CN102351874B - New erigeroster compound with medicinal activity - Google Patents
New erigeroster compound with medicinal activity Download PDFInfo
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- CN102351874B CN102351874B CN 201110243526 CN201110243526A CN102351874B CN 102351874 B CN102351874 B CN 102351874B CN 201110243526 CN201110243526 CN 201110243526 CN 201110243526 A CN201110243526 A CN 201110243526A CN 102351874 B CN102351874 B CN 102351874B
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Abstract
The invention relates to a new compound with a structural formula (I) or a pharmaceutically acceptable salt thereof. The compound can be obtained by extracting and separating the dried complete herb of Erigeron breviscapus (Vant.) Hand.-Mazz. The compound has the effects of resisting inflammatory response, resisting platelet aggregation, resisting thrombus and expanding blood vessels, and can be used for preparing medicaments for treating heart cerebrovascular diseases.
Description
Technical field
The present invention relates to a kind ofly have the new compound of anti-inflammatory response, platelet aggregation-against, antithrombotic and vasodilative effect and acceptable salt pharmaceutically thereof, and contain this compound as the medicinal compositions of the treatment cardiovascular and cerebrovascular diseases of activeconstituents.New compound Herba Erigerontis ester (Erigeroster), preparation method and the application in pharmacy thereof of from Herba Erigerontis, extracting specifically.
Background technology
Up to now, be that the cardiovascular and cerebrovascular diseases sickness rate of representative is high with coronary heart disease, cerebral apoplexy (cerebral apoplexy), its case fatality rate occupies human all kinds of disease death rates first place.Seek new, effectively to treat cardiovascular and cerebrovascular diseases medicament be difficult point and the focus that current pharmacy and clinical medicine circle are paid special attention to.
Herba Erigerontis has another name called Herba Erigerontis, is the dry herb of composite family bitter fleabane platymiscium Erigeron Breviscapus (Vant.) Hand.-Mazz., has expelling cold and relieving exterior syndrome, dispels rheumatism the effect of activating collaterals to relieve pain.The Zhang Renwei of institute of materia medica, Yunnan etc. is separated to flavonoid activeconstituents scutellarin first from Herba Erigerontis, and be scutellarin that mixture main, that contain a small amount of breviscapine (apigenin glycosides) calls Breviscarpine (breviscapin) [Zhang Renwei, Yang Shengyuan, Lin Yongyue, Acta Pharmaceutica Sinica (1981), 16 (1), 68-6].Except scutellarin, patent CN1136434 discloses two coffic acid quininic acid ester compounds 3,5-two caffeoyl quinic acids and 3,4-, two caffeoyl quinic acids (3,4-dicaffeoyl quinic acid)].CN1064236C then discloses Jiao Meikangsuan (promenonic acid) and bitter fleabane glycosides (erigenoide) is being used aspect the treatment cardiovascular and cerebrovascular diseases.Zhang Weidongs etc. have been applied for activeconstituents 1-(2 '-gamma-pyrone)-6-coffee acyl-β-preparation of D-glucoside and preparation method's the patent CN1252276 that are separated to from Herba Erigerontis.Patent CN1462750 discloses activeconstituents Erigeroster B of being separated to and preparation method thereof and the application in pharmacy from Herba Erigerontis, patent CN101974010A, CN101974011A and the CN101974012A of inventor's application disclose Herba Erigerontis acid, Herba Erigerontis acid methyl esters and Herba Erigerontis acetoacetic ester and preparation method thereof and the application in pharmacy respectively.In addition, do not see that as yet other new compounds of finding are open in Herba Erigerontis.
Up to now, the medicine that extracts in Herba Erigerontis, have treatment cardiovascular and cerebrovascular diseases activity is a lot.Wherein major part is the mixture of multiple compound, though these medicines have therapeutic action, multiple composition must cause following problem: the homogeneity of curative effect is poor, quality control difficulty, side effect are difficult to control (injection is especially obvious).The effective medicine of single compounds only has Breviscapine, is difficult to satisfy complicated clinical medicine demand.
