CN106397253B - A kind of crocetin derivative GX-E and preparation method thereof and the application in preventing or treating cardiovascular and cerebrovascular disease - Google Patents
A kind of crocetin derivative GX-E and preparation method thereof and the application in preventing or treating cardiovascular and cerebrovascular disease Download PDFInfo
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- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/09—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton
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- C07C231/00—Preparation of carboxylic acid amides
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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Abstract
The present invention relates to a kind of crocetin amide GX E and preparation method thereof, and preparation method includes the following steps：1) crocetin, EDCl (1 ethyl (3 dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate), HOBt (1 hydroxybenzotriazole) are taken in reaction bulb；Under condition of ice bath, Et is added in3N、CH2Cl2, organic amine compound is added, is reacted 28 hours at 0 DEG C, ambient temperature overnight；2) after the reaction was complete, stop reaction；Reaction solution is filtered, removes solvent, adds in EA dissolvings, washing；After removing solvent, crude product is obtained；3) crude product with silicagel column is detached, elutes, obtain product；West safflower amide derivatives GX B of the present invention overcome crocetin liposoluble it is extremely low caused by bioavilability it is low the problem of, the oral preparations such as piece agent, sustained-release tablet, granule, suspension can be prepared for preventing or treating cardiovascular and cerebrovascular disease, clinical practice is extensive.
Description
Technical field
The present invention relates to a kind of new crocetin derivatives, and in particular to the pharmaceutically acceptable amide of crocetin and its preparation
The application of method and the derivative in cardiovascular and cerebrovascular disease is prevented and treated.
Background technology
West safflower (Crocus sativus L.) is also known as safflower, is Iridaceae crocus plant safron Crocus
The drying column cap of sativus L..West safflower is a kind of rare Chinese medicine, is treating or preventing cardiovascular and cerebrovascular disease and is swelling
Knurl, inflammation, pain inhibit and extensive to protective effect etc. the clinical practice of liver, kidney, nervous system, and curative effect is shown
It writes.
The main pharmacodynamics substance of west safflower includes crocetin, crocin, crocetin dimethyl ester, west safflower bitter principle
Deng additionally containing eucalyptus brain, firpene, multivitamin.Both at home and abroad modern research shows that crocetin (crocetin) is western red
Flower plays the main active component of cardiovascular and cerebrovascular curative effect in vivo.There is crocetin how unsaturated to be conjugated olefin(e) acid structure, belong to class
Carrotene substance has in anti-disease of cardiovascular system, anti-oxidant, antiatherosclerosis, prevention diabetic complication etc.
Specific bioactivity.
In recent years, preventive and therapeutic effect of the crocetin in disease of cardiovascular system becomes the research hotspot of many scholars, greatly
Quantity research achievement also indicates that crocetin has good cardiovascular protective effect, and its effect is multiple target point, multipath.This
A little achievements in research imply that crocetin has good development prospect, get a good chance of being developed into novel prevention cardiovascular system
The drug of disease is worth further investigation.
However, the fat-soluble and water solubility of crocetin is poor, it is extremely difficult to be dissolved in water and except pyridine and similar to pyridine
Common organic solvent other than organic base, it is difficult to reach higher drug concentration and dosage, in addition, since drug is fat-soluble
It is higher easily to be absorbed by gastrointestinal tract epithelial cell mucous membrane, and crocetin is since its is fat-soluble very poor, so as to cause to give birth to
Object availability is low, and clinical practice is extremely limited.
Meanwhile solubility problem is solved by crocetin derivative, still there are many technological difficulties, such as derivant structure
It is unstable, active the problems such as reducing.For this purpose, this research carries out structural modification based on crocetin, to acquire dissolving
Property is preferable, and cardiovascular and cerebrovascular activity is suitable with crocetin ontology or even more preferably new drug lead compound.
Invention content
Present invention aims at provide a kind of crocetin amide derivatives with and preparation method thereof and purposes.
