CN112500384B - Application of flavonoid sulfate in acidic condition - Google Patents
Application of flavonoid sulfate in acidic condition Download PDFInfo
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- CN112500384B CN112500384B CN202011419841.8A CN202011419841A CN112500384B CN 112500384 B CN112500384 B CN 112500384B CN 202011419841 A CN202011419841 A CN 202011419841A CN 112500384 B CN112500384 B CN 112500384B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
Abstract
The invention provides an application of flavonoid sulfate under an acidic condition, which comprises the steps of uniformly mixing flavonoid, dicyclohexylcarbodiimide and tetrabutylammonium bisulfate in proportion, adding a proper amount of cosolvent, standing, distilling under reduced pressure, fully removing the cosolvent, dissolving with a proper amount of methanol, and centrifugally filtering to obtain a methanol solution of the flavonoid sulfate tetrabutylammonium. Removing methanol in the obtained solution, redissolving the product with a small amount of methanol, centrifugally filtering, adding saturated solution of potassium acetate or sodium acetate in methanol into the filtrate, reacting to generate flavonoid compound potassium sulfate and tetrabutylammonium acetate, dissolving tetrabutylammonium acetate in methanol, and centrifugally filtering to obtain the flavonoid compound potassium (sodium) sulfate. The invention also provides application of the flavonoid sulfate in the field of hemostasis and coagulation under an acidic condition. The invention has simple synthesis process condition and lower cost, and the application under the acidic condition can provide a research and development direction for the preparation for treating traumatic hemorrhage or gastrointestinal tract hemorrhage.
Description
Technical Field
The invention relates to the field of biological medicine preparation research, in particular to application of flavonoid sulfate in acidic condition.
Background
The flavonoid compounds are formed by connecting two benzene rings (A ring and B ring) with phenolic hydroxyl groups with each other through a central three-carbon atom (C ring), namely a series of compounds taking C6-C3-C6 as a basic framework. Flavonoids are widely present in various tissues and organs of plants and are important secondary metabolites of plants. The flavonoid compounds which have been found at present are more than 10000, and are mainly classified into flavonoid, flavonols, flavanones (alcohols), isoflavones, chalcones, anthocyanidins, flavanols and the like according to the oxidation degree of a carbon chain of an intermediate C ring, whether the intermediate C ring forms a ring, the position (2-position or 3-position) of a connecting B ring and the like.
The flavonoid compounds have wide physiological activities, such as oxidation resistance, tumor resistance, cardiovascular disease resistance, bacteria resistance, virus resistance, digestive tract ulcer and inflammation inhibition, liver protection, depression resistance, aging resistance, diabetes resistance, osteoporosis resistance, neuroprotection, immunoregulation, fatigue resistance and the like, and have wide application in the fields of food, medicine and health care.
However, flavonoids have poor solubility and poor stability, and greatly limit the exertion of biological efficacy. Therefore, the flavonoid compound is structurally modified, the solubility and other performances of the flavonoid compound are improved, the biological activity of the flavonoid compound is improved, and the biological function of the flavonoid compound is increased, so that the flavonoid compound is an important way for developing and applying the flavonoid compound. The hydroxyl groups of the A ring and the B ring of the flavonoid compound can be subjected to esterification reaction under a certain condition to form the compounds such as sulfuric acid ester or phosphoric acid ester of the flavonoid compound, and the compounds are further reacted with NaCl, KCl, sodium acetate or potassium acetate and the like to form sodium (potassium) sulfate or sodium (potassium) phosphate of the flavonoid compound, so that the water solubility of the flavonoid compound is improved. Sulfate esters of flavonoids, such as luteolin-7-sulfate, are also present in plants, such as eclipta alba. The flavonoid compound is used as a substrate, and the sulfate of various flavonoid compounds can be efficiently obtained by adopting artificial synthesis. The flavonoid compound has the functions of dilating coronary blood vessel, inhibiting the aggregation of red blood cells and platelets and the activity of related thrombin, so that the flavonoid compound has the functions of anticoagulation and hemostasis. Studies show that both quercetin-7-sodium sulfate and quercetin-7, 4' -disodium disulfate have the ability of inhibiting platelet aggregation, which indicates that the sulfuric acid esters of flavonoids also have an anticoagulant effect.