In view of as above reason, the inventor is through further investigation, the compound that extraction separation makes new advances from Herba Erigerontis: Herba Erigerontis ester (Erigeroster), have anti-inflammatory response, platelet aggregation-against, antithrombotic and vasodilation effect through evidence Herba Erigerontis ester, can be used for the medicine for the preparation of the treatment cardiovascular and cerebrovascular diseases, and the extraction preparation method of Herba Erigerontis ester is provided.
Summary of the invention
The present invention is directed to the prior art blank, disclose pharmaceutically acceptable salt of new activeconstituents Herba Erigerontis ester (hereinafter to be referred as " The compounds of this invention " or " Herba Erigerontis ester ") or its.The invention provides following technical scheme:
Have following structural formula compound Herba Erigerontis ester:
The The compounds of this invention structured data is as follows:
HRESIMS：m/z?567.1111[M+Na]
+(cal?for?C
26H
24O
13Na.567.1114)，[α]
D 26.3，-80°(0.060，CH
3OH)；
IR (KBr compressing tablet): 3450,1690,1635,1530,1600,1285,760cm
-1
UVλmax(MeOH)：217(12105)，245(6388)，301(14580)，331(25084)nm；
1H?NMR(400MHz，DMSO-d6，ppm)：2.17(2H，m，H-2α，H-2β)，4.18(1H，m，H-3)，4.25(1H，m，H-6)，4.55(1H，m，H-5)，4.82，4.89(2H，m，H-9)，4.98(1H，m，H-4)，6.18，6.25(each?1H，d，J＝16Hz，H-2’，H-2”)，6.74(2H，m，H-6’，H-6”)，6.92(2H，m，H-9’，H-9”)，7.03(2H，m，H-5’，H-5”)，7.46，7.50(each?1H，d，J＝16Hz，H-3’，H-3”)，
13C?NMR(100MHz，DMSO-d6，ppm)：105.3(C-1)，40.6(C-2)，62.4(C-3)，70.9(C-4)，74.4(C-5)，78.1(C-6)，63.7(C-9)，166.9(C-10)，165.9(C-1’)，114.2(C-2’，C-2”)，146.2(C-3’，C-3”)，125.9(C-4’，C-4”)，115.2(C-5’，C-5”)，146.1(C-6’，C-6”)，149.1(C-7’，C-7”)，116.3(C-8’，C-8”)，121.8.(C-9’，C-9”)。
This compound is new compound, and is identical with disclosed compound Erigeroster B skeleton among the patent CN1462750, but the substituting group position difference, Erigeroster B is to form caffeic acid ester at 3,6, the Herba Erigerontis ester that this patent relates to then is 4,6 and forms caffeic acid ester.
The said salt of the present invention refers to pharmacy acceptable salt, for example with sodium hydroxide, and the salt that alkali such as potassium hydroxide form.
Pharmaceutically acceptable carrier of the present invention refers to the pharmaceutical carrier of pharmaceutical field routine, for example: thinner, vehicle such as water etc., weighting agent such as starch, sucrose etc.; Tamanori such as derivatived cellulose, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerine; Disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin and soap clay; Lubricant such as talcum powder, calcium stearate and magnesium and polyoxyethylene glycol etc.Can also in composition, add other assistant agents such as flavouring agent, sweeting agent etc. in addition.
The invention provides the method for the The compounds of this invention of preparation claim 1: herb or the over-ground part of getting Herba Erigerontis, pulverize, extract three times with the 0-95% aqueous ethanolic solution, merge No. three times extracting solution, concentrating under reduced pressure, polyamide resin chromatography on the concentrated solution, wash with water earlier, use the ethanol elution of 70-90% again, concentrating under reduced pressure behind the collection 70-90% ethanol eluate, this part with silica gel column chromatography after, separate preparing the Herba Erigerontis ester again with high performance liquid chromatography.
