase inhibition. The structural formula of the compounds is shown in the following general formula (I). The chromone ketoside compounds are separated from aloe plants by a plurality of separation means, and can be used for preparing medicaments for preventing and/or treating senile dementia.
Description
Technical field:
The present invention relates to a kind of chromone ketoside compounds, specifically relate to a kind of beta-secretase that has that from aloe plant, extracts and suppress active chromone ketoside compounds.
Background technology:
Senile dementia, have another name called alzheimer's disease (Alzheimer ' s disease, AD) morbidity becomes more and more serious problem in the China of aging population, and clinical manifestation is that cognitive disorder, memory are faded, finally lost elaborative faculty, dyskinesia and can't take care of oneself.The main medicine of clinical application for many years is an anticholinesterase, and this class medicine plays relief of symptoms by acting on cholinergic nerve system, but can not stop the generation and the development of disease.Modern pathology Mechanism Study thinks that the improper accumulation of amyloid-beta (A β) is the most important origin cause of formation of senile dementia.Beta-secretase is with the morbidity of senile dementia and carries out a closely-related novel targets.It is that amyloid precursor protein (APP) is cracked into crucial rate-limiting enzyme in the process of A β; Prove that in animal body the inhibitor of beta-secretase can reduce the level of A β greatly, and improvement and the similar disease symptom of AD.Great majority are polypeptide and intend peptides in the beta-secretase inhibitor of now having reported, and it is synthetic small molecules heterogeneous ring compound that minority is only arranged.Found several beta-secretase inhibitors from natural product, for example catechol, hispidin and tannin compounds tellimagrandin II etc. are to the inhibiting IC of beta-secretase
5010
-5～10
-6M.
Aloe (Aloe vera var. chinensis) is a Liliaceae Aloe perennial evergreen meat herbaceous plant, originates in Africa, and major part is grown in the torrid zone and subtropical zone, and also there is cultivation in China Guangdong, Yunnan, Fujian and some areas, the north.
Aloe is a kind of multiple bioactive edible and medicinal plant that has, each section such as the history in existing thousand of folk tradition herbal medicine, that range of application relates to is inside and outside, woman, youngster, skin, face.Shennong's Herbal, Compendium of Material Medica in China, " Greece's book on Chinese herbal medicine " in Europe, all on the books in the classic medicine books such as " Dong-eui-bo-gams " of Korea.China's nineteen ninety-five version pharmacopeia has been recorded Aloe vulgaris and Aloe ferox Miller as conventional Chinese medicine, is used for diseases such as constipation, infantile malnutrition, infantile convulsion, wet moss.
Though, also do not have the report of the beta-secretase inhibitor of new texture about discovery to the existing research of aloetic chemical ingredients.
In Chinese patent application 200610092036.2, disclose aloeresin D and mainly contained neurocyte protection effect, beta-secretase enzyme inhibition activity and the effect of potential anti-senile dementia thereof of the Aloe extract of aloeresin.And do not appear in the newspapers about the pharmacologically active and the potential medicinal use thereof of chromone ketoside compounds in the aloe.
Summary of the invention:
The technical problem that will solve of the present invention is to provide a kind of chromone ketoside compounds.
The another technical problem that will solve of the present invention is to provide the preparation method of this compound.
The another technical problem that will solve of the present invention is to provide a kind of composition, comprises at least one described compound and pharmaceutical carrier and/or vehicle.
A technical problem again that will solve of the present invention is to provide the purposes of this compound.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
Chromone ketoside compounds of the present invention is shown in logical formula I:
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
2Be selected from hydrogen, the phenyl and replace or unsubstituted phenylpropenoyl; Substituting group on the phenyl is selected from hydroxyl, C
1-4Alkoxyl group;
R
3Be selected from and replace or unsubstituted C
1-6Straight or branched alkyl, replacement or unsubstituted C
1-6The straight or branched thiazolinyl; Substituting group is selected from hydroxyl, ketone group.
Preferred R
1Be selected from hydroxyl, methoxyl group;
Preferred R
2Be selected from the phenylpropenoyl that has hydroxyl or methoxyl group replacement on hydrogen, the phenyl;
In other words, promptly hydroxyl becomes ester with various cinnamic acids, and preferred cinnamic acid is selected from coumaric acid, coffic acid, forulic acid, TRANSCINNAMIC ACID.
Preferred R
3Be selected from propenyl, (S)-the Virahol base, (R)-the Virahol base, propylene-glycol-based, acetonyl.
According to the present invention, the compound shown in the preferably logical formula I comprises, but is not limited to the compound shown in the general formula (IA):
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
3Be selected from and replace or unsubstituted C
1-6Straight or branched alkyl, replacement or unsubstituted C
1-6The straight or branched thiazolinyl; Substituting group is selected from hydroxyl, ketone group.
According to the present invention, the compound shown in the preferred general formula (IA) comprises, but is not limited to the compound shown in the general formula (IAa):
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group.
According to the present invention, the compound shown in the preferred general formula (IA) comprises, but is not limited to the compound shown in the general formula (IAb):
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
31And R
32Independently be selected from hydrogen, hydroxyl, ketone group.
According to the present invention, the compound shown in the preferably logical formula I comprises, but is not limited to the compound shown in the general formula (IB):
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
3Be selected from and replace or unsubstituted C
1-6Straight or branched alkyl, replacement or unsubstituted C
1-6The straight or branched thiazolinyl; Substituting group is selected from hydroxyl, ketone group.
According to the present invention, the compound shown in the preferred general formula (IB) comprises, but is not limited to the compound shown in the general formula (IBa):
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group.
According to the present invention, the compound shown in the preferred general formula (IB) comprises, but is not limited to the compound shown in the general formula (IBb):
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
31And R
32Independently be selected from hydrogen, hydroxyl, ketone group.
According to the present invention, preferred compound is including but not limited to following compound: wherein compound 1,2,3 and 4 is newfound compounds;
Wherein, The compounds of this invention is prepared from through extraction, separation and purifying from aloe plant, wherein preferred drag-line aloe and noble aloe.