Technical scheme is as follows：
A kind of crocetin amide GX-E, structural formula are as follows：
A kind of method for preparing crocetin amide GX-E, includes the following steps：
(1) crocetin, EDCl (1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate), HOBt (1- are taken
Hydroxybenzotriazole) in reaction bulb；Under condition of ice bath, Et3N, CH2Cl2 are added in, organic amine compound is added, at 0 DEG C
Lower reaction 2-8 hours, ambient temperature overnight；
(2) after the reaction was complete, stop reaction；Reaction solution is filtered, removes solvent, adds in EA dissolvings, washing；Remove solvent
Afterwards, crude product is obtained；
(3) crude product with silicagel column is detached, elutes, obtain product.
Specifically, organic amine compound is diethylamine in step (1).
Specifically, the reaction time is preferably 4 hours in step (1).
Specifically, the molar ratio of the crocetin in step (1) and diethylamine is 1: 1-1: 8.
Preferably, the molar ratio of the crocetin in step (1) and diethylamine is 1: 2.
Specifically, the washing methods in step (2) reaction is：Successively with hydrochloric acid, sodium bicarbonate, water washing, wash respectively
2-5 times.
Preferably, the washing methods in step (2) reaction is：Successively with hydrochloric acid, sodium bicarbonate, water washing, 3 are washed respectively
It is secondary.
Specifically, the method for elution is in step (3)：It is first eluted with CHCl3, then is carried out with CHCl3: CH3OH=10: 1
Elution.
At present, crocetin there are it is fat-soluble extremely low the problem of, 0.1g crocetins insoluble in 1000ml ethyl alcohol, chloroform-
The organic solvents such as ethyl alcohol, lead to that crocetin bioavilability is extremely low, and clinical practice is limited.
Crocetin GX-1 structures are as follows：
The present invention is by screening a large amount of crocetin derivative, to solve the fat-soluble low caused biology of crocetin
The problem of availability reduces.The present invention has synthesized a series of crocetin derivatives, such as GX-M, GX-N.
Crocetin amide GX-M, structural formula are as follows：
Crocetin amide GX-N, structural formula are as follows：
Crocetin amide derivatives GX-E of the present invention, compared with similar crocetin derivative GX-M, GX-N,
It under identical drug concentration, is detected by mitochondria activity reagent, GX-E activity is substantially better than GX-M, GX-N or even excellent son west
Safflower acid GX-1 has significant protective effect to anoxic cell induction H9c2 Myocytes Anoxias damage, can effectively prevent or
Treat cardiovascular and cerebrovascular disease.
Crocetin amide derivatives GX-E of the present invention, it is fat-soluble to be also far above crocetin GX-1, it is easier to
It is absorbed by gastrointestinal tract epithelial cell mucous membrane, bioavilability is greatly improved for crocetin.
West safflower amide derivatives GX-E of the present invention proves that the compound is safe and effective by cytotoxicity experiment,
Bioactivity is there is no reducing while GX-E fat-soluble promotions, even better than crocetin, overcomes crocetin liposoluble pole
The problem of bioavilability caused by low is low, GX-E can prepare piece agent, sustained-release tablet, granule, suspension, dripping pill, note
The dosage forms such as agent are penetrated for preventing or treating cardiovascular and cerebrovascular disease, clinical practice is more extensive.
Description of the drawings
The high-resolution MS collection of illustrative plates of Fig. 1, GX-E：GX-E C28H42N2O2Found：[M+H]+439.3318Calcd：[M+H]+
439.3319(0.24ppm)
The RESOLUTION NMR collection of illustrative plates of Fig. 2, GX-E：GX-E：1H NMR spectrum
The RESOLUTION NMR collection of illustrative plates of Fig. 3, GX-E：GX-E：13C NMR spectrum
Specific embodiment
Embodiment 1：Prepare crocetin derivative GX-E
Crocetin GX-1 (purchased from Sigma companies) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg) are taken,
HOBt (1.25mmol, 169mg) is in 100ml reaction bulbs.Under condition of ice bath, add in Et3N (2.5mmol, 350 μ l) and
CH2Cl220ml is eventually adding diethylamine (1.0mmol, 112 μ l), 4h is reacted under the conditions of 0 DEG C, and then room temperature reaction is stayed overnight.
