CN101633652B - Baicalein-8-sodium sulfonate and preparation method thereof and pharmaceutical use thereof - Google Patents
Baicalein-8-sodium sulfonate and preparation method thereof and pharmaceutical use thereof Download PDFInfo
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- CN101633652B CN101633652B CN2009100231611A CN200910023161A CN101633652B CN 101633652 B CN101633652 B CN 101633652B CN 2009100231611 A CN2009100231611 A CN 2009100231611A CN 200910023161 A CN200910023161 A CN 200910023161A CN 101633652 B CN101633652 B CN 101633652B
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Abstract
The invention belongs to the technical field of a heterocyclic compound, in particular to the heterocyclic compound which contains a heterocyclic non-hydrogenated six-membered ring, and takes an oxygen atom as the only heterocyclic atom to connect with a benzene ring and a fused aromatic ring at a position 2. The invention provides baicalein-8-sodium sulfonate and a preparation method thereof, and the process comprises the following steps: adding a reactant baicalein and a sulfonating agent into solvent, allowing the reactant to chemically react with the sulfonating agent to obtain the mixture of the compound in the invention and unreacted reactants, and purifying the mixture by a conventional separation method to obtain the purified product of the compound. The invention further provides an anti-aging medicine and composition, the baicalein-8-sodium sulfonate with therapeutically effective amount, a pharmaceutically acceptable carrier, and application of the baicalein-8-sodium sulfonate in preparing the anti-aging medicine.
Description
Technical field
The invention belongs to the heterogeneous ring compound technical field, be specifically related to heterocycle not hydrogenant contain six-membered ring, Sauerstoffatom is arranged as ring hetero atom is only arranged, with other ring condensed heterocycle compound.
Background technology
The strong oxidizing property of active oxygen radical can make unsaturated fatty acids generation peroxidation, generates lipid peroxide, and the injury microbial film promotes aging, brings out multiple disease.Scutellarin is the main component of the root of large-flowered skullcap; belong to flavonoid compound, have antibiotic, antiviral, anti-inflammatory, anti-allergic, anti-oxidant, remove multiple pharmacological effect such as oxyradical, anticancer, antitumor, anti-freezing thrombosis and protection liver, cardiovascular and cerebrovascular, neurone.Research thinks that the part pharmacologically active of flavones is relevant with its removing active oxygen radical.But relatively poor because of the scutellarin compound water soluble, cause absorption of human body slow and bioavailability is low, limited its application in clinical.For this reason, the present invention is the scutellarin sulfonation, give introduce in the molecular structure sulfonic group increase water-soluble, to improve the effect of scutellarin when the clinical use.
Summary of the invention
The objective of the invention is to overcome the shortcoming of above-mentioned scutellarin, provide water-soluble high new compound: scutellarin-8-sodium sulfonate with pharmaceutical use.
Another object of the present invention is to provide a kind of method for preparing above-claimed cpd.
Further purpose of the present invention is to provide antidotal medicine of a kind of treatment and composition.
The 4th purpose of the present invention is to provide a kind of above-claimed cpd and the application of composition in preparation treatment antiaging agent.
The chemical name of scutellarin of the present invention-8-sodium sulfonate is 5,6,7-trihydroxy-isoflavone-8-sodium sulfonate, its chemical structure such as following formula (1).
Formula (1)
The method that the employing chemical reaction prepares scutellarin of the present invention-8-sodium sulfonate is as follows:
(1) add solvent and following formula (2) scutellarin in reactor, stir adding sulphonating agent down, scutellarin and sulphonating agent carry out
Formula (2)
Chemical reaction, the mol ratio of used scutellarin and sulphonating agent are 1: 1～1: 10, and making the temperature of reaction solution with register is 20～110 ℃, react 0.5 hour～14 hours, get the mixture of scutellarin-8-sulfonic acid and unreacted reactant.
Formula (2) formula (1)
(2) mixture with (1) reaction is cooled to room temperature, pouring cumulative volume into is the sodium chloride solution of 1～5 times of amount 10～20% of reaction mixture, fully stir, leave standstill and generate precipitation, use conventional separation method, claim 1 Chinese style (1) compound separation is come out, obtain crude product, 1～5 times of amount amount weight ratio that adds the crude product amount again is that 10～20% sodium chloride solutions make its purifying, obtains the pure product of claim 1 Chinese style (1) compound.
Among the preparation method of scutellarin of the present invention-8-sodium sulfonate, the used solvent of chemical reaction is the sulfuric acid of 70-98%, and used sulphonating agent can be the vitriol oil or chlorsulfonic acid or oleum or sulphur trioxide.