In the process of researching the eclipta alba anticoagulant active ingredient, the pH value is found to have important influence on the anticoagulant activity of the extract (Chinese invention patent has been applied for by researches such as eclipta alba anticoagulant activity and the like, and patent application numbers are 201911322326.5 and 202010416759.3); further research shows that the main anticoagulant substance in eclipta is a yellow compound, and the main component of the main anticoagulant substance is luteolin-7-sulfate, which has strong direct agglutination erythrocyte activity under acidic conditions and can cause soluble fibrinogen to become insoluble floccules through separation and identification. We speculate that: the sulfate esters of other flavonoids may also have the activity to directly agglutinate erythrocytes and cause soluble fibrinogen to become insoluble floc under acidic conditions. The activity test shows that the sulfate salt of the flavonoid compounds can not agglutinate red blood cells under neutral or alkaline conditions and has no obvious flocculation effect on fibrinogen, but can directly agglutinate red blood cells under acidic conditions and lead the soluble fibrinogen to be changed into insoluble floccules, thus having anticoagulation activity. At present, no related report is found at home and abroad, and no related application is found.
Disclosure of Invention
The invention aims to further develop the biological functions and application range of flavonoid compounds, and provides a synthesis method of flavonoid compound sulfate, and the application of the flavonoid compound sulfate in the medical fields of hemostasis, coagulation and the like under the condition of the hydrochloride of the flavonoid compound sulfate.
The invention adopts the technical scheme that:
a method for synthesizing flavonoid sulfate comprises the following steps:
1) Uniformly mixing three substances according to the ratio of flavonoid compounds including dicyclohexylcarbodiimide, tetrabutylammonium bisulfate and 1-20:1-10 (molar ratio), adding a proper amount of cosolvent, reacting for 1-72 hours at 4-50 ℃, distilling under reduced pressure at 45-60 ℃, fully removing the cosolvent, dissolving with a proper amount of methanol, and centrifugally filtering to obtain a methanol solution of tetrabutylammonium bisulfate of flavonoid compounds;
2) Removing methanol in the obtained solution, redissolving the product with a small amount of methanol, centrifugally filtering, further removing a small amount of precipitated impurities, adding a saturated solution of potassium acetate or sodium acetate and methanol into the filtrate, reacting to generate flavonoid compound potassium sulfate or flavonoid compound sodium sulfate and tetrabutylammonium acetate, dissolving tetrabutylammonium acetate in methanol, centrifugally filtering, and washing the precipitate with methanol to obtain the flavonoid compound potassium sulfate or flavonoid compound sodium sulfate.
In the step 1), the cosolvent is pyridine.
The method for removing the methanol in the step 2) is as follows: and removing the methanol through decompression and distillation under the condition of 45-60 ℃.
In the step 2), the obtained flavonoid compound sulfate salt is flavonoid compound potassium sulfate or flavonoid compound sodium sulfate.
In the step 2), the conversion rate of the obtained flavonoid sulfate is 70-96%.
Application of flavonoids sulfate in hemostasis and coagulation under acidic condition is provided.
The acidic condition is one or more of tartaric acid, citric acid, oxalic acid, malic acid, succinic acid, malonic acid, ascorbic acid and maleic acid.
The hemostatic and blood coagulation fields comprise the fields of medicines, medical treatment, sanitary materials and medical instruments.
The invention has the technical effects that:
1. the purified flavonoid sulfate has the function of stopping blood coagulation under the acidic condition, and provides a definite direction and a wide space for developing a high-efficiency low-toxicity therapeutic preparation for traumatic hemorrhage or gastrointestinal tract hemorrhage.
2. The synthesis process condition of flavonoid sulfate is simple, the content of a plurality of flavonoid compounds in plants is extremely high, the price is low, and even the flavonoid compounds can be produced by microbial fermentation, so the invention has great production potential when being applied to the preparation for treating traumatic hemorrhage or gastrointestinal tract hemorrhage.
Drawings
FIG. 1 aggregation of erythrocytes by potassium sulfate mixtures of flavonoids. Wherein a is a luteolin sulfate potassium salt mixture, b is a quercetin sulfate potassium salt mixture, c is a dihydroquercetin sulfate potassium salt compound, d is a apigenin sulfate potassium salt mixture, e is a myricetin sulfate potassium salt mixture, f is a dihydromyricetin sulfate potassium salt mixture, g is a kaempferol sulfate potassium salt mixture, and h is a baicalein sulfate potassium salt compound.
FIG. 2 shows the aggregation of erythrocytes by a portion of potassium 7-sulfate and dipotassium 7, 4' -disulfate. Wherein a is luteolin-7-potassium sulfate, b is luteolin-7, 4 '-dipotassium disulfate, c is quercetin-7, 4' -dipotassium disulfate, d is dihydroquercetin-7, 4 '-dipotassium disulfate, e is apigenin-7-potassium sulfate, f is apigenin-7, 4' -dipotassium disulfate, g is myricetin-7, 4 '-dipotassium disulfate, h is kaempferol-7-potassium sulfate, i is kaempferol-7, 4' -dipotassium disulfate.