The present invention also provides the preparation method of compound.
Compound 1,2,5,6,7,8,9 of the present invention and 10 preparation methods may further comprise the steps:
(1) get exsiccant aloe ointment with 70～100% alcohol reflux 2～5 times, united extraction liquid is made medicinal extract;
(2) with above-mentioned medicinal extract through silica gel column chromatography, be 75～80: 15～25 with volume ratio: chloroform-methanol-water elution of 1～3 is divided into 5 components: Fr. I～Fr. V;
(3) with the Fr. II that obtains in the step (2) through silica gel column chromatography, volume ratio is that 50～90: 50～50 chloroform-methanol gradient elution is divided into 3 components: Fr. II-1, Fr. II-2, Fr. II-3;
(4) be prepared into compound 1 and compound 6 with obtaining Fr. II-2 in the step (3) through thin-layer chromatography;
(5) the Fr. II-3 that obtains in the step (3) is got compound 5 and compound 2 through RPLC,
(6) get compound 9 and compound 8 with obtaining Fr. II-3 in the step (3) through rp-hplc analysis;
(7) with the Fr. IV that obtains in the step (2) through hydroxypropyl dextrane gel column chromatography, be that 1: 0～0: 1 methanol-water elutriant gradient elution is divided into 11 components: Fr. IV-1～IV-11 through volume ratio;
(8) will separate the Fr. IV-8 that obtains in the step (7) through silica gel column chromatography, volume ratio is that 20～30: 70～80 methanol-water elutriant wash-out is divided into three components: Fr. IV-8-1～Fr. IV-8-3;
(9) separation in the step (8) is obtained Fr. IV-8-2 and get compound 7 and compound 10 through thin-layer chromatography.
Compound 1,2,5,6,7,8,9 of the present invention and 10 preparation method are preferably:
(1) get exsiccant aloe ointment with mass percent concentration 90～98% alcohol reflux 3～5 times, united extraction liquid, decompression and solvent recovery obtains medicinal extract;
(2) medicinal extract that step (1) is made is with 60～100 order silica gel column chromatographies, is that 80: 20: 2 chloroform-methanol-water elutions are divided into 5 components: Fr. I～Fr. V with the volume ratio of 40～80 times of medicinal extract weight;
(3) with the Fr. II that obtains in the step (2) through 100～200 order silica gel column chromatographies, with 50～80 times of weight of Fr. II weight, volume ratio is 90: 10,80: 20,50: 50 chloroform-methanol gradient elution was divided into three components: Fr. II-1～Fr. II-3;
(4) be that 85: 15: 1 thin-layer chromatography of chloroform-methanol-water is prepared into compound 1 and compound 6 with obtaining Fr. II-2 in the step (3) through development system;
(5) the Fr. II-3 that obtains in the step (3) is prepared into compound 5 and compound 2 through RPLC; The condition of RPLC is: stationary phase 250 * 20mm, 10 μ m Unicorn ODS posts, and moving phase: volume ratio is 55: 45 a methanol-water, flow velocity 3.0mL/min;
(6) get compound 9 and compound 8 with obtaining Fr. II-3 in the step (3) through rp-hplc analysis; The condition of RPLC is: stationary phase is 250 * 20mm, 10 μ m Unicorn ODS posts, and moving phase is that volume ratio is methanol-water-trifluoroacetic acid of 31: 69: 0.1, flow velocity 3.0mL/min;
(7) the Fr. IV that obtains in the step (2) is first through sephadex LH-20 hydroxypropyl dextrane gel column chromatography, through methanol-water gradient elution gradient elution, the volume ratio of methanol-water was followed successively by 0: 10,1: 9,2: 8,3: 7,4: 6,5: 5,6: 4,7: 3,8: 2,9: 1,10: 0,, wash-out is divided into 11 components, is respectively: Fr. IV-1～IV-11; Wherein,
(8) will separate the anti-phase C-18 silica gel column chromatography of Fr. IV-8 usefulness that obtains in the step (7), volume ratio is 30: 70 methanol-water wash-outs, is divided into three components: Fr. IV-8-1～Fr. IV-8-3;
(9) be that 75: 25: 2 thin-layer chromatographies of chloroform-methanol-water are prepared into compound 7 and compound 10 with obtaining Fr. IV-8-2 in the step (8) through development system.
Compound 3,4,11,12 of the present invention and 13 preparation methods may further comprise the steps:
(1) get fresh aloe and in lower alcohol, soaked 6～8 days, filter, get Aloe extractum behind the concentrating under reduced pressure,
(2) with step (1) medicinal extract be suspended in 4～5 times the water, extract respectively 3～5 times with sherwood oil, ethyl acetate and propyl carbinol;
(3) with acetic acid ethyl ester extract through 100～200 order silica gel column chromatographies, be 92: 8～90: 10 chloroform-methanol gradient elutions with volume ratio, be divided into 11 component Fr. I～Fr. XI;
(4) with component Fr. IV through hydroxypropyl dextrane gel electrophoresis, be 1: 9～2: 8 methanol-water wash-out with volume ratio, five component Fr. IV 1-to Fr. IV-5;
(5) the Fr. IV-3 with step (4) gained makes compound 13 through RPLC,
(6) with the component Fr. VII of step (3) gained through hydroxypropyl dextrane gel column chromatography, be that 10: 90～20: 80 methanol-water wash-out is divided into 11 components: Fr. VII-1～Fr. VII-11 with volume ratio;
(7) the component Fr. VII-10 with step (6) gained gets compound 4, compound 11 and compound 12 through thin-layer chromatography;
(8) with the component Fr. IX of step (3) gained after the decolouring of hydroxypropyl dextrane gel column chromatography, be prepared into compound 3 with thin-layer chromatography.
