CN101121662A - Chlorogenic acid ester derivative, preparation method and application thereof in pharmaceutical preparation - Google Patents
Chlorogenic acid ester derivative, preparation method and application thereof in pharmaceutical preparation Download PDFInfo
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Abstract
The invention is a preparation method for chlorogenic ester derivative and the application of the method in the drug preparation. The structure of the chlorogenic ester derivative is shown in diagram (I). the compounds of raw materials of the chlorogenic acid is dissolved in the organic solvent; with the protection of the inert gas and the temperature below 0 Celsius system, the acylating reagent is stired and dropped; after the dropping, the temperature naturally rises to the room temperature, and the material is stired for the esterification; the reactive solvent and water-soluble and / or volatile by-product produced in the reaction are removed; after the compression, the derivatives can be acquired. The chlorogenic ester derivative can not only be used in the preparation of the relevant medicine with the effect of protecting the liver and the function of the immune regulation basically similar to the chlorogenic acid, but also has better chemical stability, facilitating the preparation, storage of the raw materials and the production of the preparation reagents; the chlorogenic ester derivative is conducive to the control of the vivo absorption and distribution, and improves the vivo bioavailability.
Description
Technical field
The present invention relates to a kind of derivative, preparation method and the application in medication preparation thereof of chlorogenic acid.
Background technology
Chlorogenic acid (chlorogenic acid) is that a kind of leaf from dicotyledons (as Folium Lonicerae, coffee berry, Sunflower Receptacle etc.) separates the phenolic compound that obtains with fruit, extensively be present in various medicinal plants such as the Japanese Honeysuckle etc., also be many herbal medicine (as the bark of eucommia, Japanese Honeysuckle, oriental wormwood etc.) and compound Chinese medicinal preparation antisepsis and anti-inflammation, clearing heat and detoxicating main active ingredient, become one of leading indicator of Chinese herbal and crude drugs preparations quality control at present.Chlorogenic acid is a kind of phenylpropyl alcohol chlorins compound that plant materials produces through shikimic acid pathway in the aerobic repiration process, be a kind of by coffic acid (caffeic acid) and quinic acid (quinovic acid, quinic acid, be 1-hydroxyl six hydrogen gallic acids) depside that forms of condensation, the different name caffeotannic acid, chemical name is 3-O-caffetannic acid (3-O-caffeoylquinic acid), and chemical formula is C
16H
18O
9, structure is suc as formula shown in (II), its semihydrate is a needle-like crystal, the time become anhydrous compound, soluble in water, ethanol, acetone are slightly soluble in ethyl acetate, are faint yellow solid under the normal temperature.
The chlorogenic acid Pharmacological action study is had comprising of bibliographical information at present:
1, to the restraining effect of Unidasa and G-6-Pase: wydase (HAase) is one of enzyme of cracking mucopolysaccharide, but the decomposition of catalysis hyaluronic acid (HA) is related to the permeability and the inflammatory reaction of vascular system.A kind of mucopolysaccharide that HA is made up of uronic acid and acetylglucosamine has multiple function, as curing wound, makes skin moisturizing health, lubricates the joint and prevents inflammation etc.Find 3 from the ethyl acetate extract of echinacea angustifolia (Echinacea amgustifolia DC) root, 5-cynarin (anghirol) and chlorogenic acid have stronger inhibition HAase activated effect.Animal is intravital to be studies have shown that, uses chlorogenic acid can reduce by (the glycogen decomposition causes) the hyperglycemia peak value that uses hyperglycemic-glycogenolytic factor to cause.Therefore, chlorogenic acid can the lowering blood glucose level, improves the concentration of liver glucose-6-phosphoric acid and liver starch.
2, the removing of free radical and lipoid peroxidization resistant: chlorogenic acid suppresses lipoxidase activity in the prostaglandin metabolism; suppress the oxidation of vitamin A; protection suprarenin is avoided oxidation; vitamin antagonist A acid (retinoic acid) 5; the epoxidised biological activity of 6-, methyl chlorogenate and cynarin can suppress plastosome and foundation of microsomal Lipid Peroxidation.Chlorogenic acid and 3, the 5-cynarin belongs to micromolecular compound, can with the peroxy radical rapid reaction, so they are potential important biological anti-oxidants.Its possible anti-oxidant mechanism is: pyrocatechol (catechols) part is accepted the hydrogen atom donor as peroxy radical, changes into the low activity product then.But so their terminating chain free radical reactions.