Except above-mentioned preparation method, certain methods well known to those skilled in the art also can distribute extraction back with various just anti-phase chromatography methods to prepare The compounds of this invention with ethyl acetate extraction, concentrated solution with solvent such as aforementioned Herba Erigerontis herb for the preparation of the Herba Erigerontis ester.
Pharmacodynamics test research
One. the pharmacological action for the treatment of cardiac and cerebral vascular diseases
1. to the influence of different inductor induced platelet aggregations
1.1 material
Herba Erigerontis ester: 20mg/kg irritates stomach;
Blank group: physiological saline;
Positive control: acetylsalicylic acid.
1.2 experimental technique
Cavy grouping (8 every group) was irritated stomach 5 days, blank physiological saline.Last administration rear neck artery blood sampling in 1 hour, with the Sodium Citrate anti-freezing, mixing, centrifugal, merge supernatant liquor as PRP (platelet rich plasma), platelet count; Remaining blood plasma is centrifugal, gets supernatant liquor as PPP (platelet poor plasma); With the PPP zeroing, to get PRP300 μ l and add opacity tube, 37 ℃ of incubations add inductor PAF (platelet activation factor), assemble different time, record data.The results are shown in Table 1.
The influence of the cavy platelet aggregation that table 1. pair platelet activation factor is induced
Compare with the blank group
*P＜0.01
Test structure and above-mentioned experimental result with the ADP inductor are similar.
By The above results as can be known, the Herba Erigerontis ester can suppress platelet aggregation (aggegation), the reduction MA that different inductors are induced, and effect and acetylsalicylic acid are similar.
2. to the thrombotic influence of rats in vitro
Take off according to the pharmacology known method and to measure wet weight of thrombus and thrombus dry weight respectively.
The result shows, in rat artery-thrombotic experiment of venous blood flow coronary artery bypass grafting, compares Herba Erigerontis ester group P＜0.01 with model control group; In rats in vitro thrombosis process, the Herba Erigerontis ester makes wet weight of thrombus than control group significant difference (P＜0.01) be arranged relatively.
Two. the pharmacological action of anti-inflammatory aspect: p-Xylol causes the influence of mouse skin capillary permeability
The compounds of this invention: 20mg/kg irritates stomach;
Control group: physiological saline;
Experimental technique
" herbal pharmacology research methodology " with reference to the Qi Chen chief editor makes the animal inflammatory model, the results are shown in following table:
Compare with control group
*P＜0.01
Three. the vasoactive test
The influence (n=10) that table 2. Herba Erigerontis ester induces rabbit aorta to shrink to phyenlephrinium
*Contrast before P＜0.01vs administration
In view of the Herba Erigerontis ester has above pharmacologically active, therefore envisioning the Herba Erigerontis ester can be used for treating cardiovascular and cerebrovascular diseases, especially coronary heart disease, cerebral apoplexy (apoplexy).
The compounds of this invention can be separately or is made oral dosage forms such as tablet, capsule, dripping pill, granule or injection liquid, injectable dosage forms such as freeze-dried with the auxiliary material of other medicinal permission by prior art.
Embodiment
Embodiment 1: the extracting and preparing technique of Herba Erigerontis ester
Get the herb 50kg of Herba Erigerontis, pulverize, extract three times with 40% aqueous ethanolic solution, merge No. three times extracting solution, concentrating under reduced pressure, polyamide resin chromatography on the concentrated solution, wash with water earlier, use 70% ethanol elution again, collect concentrating under reduced pressure behind 70% ethanol eluate, this part with silica gel column chromatography after, separate preparing Herba Erigerontis ester (Erigeroster) 50g again with high performance liquid chromatography.