Compound 3,4,11,12 of the present invention and 13 preparation methods are preferably:
(1) get fresh aloe soaking at room temperature 6～8 days in lower alcohol, filter, behind the concentrating under reduced pressure Aloe extractum,
(2) with step (1) medicinal extract be suspended in 4～5 times the water, extract respectively 3～5 times with sherwood oil, ethyl acetate and propyl carbinol;
(3) with acetic acid ethyl ester extract through 100～200 order silica gel column chromatographies, be 92: 8,90: 10 chloroform-methanol gradient elutions with volume ratio, be divided into 11 component Fr. I～Fr. XI;
(4) with component Fr. IV through hydroxypropyl dextrane gel electrophoresis, be 20～80 methanol-water wash-out with volume ratio, five part Fr. IV～1 to Fr. IV～5;
(5) the Fr. IV-3 with step (4) gained makes compound 13 through RPLC, the condition of RPLC is: solid-state is 10 μ m, 250 * 20mm Unicorn ODS post mutually, liquid state is 27: 73 acetonitrile/water mutually for volume ratio, and flow velocity is 3.0mL/min;
(6) with the component Fr. VII of step (3) gained through hydroxypropyl dextrane gel column chromatography, be that 20: 80 methanol-water wash-out is divided into 11 and component: Fr. VII-1～Fr. VII-11 with volume ratio;
(7) be that volume ratio is that chloroform-methanol-water thin-layer chromatography of 85: 15: 1 is prepared into compound 4, compound 11 and compound 12 with the component Fr. VII-10 of step (6) gained through development system;
(8) with the component Fr. IX of step (3) gained after the decolouring of hydroxypropyl dextrane gel column chromatography, be that 80: 20: 2 thin-layer chromatography of chloroform-methanol-water is prepared into compound 3 with the development system volume ratio.
The invention still further relates to the application of described compound in suppressing beta-secretase, anti-oxidant and neuroprotective cell.
The invention still further relates to the application of described compound in treatment senile dementia and preparation treatment senile dementia disease drug.
The present invention is activity index with the beta-secretase, adopt active method of following the trail of, utilize multiple extraction, separation means, comprise solvent-extraction process, solvent extration, the macroporous adsorbent resin method, positive and negative silica gel column chromatography, methods such as sephadex LH-20 column chromatography and preparation high performance liquid phase, systematic study Aloe vulgaris and noble aloetic chemical ingredients, therefrom obtaining 13 has beta-secretase and suppresses active chromone ketoside compounds (formula 1～13), wherein 4 is the chromone ketoside compounds of new texture, is respectively C-2 '-decoumaroyl-aloeresin G (formula 1), allo-aloeresin D (formula 2), 2 '-O-coumaroyl-aloesinol (formula 3), 2 '-O-[p-methoxy-(E)-cinnamoyl]-aloesinol (formula 4).
The present invention separates 13 chromone ketoside compounds obtaining and has good beta-secretase enzyme inhibition activity, can resist the radical that produces in the A β polymerization process to nerve cell damage.Therefore, above-mentioned effective constituent and derivative thereof and active principle might generate from minimizing A β and resist senile dementia, can be used as the active drug of preparation treatment and prevention senile dementia.
Invention also relates to one or more pharmaceutical compositions as active ingredient with The compounds of this invention.This pharmaceutical composition can be according to method preparation well known in the art.Can be by the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, make any formulation that is suitable for human or animal's use.The weight percent content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95%.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For The compounds of this invention is made tablet, can be extensive use of various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in the administration unit, the effective constituent The compounds of this invention can be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also the effective constituent The compounds of this invention particle or micropill be can be made with thinner, tamanori, disintegrating agent earlier, hard capsule or soft capsule placed again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.
For The compounds of this invention is made injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching the medication purpose, strengthen result of treatment, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.Compound of the present invention or composition can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.
Technical superiority of the present invention is:
13 chromone ketoside compounds provided by the invention, comprise 4 new chromone ketoside compounds, show through active determination test, has tangible beta-secretase enzyme inhibition activity, wherein the particularly remarkable (IC of the activity of new compound C-2 '-decoumaroyl-aloeresin G (1) and compd A loeresin D (5)
50Be respectively 20.5 μ M and 39.0 μ M).Chromone ketoside compounds is to suppress the main effective constituent that A β generates in the plant aloe, and mechanism of action and drug effect are clear and definite, for the active drug that further prepares treatment and prevention senile dementia has been established basic substance.
Embodiment:
Below with reference to embodiment invention is described further, but does not limit the scope of the invention.
Aloe vulgaris (Aloe vera L.) ointment is available from pharmacy of Tongrentang, aqueous extract.
The preparation of embodiment 1. compound 1-13
Exsiccant Aloe vulgaris (Aloe vera L.) ointment (250.0g) is with 95% ethanol (5.0L) refluxing extraction 3 times, united extraction liquid, decompression and solvent recovery, the medicinal extract 200.0g that obtains is with 60～100 purpose silica gel (1.0kg) column chromatographies, and volume ratio is that elutriant (10.0L) wash-out of 80: 20: 2 chloroform-methanol-water is divided into 5 parts: Fr. I～Fr. V.
Fr. II (5.2g) is through 100-200 purpose silica gel column chromatography (300g), with volume ratio is 90: 10～50: 50 chloroform-methanol gradient elutions, and volume ratio is 90: 10,80: 20, each 4000mL of mixing elutriant of 50: 50 chloroform-methanols is divided into 3 parts: Fr. II-1～Fr. II-3.
Fr. II-2 (2.6g) gets compound 1 (5.0mg, R through thin-layer chromatography preparation (the development system volume ratio is 85: 15: 1 chloroform-methanol-water) wash-out
f=0.50) and compound 6 (2.0mg, R
f=0.46).
Fr. II-3 (0.2g) through reversed phase high efficiency liquid phase preparation (Unicorn ODS, 10 μ m, 250 * 20mm), elutriant be volume ratio be 55: 45 methanol (flow velocity 3.0mL/min) compound 5 (60.0mg, t
R=29.2min) and compound 2 (5.0mg, t
R=37.8min).