3, anticancer change effect: chlorogenic acid is a kind of important substance in the plant metabolism, also is the inhibitor of short phorbol ester active tumour.The different originality compositions of resistance such as the contained chlorogenic acid of the variation originality restraining effect (Antimutagenicity) that recent Japanese scholar has studied bark of eucommia tea and Folium Eucommiae, Geniposide, Geniposidic acid are relevant, and it is significant to the prevention of tumour to have disclosed bark of eucommia tea.
4, preventing cardiovascular disease: chlorogenic acid is a kind of main phenolic compound in the coffee.Daily people's daily intake of quoting coffee is 0.5-1g.Chlorogenic acid and coffic acid external be antioxidant, therefore may effect be arranged to preventing cardiovascular disease.
5, antibiotic, antivirus action: chlorogenic acid and isochlorogenic acid have stronger inhibition and a killing action to various pathogens and virus, also have cholagogic, step-down, anti-inflammatory and significantly increase gastrointestinal peristalsis and promote pharmacological actions such as gastric secretion.
Have with the report of chlorogenic acid as the related drugs of effective constituent preparation: it is the medicine that feedstock production becomes pharmaceutically to can be applicable to clinical various formulations with the high-purity chlorogenic acid that Chinese patent CN 200410022438.6 discloses a kind of, and employing content is that the chlorogenic acid of 95%-105% is made various injection liquids, aseptic powder injection, various tablet, capsule, oral liquid, eye drop, ointment, the various sustained-release preparation that contains 1mg-3g.Application number be CN 02829404.1 disclose a kind of compound chlorogenic acid that is separated to from betel leaf extract or other source in treatment new purposes acute and chronic granulocytic leukemia and the Lymphocytic leukemia, and contain being used for the treatment of of chlorogenic acid and pharmaceutically acceptable additive acute and chronic granulocytic leukemia and the pharmaceutical composition of Lymphocytic leukemia, the chlorogenic acid (CA) and/or 3-o-p-coumaroyl guinic acid (PCQ) and the pharmaceutically acceptable additive that comprise significant quantity.Leukemia is the grain system cells paraplasm of marrow and a kind of malignant tumour of causing, shows that chlorogenic acid can be by suppressing leukocytic hyperplasia, thereby is the effect that leukemia on the ordinary meaning has treatment to acute and chronic myelocytic leukemia.Publication number is to disclose the rare acyl quininic acid of class phenylpropyl alcohol ester derivative (being chlorogenic acid), preparation method in the Chinese patent literature of CN 1552690A and comprised purposes in the virus disease of SARS in treatment, prevention.
Because chlorogenic acid is a kind of polyphenolic compound, under alkaline condition, has good water-solubility, but owing to have polyphenol group and ethylene linkage in the structure, unstable chemcial property, see the auroral poles easy oxidation discoloration, this brings sizable difficulty and problem to many-sides such as its preparation as medicine material, preservation and preparation productions.On the other hand, extensively distribute in vivo after the chlorogenic acid administration, lack target and be difficult to control, make that the drug level that arrives the sufferer tissue is relatively low, bioavailability is low in the body, necessary escalated dose can cause corresponding toxic side effect to increase the weight of to satisfy necessary treatment concentration thus during treatment, causes untoward reaction.
Summary of the invention
In view of the foregoing, the present invention's purpose at first provides a kind of ester derivative of chlorogenic acid, makes it can have more stable chemical property, to make things convenient for it as preparation, preservation and the preparation production that will use raw material.On this basis, further aim of the present invention provides the preparation method of said this chlorogenic acid ester derivative.A further object of the present invention provides the application of said this chlorogenic acid ester derivative in medication preparation, the particularly application in the medication preparation aspect having function of protecting the liver and immunoregulation effect.
The said chlorogenic acid ester derivative of the present invention is the derivative of a kind of structure suc as formula the fatty acid ester of the 3-O-caffetannic acid shown in (I).
Wherein: the R in the formula is C
1-18Acyl group, R
1, R
2, R
3, R
4Be respectively H or C
1-18Acyl group, particularly R, R
1, R
2, R
3, R
4Be respectively C
2-12Acyl group; M is H, or comprises as Na, K, NH
4, Mg, Ca etc. are at interior monovalence commonly used or divalent-metal ion.
