CN1216891C - Compound of geniposide acid, gentio-bioside medication and its preparation method - Google Patents
Compound of geniposide acid, gentio-bioside medication and its preparation method Download PDFInfo
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- CN1216891C CN1216891C CN 03109126 CN03109126A CN1216891C CN 1216891 C CN1216891 C CN 1216891C CN 03109126 CN03109126 CN 03109126 CN 03109126 A CN03109126 A CN 03109126A CN 1216891 C CN1216891 C CN 1216891C
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Abstract
The present invention discloses a compound of geniposide acid and gentian bioside medication and a preparation method thereof, and relates to a medicine compound of a single active component. The present invention uses a water soluble extract of gardenia as a raw material; water soluble impurities are separated by primary column chromatography for obtaining the converted raw material; a primary extract of a target compound is obtained by conversion and secondary column chromatography; then, the target compound is obtained by purification; the medicine compound of geniposide acid and gentian bioside is compounded with baicalin, nacre and cholic acid; protective action on vascular endothelial cells and ischemia cerebral nerve cells is stronged than the compatibility of a total gardenia extract, a gardenia effective part and traditional Chinese medicine.
Description
Technical field
The present invention relates to that a kind of single-activity composition that extracts---genipic acid gentiobiose glycosides and preparation method thereof belongs to technical field of traditional Chinese medicines from the Chinese medicine cape jasmine.
Background technology
Cape jasmine is the fruit of madder wort mountain Cape jasmine Gardenia jasminoides Ellis., and the property bitter cold is nontoxic.Go into the heart, liver, lung, stomach warp.Energy heat-clearing and fire-purging, cool blood.Cure mainly pyreticosis restlessness of asrhenia type and insomnia, jaundice, gonorrhoea, quench one's thirst, hot eyes, pharyngalgia, haematemesis, bleeding from five sense organs or subcutaneous tissue, bloody flux, hematuria, pathopyretic ulcer, sprain and swell and ache.The clinical diseases such as acute icterohepatitis, hemostasis, sprain and contusion that are used for.The Fructus Gardeniae Preparatus cooling blood for hemostasis is used for blood-head and tells nosebleed, the hematuria uterine bleeding.
Modern study is found, contain many chemical ingredientss in the Gardenia Ellis plant, as flavonoid (gardenin class), cyclenes ether glucoside (cape jasmine glucoside), triterpenes (flower of Capa Jasmine acids), organic acid ester (chlorogenic acid, Stigma Croci acids etc.), also contain D-N.F,USP MANNITOL, sterols, triterpenoid saponin, long chain alkane, alcohol and pigment etc. in addition.In spending, fruit and cauline leaf also contain compositions such as volatile oil, polysaccharide.
The main effect of Chinese medicine compound prescription QINGKAILING is that clearing heat and detoxicating, inducing resuscitation is had one's ideas straightened out.It mainly is made up of cow-bezoar, nacre, Root of Indigowoad, Cornu Bubali, the root of large-flowered skullcap, cape jasmine, Japanese Honeysuckle etc.Wherein the main effect of cape jasmine is a heat-clearing and fire-reducing, bitter cold, and the thoughts of returning home, lung, tri-jiao channel are main flavour of a drug wherein, and be similar to root of large-flowered skullcap effect in the compound, the two mutual reinforcement between and using.As medicinal material, basal component of cape jasmine and the existing more research of effect, different component groups demonstrates different activity in the animal effect experiment.At present, specifically the be used as medicine form of cape jasmine in QINGKAILING roughly comprises the extract of iridoid, organic acid and pigment three major types composition, and mainly the mode compatibility by water extract-alcohol precipitation is used as medicine.Present existing research only finds that cape jasmine has certain effect in indivedual effect experiments, played the effect of certain protection, mediation.
Summary of the invention
The objective of the invention is problem at cape jasmine complicated component, quality control difficulty, through extracting, separate and transforming, obtain a kind of micro-single component of biologically active from the extract of Chinese medicine cape jasmine, the initiative quality control is simple, determined curative effect, the new raw material medicine that mechanism is clear and definite.
A kind of genipic acid gentiobiose glycosides medical compounds provided by the invention, its chemical structural formula:
Medical compounds of the present invention can prepare as follows:
(1) at first the Chinese medicine cape jasmine is prepared into water soluble extract, makes water soluble extract then, the water wash-out through macroporous resin column chromatography;
(2) continue wash-out with 30～50% aqueous ethanolic solutions, collect ethanol eluate, regulate the pH 7.5～14 of elutriant;
(3) alcohol is removed in the evaporation of the ethanol eluate in the step (2), pH is transferred to below 7.5 again, through the macroporous resin chromatography, the ethanol elution with 10～20%, evaporate to dryness promptly get this compound.