Whether generated using TLC and LC-MS detection products.Stop reaction, reaction solution is filtered, solvent is removed in vacuum, add in 10ml EA
Dissolving, is washed 3 times with 2%HCl, each 10ml of 5%NaHCO3, H2O successively, solvent is removed in vacuum and obtains crude product respectively.It will slightly produce
Object GX-E is detached with silicagel column, and the CHCl3 of first 4-5 column volumes is eluted, and then increases eluant, eluent polarity CHCl3:
CH3OH=10: 1 is eluted.GX-E is obtained, and its structure is characterized with NMR.Yellow powder, yield：72%.
Embodiment 2：Prepare crocetin derivative GX-M：
Take crocetin GX-1 (purchased from Sigma companies) (0.5mmol, 164mg) respectively, EDCI (1.25mmol,
239mg), HOBt (1.25mmol, 169mg) is in 25ml reaction bulbs.Under condition of ice bath, Et3N (2.5mmol, 350 μ l) is added in
And CH2Cl220ml, 4- fluorobenzene methylamine (1.1mmol, 125 μ l) is eventually adding, 4h is reacted under the conditions of 0 DEG C, is then reacted at room temperature
Overnight.Whether generated using TCL and LC-MS detection products, after determining that the reaction was complete, stop reaction.Reaction solution is filtered, vacuum
Solvent is removed, 10ml EA dissolvings is added in, is washed respectively 3 times with 2%HCl, each 10ml of 5%NaHCO3, H2O successively, last vacuum
It removes solvent EA and obtains crude product.Obtained crude product purified by silica gel column is detached, is washed with the CHCl3 of three column volumes
It is de-.Product GX-M crude products are obtained, then silica gel post separation again, with the solvent (petroleum ether: ethyl acetate=20 of two column volumes
: 1) it is eluted, finally obtains product GX-M, and its structure, yield are characterized with NMR：75%.
Embodiment 3：Prepare crocetin derivative GX-N：
Take crocetin GX-1 (purchased from Sigma companies) (0.5mmol, 164mg) respectively, EDCI (1.25mmol,
239mg), HOBt (1.25mmol, 169mg) is in 25ml reaction bulbs.Under condition of ice bath, Et3N (2.5mmol, 350 μ l) is added in
And CH2Cl220ml, 3,5- difluorobenzylamines (1.1mmol, 130 μ l) are eventually adding, 4h are reacted under the conditions of 0 DEG C, then room temperature is anti-
It should stay overnight.Whether generated using TCL and LC-MS detection products, after determining that the reaction was complete, stop reaction.Reaction solution is filtered, very
Sky removes solvent, adds in 10ml EA dissolvings, is washed respectively 3 times with 2%HCl, each 10ml of 5%NaHCO3, H2O successively, last true
Sky removes solvent EA and obtains crude product.Obtained crude product purified by silica gel column is detached, is washed with the CHCl3 of three column volumes
It is de-.Product GX-N crude products are obtained, then silica gel post separation again, with the solvent (petroleum ether: ethyl acetate=10 of two column volumes
: 1) it is eluted.Product GX-N is finally obtained, and its structure, yield are characterized with NMR：68%.
Embodiment 4：Prepare crocetin derivative GX-E
Crocetin GX-1 (purchased from Sigma companies) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg) are taken,
HOBt (1.25mmol, 169mg) is in 100ml reaction bulbs.Under condition of ice bath, add in Et3N (2.5mmol, 350 μ l) and
CH2Cl220ml is eventually adding diethylamine (1.5mmol), 2h is reacted under the conditions of 0 DEG C, and then room temperature reaction is stayed overnight.Utilize TLC
Whether generated with LC-MS detection products.Stop reaction, reaction solution is filtered, solvent is removed in vacuum, add in 10ml EA dissolvings, according to
Secondary 2%HCl, each 10ml of 5%NaHCO3, H2O are washed 3 times, solvent are removed in vacuum and obtains crude product respectively.Crude product GX-E is used
Silicagel column is detached, and the CHCl3 of first 4-5 column volumes is eluted, and then increases eluant, eluent polarity CHCl3: CH3OH=10: 1
It is eluted.GX-E is obtained, and its structure is characterized with NMR.Yellow powder, yield：68%.