In the compound of the above-mentioned formula of the present invention (I) structure, particularly R wherein is said acyl group, R
1, R
2, R
3, R
4Be 3-O-caffeoylquinic acids-1-ester compound of H, R, R
3, R
4Be said acyl group, R
1, R
2For the 3-O-caffeoylquinic acids-1,3 of H ', 4 '-three ester compounds and, R, R
1, R
2, R
3, R
4Be the 3-O-caffeoylquinic acids-1,4 of said acyl group, 5,3 ', 4 '-the five-ester compounds.
In the chlorogenic acid ester derivative of the above-mentioned form of the present invention, because the active-OH in the structure has changed into ester group, can improve its chemical stability greatly, comprise oxidation-resistance and acid-proof alkaline, the production and the stability of medicine between the shelf lives that help its preparation as the active constituents of medicine raw material, preservation and preparation process help to guarantee to enter intravital effective active component content and functioning efficiency.Simultaneously, the corresponding increase of ester dissolubility of this derivative after esterification, the prolongation of effective acting time in vivo when also helping it as active constituents of medicine, improved the long-lasting of medicine, and help it and move to the sufferer tissue, and then hydrolysis goes out a large amount of chlorogenic acid performance pharmacological agent effects gradually, has improved its target in some histoorgan.
The preparation of the chlorogenic acid ester derivative of the above-mentioned formula of the present invention (I) structure formation; corresponding chlorogenic acid or the starting compound that has a corresponding protecting group can be dissolved in the organic solvent; in protection of inert gas commonly used such as nitrogen be lower than under 0 ℃ and the agitation condition, slowly drip acylating reagents commonly used such as carboxylic acid halides, acid anhydrides.After dripping, can rise to room temperature naturally and stir and carry out esterification, remove the water-soluble and/or volatile byproducts that reaction solvent and reaction produce, obtain said product after concentrating.
In above-mentioned preparation method; if what use is carboxylic acid halides class acylating reagent; be to guarantee carrying out smoothly of esterification, in the organic solution of the starting compound of said dissolving chlorogenic acid, can also use alkaline components as inorganic or organic class commonly used such as yellow soda ash, piperidines.
After having used said alkaline components, in reaction process, can produce the by product composition of corresponding inorganic salt or organic salt.Therefore after esterification is finished, can by as filter, place the medium mode of frozen water that it is removed from product mixtures.This step operation preferably also is to carry out under the protection as rare gas elementes such as nitrogen commonly used.
Saidly remove reaction solvent and/or volatile byproducts, and/or spissated operation, carry out to good in the mode that adopts underpressure distillation.
With the chlorogenic acid ester derivative of the above-mentioned formula of the present invention (I) structure as the active drug activeconstituents, with acceptable subsidiary material in the pharmacy, pharmaceutical preparation mode according to present routine, promptly can prepare and wherein can comprise especially for the corresponding preparations form medicine of clinical use as having medicines such as liver-protecting efficacy and immunoregulation effect.For example, with effective medicinal ingredients of above-mentioned composition form, auxiliary added ingredients combination such as corresponding pharmaceutical excipient with acceptable in the medicine or carrier, and, can become the pharmaceutical preparation of corresponding oral type or injection-type by corresponding pharmaceutical methods processing.As, oral property pharmaceutical preparations such as tablet, controlled release agent, dripping pill, granule, capsule, micropill, or, can also become as injection-type pharmaceutical preparations such as powder pin, liquid drugs injections as the pharmaceutical preparation of external application forms such as sprays, nasal drop.For example, with the chlorogenic acid ester derivative of formula (I) structure as the active drug activeconstituents, with can received weighting agent in oral preparations, after auxiliary interpolation composition that tamanori, disintegrating agent, lubricant etc. are commonly used mixes, routinely corresponding preparations processing method is handled, and can prepare the oral pharmaceutical of the solid