Among scutellarin of the present invention-8-sodium sulfonate preparation method, the preferred temperature of sulfonation reaction is 20-110 ℃, and the preferred time of reaction is 0.5-14 hour.
Among the preparation method of scutellarin of the present invention-8-sodium sulfonate, the optimum temps of chemical reaction is 100 ℃, and the Best Times of chemical reaction is 12 hours.
Pharmaceutical composition of the present invention contains the above-mentioned formula (1) for the treatment of significant quantity and is activeconstituents, and contains one or more pharmaceutically acceptable carriers.
Compound of the present invention and drug regimen can be used for preparing the application in the treatment antiaging agent.
Effective constituent scutellarin of the present invention-8-sodium sulfonate preparation treatment antiaging agent uses with the form of conventional medicinal preparations: described conventional medicinal preparations contains the scutellarin-8-sodium sulfonate as activeconstituents, and this activeconstituents mixes with the solid or the liquid excipient of the organic or inorganic of parenteral admin as being suitable in the stomach and intestine with pharmaceutically acceptable carrier in preparation.This medicinal preparations can be solid form such as tablet, particle collection, pulvis, capsule; Also can be liquid form such as injection, suspension agent, syrup and emulsion etc.
Can contain auxiliary substance, stablizer, wetting agent and other additive commonly used in the above-mentioned preparation, as lactose, citric acid, tartrate, stearic acid, Magnesium Stearate, terra alba, sucrose, W-Gum, talcum powder, gelatin, agar, pectin, peanut oil, sweet oil, theobroma oil, ethylene glycol, glucose, vovocan, Xylotox and xitix etc.
Above-mentioned preparation can be made according to the preparation technology of various preparation routines.
Medicinal compositions of the present invention preferably contains the activeconstituents that weight ratio is 0.1-99.5%, most preferably contains the activeconstituents that weight ratio is 0.5-95%.
Activeconstituents scutellarin of the present invention-8-sodium sulfonate is made the oral pharmaceutical of various formulations, become human oral, the content of scutellarin in the medicine-8-sodium sulfonate should be 150mg every day, three times on the one, the content of scutellarin-8-sodium sulfonate should be 50mg in each medicine, 14 days is a course of treatment, treats 2-3 the course of treatment.Adult's intramuscular injection, scutellarin in the medicine-8-sodium sulfonate content should be 80mg every day, and twice, 14 day on the one is a course of treatment, treats 2 courses of treatment; Intravenous drip, adult's consumption, the content of scutellarin in the medicine-8-sodium sulfonate should be 80mg every day, and once-a-day, 14 days is a course of treatment, treats 2 courses of treatment.Oral pharmaceutical or injectable drug, children is taken the circumstances into consideration decrement.
The contriver is that DPPH (1, the bitter diazanyl free radical of 1-phenylbenzene-2-) method has been done the experiment of removing free radical with activeconstituents scutellarin of the present invention-8-sodium sulfonate employing.This method is simple to operation, and is with a high credibility.Test-results shows that activeconstituents scutellarin of the present invention-8-sodium sulfonate has the effect of good removing free radical, if use it for clinical trial, expection will have removes the free radical effect preferably, thereby plays antidotal result of treatment.Advantages such as preparation method of the present invention adopts the electrophilic substitution reaction method, and it is easy to have technology, and used equipment is simple, the yield height of product and production cost are low.
Fig. 1 is the inhibiting rate curve of scutellarin of the present invention-8-sodium sulfonate solution to DPPH.
In Fig. 1, X-coordinate is the logarithm of concentration, and ordinate zou is an inhibiting rate.
Concrete experiment method
The present invention is described in more detail for following embodiment, but the invention is not restricted to these embodiment.
One, scutellarin-8-sodium sulfonate prepares embodiment
Embodiment 1
In the present embodiment, earlier scutellarin is added in the reactor, also add solvent 80% sulfuric acid gradually with the stirrer stirring up to scutellarin is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of the scutellarin and the vitriol oil is 1: 5, after the stirrer stirring, making the temperature of reaction solution with register is 100 ℃, reacts 12 hours, obtains the mixture of scutellarin-8-sulfonic acid and unreacting material, be cooled to room temperature, the amount weight ratio that adds 5 times of reactant cumulative volumes is 10% sodium chloride aqueous solution, fully stirs, and leaves standstill and separates out white precipitate, filter, obtain scutellarin-8-sodium sulfonate crude product; The amount weight ratio that adds 5 times of amounts with recrystallization method in scutellarin-8-sodium sulfonate crude product is that 10% sodium chloride aqueous solution carries out purifying, obtains scutellarin-8-sulfonic acid sodium pure product (productive rate 85%).