Water soluble extract described in the above-mentioned steps (1) is with the cape jasmine water, the solution of different concentration ethanol, methyl alcohol or acetone extraction; The pH value of its water soluble extract can be controlled in below 6.5 or the pH value of the aqueous ethanolic solution of in above-mentioned steps (2) wash-out being used can be controlled in below 7.5.
Can also adopt following scheme among the present invention: the pH value of the water soluble extract in the step (1) is controlled at below 6.5, and the pH value of the aqueous ethanolic solution that wash-out in the step (2) is used is controlled at below 7.5 simultaneously.
Among the preparation method of the present invention, described macroporous resin can adopt D101 type macroporous resin or AB-8 type macroporous resin.
Pharmaceutical composition provided by the invention is to be the pharmaceutical composition of active ingredient composition with genipic acid gentiobiose glycosides.
It is a kind of with genipic acid gentiobiose glycosides brain injury that to be active ingredient cause in treatment ischemic, anoxic and the application in the blood vessel injury disease medicament that the present invention also provides.
The present invention is directed to the problem of cape jasmine complicated component, quality control difficulty, through extracting, separate and transforming, obtain a kind of micro-single component of biologically active from the extract of Chinese medicine cape jasmine, the initiative quality control is simple, determined curative effect, the new raw material medicine that mechanism is clear and definite.Target compound is a white powder, and purity 85%-99% identifies that through modern Wave Spectrum its structure is genipic acid-1-O-gentiobiose glycosides.Pharmacological evaluation shows, is that the pharmaceutical composition of active ingredient has better action with this medical compounds in brain injury that treatment ischemic, anoxic cause and blood vessel injury disease.With baicalin, nacre and cholic acid compatibility, the provide protection of vascular endothelial cell and ischemic cranial nerve cell is better than the compatibility of cape jasmine general extractive, active component of cape jasmine and above-mentioned Chinese medicine.Can be used as bulk drug with the new Chinese medicine of above-mentioned three flavor medicinal material compatibilities.
Embodiment
Structural analysis
Compound (I) is white powder, and is soluble in water, can be dissolved in methyl alcohol, is insoluble to organic solvents such as ethanol, acetone, propyl carbinol, ethyl acetate.(I) ESI-MS negative ion mode shows 535 quasi-molecular ion (M-1); Positive ion shows 559 quasi-molecular ion (M+Na), and the molecular weight that this compound is described is 536.The fragmention that M-162 and M-324 are arranged in the mass spectrum illustrates that this compound may contain the structure fragment of two hexoses.In conjunction with
1H-NMR and
13C-NMR, the molecular formula of inferring this compound is C
22H
32O
15, degree of unsaturation is 7.In the structure of compound (I), two hexose (C
12H
20O
10) be C in addition partly
10H
12O
5, degree of unsaturation is 5.With the similar of the main component genipic acid of cape jasmine,
1H-NMR and
13There are three hemiacetal signals (δ 5.11, and δ 4.53, and δ 4.21, and δ 96.5, and δ 98.5, δ 103.2ppm) to support this inference among the C-NMR.In conjunction with
1H-
1H-COSY, HMQC, HMBC, Geniposide and compound (I) under the same terms
1H-NMR and
13C-NMR ownership and contrast see Table 1.The comparative result of table 1 shows that compound (I) is compared with the structure of Geniposide, does not have the H signal of three H of δ 3.64ppm and the C signal of δ 50.9ppm, does not promptly have C
11Methoxyl group on the carboxyl of position.But compound (I)
1H-NMR has shown the unimodal of δ 11.9ppm, and C is described
11It is the free carboxyl.HMBC shows that 2 monosaccharide residues are the disaccharide that (1-6) connects, and after the hydrolysis, TLC shows that monose is glucose.The end group H and the C of sugar
2The coupling constant of position H is 7.8ppm, shows that two monose are beta comfiguration.
In sum, the structure of compound (I) is genipic acid-1-O-gentiobiose glycosides.(I) structural formula is seen figure I; H-H coupling relation is seen figure II (arrow is represented correlationship) with C-H coupling relation; Main long-range correlationship is seen figure III (arrow is represented correlationship).