Fr. earlier (sephadex LH-20,100g) column chromatography are 0: 1～1: 0 methanol-water gradient elution with volume ratio to IV (4.2g) through the hydroxypropyl dextrane gel, the volume ratio of methyl alcohol in mixing elutriant increases by 10% successively, and the volume ratio of promptly mixing methanol-water in the elutriant is 0: 10,1: 9,2: 8,3: 7,4: 6,5: 5,6: 4,7: 3,8: 2,9: 1,10: 0, every part of volume that mixes elutriant is 350mL, is divided into 11 parts: Fr. IV-1～IV-11; Wherein Fr. IV-8 (233.0mg) is with anti-phase C-18 silica gel column chromatography, volume ratio is 30: 70 methanol-water wash-outs, be divided into 3 parts again: Fr. IV-8-1～Fr. IV-8-3:Fr. IV-8-2 (100.0mg) gets compound 7 (30.0mg, R through thin-layer chromatography preparation (development system chloroform-methanol-water 75: 25: 2)
f=0.56) and compound 10 (3.4mg, R
f=0.44).
Fr. II-3 (0.2g) through reversed phase high efficiency liquid phase preparation (Unicorn ODS, 10 μ m, 250 * 20mm) elutriants be volume ratio be 31: 69: 0.1 methanol-water-trifluoroacetic acid (flow velocity 3.0mL/min) compound 9 (6.0mg, t
R=49.6min) and compound 8 (10.2mg, t
R=54.0min).
C-2 '-decoumaroyl-aloeresin G (compound 1): white unformed powder, m.p.119 ℃;
(c 0.33, MeOH); ESI-MS m/z 415[M+Na]
+, HR-ESI-MS m/z 393.1592[M+H]
+(calcd for C
20H
25O
8: 393.1549); UV (MeOH) λ
Max(log ε): 209.0 (3.27), 250.0 (2.93), 259 (3.01), 275.0 (2.75sh), 308 (2.95) nm; IR (KBr): v
Max: 3390,2925,2856,1657,1626,1454,1383,1331,1296,1122,1080,1043,903,850,550cm
-1 1H-NMR (CD
3OD, 400MHz): 7.03 (1H, m, H-10), 6.80 (1H, s, H-6), 6.20 (1H, d, J=15.6Hz, H-9), 5.95 (1H, s, H-3), 4.71 (1H, d, J=10.0Hz, H-1 '), 4.06 (1H, t, 9.6Hz, H-2 '), 3.90 (3H, s, 7-OCH
3), 3.84 (1H, dd, J=12.0,2.0Hz, H-6b '), 3.64 (1H, m, H-6a '), 3.44 (2H, m, H-3 ', H-4 '), 3.25 (1H, m, H-5 '), 2.74 (3H, s, 5-CH
3), 1.92 (3H, d, J=6.8Hz, H-11);
13C-NMR (CD
3OD, 125MHz): 182.7 (C-4), 162.7 (C-2), 162.5 (C-7), 158.8 (C-1a), 144.0 (C-5), 139.0 (C-10), 124.7 (C-9), 117.4 (C-4a), 113.3 (C-8), 112.8 (C-6), 109.8 (C-3), 82.9 (C-5 '), (80.3 C-3 '), 75.1 (C-1 '), 72.4 (C-2 '), (72.3 C-4 '), 63.0 (C-6 '), 56.9 (7-OCH
3), 23.6 (5-CH
3), 18.4 (C-11).
Allo-aloeresin D (compound 2): faint yellow unformed powder, m.p.124 ℃;
(c 0.01, MeOH); HR-ESI-MS m/z:557.2012[M+H]
+(calcd for C
29H
32O
12: 557.2023); UV (MeOH) λ
Max(log ε): 211.0 (4.35), 226.0 (4.33), 252.0 (4.11sh), 294 (4.13) nm; IR (KBr): v
Max: 3361,1718,1653,1599,1514,1458,1383,1161,984,837,721cm
-1 1H-NMR (CD
3OD, 500MHz): 6.93 (2H, d, J=8.5Hz, H-5 ", H-9 "), 6.74 (1H, s, H-6), 6.59 (1H, d, J=12.5Hz, H-3 "), 6.48 (2H; d, J=8.5Hz, H-6 ", H-8 "), 6.10 (1H, s, H-3); 5.66 (1H, d, J=10.0Hz, H-2 "), 5.49 (1H, d, J=12.5Hz, H-2 "), 5.06 (1H, d, J=10.0Hz, H-1 '), 4.41 (1H, m; H-10), 3.90 (1H, m, H-6b '), 3.85 (3H, s, 7-OCH
3), 3.60 (2H, m, H-3 ', H-6a '), 3.48 (1H, m, H-4 '), 3.40 (1H, m, H-5 '), 2.86 (1H, dd, J=10.5,4.0Hz, H-9a), 2.68 (3H, s, 5-CH
3), 2.67 (1H, d, J=10.0Hz, H-9b), 1.23 (3H, d, J=6.0Hz, H-11);
13C-NMR (CD
3OD, 75MHz): 182.3 (C-4), 167.6 (C-1 "); 167.4 (C-2), 162.1 (C-7), 160.0 (C-7 "), 159.8 (C-1a), 145.0 (C-3 "), 144.6 (C-5); 133.2 (C-5 ", C-9 "), 127.0 (C-4 "), 117.2 (C-4a), 115.7 (C-2 ", C-6 ", C-8 "), 112.7 (C-6), 112.5 (C-3); 111.8 (C-8), 83.0 (C-5 '), 77.7 (C-3 '); 73.4 (C-2 '); 72.8 (C1 '), 72.4 (C-4 '), 65.9 (C-10); 63.1 (C-6 '), 57.0 (7-OCH
3), 44.6 (C-9), 23.7 (5-CH
3), 23.6 (C-11).
Bright product 5.0kg one week of soaking at room temperature in methyl alcohol (15L) of noble aloe (Aloe noblis), cooling bath is filtered, concentrating under reduced pressure gets medicinal extract 210g.Medicinal extract is suspended in the 1L water, use respectively sherwood oil (3 * 500mL), ethyl acetate (3 * 800mL) and propyl carbinol (3 * 800mL) extraction.