Adopt the scutellarin-8-sodium sulfonate of this examples preparation, after tested, its physicochemical property is as follows:
White needle-like crystals, fusing point are 290 ℃ (decomposition); Solubleness in water is 8%, and is soluble in water.
The scutellarin of present embodiment-8-sodium sulfonate molecular structure is as follows through the infrared spectrometer test result:
IRv(cm
-1，KBr)：3541.6，3443.1，1672.3，1618.6，1580.4，1450.1，1366.0，1315.3，1268.8，1213.5，1158.5，1109.0，1044.4，1029.2，849.2，778.7，767.8，684.6，654.8，627.3，586.3，535.1cm
-1。
The H of the scutellarin of present embodiment-8-sodium sulfonate is as follows with the nuclear magnetic resonance analyser test result:
1H?NMR(DMSO-d
6，300MHz)δ(ppm)：7.04(1H，s，H-C3)，8.30(2H，d，J＝6.72，H-C2′，H-C6′)，7.58(2H，d，J＝6.72，H-C3′，H-C5′)，7.57(1H，s，H-C4′)。
C, the H results of elemental analyses of the scutellarin of present embodiment-8-sodium sulfonate are as follows:
Anal.calcd?for?C
15H
9NaO
8S：C48.39，H?2.44；found?C?48.16，H?2.19。
Embodiment 2
In the present embodiment, earlier scutellarin is added in the reactor, also add solvent 70% sulfuric acid gradually with the stirrer stirring up to scutellarin is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of the scutellarin and the vitriol oil is 1: 8, making the temperature of reaction solution with register is 110 ℃, reacted 0.5 hour, obtain the mixture of scutellarin-8-sulfonic acid and unreacted reactant, be cooled to room temperature, add 1 times of volume 20% sodium chloride aqueous solution, place, obtain white scutellarin-8-sodium sulfonate precipitation, separate scutellarin-8-sodium sulfonate subsequently, and make its purifying, and separation and purifying are raw materials used to be 20% sodium chloride aqueous solution of 1 times of reactant cumulative volume, other technological process is identical with embodiment 1.
Embodiment 3
Earlier scutellarin is added in the reactor, also add solvent 85% sulfuric acid gradually with the stirrer stirring up to scutellarin is fully dissolved, add the sulphonating agent chlorsulfonic acid again, the mol ratio of scutellarin and chlorsulfonic acid is 1: 10, after the stirrer stirring, making the temperature of reaction solution with register is 20 ℃, reacted 10 hours, obtain the mixture of scutellarin-8-sulfonic acid and unreacted reactant, add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain white scutellarin-8-sodium sulfonate precipitation, separate scutellarin-8-sodium sulfonate subsequently, and make its purifying, separate raw materials used and proportioning is identical with embodiment 1 with purifying.
Embodiment 4
In the present embodiment, earlier scutellarin is added in the reactor, also add solvent 85% sulfuric acid gradually with the stirrer stirring up to scutellarin is fully dissolved, feed the sulphonating agent sulphur trioxide again, the mol ratio of scutellarin and sulphur trioxide is 1: 3, after the stirrer stirring, making the temperature of reaction solution with register is 40 ℃, reacts 7 hours, obtains the mixture of scutellarin-8-sulfonic acid and unreacted reactant, be cooled to room temperature, add 2 times of volume 10% sodium chloride aqueous solutions, place, obtain white scutellarin-8-sodium sulfonate precipitation, separate scutellarin-8-sodium sulfonate subsequently and make its purifying, separate raw materials used and proportioning is identical with embodiment 1 with purifying.
Embodiment 5
In the present embodiment, earlier scutellarin is added in the reactor, also add solvent 80% sulfuric acid gradually up to scutellarin is fully dissolved with the stirrer stirring, feed the sulphonating agent oleum again, scutellarin and oleum branch mol ratio are 1: 4.After the stirrer stirring, be warming up to 60 ℃, reacted 1 hour, obtain the mixture of scutellarin-8-sulfonic acid and unreacted reactant, be cooled to room temperature, add 3 times of volume 10% sodium chloride aqueous solutions, obtain scutellarin-8-sodium sulfonate crude product, and make its purifying.Separate raw materials used and proportioning is identical with embodiment 1 with operation with purifying.
