CN101020684A - Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use - Google Patents
Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use Download PDFInfo
- Publication number
- CN101020684A CN101020684A CN 200710017326 CN200710017326A CN101020684A CN 101020684 A CN101020684 A CN 101020684A CN 200710017326 CN200710017326 CN 200710017326 CN 200710017326 A CN200710017326 A CN 200710017326A CN 101020684 A CN101020684 A CN 101020684A
- Authority
- CN
- China
- Prior art keywords
- sodium sulfonate
- formula
- prunusetin
- formononetin
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to heterocyclic compound technology, and is especially new compounds formononetin-3'-sodium sulfonate and prunetin-3'-sodium sulfonate and their preparation process. Their preparation process includes adding reactant formononetin or prunetin into solvent and sulfonating agent to produce chemical reaction, and subsequent separation and purification through conventional method to obtain purified product formononetin-3'-sodium sulfonate or prunetin-3'-sodium sulfonate. The present invention also provides medicine composition comprising formononetin-3'-sodium sulfonate or prunetin-3'-sodium sulfonate in effective treating amount and pharmaceutically acceptable carrier and its application in preparing medicine for treating hyperlipemia and fatty liver.
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 only ring hetero atom being arranged, condense the heterogeneous ring compound that aromatic ring only is connected in position 2 with phenyl ring.
Background technology
Isoflavonoid is one of activeconstituents in the natural product, has higher pharmaceutical use, and onocol and prunusetin all belong to isoflavonoid.Onocol is distributed widely in the edible and medicinal plant such as pea, cowpea, soybean, pricklyfruit licorice, Radix Puerariae and red clover, has tangible reducing blood-fat, antitumor, anti peroxidation of lipid, osteoporosis, inhibition Helicobacter pylori isoreactivity; Prunusetin mainly is present in the plants such as red clover, Yunnan Caulis Spatholobi, has antitumor, reducing blood-fat, treatment osteoporosis, improves purposes such as Woman climacteric symptom.Onocol and prunusetin isoflavonoid, because of water-soluble and fat-soluble all very low, bioavailability is low as medicine the time, produce effects is slow, and can only make medicinal preparation for oral administration.For this reason, the present invention is onocol and prunusetin sulfonation, give introduce in their molecular structure sulfonic group increase water-soluble, to improve onocol and the prunusetin effect when the clinical use.
Summary of the invention
The objective of the invention is to overcome the shortcoming of above-mentioned onocol and prunusetin, two kinds of water-soluble high new compounds with pharmaceutical use are provided: formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate.
Another object of the present invention is to provide a kind of method for preparing above-mentioned two compounds.
Further purpose of the present invention is to provide a kind of medicine and composition for the treatment of hyperlipidaemia and fatty liver disease.
The 4th purpose of the present invention is to provide a kind of above-claimed cpd and the application of composition in the medicine of preparation treatment hyperlipidaemia and fatty liver disease.
Formononetin-3 '-of the present invention '-sodium sulfonate and prunusetin-3 '-chemical name of sodium sulfonate be respectively 7-hydroxyl-4 '-methoxyl group isoflavones-3 '-sodium sulfonate and 4 '; 5-dihydroxyl-7-methoxyl group isoflavones-3 '-sodium sulfonate, their chemical structure is used following formula (1) and formula (2) expression respectively:
Formula (1), formononetin-3 '-'-sodium sulfonate: R
1=R
2=H R
3=CH
3
Formula (2), prunusetin-3 '-sodium sulfonate: R
1=CH
3R
2=OH R
3=H
Adopt chemical reaction prepare formononetin-3 '-of the present invention '-method of sodium sulfonate is as follows:
(1) in reactor, adds solvent and following formula (3) onocol, make onocol be dissolved in the solvent fully under stirring, add sulphonating agent again, make onocol and sulphonating agent carry out chemical reaction, the mol ratio of used onocol and sulphonating agent is 1: 1～1: 10, making the temperature of reaction solution with register is 20～100 ℃, reacted 5 minutes～10 hours, formononetin-3 '-'-mixture of sulfonic acid and unreacted reactant.
Formula (3) onocol
(2) (1) post reaction mixture is cooled to room temperature, the sodium chloride solution that adds 1～5 times of amount 10～20% of reactant cumulative volume, fully stir, leave standstill and generate precipitation, use conventional separation method, formula (1) compound separation is come out, obtain crude product, the sodium chloride solution that adds 1～5 times of amount 10～20% of crude product amount again makes its purifying, obtains the pure product of compound formula (1).