Ethyl acetate part (13.0g) is through silica gel column chromatography (100～200 orders, 400g), with 92: 8～90: 10 chloroform-methanol gradient elutions of volume ratio, volume ratio 92: 8, each 6000mL of chloroform-methanol mixing elutriant of 90: 10 is divided into 11 parts: Fr. I～Fr. XI.
Wherein (sephadex LH-20 60g), is 20: 80 methanol-water wash-outs with volume ratio to Fr. IV (943mg), gets five parts (Fr. IV-1 is to Fr. IV-5) through the hydroxypropyl dextrane gel.
Fr. (Unicorn ODS, 10 μ m, 250 * 20mm) elutriants are that volume ratio is 27: 73 CH to IV-3 (120mg) through the preparation of reversed phase high efficiency liquid phase
3CN/H
2O (flow velocity 3.0mL/min) gets compound 13 (35mg, t
R=53.8min).
Fr. VII (1.6g) is through hydroxypropyl dextrane gel (sephadex LH-20,60g) column chromatography, with volume ratio is that 20: 80 methanol-water wash-outs are divided into 11 parts: Fr. VII-1～Fr. VII-11:Fr. VII-10 (309mg) gets compound 4 (40.0mg, R through thin-layer chromatography preparation (development system chloroform-methanol-water 85: 15: 1)
f=0.54), compound 11 (140.0mg, R
f=0.47) and compound 12 (7.0mg, R
f=0.38).
Fr. (sephadex LH-20,60g) column chromatography decolouring (moving phase is methyl alcohol) gets compound 3 (50.0mg, R with thin-layer chromatography preparation (the development system volume ratio is chloroform-methanol-water of 80: 20: 2) to IX (1.7g) again through the hydroxypropyl dextrane gel earlier
f=0.44).
2 '-O-coumaroyl-aloesinol (compound 3): the unformed powder of yellow-white,
(c0.105, MeOH); HR-ESI-MS m/z:541.1716[M-H]
+(calcd for C
28H
29O
11: 541.1710);
1H-NMR (CD
3OD, 400MHz): 7.35-7.39 (3H, m, H-3 ", H-5 ", H-9 "); 6.84 (2H, d, J=8.4Hz, H-6 ", H-8 "), 6.50 (1H; s, H-6), 6.04 (1H, s, H-3); 6.01 (1H, d, J=16.0Hz, H-2 "), 5.67 (1H, t, J=10.0,9.6Hz, H-2 '), 5.15 (1H, d, J=10.0Hz, H-1 '), 4.32 (1H, m, H-10), 3.42-3.88 (5H, m, H-3 ', H-4 ', H-5, ' H-6 '), 2.82 (1H, dd, J=14.0,7.6Hz, H-9a), 2.75 (1H, dd, J=13.6,5.6Hz, H-9b), 2.58 (3H, s, 5-CH
3), 1.25 (3H, d, J=6.0Hz, H-11);
13C-NMR (CD
3OD, 75MHz): 182.2 (C-4), 168.0 (C-1 "); 167.2 (C-2), 161.3 (C-7), 161.2 (C-7 "), 160.4 (C-1a), 146.2 (C-3 "), 143.5 (C-5); 131.0 (C-5 ", C-9 "), 128.3 (C-4 "), 117.0 (C-4a), 116.7 (C-6 ", C-8 "), 116.3 (C-6), 115.8 (C-2 "), 112.1 (C-3); 110.0 (C-8), 82.8 (C-5 '), 77.9 (C-3 '); 74.0 (C-2 '), 73.0 (C-1 '), 72.1 (C-4 '); 66.7 (C-10); 63.1 (C-6 '), 44.3 (C-9), 23.5 (5-CH
3), 23.5 (C-11).
2 '-O-[p-methoxy-(E)-cinnamoyl]-aloesinol (compound 4): the unformed powder of yellow-white, HR-ESI-MS m/z:557.1998[M+H]
+ 1H-NMR (CD
3OD, 400MHz): 7.35-7.39 (1H, m, H-3 "), 7.25 (2H, d, J=8.4Hz, H-5 ", H-9 "), 6.69 (2H, d, J=8.4Hz, H-6 ", H-8 "), 6.50 (1H, s; H-6), 6.04 (1H, d, J=16.0Hz, H-2 "), 6.02 (1H, s, H-3), (5.68 1H, t, J=10.0,9.6Hz, H-2 '), 5.12 (1H, d, J=10.0Hz, H-1 '), 4.32 (1H, m, H-10), 3.40-3.90 (5H, m, H-3 ', H-4 ', H-5, ' H-6 '), 3.74 (3H, s, 7 " OCH
3), 2.82 (1H, dd, J=13.6,7.2Hz, H-9a), 2.75 (1H, dd, J=13.6,5.2Hz, H-9b), 2.56 (3H, s, 5-CH
3), 1.24 (3H, d, J=6.0Hz, H-11);
13C-NMR (CD
3OD, 75MHz): 182.2 (C-4), 168.2 (C-1 "); 167.2 (C-2), 161.2 (C-7 "), 160.4 (C-7), 160.4 (C-1a), 146.6 (C-3 "), 143.5 (C-5); 131.1 (C-5 ", C-9 "), 127.1 (C-4 "), 116.9 (C-4a), 116.8 (C-6 ", C-8 "), 116.3 (C-2 "), 115.7 (C-6), 112.1 (C-3); 109.9 (C-8), 82.8 (C-5 '), 77.9 (C-3 '); 74.0 (C-2 '); 72.9 (C-4 '), 72.2 (C-1 '), 63.1 (C-10); 62.4 (C-6 '), 56.1 (7-OCH
3), 44.6 (C-9), 23.5 (5-CH
3), 23.3 (C-11).
Determining of embodiment 2, compound 2,3,4 absolute configurations
New compound 2,3 contains a chiral carbon (C-10) in 4 the structure, its structure determination need be determined absolute configuration.According to the literature, it is very approaching that C-10 is configured as the optical value of two kinds of diastereomers of R and S, can't be used to judge absolute configuration; And two kinds of diastereomers of the chromone glycosides compound (as compound 7) of the no acyl substituted in C-2 ' position of glucose retention time RT difference on HPLC not only; and their optically-active is also inequality; can determine the C-10 position steric configuration of compound 2,3 and 4 in view of the above.