Embodiment 2: the extracting and preparing technique of Herba Erigerontis ester
Get the herb 50kg of Herba Erigerontis, pulverize, extract three times with 70% aqueous ethanolic solution, merge No. three times extracting solution, concentrating under reduced pressure, polyamide resin chromatography on the concentrated solution, wash with water earlier, use 80% ethanol elution again, collect concentrating under reduced pressure behind 80% ethanol eluate, this part with silica gel column chromatography after, separate preparing Herba Erigerontis ester (Erigeroster) 60g again with high performance liquid chromatography.
Embodiment 3: the extracting and preparing technique of Herba Erigerontis ester
Get the over-ground part 50kg of Herba Erigerontis, pulverize, with extraction with aqueous solution three times, merge No. three times extracting solution, concentrating under reduced pressure, polyamide resin chromatography on the concentrated solution, wash with water earlier, use 50% ethanol elution again, collect concentrating under reduced pressure behind 50% ethanol eluate, this part with silica gel column chromatography after, separate preparing Herba Erigerontis ester (Erigeroster) 40g again with high performance liquid chromatography.
The preparation technology of the tablet of embodiment 4, Herba Erigerontis ester
After Herba Erigerontis ester 10g and starch mixed, add 10% starch slurry 10g and make softwood, cross 14 mesh sieves and granulate, dry under 70-80 ℃ of temperature, cross the whole grain of 12 mesh sieves, after adding Magnesium Stearate 2g and mixing, be pressed into 1000, namely.Every contains Herba Erigerontis ester 10mg.
The capsule preparation technology of embodiment 5, Herba Erigerontis ester
Get 10g Herba Erigerontis ester, after adding the starch 30g of 80 ℃ of dryings and stearyl ester magnesium 2g and mixing, be distributed into 1000 capsules, every capsules contains Herba Erigerontis ester 10mg.
The injection liquid preparation of embodiment 6. Herba Erigerontis esters
Get 10g Herba Erigerontis ester and be dissolved in the cold distilled water for injection of 5000ml, 85g sodium-chlor, 2g sodium hydroxide mixed dissolution are in the distilled water for injection of 1000ml heat.Two kinds of solution are mixed, add water to 10000ml, regulate the pH value and filter at the 5.0-7.0 filter stick, membrane filtration adds nitrogen envelope bottle after clarity test is qualified, and at 115 ℃, sterilization made the Herba Erigerontis ester injection after 25 minutes under the 10atm pressure.
The freeze-dried preparation of injection of embodiment 7. Herba Erigerontis esters
Get an amount of potassium hydroxide, sodium-chlor, N.F,USP MANNITOL, add 1600 milliliters of dissolvings of injection water, add gac 3.2g, absorb 30 minutes depyrogenations, remove by filter activated carbon, add Herba Erigerontis ester 10g in filtrate, regulating pH is 6.0～7.3, and millipore filtration filters, add the injection water to 2000ml, be packed as 1000, lyophilize, namely.
Claims (5)
1. have pharmaceutically acceptable salt of following structural formula compound Herba Erigerontis ester or its:
2. the preparation method of the compound of a claim 1, it is characterized in that getting the herb of Herba Erigerontis, pulverize, extract three times with the 0-95% aqueous ethanolic solution, merge No. three times extracting solution, concentrating under reduced pressure, the polyamide resin chromatography washes with water earlier on the concentrated solution, use the ethanol elution of 70-90% again, collect concentrating under reduced pressure behind the 70-90% ethanol eluate, this part with silica gel column chromatography after, separate preparing the Herba Erigerontis ester again with high performance liquid chromatography.
3. the preparation method of the compound of a claim 1, it is characterized in that getting the over-ground part of Herba Erigerontis, pulverize, extract three times with the 0-95% aqueous ethanolic solution, merge No. three times extracting solution, concentrating under reduced pressure, the polyamide resin chromatography washes with water earlier on the concentrated solution, use the ethanol elution of 70-90% again, collect concentrating under reduced pressure behind the 70-90% ethanol eluate, this part with silica gel column chromatography after, separate preparing the Herba Erigerontis ester again with high performance liquid chromatography.