preparation forms such as sustained release dosage, control-released agent of corresponding tablet, pill, granule, capsule or appropriate form.Wherein, said weighting agent can be just like starch, dextrin, Icing Sugar, pregelatinized Starch, lactose, glucose, Microcrystalline Cellulose, lime carbonate, calcium sulfate, Calcium hydrogen carbonate etc.; Said tamanori can be just like hypromellose, polyvidone, starch slurry, dextrin slurry, syrup, rubber cement, sodium alginate, polyoxyethylene glycol, peach gum, gum arabic etc.; Said disintegrating agent can be just like croscarmellose sodium, polyvinylpolypyrrolidone, sodium starch glycolate, hydroxypropylated starch, low-substituted hydroxypropyl cellulose citric acid, tartrate, acid anhydrides, sodium bicarbonate, yellow soda ash.Said lubricant can be just like Magnesium Stearate (sodium), talcum powder, micropowder silica gel, whiteruss, polyoxyethylene glycol etc.During preparation soft gelatin pharmaceutical preparation, used substrate material can be just like vegetables oil (salad oil, Viscotrol C, hydrogenated soybean oil), polyoxyethylene glycol (300,400,6000) etc.; Used antioxidant can be just like S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine, xitix, halfcystine, butyl hydroxy anisol, two fourth cresylol, vitamin-E) etc.When preparing oral sustained-release preparation, used retarding agent can be just like beeswax, carnauba wax, hydrogenated vegetable oil, stearyl alcohol, glyceryl monostearate, cellulose acetate phthalate, L-or S-acrylic resin, hypromellose phthalate, acetic acid hypromellose succinate, methylcellulose gum, Xylo-Mucine, hypromellose, polyvidone, carbopol, sodium alginate, chitosan, ethyl cellulose, polymethacrylate, non-toxic polyvinyl chloride, polyethylene, ethylene-vinyl acetate copolymer, silicon rubber etc.; Used thickening material can be just like gelatin, polyvidone, Xylo-Mucine, polyvinyl alcohol, dextran.
Embodiment by the following examples is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Embodiment
The preparation of embodiment 1 3-caffeoylquinic acids-1-acetic ester
3-caffeoyl-quininic acid 10mmol is dissolved in 10ml acetone, adds an amount of phosphoric acid, expense is 24 hours at normal temperatures, and solvent is deviate from underpressure distillation, gets 3-caffeoyl-4,5-O-isopropylidene quininic acid.With this 3-caffeoyl-4,5-O-isopropylidene quininic acid 10mmol, solid sodium carbonate 30mmol; 40ml THF joins in the round-bottomed flask of 100ml; the reaction system nitrogen protection is cooled to below 0 ℃, slowly drips acetate acyl chlorides 15mmol; naturally be warming up to room temperature then; reaction is spent the night, and removes by filter hydrochloride, and concentrating under reduced pressure is removed THF; to concentrate oily matter adds in the 20g frozen water; stirring reaction is 24 hours under nitrogen protection, removes protecting group, activated carbon decolorizing 20min; filter; be concentrated into about 10ml, product is dissolved among the THF, and employing silica gel is stationary phase; the THF/ acetonitrile is that the mode of moving phase is separated purification, gets 3-caffeoylquinic acids-1-acetic ester.
Embodiment 2 3-caffeoylquinic acids-1,3 ', the preparation of 4 ' triacetate
The 3-caffeoyl-4 that will obtain by embodiment 1 mode, 5-O-isopropylidene quininic acid 10mmol, solid sodium carbonate 60mmol; 50ml THF joins in the round-bottomed flask of 100ml; the reaction system nitrogen protection is cooled to below 0 ℃, slowly drips acetate acyl chlorides 35mmol; naturally be warming up to room temperature then; reaction is spent the night, and removes by filter hydrochloride, and concentrating under reduced pressure is removed THF; to concentrate oily matter adds in the 20g frozen water; stirring reaction is 24 hours under nitrogen protection, removes protecting group, activated carbon decolorizing 20min; filter; concentrate, 3-caffeoylquinic acids-1,3 '; 4 '-the triacetate crude product, adopt the chromatographic separation mode of embodiment 1 to obtain pure product.
Embodiment 3 3-caffeoylquinic acids-1,4,5,3 ', 4 '-pentaacetate synthetic
3-caffeoylquinic acids 10mmol is dissolved in the 10ml acetone, adds diacetyl oxide 25ml, nitrogen protection in the round-bottomed flask of 100ml; be cooled to below 0 ℃, slowly drip the acetone soln of 3-caffeoylquinic acids, be warming up to room temperature then naturally; reaction is spent the night; dense acetone, excessive acetic anhydride via and the acetate removed of high vacuum decompression gets 3-caffeoylquinic acids-1,4; 5; 3 ', 4 '-the pentaacetate solid, with acetone handle product.