Embodiment 5：Prepare crocetin derivative GX-E
Crocetin GX-1 (purchased from Sigma companies) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg) are taken,
HOBt (1.25mmol, 169mg) is in 100ml reaction bulbs.Under condition of ice bath, add in Et3N (2.5mmol, 350 μ l) and
CH2Cl220ml is eventually adding diethylamine (4mmol), 4h is reacted under the conditions of 0 DEG C, and then room temperature reaction is stayed overnight.Using TLC and
Whether LC-MS detection products generate.Stop reaction, reaction solution is filtered, solvent is removed in vacuum, add in 10ml EA dissolvings, successively
It is washed respectively 2 times with 2%HCl, each 10ml of 5%NaHCO3, H2O, solvent is removed in vacuum and obtains crude product.By crude product GX-E silicon
Rubber column gel column is detached, and the CHCl3 of first 4-5 column volumes is eluted, then increase eluant, eluent polarity CHCl3: CH3OH=10: 1 into
Row elution.GX-E is obtained, and its structure is characterized with NMR.Yellow powder, yield：61%.
Embodiment 6：Prepare crocetin derivative GX-E
Crocetin GX-1 (purchased from Sigma companies) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg) are taken,
HOBt (1.25mmol, 169mg) is in 100ml reaction bulbs.Under condition of ice bath, add in Et3N (2.5mmol, 350 μ l) and
CH2Cl220ml is eventually adding diethylamine (0.5mmol), 8h is reacted under the conditions of 0 DEG C, and then room temperature reaction is stayed overnight.Utilize TLC
Whether generated with LC-MS detection products.Stop reaction, reaction solution is filtered, solvent is removed in vacuum, add in 10ml EA dissolvings, according to
Secondary 2%HCl, each 10ml of 5%NaHCO3, H2O are washed 5 times, solvent are removed in vacuum and obtains crude product respectively.Crude product GX-E is used
Silicagel column is detached, and the CHCl3 of first 4-5 column volumes is eluted, and then increases eluant, eluent polarity CHCl3: CH3OH=10: 1
It is eluted.GX-E is obtained, and its structure is characterized with NMR.Yellow powder, yield：57%.
Embodiment 7：Prepare crocetin derivative GX-E
Crocetin GX-1 (purchased from Sigma companies) (0.5mmol, 164mg), EDCI (1.25mmol, 239mg) are taken,
HOBt (1.25mmol, 169mg) is in 100ml reaction bulbs.Under condition of ice bath, add in Et3N (2.5mmol, 350 μ l) and
CH2Cl220ml is eventually adding diethylamine (2.0mmol), 4h is reacted under the conditions of 0 DEG C, and then room temperature reaction is stayed overnight.Utilize TLC
Whether generated with LC-MS detection products.Stop reaction, reaction solution is filtered, solvent is removed in vacuum, add in 10ml EA dissolvings, according to
Secondary 2%HCl, each 10ml of 5%NaHCO3, H2O are washed 3 times, solvent are removed in vacuum and obtains crude product respectively.Crude product GX-E is used
Silicagel column is detached, and the CHCl3 of first 4-5 column volumes is eluted, and then increases eluant, eluent polarity CHCl3: CH3OH=10: 1
It is eluted.GX-E is obtained, and its structure is characterized with NMR.Yellow powder, yield：65%.