Therefore, earlier, obtain C-2 ' position and remove acyl group product 2a 2-4 basic hydrolysis respectively, 3a and 4a, by mensuration compound 2a, 3a, the optical value of 4a be respectively
(c 0.24, MeOH) },
(c0.24, MeOH) } and
(c 0.25, MeOH) }, the absolute configuration of inferring C-10 position in the compound 2,3 and 4 be respectively (R)-, (S)-and (S)-configuration.
Basic hydrolysis:
New compound 2 is identical with the hydrolysate (being that the acyl group product is removed in C-2 ' position) of compound 5, but compound 2 amounts are few, are dissolved in 0.5mL methyl alcohol so get compound 5 (20mg) earlier, stirs to drip 30%K down
2CO
3-H
2O 0.5mL stirred under the room temperature after 7.5 hours, added the dilution of 10.0mL water.Successively with ethyl acetate and n-butanol extraction, (developping agent is CHCl to n-butanol layer through the silica gel thin-layer preparation
3-CH
3OH-H
2O75: 25: 2, R
f=0.54) obtains compound 5a (5.4mg).Retention time RT=5.3min on the analysis mode high performance liquid phase (moving phase: CH
3OH-H
2O 30: 70, flow velocity: 1mL/min, λ
Max=300nm).Compound 2 (2.0mg) also is hydrolyzed with identical method, obtains corresponding hydrolysate 2a (not separating), through relatively 2a is identical with the retention time of compound 5a on high performance liquid phase.
8-C-glucosyl-7-methoxyl-(R)-aloesol (5a): white unformed powder, m.p.145 ℃;
(c 0.24, MeOH); ESI-MS:m/z=433.2[M+Na]
+ 1H-NMR (500MHz, CD
3OD): δ=1.24 (3H, d, J=6.0Hz, H-11), 2.58 (2H, dd, J=9.5,5.0Hz, H-9), 2.73 (3H, s, H-12), 3.32-3.44 (3H, m, H-3 ', H-4 ', H-5 '), 3.60 (1H, m, H-6 ' α), 3.84 (1H, m, H-6 ' β), 3.89 (3H, s, OCH
3-7), 4.12 (1H, t, J=10.0Hz, H-2 '), 4.323 (1H, m, H-10), 4.94 (1H, d, J=10.0Hz, H-1 '), 6.03 (1H, s, H-3), 6.86 (1H, s, H-6).
Compound 3 (10mg) is dissolved in 0.5mL methyl alcohol, stirs to drip NaOH-H down
2O (2.8mg/mL) 0.5mL behind the stirring 30min, adds the dilution of 15.0mL water under the room temperature.Use n-butanol extraction, anhydrous Na
2SO
4Dry organic layer, reclaim under reduced pressure, (developping agent is CHCl in the thin layer preparation
3-CH
3OH-H
2O 80: 20: 2, R
f=0.27) gets compound 3a (2.8mg).Optical value be
(c0.24, MeOH) }, (+)-ESI-MS (m/z): 419.1[M+Na], (-)-ESI-MS (m/z): 395.3[M-H].
Compound 4 (10.7mg) is dissolved in 0.5mL methyl alcohol, stirs to drip NaOH-H down
2O (3.0mg/mL) 0.5mL behind the stirring 30min, adds the dilution of 15.0mL water under the room temperature.Use n-butanol extraction, anhydrous Na
2SO
4Dry organic layer, reclaim under reduced pressure, (developping agent is CHCl in the thin layer preparation
3-CH
3OH-H
2O 80: 20: 2, R
f=0.27) gets compound 4a (4.0mg).Optical value be
(c 0.25, MeOH) }, (+)-ESI-MS (m/z): 419.1[M+Na], (-)-ESI-MS (m/z): 395.3[M-H].
Structural formula (2a-5a)
Pharmacological evaluation
Experimental example 1 beta-secretase suppresses active mensuration
Utilize FRET (fluorescence resonance energy transfer) method (FRET) to measure the vitro inhibition activity of compound to BACE-1.Specifically be exactly with 4 μ M fluorescence peptide substrates Mca-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Arg-Lys (Dnp)-Arg-Arg-NH
2, 2 μ g/ml recombinant human B ACE-1 (R﹠amp; D company) and the testing compound of different concns add in the 50mM sodium acetate buffer (pH4.0), making final volume is 100 μ l.
Set fluorescence microplate reader (SpectraMAX Gemini XS type, Molecular Devices company) and excite with emission wavelength and be respectively 320nm and 405nm, read the fluorescence intensity behind the initial and 25 ℃ of insulation 60min of reaction.Inhibiting rate calculates according to following formula:
Inhibiting rate (%)=[1-(F
S-F
S0)/(F
C-F
C0)] * 100%
F wherein
S0And F
SBe respectively the fluorescence intensity after testing compound reaction initial sum is incubated 60min, F
C0And F
CBe respectively the fluorescence intensity after negative control reaction initial sum is incubated 60min.Utilize software Prism 3.0 to make the nonlinear fitting curve of inhibiting rate, calculate IC compound concentration to be measured
50Value.Concrete outcome is as follows:
The beta-secretase enzyme inhibition activity of chromone ketoside compounds 1-13
* positive control be N-Benzyloxycarbonyl-Val-Leu-leucinal (Z-Val-Leu-Leu-CHO,
565749).
Claims (18)
1. chromone ketoside compounds shown in logical formula I:
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
2Be selected from hydrogen, the phenyl and replace or unsubstituted phenylpropenoyl; Substituting group on the phenyl is selected from hydroxyl, C
1-4Alkoxyl group;
R
3Be selected from and replace or unsubstituted C
1-6Straight or branched alkyl, replacement or unsubstituted C
1-6The straight or branched thiazolinyl; Substituting group is selected from hydroxyl, ketone group.