4. pharmaceutical composition, its compound that contains claim 1 is as activeconstituents and pharmaceutically acceptable carrier.
5. the application of the compound of claim 1 in the medicine of preparation treatment cardiovascular and cerebrovascular diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110243526 CN102351874B (en) | 2011-08-24 | 2011-08-24 | New erigeroster compound with medicinal activity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110243526 CN102351874B (en) | 2011-08-24 | 2011-08-24 | New erigeroster compound with medicinal activity |
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| CN102351874A CN102351874A (en) | 2012-02-15 |
| CN102351874B true CN102351874B (en) | 2013-09-11 |
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Families Citing this family (1)
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| CN102766179B (en) * | 2012-05-18 | 2013-09-25 | 云南施普瑞生物工程有限公司 | Extraction separation method of Erigeron Breviscapus related substance |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1462750A (en) * | 2003-04-22 | 2003-12-24 | 中国科学院昆明植物研究所 | Erigeron ester B and its preparation method as well as application in pharmacy |
| US20090214454A1 (en) * | 2008-02-25 | 2009-08-27 | Inha-Industry Partnership Institute | Method for skin whitening using (2z, 8z) - matricaria acid methyl ester |
| CN101974011A (en) * | 2010-10-26 | 2011-02-16 | 云南生物谷灯盏花药业有限公司 | New compound methyl brevicate with medical activity |
| CN101974012A (en) * | 2010-10-26 | 2011-02-16 | 云南生物谷灯盏花药业有限公司 | Novel compound ethyl brevicate with pharmaceutical activity |
| CN101974010A (en) * | 2010-10-26 | 2011-02-16 | 云南生物谷灯盏花药业有限公司 | New compound erigeron breviscapus acid with officinal activity |
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2011
- 2011-08-24 CN CN 201110243526 patent/CN102351874B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1462750A (en) * | 2003-04-22 | 2003-12-24 | 中国科学院昆明植物研究所 | Erigeron ester B and its preparation method as well as application in pharmacy |
| US20090214454A1 (en) * | 2008-02-25 | 2009-08-27 | Inha-Industry Partnership Institute | Method for skin whitening using (2z, 8z) - matricaria acid methyl ester |
| CN101974011A (en) * | 2010-10-26 | 2011-02-16 | 云南生物谷灯盏花药业有限公司 | New compound methyl brevicate with medical activity |
| CN101974012A (en) * | 2010-10-26 | 2011-02-16 | 云南生物谷灯盏花药业有限公司 | Novel compound ethyl brevicate with pharmaceutical activity |
| CN101974010A (en) * | 2010-10-26 | 2011-02-16 | 云南生物谷灯盏花药业有限公司 | New compound erigeron breviscapus acid with officinal activity |
Non-Patent Citations (4)
| Title |
|---|
| Min Gao,等.Two-step purification of scutellarin from Erigeron breviscapus (vant.) Hand. Mazz. by high-speed counter-current chromatography.《Journal of Chromatography B》.2006,第838卷(第11期),第139-143页，参见第139页摘要、引言部分. |
| Two-step purification of scutellarin from Erigeron breviscapus (vant.) Hand. Mazz. by high-speed counter-current chromatography;Min Gao,等;《Journal of Chromatography B》;20060621;第838卷(第11期);第139-143页，参见第139页摘要、引言部分 * |
| 周建中,等.灯盏细辛注射液对自发性高血压大鼠心室及血管重构的影响.《中国中西医结合杂志》.2002,第22卷(第2期),参见第122-125页全文. * |
| 董媛，等.灯盏细辛中4种酚酸类有效成分的HPLC法测定.《中国医药工业杂志》.2010,第41卷(第6期),第447-449页，参见全文. * |
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