Embodiment 4 3-caffeoylquinic acids-1,3 ', 4 '-tripalmitate synthetic
The 3-caffeoyl-4 that will obtain by embodiment 1 mode, 5-O-isopropylidene quininic acid 10mmol, solid sodium carbonate 50mmol; 50ml THF joins in the round-bottomed flask of 100ml; the reaction system nitrogen protection is cooled to below 0 ℃, slowly drips the THF solution 40mmol of palmitic acid chloride; naturally be warming up to room temperature after 2 hours; reaction is spent the night, and removes by filter hydrochloride, and concentrating under reduced pressure falls THF; to concentrate oily matter adds in the 20g frozen water; stirring reaction is 24 hours under nitrogen protection, removes protecting group, activated carbon decolorizing 20min; filter; concentrate, 3-caffeoylquinic acids-1,3 '; 4 '-the cetylate crude product, adopt the chromatographic separation mode of embodiment 1 to obtain pure product.
Embodiment 5 3-caffeoylquinic acids-1,4,5,3 ', 4 '-five cetylates synthetic
With 3-caffeoylquinic acids 10mmol; 50mlTHF joins in the round-bottomed flask of 250ml; add a certain amount of piperidines; the reaction system nitrogen protection; be cooled to below 0 ℃, slowly drip the THF solution 90mmol of palmitic acid chloride, keep 0 ℃ of reaction 2 hours; naturally be warming up to room temperature then, spend the night.Filter, concentrating under reduced pressure is removed volatile organic matters such as THF, 3-caffeoylquinic acids-1,3 ', 4 '-the tripalmitate crude product, adopt the chromatographic separation mode of embodiment 1 to obtain pure product
Embodiment 6 contains 0.9% sodium-chlor intravenous fluid of 3-caffeoylquinic acids-1-acetic ester
Prescription one:
3-caffeoylquinic acids-1-acetic ester 1g
Citric Acid 1.0g
Sodium Citrate 0.5g
Sodium-chlor 18g
Water for injection 2000ml
Make 1000 of the injections of 2ml altogether by the routine operation of injection, every contains
1 milligram of 3-caffeoylquinic acids-1-acetic ester
Prescription two:
3-caffeoylquinic acids-1-acetic ester 3000g
Sodium-chlor 4500g
Water for injection 500,000ml
Make 1000 bottles of the injections of 500ml altogether by the routine operation of injection, every bottle contains 3-caffeoylquinic acids-1-acetic ester 3 grams.
Prevent 3-caffeoylquinic acids-esterolytic stablizer of 1-acetate: as cyclodextrin inclusion compound, tensio-active agent (Pu Lulangnike).
Antioxidant: S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine, xitix, halfcystine.
Physiology available pH value conditioning agent: L-glutamic acid, L-aspartic acid, xitix, hydrochloric acid, acetic acid.
The sterile powder injection of embodiment 7 sodium chloride-containing
Prescription one:
3-caffeoylquinic acids-1,3 ', 4 ' triacetate 1g
Sodium-chlor aseptic powder 18g
Make 1000 of 2ml powder injection altogether by the routine operation of sterile powder injection, every contains 1 milligram of chlorogenic acid
Prescription two:
3-caffeoylquinic acids-1,3 ', 4 ' triacetate aseptic powder 3000g
Sodium-chlor aseptic powder 45g
Make 1000 of 5ml powder injection altogether by the routine operation of sterile powder injection, every contains chlorogenic acid 3 grams
Prescription three～four: respectively each composition of writing out a prescription among the embodiment 1 is made the aseptic freeze-dried powder injection of 3-caffeoylquinic acids-1-acetic ester sodium-chlor through the freeze-drier lyophilize.