Table 1: compound (I)
1H-NMR and
13The C-NMR full ownership and with the contrast of Geniposide
| Sequence number | H (Geniposide) | H(I) | C |
| δ (ppm) peak type coupling is normal | δ (ppm) peak type coupling is normal | Geniposide (I) | |
| 1 3 4 5 6a 6b 7 8 9 10a 10b 11 OMe C 11OOH 1′ 2′ 3′ 4′ 5′ 6a′ 6b′ 1″ 2″ 3″ 4″ 5″ 6a″ 6b″ | 5.11 d 6.8 7.46 s - - - 3.06 m dd 0.8，7.8 2.05 dd 7.8，7.0 2.68 d 0.8 - 2.64 dd 7.0，6.8 4.14 dd 14.6，5.1 3.97 dd 14.6， - 3.64 s / 4.53 d 7.87.8 2.98 m 3.10 m 3.42 m 3.67 m 2.98 m 3.11 m | 5.11 d 6.8 7.41 s - - - 3.06 m 2.10 dd 0.8， 2.65 dd 7.0， 5.70 s 2.57 dd 7.0，6.8 4.00 Broad 14.6 4.12 Broad 14.6 - 11.9 s 4.53 d 7.8 3.04 m 3.16 m 3.00 m 3.00 m 3.63 m 3.43 m 4.21 d 7.8 2.89 m 3.0-3.2 m 3.0-3.2 m 3.0-3.2 m 3.55 m 3.42 m | 95.6 96.5 151.5 151.0 110.9 111.2 34.4 34.9 37.9 38.0 125.4 126.1 144.0 144.0 45.8 45.5 59.3 59.4 166.8 168.0 50.9 98.5 98.9 69-77 70-77 69-77 70-77 69-77 70-77 69-77 70-77 60.9 68.0 103.2 70-77 70-77 70-77 70-77 61.0 |
Embodiment 1:
Dry cape jasmine fruit 2.5kg, 70% ethanol refluxed 40 minutes for 10 liters.Alcohol liquid is concentrated into does not have alcohol, and the preparation water soluble extract is crossed macropore Resin A B-8, and the post fineness ratio is 60mm * 900mm, flow velocity 30ml/min.Difference water, 50% ethanol (pH5.0) wash-out, alcohol eluen is regulated pH to 7.5, and 40 ℃ of concentrating under reduced pressure are neutralized to pH4.0, go alcohol through macroporous resin column AB-8, and the post fineness ratio is 30mm * 500mm, 15% ethanol elution, drying; 95% ethyl alcohol recrystallization gets genipic acid gentiobiose glycosides 3.37g, purity 88.6% (HPLC-MS detects, and normalization method is quantitative).
Embodiment 2
Dry cape jasmine fruit 2.3kg, 20 liters of soaked overnight of clear water are boiled the back and are continued heating 20 minutes.Nylon net filter.Filtrate is concentrated into 1 liter, adds 95% ethanol to determining alcohol 60%; Filter, concentrate, remove ethanol, make water soluble extract.Cross macroporous resin D101, the post fineness ratio is 60mm * 900mm, flow velocity 30ml/min.Water, 30% ethanol elution are regulated elutriant pH to 14 respectively.The alcohol eluen atmospheric evaporation is removed ethanol wherein, regulates pH value 6.0, and through macroporous resin column, the post fineness ratio is 30mm * 500mm, and 15% ethanol elution, resin are the SP20 of Mitsubishi, and all the other are handled with 1, get genipic acid gentiobiose glycosides 3.31g, purity 55.3%.
Embodiment 3
Dry cape jasmine fruit 2.3kg, methanol extraction.Resin is D101, and the post fineness ratio is 60mm * 900mm, and PH is adjusted to 4.5-5.0 before the last sample, difference water, 30% ethanol (pH6.5) wash-out, alcohol eluen is regulated pH to 8.3, and 50 ℃ of concentrating under reduced pressure are regulated pH value 7.5, through big D101 hole resin column, the post fineness ratio is 500mm * 30mm, 15% ethanol elution, and all the other are handled with 1, get genipic acid gentiobiose glycosides 2.83g, purity 64.0%.
Embodiment 4
Dry cape jasmine fruit 2.7kg, 50% aqueous acetone solution refluxing extraction.All the other are handled with 1, get genipic acid gentiobiose glycosides 2.71g, purity 54.0%.
Purity testing: HPLC/DAD analyzes.Moving phase: 20% methanol-water, detect wavelength: 248nm.
Embodiment 5
Biological activity test:
Compound " QINGKAILING " is prevented the too many levels effect of cerebral ischemia cascade reaction, and outstanding behaviours is in the middle of the compatibility of cholic acid, baicalin, Fructus Gardeniae extract, nacre hydrolyzed solution.These compatibility of drugs have better action at the inhibition peroxidatic reaction of lipid aspect brain micro blood vessel endothelium cell and neuronic damage, simultaneously, also shown the effect advantage in the regulation and control nerve growth factor production aspect the opposing damage of neuroprotective unit.For further determining the effect of compound (I), carried out following cut-and-try work.