Embodiment 8：Crocetin and its experiment of series derivates anti-myocardial anoxia functions
1st, GX-1, GX-E, GX-M, appropriate GX-N are taken, it is dense to be configured to 1mM with absolute ethyl alcohol by preparation method such as embodiment 1-3
Degree, be stored in -20 DEG C of KRB cultural buffer (NaCl 115mM, KCl 4.7mM, CaCl22.5mM, NaHCO324mM,
KH2PO41.2mM, MgSO47H2O1.2mM, HEPES 10mM, 0.01%BSA), KRB wash buffer (KRB cultural
Buffer without FBS), it is stayed overnight using preceding nitrogen balance；MTT, purchased from Sigma companies；Mitochondria activity measure reagent
Box, purchased from Abcam companies；DMEM culture mediums and fetal calf serum are purchased from and Gibco companies.RSE is ginseng extract (Macao
The self-control of traditional Chinese medicine quality research National Key Laboratory of University of Science and Technology), which has been found have anoxia-induced apoptosis on the mold
Myocardial cell protection acts on.
2nd, cell culture：With cardiac muscle cell selection rat into Fibrillar myocardial muscle cell, H9c2 (CRL-1446) is purchased from for experiment
ATCC companies.The cell in culture is taken out, incline culture medium, and with PBS rinses one time, incline PBS, adds in the trypsase of 1ml,
37 DEG C of digestion 1min add in culture medium and stop digestion, and 1000rpm centrifugation 5min abandon supernatant, add in culture medium and cell is resuspended.
It is 5 × 104/ml with cell counting board adjustment cell concentration, cell suspension is added in 96 orifice plates, per 100 μ l of hole, is put into CO2
Culture 48h in incubator (5%CO2,37 DEG C).
3rd, experiment packet：H9c2 cardiac muscle cell is divided into Normal group, anoxia model group (Myocytes Anoxia induction damage
Wound model group), RSE positive controls (ginseng extract RSE is as positive controls), GX-1 groups, GX-E groups, GX-D groups and
GX-E groups.Normal group is without any processing, remaining each group is inclined culture medium, and it is primary to add in KRB wash buffer rinses,
Incline KRB wash buffer, adds in drug containing KRB cultural buffer：RSE final concentration of 200 in RSE positive controls
μ g/ml, GX each group final concentrations are 10nM.
4th, Myocytes Anoxia induced damage：After each group administration, immediately by 96 orifice plates merging anoxic cell (billups-
Rothenberg, Inc.), with nitrogen saturation anoxic cell 5min, sealing anoxic cell makes its internal formation low-oxygen environment, and
It is put into 37 DEG C of CO2 incubators, starts anoxic.After 3h, 96 orifice plates are taken out from anoxic cell, drug containing of inclining KRB
Cultural buffer add in 100 μ l culture mediums.
5th, cell activity and mitochondria activity detection：Cytoactive detection：10 μ l MTT are added in per hole, 37 DEG C are protected from light incubation
4h adds 10%SDS-HCL (0.01M) overnight, is detected under 570nm wavelength.Mitochondria activity detects：100 μ l are added in per hole
Mitochondria activity measure reagent, 37 DEG C are protected from light incubation 4h, fluorescence intensity (excitation wavelength：550nm, launch wavelength 590nm).
Conclusion：Show that compared with Normal group (100% ± 0.04), anoxic cell inducing hypoxia is notable by detection
Reduce H9c2 myocyte survivals rate (18.9% ± 0.03, p ＜ 0.001)；The 200 μ g/ml group H9c2 hearts of positive control RSE
Myocyte's survival rate (33.5% ± 0.01) is significantly increased (p ＜ 0.001) compared with anoxia-induced apoptosis group.As a result the anoxia-induced apoptosis heart is shown
Myocyte model success.
GX-E is to shown in hypoxia inducible myocardial cell injury protective effect table 1 specific as follows：
Table 1：Tetra- kinds of compounds of GX are to hypoxia inducible myocardial cell injury protective effect (mitochondria activity reagent detection knot
Fruit)
| Serial number | Group | H9c2 cardiac muscle cell's mitochondria survival rate |
| 1 | NORMAL (Normal group) | 1.00 |
| 2 | HYPOXIA (anoxia model group) | 0.42 |
| 3 | GX-1 | 0.65 |
| 4 | GX-E | 0.71 |
| 5 | GX-M | 0.29 |
| 6 | GX-N | 0.39 |
Conclusion：Mitochondria activity reagent testing result is as shown in table 1, and GX series compounds are presented respectively under 1 μM of dosage
To the different role of anoxic myocardial, under identical drug concentration, GX-E activity is substantially better than crocetin GX-1, while with
Crocetin derivative GX-M, GX-N are compared, and the activity of GX-E is more excellent, to the induction H9c2 Myocytes Anoxia damages of anoxic cell
There is significant protective effect.