2. compound according to claim 1 is characterized in that,
R
1Be selected from hydroxyl, methoxyl group;
R
2Be selected from the phenylpropenoyl that has hydroxyl or methoxyl group replacement on hydrogen, the phenyl;
R
3Be selected from propenyl, (S)-the Virahol base, (R)-the Virahol base, propylene-glycol-based, acetonyl.
3. compound according to claim 1 is characterized in that, described compound shown in general formula (IA),
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
3Be selected from and replace or unsubstituted C
1-6Straight or branched alkyl, replacement or unsubstituted C
1-6The straight or branched thiazolinyl; Substituting group is selected from hydroxyl, ketone group.
4. compound according to claim 3 is characterized in that, described compound shown in general formula (IAa),
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group.
5. compound according to claim 3 is characterized in that, described compound shown in general formula (IAb),
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
31And R
32Independently be selected from hydrogen, hydroxyl, ketone group.
6. compound according to claim 1 is characterized in that, described compound shown in general formula (IB),
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
3Be selected from and replace or unsubstituted C
1-6Straight or branched alkyl, replacement or unsubstituted C
1-6The straight or branched thiazolinyl; Substituting group is selected from hydroxyl, ketone group;
R ' is selected from hydrogen, hydroxyl or C
1-3Alkoxyl group.
7. compound according to claim 6 is characterized in that, described compound shown in general formula (IBa),
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R ' is selected from hydrogen, hydroxyl or C
1-3Alkoxyl group.
8. compound according to claim 6 is characterized in that, described compound shown in general formula (IBb),
Wherein, R
1Be selected from hydroxyl or C
1-6The straight or branched alkoxyl group;
R
31And R
32Independently be selected from hydrogen, hydroxyl, ketone group;
R ' is selected from hydrogen, hydroxyl or C
1-3Alkoxyl group.
9. compound according to claim 1 is characterized in that, described compound is selected from:
10. as each described compound in the claim 1～9, it is characterized in that described compound is prepared from through extraction, separation and purifying from aloe plant.
11. prepare the method for the described compound of claim 9, it is characterized in that, may further comprise the steps:
(1) get exsiccant aloe ointment with 70～100% alcohol reflux 2～5 times, united extraction liquid is made medicinal extract;
(2) with above-mentioned medicinal extract through silica gel column chromatography, be 75～80: 15～25 with volume ratio: chloroform-methanol-water elution of 1～3 is divided into 5 components: Fr. I～Fr. V;
(3) with the Fr. II that obtains in the step (2) through silica gel column chromatography, volume ratio is that 50～90: 50～50 chloroform-methanol gradient elution is divided into 3 components: Fr. II-1, Fr. II-2, Fr. II-3;
(4) be prepared into compound 1 and compound 6 with obtaining Fr. II-2 in the step (3) through thin-layer chromatography;
(5) the Fr. II-3 that obtains in the step (3) is got compound 5 and compound 2 through RPLC,
(6) get compound 9 and compound 8 with obtaining Fr. II-3 in the step (3) through rp-hplc analysis;
(7) with the Fr. IV that obtains in the step (2) through hydroxypropyl dextrane gel column chromatography, be that 1: 0～0: 1 methanol-water elutriant gradient elution is divided into 11 components: Fr. IV-1～IV-11 through volume ratio;
(8) will separate the Fr. IV-8 that obtains in the step (7) through silica gel column chromatography, volume ratio is that 20～30: 70～80 methanol-water elutriant wash-out is divided into three components: Fr. IV-8-1～Fr. IV-8-3;
(9) separation in the step (8) is obtained Fr. IV-8-2 and get compound 7 and compound 10 through thin-layer chromatography.
12. preparation method as claimed in claim 11 is characterized in that, may further comprise the steps:
(1) get exsiccant aloe ointment with mass percent concentration 90～98% alcohol reflux 3～5 times, united extraction liquid, decompression and solvent recovery obtains medicinal extract;
(2) medicinal extract that step (1) is made is with 60～100 order silica gel column chromatographies, is that 80: 20: 2 chloroform-methanol-water elutions are divided into 5 components: Fr. I～Fr. V with the volume ratio of 40～80 times of medicinal extract weight;
(3) with the Fr. II that obtains in the step (2) through 100～200 order silica gel column chromatographies, with 50～80 times of weight of Fr. II weight, volume ratio is 90: 10,80: 20,50: 50 chloroform-methanol gradient elution was divided into three components: Fr. II-1～Fr. II-3;
(4) be that 85: 15: 1 thin-layer chromatography of chloroform-methanol-water is prepared into compound 1 and compound 6 with obtaining Fr. II-2 in the step (3) through development system;
(5) the Fr. II-3 that obtains in the step (3) is prepared into compound 5 and compound 2 through RPLC; The condition of RPLC is: stationary phase 250 * 20mm, 10 μ m Unicorn ODS posts, and moving phase: volume ratio is 55: 45 a methanol-water, flow velocity 3.0mL/min;
(6) get compound 9 and compound 8 with obtaining Fr. II-3 in the step (3) through rp-hplc analysis; The condition of RPLC is: stationary phase is 250 * 20mm, 10 μ m Unicorn ODS posts, and moving phase is that volume ratio is methanol-water-trifluoroacetic acid of 31: 69: 0.1, flow velocity 3.0mL/min;
(7) the Fr. IV that obtains in the step (2) is first through sephadex LH-20 hydroxypropyl dextrane gel column chromatography, through the methanol-water gradient elution, the volume ratio of methanol-water was followed successively by 0: 10,1: 9,2: 8,3: 7,4: 6,5: 5,6: 4,7: 3,8: 2,9: 1,10: 0, wash-out is divided into 11 components, is respectively: Fr. IV-1～IV-11;
(8) will separate the anti-phase C-18 silica gel column chromatography of Fr. IV-8 usefulness that obtains in the step (7), volume ratio is 30: 70 methanol-water wash-outs, is divided into three components: Fr. IV-8-1～Fr. IV-8-3;
(9) be that 75: 25: 2 thin-layer chromatographies of chloroform-methanol-water are prepared into compound 7 and compound 10 with obtaining Fr. IV-8-2 in the step (8) through development system.