Embodiment 83-caffeoylquinic acids-1,3 ', 4 '-5% glucose injection liquid in use for intravenous injection of tripalmitate
Prescription one:
3-caffeoylquinic acids-1,3 ', 4 '-tripalmitate 2g
Citric Acid 1.0g
Sodium Citrate 0.5g
Glucose 100g
Water for injection 2000ml
Make 1000 of the injections of 2ml altogether by the routine operation of injection, every contain 3-caffeoylquinic acids-1,3 ', 4 '-2 milligrams of tripalmitates
Prescription two:
3-caffeoylquinic acids-1,3 ', 4 '-tripalmitate 1500g
Glucose 1000g
Water for injection 20,000ml
Make 1000 of the injections of 20ml altogether by the routine operation of injection, every contains 3-caffeoylquinic acids-1,3 ', 4 '-tripalmitate, 1.5 grams
Prescription three:
3-caffeoylquinic acids-1,3 ', 4 '-tripalmitate 3000g
Glucose 50,000g
Water for injection 1,000,000ml
Make 1000 bottles of the injections of 1000ml altogether by the routine operation of injection, every bottle contain 3-caffeoylquinic acids-1,3 ', 4 '-tripalmitate 3 grams
3-caffeoylquinic acids-1,3 ', 4 '-purity of tripalmitate is greater than 95%.
Prevent 3-caffeoylquinic acids-1,3 ', 4 '-stablizer of tripalmitate hydrolysis: as cyclodextrin inclusion compound, tensio-active agent (Pu Lulangnike).
Antioxidant: S-WAT, sodium bisulfite, Sodium Pyrosulfite, Sulfothiorine, xitix, halfcystine.
Physiology available pH value conditioning agent: L-glutamic acid, L-aspartic acid, xitix, hydrochloric acid, acetic acid.
Embodiment 93-caffeoylquinic acids-1,4,5,3 ', 4 '-five cetylate tablets
Prescription one:
3-caffeoylquinic acids-1,4,5,3 ', 4 '-five palm 1.00g
Acid esters
Weighting agent 180.00g
Disintegrating agent 10.00g
Tamanori 6.00g
Lubricant 3.00g
Amount to 200.00g
Press the preparation of tablet ordinary method, make 1000 altogether, every contains chlorogenic acid 1mg.
Prescription two:
3-caffeoylquinic acids-1,4,5,3 ', 4 '-five cetylate 100.00g
Weighting agent 170.00g
Disintegrating agent 15.00g
Tamanori 10.00g
Lubricant 5.00g
Amount to 300.00g
Press the preparation of tablet ordinary method, make 1000 altogether, every contains chlorogenic acid 0.1g.
Prescription three:
3-caffeoylquinic acids-1,4,5,3 ', 4 '-five cetylate 300.00g
Weighting agent 155.00g
Disintegrating agent 20.00g
Tamanori 15.00g
Lubricant 10.00g
Amount to 500.00g
Press the preparation of tablet ordinary method, make 1000 altogether, every contains chlorogenic acid 0.3g.
3-caffeoylquinic acids-1,4,5,3 ', the purity of 4 '-five cetylates is greater than 95%.
Weighting agent: as starch, dextrin, Icing Sugar, pregelatinized Starch, lactose, glucose, Microcrystalline Cellulose, lime carbonate, calcium sulfate, Calcium hydrogen carbonate.
Tamanori: as hypromellose, polyvidone, starch slurry, dextrin slurry, syrup, rubber cement, sodium alginate, polyoxyethylene glycol, peach gum, gum arabic.
Disintegrating agent: as croscarmellose sodium, polyvinylpolypyrrolidone, carboxymethylstach sodium, hydroxypropylated starch, low-substituted hydroxypropyl cellulose, citric acid, tartrate, acid anhydrides, sodium bicarbonate, yellow soda ash.
Lubricant: as Magnesium Stearate, talcum powder, micropowder silica gel, whiteruss, polyoxyethylene glycol.
Embodiment 10 3-caffeoylquinic acids-1,4,5,3 ', 4 '-the pentaacetate capsule
Prescription one:
3-caffeoylquinic acids-1,4,5,3 ', 4 '-pentaacetate 1.00g
Weighting agent 184.00g
Tamanori 5.00g
Lubricant 10.00g
Amount to 200.00g
Press the preparation of capsule ordinary method, make 1000 capsules altogether, every capsules contains chlorogenic acid 1mg.
Prescription two:
3-caffeoylquinic acids-1,4,5,3 ', 4 '-pentaacetate 100.00g
Weighting agent 85.00g
Tamanori 5.00g
Lubricant 10.00g
Amount to 200.00g
Press the preparation of capsule ordinary method, make 1000 capsules altogether, every capsules contains chlorogenic acid 0.1g.