Embodiment 9：GX-1, GX-E solubility experiment compare
0.1g solid samples (crocetin (GX-1) and its derivative (GX-E)) is taken to add 1mL ethyl alcohol/chlorine in test tube
After imitation-carbinol (10: 1) oscillation, 100mL and 1000mL can be added to by, which not dissolving such as, sees whether to dissolve, concrete outcome such as the following table 2 institute
Show：
2 solubility experiment deck watch of table
Note："+" represents dissolving in table；"-" represents insoluble；If the phenomenon that between dissolving and between not dissolving, with symbol
Number " ± " represent；"/" expression is not required to the project of experiment.
Conclusion：The fat-soluble of GX-E it can be seen from the experimental result of above-mentioned table 2 after structural modification is substantially better than
Crocetin.
Claims (10)
1. a kind of crocetin amide GX-E, structural formula are：
2. the preparation method of crocetin amide GX-E according to claim 1, which is characterized in that the preparation method packet
Include following steps：
1) crocetin, EDCl (1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate), HOBt (1- hydroxyls are taken
Benzotriazole) in reaction bulb；Under condition of ice bath, Et is added in3N、CH2Cl2, organic amine compound is added, it is anti-at 0 DEG C
2-8 hours are answered, ambient temperature overnight；
2) after the reaction was complete, stop reaction；Reaction solution is filtered, removes solvent, adds in EA dissolvings, washing；After removing solvent, obtain
To crude product；
3) crude product with silicagel column is detached, elutes, obtain product.
3. the preparation method of crocetin amide GX-E according to claim 2, which is characterized in that the preparation method step
It is rapid 1) in organic amine compound be diethylamine.
4. the preparation method of crocetin amide GX-E according to claim 3, which is characterized in that the preparation method step
It is rapid 1) in the reaction time be preferably 4 hours.
5. the preparation method of crocetin amide GX-E according to claim 4, which is characterized in that the preparation method step
The molar ratio of rapid 1) crocetin and diethylamine is 1: 1-8.
6. the preparation method of crocetin amide GX-E according to claim 5, which is characterized in that the preparation method step
The molar ratio of rapid 1) crocetin and diethylamine is 1: 2.
7. the preparation method of crocetin amide GX-E according to claim 6, which is characterized in that the preparation method step
It is rapid 2) react in washing methods be：Successively with hydrochloric acid, sodium bicarbonate, water washing, wash 2-5 times respectively；
8. the preparation method of crocetin amide GX-E according to claim 7, which is characterized in that the preparation method step
It is rapid 2) react in washing methods be：Successively with hydrochloric acid, sodium bicarbonate, water washing, wash 3 times respectively；
9. the preparation method of crocetin amide GX-E according to claim 8, which is characterized in that the preparation method step
It is rapid 3) react in the method that elutes be：First use CHCl3Elution, then use CHCl3∶CH3OH=10: 1 is eluted.
10. crocetin amide GX-E according to claim 1 or the preparation according to any one of claim 2-9
The purposes of crocetin amide GX-E prepared by method in the drug for treating and preventing angiocardiopathy is prepared.
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| CN103724219A (en) * | 2012-10-15 | 2014-04-16 | 南京大学 | Crocetin amides derivative and preparation method and application thereof |
| CN104434785A (en) * | 2014-11-21 | 2015-03-25 | 威海诺达药业集团有限公司 | Crocetin salt injection and preparation process thereof |
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| CN103724219A (en) * | 2012-10-15 | 2014-04-16 | 南京大学 | Crocetin amides derivative and preparation method and application thereof |
| CN104434785A (en) * | 2014-11-21 | 2015-03-25 | 威海诺达药业集团有限公司 | Crocetin salt injection and preparation process thereof |
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