Make MCAT (Middle Cerebral Artery Thrombosis MCAT) cerebral infarction model with the Waster rat, the biological effect of the different compatibilities of comparison of aforementioned four parts is measured cerebral tissue SOD, MDA, NOS content.Full side is contrast with QINGKAILING, has observed three kinds of prescriptions altogether, and wherein, A side is the compatibility of cape jasmine medicinal material general extractive, and B is the compatibility of the active principle that contains jasminoidin of cape jasmine, and C side is the compatibility of genipic acid gentiobiose glycosides.The prescription ratio is amounted to by the former side of QINGKAILING, and C side specifically consists of: 1000 ml solns contain cholic acid 3.25 grams, baicalin 5.0 grams, 10 milligrams of genipic acid gentiobiose glycosides, nacre 50 grams; Dosage is 1 milliliter of every kg body weight of injection.Result such as table 1:
Table 1: genipic acid gentiobiose glycosides activity test result
| Group | Number of animals | SOD | MDA | NOS |
| Group C side, group B side, normal group model group positive control A side group | 10 10 10 10 10 10 | 136.4±23.11 110.2±28.74* 113.8±23.55* 123.8±15.81 124.9±19.61 131.5±28.04 | 0.94±0.365 1.51±0.532 *1.32±0.553 *1.14±0.368 Δ1.03±0.379 Δ0.95±0.286 ΔΔ* | 0.53±0.315 1.88±0.526 *1.11±0.513 *ΔΔ1.08±0.752 *ΔΔ1.43±0.939 1.34±0.701 Δ |
Compare * P＜0.05, * * P＜0.01 with normal group; Compare Δ P＜0.05, Δ Δ P＜0.01 with model group
A side is the compatibility of cape jasmine medicinal material general extractive, and B is the compatibility of the active principle that contains jasminoidin of cape jasmine, and C side is the compatibility of genipic acid gentiobiose glycosides
A, B, C three parts all have significant reduction effect for cerebral tissue MDA content, and the effect of C side's group is the most outstanding; In the influence to NOS, QINGKAILING group, A side's group, C side's group all have remarkable effect, and be the most outstanding with the above two.But from the capillary blood vessel regulatory function, NO promptly is a kind of medium that causes neuronal damage, also is that a kind of important capillary blood vessel is regulated material, at the certain phase of ischemia pathologic process its positive physiologic meaning is arranged.Can think that for ischemic injuries this important step of peroxidatic reaction of lipid process particularly, C side's group meaning is bigger.
Claims (9)
1, a kind of medical compounds genipic acid gentiobiose glycosides, its chemical structural formula:
2, a kind of preparation method of medical compounds according to claim 1, this method can make as follows:
(1) at first the Chinese medicine cape jasmine is prepared into water soluble extract, makes water soluble extract then, the water wash-out through macroporous resin column chromatography;
(2) continue wash-out with 30～50% aqueous ethanolic solutions, collect ethanol eluate, regulate pH7.5～14 of elutriant;
(3) alcohol is removed in the evaporation of the ethanol eluate in the step (2), pH is transferred to below 7.5, through the macroporous resin chromatography, the ethanol elution with 10～20%, evaporate to dryness promptly get this compound.
3. according to the described preparation method of claim 2, it is characterized in that: the water soluble extract described in the step (1) is with the cape jasmine water, the solution of different concentration ethanol, methyl alcohol or acetone extraction.
4. according to the described preparation method of claim 2, it is characterized in that: the pH with described water soluble extract in the step (1) transfers to below 6.5.
5. according to the described preparation method of claim 2, it is characterized in that: the pH value of the aqueous ethanolic solution described in the step (2) is below 7.5.
6. according to the described preparation method of claim 4, it is characterized in that: the pH value of the aqueous ethanolic solution described in the step (2) is below 7.5.
7. according to the described preparation method of the arbitrary claim of claim 2～6, it is characterized in that: described macroporous resin is a D101 type macroporous resin.
8. according to the described preparation method of the arbitrary claim of claim 2～6, it is characterized in that: described macroporous resin is an AB-8 type macroporous resin.
9. a pharmaceutical composition is characterized in that wherein containing medical compounds as claimed in claim 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03109126 CN1216891C (en) | 2003-04-04 | 2003-04-04 | Compound of geniposide acid, gentio-bioside medication and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03109126 CN1216891C (en) | 2003-04-04 | 2003-04-04 | Compound of geniposide acid, gentio-bioside medication and its preparation method |
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| Publication Number | Publication Date |
|---|---|
| CN1446816A CN1446816A (en) | 2003-10-08 |
| CN1216891C true CN1216891C (en) | 2005-08-31 |
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| CN 03109126 Expired - Fee Related CN1216891C (en) | 2003-04-04 | 2003-04-04 | Compound of geniposide acid, gentio-bioside medication and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307193C (en) * | 2005-05-24 | 2007-03-28 | 中国人民解放军第二军医大学 | Process of preparing total iridoid glycoside with cape jasmine fruit |
| CN1307191C (en) * | 2005-05-24 | 2007-03-28 | 中国人民解放军第二军医大学 | Process for preparing jasminodin and genipin-1-beta-D-gentiobioside with cape jasmine fruit |
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