Formula (3) formula (1)
With the prunusetin be lead compound prepare prunusetin of the present invention-3 '-method of sodium sulfonate is as follows:
(1) add solvent and formula (4) prunusetin in the reactor, under stirring prunusetin is dissolved in the solvent fully, add sulphonating agent again, make prunusetin and sulphonating agent carry out chemical reaction, the mol ratio of used prunusetin and sulphonating agent is 1: 1～1: 10, uses
Formula (4) prunusetin
It is 20～100 ℃ that register makes the temperature of reaction solution, reacted 5 minutes～10 hours, prunusetin-3 '-mixture of sulfonic acid and unreacted reactant.
(2) (1) post reaction mixture is cooled to room temperature, the sodium chloride solution that adds 1～5 times of amount 10～20% of reactant cumulative volume, fully stir, leave standstill and generate precipitation, use conventional separation method, compound separation is come out, obtain crude product, 1～5 times of amount 10～20% sodium chloride solution that adds the crude product amount again make its purifying, obtain the pure product of compound formula (2).
Formula (4) formula (2)
Formononetin-3 '-of the present invention '-sodium sulfonate and prunusetin-3 '-preparation method of sodium sulfonate in, the used solvent of chemical reaction is 70～98% the vitriol oil, used sulphonating agent can be the vitriol oil or chlorsulfonic acid or oleum or sulphur trioxide.
Formononetin-3 '-of the present invention '-sodium sulfonate and prunusetin-3 '-preparation method of sodium sulfonate in, the preferred temperature of sulfonation reaction is 20～100 ℃, the preferred time of reaction is 30 minutes～8 hours.
Formononetin-3 '-of the present invention '-preparation method of sodium sulfonate in, the optimum temps of chemical reaction is 40 ℃, the Best Times of chemical reaction is 2 hours; Prunusetin-3 '-preparation method of sodium sulfonate in, the optimum temps of chemical reaction is 50 ℃, the Best Times of chemical reaction is 2.5 hours.
Pharmaceutical composition of the present invention contains the above-mentioned formula (1) or the formula (2) for the treatment of significant quantity and is activeconstituents, and contains one or more pharmaceutically acceptable carriers.
Compound of the present invention and pharmaceutical composition can be used for preparing the application in the medicine for the treatment of hyperlipidaemia and fatty liver disease.
Effective constituent formononetin-3 '-of the present invention '-sodium sulfonate and prunusetin-3 '-medicine of sodium sulfonate preparation treatment hyperlipidaemia and fatty liver disease uses with the form of conventional medicinal preparations; Described conventional medicinal preparations contain formononetin-3 '-as activeconstituents '-sodium sulfonate or prunusetin-3 '-sodium sulfonate, this activeconstituents in preparation with pharmaceutically acceptable carrier as being suitable in the stomach and intestine and the solid or the liquid excipient of the organic or inorganic of parenteral admin mix.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.
It is 0.1～99.5% activeconstituents that pharmaceutical composition of the present invention preferably contains weight ratio, most preferably contains weight ratio and be 0.5～95% activeconstituents.
Activeconstituents formononetin-3 '-of the present invention '-sodium sulfonate and prunusetin-3 '-sodium sulfonate makes the oral pharmaceutical of various formulations; become human oral; formononetin-3 '-in the medicine '-sodium sulfonate or prunusetin-3 '-content of sodium sulfonate should be 150mg every day; three times on the one; formononetin-3 '-in each medicine '-sodium sulfonate or prunusetin-3 '-content of sodium sulfonate is 50mg; 14 days is a course of treatment, treats 2～3 courses of treatment.Adult's intramuscular injection, formononetin-3 '-in the medicine '-sodium sulfonate or prunusetin-3 '-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, formononetin-3 '-in the medicine '-sodium sulfonate or prunusetin-3 '-content of 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 with activeconstituents formononetin-3 '-of the present invention '-sodium sulfonate and prunusetin-3 '-sodium sulfonate consignment test unit carried out the test of pesticide effectiveness.Test-results show activeconstituents formononetin-3 '-of the present invention '-sodium sulfonate and prunusetin-3 '-sodium sulfonate can significantly reduce cholesterol level in high fat rat blood serum and the liver; alleviate liver cell fat and drip accumulation; reduce liver enzyme activity; protection has the function of lowering fat and protecting liver effect preferably and protection blood vessel endothelium by blood vessel endothelium injury and cardiovascular disorder that Angiotensin (AngII) raises and causes.If with formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate is used for clinical trial, expection will have better therapeutic effect.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.