FIG. 3 flocculation of human fibrinogen by a mixture of flavonoids sulfate. Wherein a is a luteolin sulfate potassium salt mixture, b is a quercetin sulfate potassium salt mixture, c is a dihydroquercetin sulfate potassium salt compound, d is a apigenin sulfate potassium salt mixture, e is a myricetin sulfate potassium salt mixture, f is a dihydromyricetin sulfate potassium salt mixture, g is a kaempferol sulfate potassium salt mixture, and h is a baicalein sulfate potassium salt compound.
FIG. 4 flocculation of human fibrinogen by some of the flavonoid potassium-7-sulfate and flavonoid dipotassium-7, 4' -disulfate. Wherein a is luteolin-7-potassium sulfate, b is luteolin-7, 4 ' -dipotassium disulfate, c is apigenin-7-potassium sulfate, d is apigenin-7, 4 ' -dipotassium disulfate, e is quercetin-7, 4 ' -dipotassium disulfate, f is kaempferol-7-potassium sulfate, g is kaempferol-7, 4 ' -dipotassium disulfate, and h is myricetin-7, 4 ' -dipotassium disulfate.
Description of the embodiments
The present invention will be further clearly and completely illustrated by the following examples.
Examples
The synthesis of the sulfate salt of flavonoids is carried out as follows:
uniformly mixing three substances according to the ratio of flavonoid compounds, namely Dicyclohexylcarbodiimide (DCC), namely Tetrabutylammonium Bisulfate (TBAHS) =1:1-20:1-10 (molar ratio), adding a proper amount of pyridine to dissolve the three substances, reacting for 1-72 hours at 4-50 ℃, performing reduced pressure distillation at 45-60 ℃, fully removing pyridine, dissolving with a proper amount of methanol, performing centrifugal filtration to obtain a methanol solution of the tetrabutylammonium bisulfate of the flavonoid compounds, performing reduced pressure distillation at 45-60 ℃ to remove methanol, re-dissolving the product with a small amount of methanol, performing centrifugal filtration, further removing a small amount of precipitated impurities, adding potassium acetate or sodium acetate methanol saturated solution into the filtrate, reacting to generate potassium sulfate of the flavonoid compounds or sodium sulfate of the flavonoid compounds and tetrabutylammonium acetate, performing centrifugal filtration after dissolving tetrabutylammonium acetate in methanol, and washing the precipitate with methanol to obtain the product potassium sulfate of the flavonoid compounds or sodium sulfate of the flavonoid compounds.
Examples
The separation and identification of the monomer compounds of flavonoid compound-7-sulfate and flavonoid compound-7, 4' -disulfate comprise the following test procedures:
separating the flavonoid compound potassium sulfate or the flavonoid compound sodium sulfate mixture obtained in the example 1 by adopting reverse phase medium pressure liquid chromatography under the elution condition that deionized water is methanol=1:0- … -0:1, detecting the wavelength 254 nm, collecting corresponding components according to an absorption peak to obtain the flavonoid compound-7-potassium sulfate (or sodium) and the flavonoid compound-7, 4' -dipotassium disulfate (or sodium), and carrying out structural identification by adopting mass spectrum and nuclear magnetic resonance data.
Examples
The flavonoid sulfate has agglutination activity on red blood cells under acidic condition, and the test process is as follows:
collecting venous blood of healthy human body by vacuum hemostix (containing anticoagulant sodium citrate), diluting 50 times with 0.9% sterile physiological saline, mixing the mixture of flavonoid sulfate salt in example 1, flavonoid potassium (or sodium) 7-sulfate and flavonoid dipotassium (or sodium) 7, 4' -disulfate monomer in example 2, preparing into sample solution with certain concentration by deionized water, 1 μl of sample solution (blank group uses 1 μl physiological saline instead of sample solution), 1 μl of tartaric acid solution (0.005M) and 3 μl of diluted blood, mixing uniformly on clean glass slide (coating area is 1 cm) 2 ) Immediately photographed under an optical microscope, the number of free and agglutinated erythrocytes was counted, and 3 replicates were made for each concentration, each replicate being taken at random 10 fields. The same concentration of Yunnan white drug powder (product batch number ZFA 1615) is used as a drug control group. The formula is adopted for calculation: erythrocyte agglutination rate = 100× (1-a t /A c ) Wherein A is t For the number of free erythrocytes in the test group, A c Red blood cell number for the blank control group.