Prescription three:
3-caffeoylquinic acids-1,4,5,3 ', 4 '-pentaacetate 300.00g
Weighting agent 85.00g
Tamanori 5.00g
Lubricant 10.00g
Amount to 400.00g
Press the preparation of capsule ordinary method, make 1000 capsules altogether, every capsules contains chlorogenic acid 0.3g.
3-caffeoylquinic acids-1,4,5,3 ', 4 '-purity of pentaacetate is greater than 95%.
Weighting agent: as starch, dextrin, Icing Sugar, pregelatinized Starch, lactose, glucose, Microcrystalline Cellulose, lime carbonate, calcium sulfate, Calcium hydrogen carbonate.
Tamanori: as hypromellose, polyvidone, starch slurry, dextrin slurry, syrup, rubber cement, sodium alginate, polyoxyethylene glycol, peach gum, gum arabic.
Lubricant: as Magnesium Stearate, talcum powder, micropowder silica gel, whiteruss, polyoxyethylene glycol.
Carried out following relevant pharmacodynamics test with multi-form chlorogenic acid monoesters of the present invention with the polyester derivative.
One, immunoregulation effect test
Get body weight 19-22 and restrain healthy kunming mice, male and female half and half are divided 10 groups, 10 every group.Reagent group 1 and reagent group 2 gavage 3-caffeoylquinic acids-1-acetic ester 50mg/kg, 25mg/kg respectively; Reagent group 3, reagent group 4 gavage respectively 3-caffeoylquinic acids-1,3 ', 4 '-triacetate 50mg/kg, 25mg/kg; Reagent group 5, reagent group 6 gavages 3-caffeoylquinic acids-1,4 respectively, 5,3 ', 4 '-pentaacetate 50mg/kg, 25mg/kg; Chlorogenic acid group abdominal injection chlorogenic acid 40mg/kg; Control group intraperitoneal injection of saline 10ml/kg.Each is organized and is administered once equal every day, and continuous 10 days, 30 minutes intravenous injection india ink 0.1ml got blood 20ul respectively at 1 minute, 5 minutes from vena orbitalis posterior after the 10th administration, were dissolved in 2ml 0.1%Na
2CO
3Shake up in the solution, put spectrophotometric instrumentation OD
600Value is by formula calculated charcoal and is engulfed (cleaning up) index.Charcoal is engulfed (cleaning up) index=(logOD
5min-logOD
1min)/(T
5min-T
1min).Test-results is as shown in table 1.
Table 1 is the result now show, the derivative of chlorogenic acid monoesters of the present invention and polyester can have the immunoregulation effect with the chlorogenic acid basically identical.
Two, tetracol phenixin is caused the treatment and the provide protection test of rats'liver damage
Get the healthy SD rat, male and female half and half, by the grouping of above-mentioned same administering mode and dosage, chlorogenic acid group abdominal injection chlorogenic acid 40mg/kg wherein, model group only gavages 0.5% Xylo-Mucine 0.8ml/.Each is organized and is administered once equal every day, continuous 10 days, after the last administration 24 hours, except that control group, all the other are respectively organized each mouse filling stomach and give 0.1% tetracol phenixin vegetable seed fluid 10ml/kg, give 0.1% tetracol phenixin liquid after 20 hours, each is organized rat aorta and gets blood, makes the mensuration of glutamic-oxal(o)acetic transaminase (AST) and gpt (ALT).Test-results is as shown in table 2.
Table 1 pair monokaryon is engulfed the influence (X ± SD) of system
| Group | Number of animals (only) | Dosage (mg/kg) | Phagocytic index |
| Reagent group 1 | 10 | 50 | 0.28±0.01 |
| Reagent group 2 | 10 | 25 | 0.17±0.01 |
| Reagent group 3 | 10 | 50 | 0.30±0.01 |
| Reagent group 4 | 10 | 25 | 0.15±0.01 |
| Reagent group 5 | 10 | 50 | 0.27±0.01 |
| Reagent group 6 | 10 | 25 | 0.17±0.01 |
| The chlorogenic acid group | 10 | 40 | 0.28±0.01 |
| Control group | 10 | - | 0.074±0.00 |
Table 2 pair tetracol phenixin causes the effect of rats'liver damage
Compare with the model knob
*P＜0.01
* *Compare with the feminine gender group P＜0.001
△ △ △P＜0.01
The experimental result of table 2 shows that the derivative of chlorogenic acid monoesters of the present invention and polyester and chlorogenic acid are at the therapeutic action and the liver-protecting efficacy that can have basically identical aspect liver injury.