Embodiment 6
In the present embodiment, earlier scutellarin is added in the reactor, also add solvent 90% sulfuric acid gradually up to scutellarin is fully dissolved with the stirrer stirring, add the sulphonating agent chlorsulfonic acid again, the mol ratio of scutellarin and chlorsulfonic acid is 1: 1.After dripping, after stirring with stirrer, be warming up to 50 ℃, react 6 hours, the mixture of reactant is cooled to room temperature, add 4 times of volume 10% sodium chloride aqueous solutions and heat, obtain scutellarin-8-sodium sulfonate crude product.Separate raw materials used and proportioning is identical with embodiment 1 with operation with purifying.
Embodiment 7
In the present embodiment, earlier scutellarin is added in the reactor, also add solvent 98% sulfuric acid gradually up to scutellarin is fully dissolved with the stirrer stirring, add the sulphonating agent vitriol oil again, the mol ratio of the scutellarin and the vitriol oil is 1: 2.After dripping, be warming up to 55 ℃, reacted 14 hours, obtain the mixture of scutellarin-8-sulfonic acid and unreacted reactant, be cooled to room temperature, add 5 times of volume 10% sodium chloride aqueous solutions and heating, obtain scutellarin-8-sodium sulfonate crude product.Separate raw materials used and proportioning is identical with embodiment 1 with operation with purifying.
Two, scutellarin-8-sodium sulfonate example of formulations
Embodiment 8
With preparation scutellarin of the present invention-1000 in 8-sodium sulfonate tablet is that used raw material of example and ratio of adjuvant are as follows:
Scutellarin-8-sodium sulfonate 50g
Starch 250g
Starch slurry (10%) 85g
Magnesium Stearate 15g
Adopt the preparation technology of conventional tablet to make, every heavy 0.4g, the content of every scutellarin-8-sodium sulfonate is 50mg.Usage: be grown up three times on the one, each 1 oral, children take the circumstances into consideration decrement.
Embodiment 9
With preparation scutellarin of the present invention-8-sodium sulfonate powder is that used raw material of example and ratio of adjuvant are as follows for 1000 bags:
Scutellarin-8-sodium sulfonate 40g
Lactose 2900g
Starch slurry (10%) 60g
Adopt the preparation technology of conventional powder to make, every bag heavy 3g, the content of every scutellarin-8-sodium sulfonate is 40mg.Usage: be grown up three times on the one, each 1 sack clothes, children take the circumstances into consideration decrement.
Embodiment 10
With preparation scutellarin of the present invention-8-sodium sulfonate 1000mL injection is example, and used raw material and ratio of adjuvant are as follows:
Scutellarin-8-sodium sulfonate 50g
Water for injection adds to 1000mL
Adopt the preparation technology of conventional method injection to make, every bottle of 2mL contains scutellarin-8-sodium sulfonate 100mg.Usage: intramuscular injection, one day twice, each 1, intravenous drip, once-a-day, each 2.
Three, the contriver has carried out the experiment of removing free radical with effective constituent scutellarin of the present invention-8-sodium sulfonate, exemplifies following experiment content and test-results thereof, proves the antidotal validity of pharmacological agent with the present invention's preparation.
The preparation of 1 solution
DPPH (1, the bitter diazanyl free radical of 1-phenylbenzene-2-) solution: is 2.0 * 10 with the dehydrated alcohol for the solvent compound concentration
-4The DPPH solution of moL/L.
DPPH is a kind of stable free radical, is purple, at the 517nm place strong absorption is arranged.When having free-radical scavengers to exist, the single electron of DPPH is shoaled its color by pairing, and the absorbancy of inhaling the wavelength place in maximum diminishes, and therefore, absorbancy herein can be used for detecting the removing situation of free radical, thus the resistance of oxidation of evaluation test sample.The DPPH method is used to study that the resistance of oxidation of medicine is more, and oxidation capacity represents that with inhibiting rate inhibiting rate is big more, and oxidation-resistance is strong more.
Scutellarin-8-sodium sulfonate stock solution: is 4.0 * 10 with the dehydrated alcohol for the solvent compound concentration
-4The scutellarin of moL/L-8-sodium sulfonate solution.