The test results show that the mixture of the flavonoid sulfate salts in the example 1, the flavonoid potassium-7-sulfate salt in the example 2 and the flavonoid dipotassium-7, 4' -disulfate have no agglutination on erythrocytes under the neutral condition without adding acid.
But has good agglutination activity on red blood cells under the acidic condition after acid addition, wherein the agglutination rate of part of potassium sulfate of flavonoid compounds on red blood cells reaches more than 95% at the concentration of 0.2 mg/ml (see figure 1 and figure 2). In addition, the different flavonoid sulfate salts have different activities of agglutinating red blood cells, wherein the mixture of glycyrrhizin and daidzein sulfate potassium salt has weak activity of agglutinating red blood cells, and the agglutination rate of the mixture of glycyrrhizin and daidzein sulfate potassium salt to red blood cells is less than 90% at 2.4 mg/ml, but the agglutination rate of daidzein-7-sulfate potassium salt and daidzein-7, 4' -disulfate dipotassium salt to red blood cells is more than 90% at the concentration of 0.8 mg/ml. After the yunnan white drug is added to the blood cell suspension, no blood cell agglutination is seen and red blood cells are rapidly ruptured whether or not the blood cell suspension is in an acidic condition.
Examples
The flocculation of fibrinogen by flavonoid sulfate under acidic conditions is tested as follows:
the fibrinogen preparation (Boya Biochemical Co., ltd., approval mark: national drug standard S20013006) 278 mg was weighed and dissolved in 58 ml physiological saline. 10 μl samples of flavonoid potassium sulfate (3.6, 7.2, 10.8, 14.4, 18 mg/ml, prepared with physiological saline; final concentrations of 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5 mg/ml after mixing with fibrinogen etc., 10 μl physiological saline instead of the blank, the same concentration of Yunnan white drug as drug control), 100 μl of tartaric acid solution of 0.003M (the non-acid sample test group and the blank were replaced with equal volumes of physiological saline) and 250 μl of fibrinogen solution were added into a 1.5 ml centrifuge tube, heated in a water bath at 36℃for 5 min, centrifuged for 1 min under 7817 g, 50 μl of supernatant was taken, 1.65 ml coom developer was added for color development, and absorbance was measured at 595 (zeroing with corresponding reference) under nm.
Blank control group reference: 360 μl of physiological saline was added to the 1.5 ml centrifuge tube; heating in water bath at 36 deg.C for 5 min, centrifuging under 7817 and g conditions for 1 min, taking 50 μl, adding 1.65 ml Coomassie Brilliant blue, and mixing uniformly to obtain reference group.
Acid sample reference: 250 μl of physiological saline, 10 μl of sample solution and 100 μl of tartaric acid solution are added into a 1.5 ml centrifuge tube, heated in a water bath at 36 ℃ for 5 min, centrifuged for 1 min under the condition of 7817 g, 50 μl is taken, 1.65 ml Coomassie brilliant blue is added, and the mixture is mixed uniformly to serve as a reference for an acid sample.
Acid-free sample reference: adding 350 μl of physiological saline and 10 μl of sample solution into a 1.5 ml centrifuge tube, heating in water bath at 36 deg.C for 5 min, centrifuging for 1 min under 7817 g condition, collecting 50 μl, adding 1.65 ml Coomassie brilliant blue color-developing agent for color development, and mixing uniformly to obtain an acid-free sample reference.
Fibrinogen flocculation rate calculation: fibrinogen flocculation rate (%) =100× (1-a t /A c ) Wherein A is t For test group absorbance, ac is blank absorbance.
The test results show that the sulfate salt mixture or monomer compound of the tested flavonoid compound has no flocculation or weak flocculation (generally less than 20%) on fibrinogen under the neutral condition without adding acid; but can lead to extremely obvious flocculation of fibrinogen under acidic conditions, and partial compounds can lead more than 90 percent of fibrinogen to form flocculent precipitate at the concentration of 0.3-0.5 mg/ml (figures 3 and 4), even a large amount of flocculent is formed when a sample, an acid solution and the fibrinogen are mixed.