13. prepare the method for the described compound of claim 9, it is characterized in that, may further comprise the steps:
(1) get fresh aloe and in lower alcohol, soaked 6～8 days, filter, get Aloe extractum behind the concentrating under reduced pressure,
(2) with step (1) medicinal extract be suspended in 4～5 times the water, extract respectively 3～5 times with sherwood oil, ethyl acetate and propyl carbinol;
(3) with acetic acid ethyl ester extract through 100～200 order silica gel column chromatographies, be 92: 8～90: 10 chloroform-methanol gradient elutions with volume ratio, be divided into 11 component Fr. I～Fr. XI;
(4) with component Fr. IV through hydroxypropyl dextrane gel electrophoresis, be 1: 9～2: 8 methanol-water wash-out with volume ratio, five component Fr. IV 1-to Fr. IV-5;
(5) the Fr. IV-3 with step (4) gained makes compound 13 through RPLC,
(6) with the component Fr. VII of step (3) gained through hydroxypropyl dextrane gel column chromatography, be that 10: 90～20: 80 methanol-water wash-out is divided into 11 components: Fr. VII-1～Fr. VII-11 with volume ratio;
(7) the component Fr. VII-10 with step (6) gained gets compound 4, compound 11 and compound 12 through thin-layer chromatography;
(8) with the component Fr. IX of step (3) gained after the decolouring of hydroxypropyl dextrane gel column chromatography, be prepared into compound 3 with thin-layer chromatography.
14. preparation method as claimed in claim 13 is characterized in that, may further comprise the steps:
(1) get fresh aloe soaking at room temperature 6～8 days in lower alcohol, filter, behind the concentrating under reduced pressure Aloe extractum,
(2) with step (1) medicinal extract be suspended in 4～5 times the water, extract respectively 3～5 times with sherwood oil, ethyl acetate and propyl carbinol;
(3) with acetic acid ethyl ester extract through 100～200 order silica gel column chromatographies, be 92: 8,90: 10 chloroform-methanol gradient elutions with volume ratio, be divided into 11 component Fr. I～Fr. XI;
(4) with component Fr. IV through hydroxypropyl dextrane gel electrophoresis, be 20～80 methanol-water wash-out with volume ratio, five part Fr. IV～1 to Fr. IV～5;
(5) the Fr. IV-3 with step (4) gained makes compound 13 through RPLC, the condition of RPLC is: solid-state is 10 μ m, 250 * 20mm Unicorn ODS post mutually, liquid state is 27: 73 acetonitrile/water mutually for volume ratio, and flow velocity is 3.0mL/min;
(6) with the component Fr. VII of step (3) gained through hydroxypropyl dextrane gel column chromatography, be that 20: 80 methanol-water wash-out is divided into 11 and component: Fr. VII-1～Fr. VII-11 with volume ratio;
(7) be that volume ratio is that chloroform-methanol-water thin-layer chromatography of 85: 15: 1 is prepared into compound 4, compound 11 and compound 12 with the component Fr. VII-10 of step (6) gained through development system;
(8) with the component Fr. IX of step (3) gained after the decolouring of hydroxypropyl dextrane gel column chromatography, be that 80: 20: 2 thin-layer chromatography of chloroform-methanol-water is prepared into compound 3 with the development system volume ratio.
15. a pharmaceutical composition is characterized in that, contain among the claim 1-9 of effective dose at least a in the compound described in each, and pharmaceutical carrier.
16. the pharmaceutical composition according to claim 15 is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or particulate delivery system.
17. each described compound suppresses application in beta-secretase, the anti-oxidant and/or neuroprotective cell drug in preparation among the claim 1-9.
18. the application of each described compound in treatment senile dementia and preparation treatment senile dementia disease drug among the claim 1-9.
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|---|---|---|---|
| CN200910081580A CN101857590A (en) | 2009-04-13 | 2009-04-13 | Chromone ketoside compounds and purification method and application thereof |
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|---|---|---|---|
| CN200910081580A CN101857590A (en) | 2009-04-13 | 2009-04-13 | Chromone ketoside compounds and purification method and application thereof |
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|---|---|
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Family
ID=42943776
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| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004113317A1 (en) * | 2003-06-20 | 2004-12-29 | Ernst-Moritz-Arndt- Universität | Novel antimicrobial chroman-4-ones |
| US20080003300A1 (en) * | 2006-06-30 | 2008-01-03 | Gaffar Maria C | Compostions containing Mg/Zn/F-CaP plus inhibitors of pro-inflammatory Cytokines (a combination of a Free-B-Ring flavonoids and a flavan) for osteoporosis prevention, therapy and treatment of bone diseases |
-
2009
- 2009-04-13 CN CN200910081580A patent/CN101857590A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004113317A1 (en) * | 2003-06-20 | 2004-12-29 | Ernst-Moritz-Arndt- Universität | Novel antimicrobial chroman-4-ones |
| US20080003300A1 (en) * | 2006-06-30 | 2008-01-03 | Gaffar Maria C | Compostions containing Mg/Zn/F-CaP plus inhibitors of pro-inflammatory Cytokines (a combination of a Free-B-Ring flavonoids and a flavan) for osteoporosis prevention, therapy and treatment of bone diseases |
Non-Patent Citations (4)
| Title |
|---|
| JÜRGEN SCHMIDT，等: "Structural investigations of 5-methylchromone glycosides from Aloe species by liquid chromatography/electrospray tandem mass spectrometry", 《EUR. J. MASS SPECTROM.》 * |
| L. DURI，等: "6-Phenylpyrones and 5-methylchromones from Kenya aloe", 《FITOTERAPIA》 * |
| LIANG LV，等: "BACE1 (β-Secretase) Inhibitory Chromone Glycosides from Aloe vera and Aloe nobilis", 《PLANTA MED》 * |
| 高博，等: "木立芦荟中BACE抑制活性成分的研究", 《药学学报》 * |
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Application publication date: 20101013 |