Description of drawings
Fig. 1 be formononetin-3 '-of the present invention '-infrared spectrogram of sodium sulfonate.
Fig. 2 be formononetin-3 '-of the present invention '-the hydrogen nuclear magnetic resonance figure of sodium sulfonate.
Fig. 3 be formononetin-3 '-of the present invention '-the nuclear magnetic resonance of carbon figure of sodium sulfonate.
Fig. 4 be prunusetin of the present invention-3 '-infrared spectrogram of sodium sulfonate.
Fig. 5 be prunusetin of the present invention-3 '-the hydrogen nuclear magnetic resonance figure of sodium sulfonate.
In Fig. 1 and Fig. 4, X-coordinate is a wave number, and ordinate zou is a specific absorption.In Fig. 2, Fig. 3 and Fig. 4, X-coordinate is chemical shift, and unit is ppm, and ordinate zou is a peak heights.
Embodiment
The present invention is described in more detail below in conjunction with drawings and Examples, but the invention is not restricted to these embodiment.One, formononetin-3 '-'-sodium sulfonate prepares embodiment
In the present embodiment, earlier onocol is added in the reactor, also add solvent 80% sulfuric acid gradually with the stirrer stirring up to onocol is fully dissolved, add the sulphonating agent vitriol oil again, onocol and sulphonating agent mol ratio are 1: 5, after the stirrer stirring, making the temperature of reaction solution with register is 60 ℃, reacts 6 hours, obtain formononetin-3 '-'-mixture of sulfonic acid and unreacting material, be cooled to room temperature, add 10% sodium chloride aqueous solution of 5 times of reactant cumulative volumes, fully stir, leave standstill and separate out white precipitate, filter, obtain formononetin-3 '-'-the sodium sulfonate crude product; With recrystallization method formononetin-3 '-'-10% sodium chloride aqueous solution that adds 5 times of amounts in the sodium sulfonate crude product carries out purifying, obtain formononetin-3 '-'-sodium sulfonate elaboration (productive rate 89%).The formononetin-3 '-of employing present embodiment preparation '-sodium sulfonate, after tested, its physicochemical property is as follows:
White needle-like crystals, fusing point are 305 ℃ (decomposition); Solubleness in water is 8.6%, and is soluble in water.
Referring to Fig. 1, the formononetin-3 '-of present embodiment '-the sodium sulfonate molecular structure is as follows through the infrared spectrometer test result:
IR v(cm
-1，KBr)：3440，1635，1498，1265，1192，1095，1022，828，725，629。
Referring to Fig. 2, the formononetin-3 '-of present embodiment '-H of sodium sulfonate is as follows with the nuclear magnetic resonance analyser test result:
1H NMR[DSMO/TMS，δ(ppm)]：8.31(s，1H，H-C
2)，7.98(d，1H，J＝8.7Hz，H-C
5)，7.88(d，1H，J＝1.8Hz，H-C
2′)，7.49(dd，1H，J＝8.6Hz，J＝1.8Hz，H-C
6′)，7.04(d，1H，J＝8.6Hz，H-C
5′)，6.96(d，1H，J＝8.7Hz，H-C
6)，6.90(s，1H，H-C
8)，3.80(s，3H，H
3CO-C
4′)。
Referring to Fig. 3, the formononetin-3 '-of present embodiment '-C of sodium sulfonate is as follows with the nuclear magnetic resonance analyser test result:
13C NMR[DSMO/TMS，δ(ppm)]：175.07(C-4)，163.15(C-7)，157.93(C-8a)，156.30(C-2)，153.66(C-4′)，134.88(C-3′)，131.69(C-5)，129.45(C-1′)，127.66(C-3)，123.62(C-6′)，123.48(C-4a)，116.95(C-6)，115.74(C-2′)，112.20(C-5′)，102.65(C-8)，56.31(CH
3)。
In the present embodiment, earlier onocol is added in the reactor, also add solvent 70% sulfuric acid gradually with the stirrer stirring up to onocol is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of onocol and sulphonating agent is 1: 8, after the stirrer stirring, making the temperature of reaction solution with register is 100 ℃, reacted 5 minutes, obtain formononetin-3 '-'-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain white formononetin-3 '-'-sodium sulfonate precipitation, separate subsequently formononetin-3 '-'-sodium sulfonate, and make its purifying, separation and purifying are raw materials used to be 20% sodium chloride aqueous solution of 1 times of reactant cumulative volume, and other technological process is identical with embodiment 1.