Claims (10)
1. chlorogenic acid ester derivative, structure is suc as formula shown in (I)
In the formula: R is C
1-18Acyl group, R
1, R
2, R
3, R
4Be respectively H or C
1-18Acyl group, M are H, monovalence or divalent-metal ion.
2. chlorogenic acid ester derivative as claimed in claim 1 is characterized in that the R in formula (I) structure, R
1, R
2, R
3, R
4Be respectively C
2-12Acyl group.
3. chlorogenic acid ester derivative as claimed in claim 1 or 2 is characterized in that the R in formula (I) structure is said acyl group, R
1, R
2, R
3, R
4Be H.
4. chlorogenic acid ester derivative as claimed in claim 1 or 2 is characterized in that the R in formula (I) structure, R
3, R
4Be said acyl group, R
1, R
2Be H.
5. chlorogenic acid ester derivative as claimed in claim 1 or 2 is characterized in that the R in formula (I) structure, R
1, R
2, R
3, R
4Be said acyl group.
6. the preparation method of structure chlorogenic acid ester derivative shown in the formula (I); it is characterized in that the starting compound of chlorogenic acid is dissolved in the organic solvent; in protection of inert gas be lower than under 0 ℃ and the agitation condition and drip acylating reagent; the dropping back rises to room temperature naturally and stirs and carry out esterification; remove the water-soluble and/or volatile byproducts that reaction solvent and reaction produce, obtain said product after concentrating.
7. preparation method as claimed in claim 6 when it is characterized in that using carboxylic acid halides class acylating reagent, also has alkaline components in the starting compound organic solution of said chlorogenic acid.
8. suc as formula the purposes of chlorogenic acid ester derivative in medication preparation of structure shown in (I), form by acceptable subsidiary material in the compound of formula (I) structure and the pharmacy.
9. purposes as claimed in claim 8 is characterized in that said medicine is a hepatic.
10. purposes as claimed in claim 8 is characterized in that said medicine is an immunoregulation druge.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2006100215920A CN101121662A (en) | 2006-08-11 | 2006-08-11 | Chlorogenic acid ester derivative, preparation method and application thereof in pharmaceutical preparation |
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| CNA2006100215920A CN101121662A (en) | 2006-08-11 | 2006-08-11 | Chlorogenic acid ester derivative, preparation method and application thereof in pharmaceutical preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102392057A (en) * | 2011-09-26 | 2012-03-28 | 浙江工业大学 | Method for synthesizing aliphatic ester chlorogenate |
| CN104814949A (en) * | 2015-03-20 | 2015-08-05 | 四川九章生物科技有限公司 | Chlorogenic acid acylate capable of improving bioavailability of chlorogenic acid and application thereof |
| CN109757372A (en) * | 2017-11-15 | 2019-05-17 | 江西农业大学 | A kind of production method rich in chlorogenic acid substance honeysuckle cell |
-
2006
- 2006-08-11 CN CNA2006100215920A patent/CN101121662A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102392057A (en) * | 2011-09-26 | 2012-03-28 | 浙江工业大学 | Method for synthesizing aliphatic ester chlorogenate |
| CN102392057B (en) * | 2011-09-26 | 2013-11-13 | 浙江工业大学 | Method for synthesizing aliphatic ester chlorogenate |
| CN104814949A (en) * | 2015-03-20 | 2015-08-05 | 四川九章生物科技有限公司 | Chlorogenic acid acylate capable of improving bioavailability of chlorogenic acid and application thereof |
| WO2016150355A1 (en) * | 2015-03-20 | 2016-09-29 | 四川九章生物科技有限公司 | Chlorogenic acid acylate capable of improving bioavailability of chlorogenic acid and use thereof |
| CN104814949B (en) * | 2015-03-20 | 2018-04-17 | 四川九章生物科技有限公司 | Improve chlorogenic acid acylate and the application of chlorogenic acid bioavilability |
| CN109757372A (en) * | 2017-11-15 | 2019-05-17 | 江西农业大学 | A kind of production method rich in chlorogenic acid substance honeysuckle cell |
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