Meanwhile, the flocculation of the synthetic products of different flavonoid compounds to fibrinogen is different, the flocculation of daidzein and glycyrrhizin to fibrinogen is weakest, and the flocculation rate is less than 80% at the concentration of 2.4 mg/ml; the same amount of tartaric acid and fibrinogen alone mixed does not cause flocculation of fibrinogen even after heating in a water bath, and the fibrinogen is still in a dissolved state, and the protein content of the solution is unchanged. This demonstrates that the sulfate salt of flavonoids is effective in acidic conditions to cause conversion of fibrinogen to insoluble proteins, thereby promoting anticoagulant activity. The Yunnan white drug powder has no flocculation to fibrinogen under neutral or acidic conditions.
The above experiments show that the flavonoid sulfate can stop coagulation at least through 2 ways under acidic conditions, has great potential in the development of therapeutic preparations for traumatic hemorrhage or gastrointestinal tract hemorrhage, and has direct procoagulant hemostatic effect in the gastrointestinal tract due to the fact that the gastrointestinal tract is an acidic environment.
Combinations not illustrated above, if apparent to those skilled in the art with reference to the present invention, are within the scope of the present invention.
Claims (2)
1. The application of flavonoid sulfate in preparing hemostatic, clotting medicaments or medical and health materials under acidic conditions, and the synthesis method of the flavonoid sulfate comprises the following steps:
1) Uniformly mixing three substances according to the ratio of flavonoid compounds, namely dicyclohexylcarbodiimide, namely tetrabutylammonium bisulfate=1:1-20:1-10, adding a proper amount of cosolvent pyridine, reacting for 1-72 hours at 4-50 ℃, performing reduced pressure distillation at 45-60 ℃, fully removing the cosolvent, dissolving with a proper amount of methanol, and centrifugally filtering to obtain a methanol solution of the flavonoid compounds, namely tetrabutylammonium sulfate;
2) Removing methanol in the solution obtained in the step 1), redissolving the product by using a small amount of methanol, centrifugally filtering, further removing a small amount of precipitated impurities, adding potassium acetate or sodium acetate methanol saturated solution into the filtrate, reacting to generate flavonoid compound potassium sulfate and tetrabutylammonium acetate, dissolving tetrabutylammonium acetate in methanol, centrifugally filtering, and washing the precipitate by using methanol to obtain the flavonoid compound potassium sulfate or flavonoid compound sodium sulfate;
the flavonoid sulfate salt is as follows: luteolin sulfate potassium salt, apigenin sulfate potassium salt, quercetin sulfate potassium salt, dihydroquercetin sulfate potassium salt, myricetin sulfate potassium salt, dihydromyricetin sulfate potassium salt, kaempferol sulfate potassium salt, and baicalein sulfate potassium salt.
2. The use of the sulfate salt of flavonoid according to claim 1 in the preparation of hemostatic, coagulogenic or medical and health materials under acidic conditions, wherein the acidic conditions are the addition of one or more of tartaric acid, citric acid, oxalic acid, malic acid, succinic acid, malonic acid, ascorbic acid and maleic acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB704516A (en) * | 1951-07-12 | 1954-02-24 | Roche Products Ltd | A blood anticoagulating agent and process for the manufacture thereof |
| WO2012068539A1 (en) * | 2010-11-19 | 2012-05-24 | Limerick Biopharma, Inc. | Use and composition of quercetin-3'-o-sulfate for therapeutic treatment |
| CN110934899A (en) * | 2019-12-20 | 2020-03-31 | 九江学院 | Extraction method and application of blood coagulation and hemostasis active ingredients of eclipta alba |
-
2020
- 2020-12-07 CN CN202011419841.8A patent/CN112500384B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB704516A (en) * | 1951-07-12 | 1954-02-24 | Roche Products Ltd | A blood anticoagulating agent and process for the manufacture thereof |
| WO2012068539A1 (en) * | 2010-11-19 | 2012-05-24 | Limerick Biopharma, Inc. | Use and composition of quercetin-3'-o-sulfate for therapeutic treatment |
| CN110934899A (en) * | 2019-12-20 | 2020-03-31 | 九江学院 | Extraction method and application of blood coagulation and hemostasis active ingredients of eclipta alba |
Non-Patent Citations (2)
| Title |
|---|
| Denis Barron等.Synthesis of flavonoid sulfates:1.Stepwise sulfation of positions 3,7, and 4' using N,N'-dicyclohexylcarbodiimide and tetrabutylammonium hydrogen sulfate.《Tecrrohedron》.1987,第第43卷卷(第第43卷期),第5197- 5202页，results 第1-2段，第5201页scheme2. * |
| 彭游等.槲皮素化学修饰与体内转运过程研究进展.《天然产物研究与开发》.2012,第398-405页. * |
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