In the present embodiment, earlier onocol is added in the reactor, also add solvent 85% sulfuric acid gradually with the stirrer stirring up to onocol is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of the onocol and the vitriol oil is 1: 3, after the stirrer stirring, making the temperature of reaction solution with register is 20 ℃, reacts 10 hours, obtain formononetin-3 '-'-mixture of sulfonic acid and unreacted reactant, add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain white formononetin-3 '-'-the sodium sulfonate precipitation, separate subsequently formononetin-3 '-'-sodium sulfonate, and make its purifying, separate raw materials used and proportioning is identical with embodiment 1 with purifying.
Embodiment 4
In the present embodiment, earlier onocol is added in the reactor, also add solvent 98% sulfuric acid gradually with the stirrer stirring up to onocol is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of the onocol and the vitriol oil is 1: 1, after the stirrer stirring, making the temperature of reaction solution with register is 80 ℃, reacts 30 minutes, obtain formononetin-3 '-'-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain white formononetin-3 '-'-the sodium sulfonate precipitation, separate subsequently formononetin-3 '-'-sodium sulfonate and make its purifying, separate raw materials used and proportioning is identical with embodiment 1 with purifying.
In the present embodiment, earlier onocol is added in the reactor, also add solvent 75% sulfuric acid gradually with the stirrer stirring up to onocol is fully dissolved, feed the sulphonating agent sulphur trioxide again, onocol and sulphur trioxide mol ratio are 1: 3, after the stirrer stirring, making the temperature of reaction solution with register is 20 ℃, reacts 8 hours, obtain formononetin-3 '-'-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain white formononetin-3 '-'-the sodium sulfonate precipitation, separate subsequently formononetin-3 '-'-sodium sulfonate and make its purifying, separate raw materials used and proportioning is identical with embodiment 1 with purifying.
In the present embodiment, earlier onocol is added in the reactor, also add solvent 75% sulfuric acid gradually up to onocol is fully dissolved with the stirrer stirring, add the sulphonating agent oleum again, the mol ratio of onocol and oleum is 1: 2, after stirring with stirrer, is warming up to 50～55 ℃, reacted 1 hour, obtain formononetin-3 '-'-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 10% sodium chloride aqueous solution, obtain formononetin-3 '-'-the sodium sulfonate crude product, and make its purifying.Separate raw materials used and proportioning is identical with embodiment 1 with operation with purifying.
In the present embodiment, earlier onocol is added in the reactor, also add solvent 75% sulfuric acid gradually up to onocol is fully dissolved with the stirrer stirring, drip the sulphonating agent chlorsulfonic acid then, the mol ratio of onocol and chlorsulfonic acid is 1: 1.After dripping, after stirring with stirrer, be warming up to 45～50 ℃, react 2 hours, the mixture of reactant is cooled to room temperature, add 10% sodium chloride aqueous solution heating back and cool off, obtain formononetin-3 '-'-the sodium sulfonate crude product, and make its purifying.Separate raw materials used and proportioning is identical with embodiment 1 with operation with purifying.
Two, prunusetin-3 '-sodium sulfonate prepares embodiment
In the present embodiment, earlier prunusetin is added in the reactor, also add solvent 80% sulfuric acid gradually with the stirrer stirring up to prunusetin is fully dissolved, add the sulphonating agent vitriol oil again, the mol ratio of the prunusetin and the vitriol oil is 1: 5, after the stirrer stirring, making the temperature of reaction solution with register is 60 ℃, reacts 2 hours, obtain prunusetin-3 '-mixture of sulfonic acid and unreacting material, be cooled to room temperature, 10% sodium chloride aqueous solution that adds 5 times of reactant cumulative volumes fully stirs, and leaves standstill and separates out white precipitate, filter, obtain prunusetin-3 '-the sodium sulfonate crude product; With recrystallization method prunusetin-3 '-10% sodium chloride aqueous solution that adds 5 times of amounts in the sodium sulfonate crude product carries out purifying, obtain prunusetin-3 '-sodium sulfonate elaboration (productive rate 79.8%).