The mensuration of 2 antioxygenations
Get the scutellarin-8-sodium sulfonate solution 2mL and 2.0 * 10 after the dilution
-4MoL/LDPPH solution 2mL adds in the same tool plug test tube, shakes up.Do reference with dehydrated alcohol behind the 30min and measure its absorbance A
i, measure 2mL 2.0 * 10 simultaneously
-4The absorbance A of moL/LDPPH solution and 2mL dehydrated alcohol mixed solution
c, and the absorbance A of 2mL scutellarin-8-sodium sulfonate and 2mL dehydrated alcohol mixed solution
j
Resistance of oxidation is represented with inhibiting rate in the DPPH method, and its formula is:
Inhibiting rate=[1-(A
i-A
j)]/A
c* 100%
Wherein: A
cDPPH solution absorbency when not adding antioxidant; A
iFor adding DPPH solution absorbency behind the antioxidant; A
jBe the absorbancy of scutellarin-8-sodium sulfonate at the mensuration wavelength.
Measure the inhibiting rate of different concns scutellarin-8-sodium sulfonate solution respectively, with the logarithm mapping scutellarin-8-sodium sulfonate inhibiting rate curve of inhibiting rate, referring to Fig. 1 to concentration to DPPH.
In scutellarin-8-sodium sulfonate inhibiting rate graphic representation 1, when scutellarin-8-sodium sulfonate concentration is 4.0x10
-4During mol/L, inhibiting rate is up to 95%, dilute 10 times after, DPPH is still had 50% scavenging(action).Trying to achieve scutellarin-8-sodium sulfonate by Fig. 1 is 4.0x10 to the half inhibiting rate IC50 (inhibiting rate is the concentration of 50% o'clock antioxidant) of DPPH
-5Mol/L, suitable with the powerful antioxidant THBQ (tertiarybutylhydroquinone) of synthetic, show that scutellarin-8-sodium sulfonate has strong restraining effect to DPPH.
3 conclusions
Scutellarin belongs to flavonoid compound on chemical structure.Flavonoid substances extensively is present in nature, and has varied physiologically active, comprising anti-oxidant, remove functions such as free radical, anticancer, antibiotic, antiviral, reducing blood-fat, hypoglycemic and immunomodulatory.Research thinks that the part pharmacologically active of flavones is relevant with its removing active oxygen radical.Scutellarin-8-sodium sulfonate has strong restraining effect to DPPH, can well play effect anti-oxidant and that remove free radical, is expected to be developed as a class and treats antidotal new drug.
Claims (5)
1. following formula (1) compound scutellarin-8-sodium sulfonate:
2. the preparation method of claim 1 Chinese style (1) scutellarin-8-sodium sulfonate compound, this method may further comprise the steps:
(1) adds following formula (2) scutellarin in the reactor, be dissolved in the solvent, add sulphonating agent again, scutellarin and sulphonating agent
Carry out chemical reaction, the mol ratio of used scutellarin and sulphonating agent is 1: 1～1: 10, and making the temperature of reaction solution with register is 20～110 ℃, reacts 0.5 hour～14 hours, gets the mixture of scutellarin-8-sulfonic acid and unreacted reactant;
(2) (1) post reaction mixture is cooled to room temperature, pouring cumulative volume into is that 1～5 times of amount of reaction mixture weight ratio is 10～20% sodium chloride solution, fully stir, leave standstill and generate precipitation, use conventional separation method, claim 1 Chinese style (1) compound separation is come out, obtain crude product, 1～5 times of weight ratio that adds the crude product amount again is that 10～20% sodium chloride solutions make its purifying, obtains the pure product of claim 1 Chinese style (1) compound.
3. according to the preparation method of described claim 1 Chinese style of claim 2 (1) compound, it is characterized in that: solvent for use is 70～98% sulfuric acid; Used sulphonating agent is the vitriol oil or chlorsulfonic acid or oleum or sulphur trioxide.
4. the antidotal pharmaceutical composition of treatment wherein has claim 1 Chinese style (1) compound and the pharmaceutically acceptable carrier for the treatment of significant quantity.
5. the application of claim 1 Chinese style (1) compound in the antidotal medicine of preparation treatment.
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| CN108658916B (en) * | 2018-05-02 | 2021-09-24 | 四川大学 | Substituent 6, 8-dimercapto-2-phenyl-4H-chromen-4-one derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1427003A (en) * | 2002-03-28 | 2003-07-02 | 复旦大学 | Baicalein 8-position substituted methylamine like derivative and its preparation method |
| CN1990481A (en) * | 2005-12-29 | 2007-07-04 | 中国科学院上海药物研究所 | Scutellarein derivative, its preparing process and application |
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| CN1427003A (en) * | 2002-03-28 | 2003-07-02 | 复旦大学 | Baicalein 8-position substituted methylamine like derivative and its preparation method |
| CN1990481A (en) * | 2005-12-29 | 2007-07-04 | 中国科学院上海药物研究所 | Scutellarein derivative, its preparing process and application |
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