The prunusetin-3 of employing present embodiment preparation '-sodium sulfonate, after tested, its physicochemical property is as follows:
White needle-like crystals, fusing point are 280 ℃ (decomposition); Solubleness in water is 7.5%, and is soluble in water.
Referring to Fig. 4, the prunusetin of present embodiment-3 '-the sodium sulfonate molecular structure is as follows through the infrared spectrometer test result:
IR v(cm
-1，KBr)：3157，1661，1613，1577，1504，1440，1263，1192，1094，1036，901，827，630。
Referring to Fig. 5, the prunusetin of present embodiment-3 '-H of sodium sulfonate is as follows with the nuclear magnetic resonance analyser test result:
1H NMR[DSMO/TMS，δ(ppm)]：12.92(s，1H，HO-C
5)，10.66(s，1H，HO-C
4′)，8.46(s，IH，H-C
2)，7.71(s，1H，H-C
2′)，7.41(d，1H，J＝6.0Hz，H-C
6′)，6.85(d，1H，J＝6.0Hz，H-C
5′)，6.69(s，IH，H-C
8)，6.43(s，1H，H-C
6)，3.87(s，3H，H
3CO-C
7)。
Embodiment 9
In the present embodiment; earlier prunusetin is added in the reactor; also add solvent 75% sulfuric acid gradually with the stirrer stirring up to prunusetin is fully dissolved; add the sulphonating agent vitriol oil again; the mol ratio of the prunusetin and the vitriol oil is 1: 8; making the temperature of reaction solution with register is 100 ℃; reacted 10 minutes; obtain prunusetin-3 '-mixture of sulfonic acid and unreacted reactant; be cooled to room temperature; add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain white prunusetin-3 '-the sodium sulfonate precipitation; separate subsequently prunusetin-3 '-sodium sulfonate; 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 8.
Earlier prunusetin is added in the reactor; also add solvent 85% sulfuric acid gradually with the stirrer stirring up to prunusetin is fully dissolved; add the sulphonating agent vitriol oil again; the mol ratio of the prunusetin and the vitriol oil is 1: 3; after the stirrer stirring; making the temperature of reaction solution with register is 20 ℃; reacted 10 hours; obtain prunusetin-3 '-mixture of sulfonic acid and unreacted reactant, add 5 times of volume 10% sodium chloride aqueous solutions, place; obtain white prunusetin-3 '-sodium sulfonate precipitation; separate subsequently prunusetin-3 '-sodium sulfonate, and make its purifying, separate raw materials used and proportioning is identical with embodiment 8 with purifying.
In the present embodiment; earlier prunusetin is added in the reactor; also add solvent 85% sulfuric acid gradually with the stirrer stirring up to prunusetin is fully dissolved; feed the sulphonating agent sulphur trioxide again; the mol ratio of prunusetin and sulphur trioxide is 1: 3; after the stirrer stirring; making the temperature of reaction solution with register is 40 ℃, reacts 7 hours, obtain prunusetin-3 '-mixture of sulfonic acid and unreacted reactant; be cooled to room temperature; add 5 times of volume 10% sodium chloride aqueous solutions, place, obtain white prunusetin-3 '-the sodium sulfonate precipitation; separate subsequently prunusetin-3 '-sodium sulfonate and make its purifying, separate raw materials used and proportioning is identical with embodiment 8 with purifying.
In the present embodiment, earlier prunusetin is added in the reactor, also add solvent 80% sulfuric acid gradually up to prunusetin is fully dissolved with the stirrer stirring, feed the sulphonating agent oleum again, the mol ratio of prunusetin and oleum is 1: 4.After stirring with stirrer, be warming up to 50～55 ℃, reacted 1 hour, obtain prunusetin-3 '-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 10% sodium chloride aqueous solution, obtain prunusetin-3 '-the sodium sulfonate crude product, and make its purifying.Separate raw materials used and proportioning is identical with embodiment 8 with operation with purifying.
In the present embodiment, earlier prunusetin is added in the reactor, also add solvent 90% sulfuric acid gradually up to prunusetin is fully dissolved with the stirrer stirring, add the sulphonating agent chlorsulfonic acid again, the mol ratio of prunusetin and chlorsulfonic acid is 1: 1.After dripping, after stirring with stirrer, be warming up to 45～50 ℃, react 2 hours, the mixture of reactant is cooled to room temperature, add 10% sodium chloride aqueous solution and heat, obtain prunusetin-3 '-the sodium sulfonate crude product.Separate raw materials used and proportioning is identical with embodiment 8 with operation with purifying.
Embodiment 14
In the present embodiment, earlier prunusetin is added in the reactor, also add solvent 98% sulfuric acid gradually up to prunusetin is fully dissolved with the stirrer stirring, add the sulphonating agent vitriol oil again, the mol ratio of the prunusetin and the vitriol oil is 1: 2.After dripping, be warming up to 55～60 ℃, reacted 1 hour, obtain prunusetin-3 '-mixture of sulfonic acid and unreacted reactant, be cooled to room temperature, add 10% sodium chloride aqueous solution and heating, obtain prunusetin-3 '-the sodium sulfonate crude product.Separate raw materials used and proportioning is identical with embodiment 8 with operation with purifying.
Three, formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-the sodium sulfonate example of formulations
With preparation formononetin-3 '-of the present invention '-sodium sulfonate or prunusetin-3 '-1000 in sodium sulfonate tablet is that used raw material of example and ratio of adjuvant are as follows:
Formononetin-3 '-'-sodium sulfonate or
Prunusetin-3 '-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, every formononetin-3 '-'-sodium sulfonate or prunusetin-3 '-content of sodium sulfonate is 50mg.Usage: be grown up three times on the one, each 1 oral, children take the circumstances into consideration decrement.
Embodiment 16
With preparation formononetin-3 '-of the present invention '-sodium sulfonate or prunusetin-3 '-sodium sulfonate powder is that used raw material of example and ratio of adjuvant are as follows for 1000 bags:
Formononetin-3 '-'-sodium sulfonate or
Prunusetin-3 '-sodium sulfonate 40g
Lactose 2800g
Starch slurry (10%) 60g
Adopt the preparation technology of conventional powder to make, every bag heavy 3g, contain formononetin-3 '-'-sodium sulfonate or prunusetin-3 '-sodium sulfonate 40mg.Usage: be grown up three times on the one, each 1 sack clothes, children take the circumstances into consideration decrement.
Embodiment 17
With preparation formononetin-3 '-of the present invention '-sodium sulfonate or prunusetin-3 '-sodium sulfonate 1000ml injection is an example, used raw material and ratio of adjuvant are as follows:
Formononetin-3 '-'-sodium sulfonate or
Prunusetin-3 '-sodium sulfonate 50g
Water for injection adds to 1000ml
Adopt the preparation technology of conventional method injection to make, every bottle of 2ml, contain formononetin-3 '-'-sodium sulfonate or prunusetin-3 '-sodium sulfonate 100mg.Usage: intramuscular injection, one day twice, each 1, intravenous drip, once-a-day, each 2.
The contriver with effective constituent formononetin-3 '-of the present invention '-sodium sulfonate or prunusetin-3 '-sodium sulfonate consignment test unit carried out the test of pesticide effectiveness; exemplify following experiment content and test-results thereof, prove with the pharmacological agent hyperlipidaemia of the present invention's preparation and the validity of fatty liver disease.
1 laboratory animal and grouping:
Select 60 of SD male rats for use, laboratory animal is available from Shaanxi Province academy of traditional Chinese medicine Experimental Animal Center (animal quality conformity certification number: the moving card of Shan doctor word 08-004 number).8 ages in week, body weight 180g～220g.20 ℃～29 ℃ of animal room temps, relative humidity 40%～55%.Rat freely drinks water, takes food, sub-cage rearing, 5 in every cage.After laboratory animal is bought normal 1 week of nursing back; be divided into 6 groups at random; be normal control group (A), model group (B), normal control group add formononetin-3 '-'-sodium sulfonate (C), model group add formononetin-3 '-'-sodium sulfonate (D), model group add prunusetin-3 '-sodium sulfonate (E) and model group add Simvastatin (F), 10 every group.
2 model copies and preparation of specimen
A group and C group are fed normal diet; All the other each groups are all fed high lipid food.High lipid food prescription: add 1.0% cholesterol, 0.35% Sodium cholic acid, 5.0% lard, 0.61% propylthiouracil in the rat standard feed; Divided by the total dose of 700,000 IU/kg in preceding 3 days and give vitamins D for 3 times and irritate stomach.Gavage physiological saline 2ml three groups every every day since the 4th week A, B, C, D, E two groups every every day gavage formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate 13.5mg, with distilled water diluting be the 2ml filling hello.The F group gavages Simvastatin 1.8mg every every day, is that the 2ml filling is fed with distilled water diluting.The experimental session rat is freely intake and ingests, the 8th fasting at weekend 12 hours, next day anesthetized rat, abdominal aortic blood, preparation serum and blood plasma are inspected by ready samples immediately.Cut hepatic tissue rapidly with icing normal saline flushing, after filter paper blotted, neutral formalin was fixed, routine paraffin wax embedding, section, HE dyeing, and light microscopic is observed the hepatic tissue morphological change down.
3 key instruments and detection method
Serum cholesterol (TC), triglyceride level (TG), liver gpt (ALT), glutamic-oxal(o)acetic transaminase (AST), alkaline phosphatase (ALP) and glutaminase based transferase (GGT) are that the Toshiba-TBA-120FR of Toshiba automatic clinical chemistry analyzer detects, and adopt a step enzyme method, two step enzyme methods and Sterol esterase oxidation enzyme process; Angiotensin (AngII), endothelin (ET), γ-radioimmunity counter is measured, and adopts the isotropic substance precipitator method.Whole testing process is finished by Xi'an second professional of the People's Hospital.
4 statistical procedures
The data mean ± standard deviation represents that statistical procedures adopts SPSS 12.0 statistical package analyses.The T check, significance level adopts P＜0.05 and P＜0.01 level.
5 results and analysis
(1) hepatic tissue morphological change
Light microscopic is observed down, the no abnormal substantially variation of normal rats liver cell, and no fat drips accumulation in the liver cell, the increase of model group hepatic tissue, the color jaundice of turning white.Liver cell exists oedema and necrosis in various degree, and visible a large amount of fat drips fat vacuole, liver lobule structure disturbance, the sex change of liver cell cavity sample, fusion in most liver cells.Formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate group liver cell lactones drips and reduces with fat vacuole and model group relatively has clear improvement, and color also is tending towards the normal control group.
(2) formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate is to rat kidney fat pad, heavy, the liver exponential influence of testis fat pad
Table 1 is respectively organized rat kidney fat pad, testis fat pad weight, liver assessment of indices result relatively
| Group | n | Body weight (g) | Kidney fat pad heavy (g) | Testis fat pad heavy (g) | The liver index |
| A group B group C group D group E |
8 8 8 8 8 8 | 326.7±40.0 397.2±26.4 * 331.0±8.7 * 355.5±11.0 **# 357.6±21.4 **# 357.0±22.7 **# | 1.6±0.68 3.2±0.25 * 1.3±0.72 # 2.2±0.47 **# 2.0±0.33 **# 2.2±0.67 **# | 1.8+0.29 2.7±0.43 * 1.9±0.28 # 2.0±0.54 **# 1.8+0.39 **# 1.8±0.57 **# | 0.25±0.056 0.34±0.049 * 0.22±0.015 # 0.26±0.044 # 0.28±0.042 0.28±0.053 |
*P＜0.01,
*Compare with normal control group (A) p＜0.05;
#Compare with model group (B group) p＜0.05
As known from Table 1, D, E group rat kidney fat pad and testis fat pad representation work are lower than the B group, and D group liver index significance is lower than the B group, illustrate formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate has the fat of reduction to act on.
(3) formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate is to the influence of rat blood serum and liver lipid
Table 2 is respectively organized Serum TC, TG, HDL-c and LDL-c measurement result relatively
| Group | n | TC(mmol/L) | TG(mmol/L) | HDL-c(mmol) | LDL-C(mmol/L) |
| A group B group C group D group E |
8 8 8 8 8 8 | 0.97±0.20 2.64±0.50 * 1.02±0.19 # 1.55±0.39 *# 1.47±0.18 *# 1.54±0.58 *# | 0.55±0.26 0.70±0.18 0.54±0.09 0.52±0.08 0.56±0.12 0.54±0.16 | 0.91±0.39 0.49±0.24 0.64±0.09 0.73±0.27 **# 0.68±0.15 **# 0.67±0.23 | 0.26±0.06 0.46±0.24 * 0.18±0.66 # 0.19±0.09 **# 0.15±0.38 *# 0.24±0.14 *# |
*P＜0.01,
*Compare with normal control group (A) p＜0.05;
#Compare with model group (B group) p＜0.05
Rat liver homogenate liquid TC respectively organized by table 3 and the TG measurement result compares
| Group | n | Homogenate TC (mol/l) | Homogenate (TG) (mol/l) |
| A group B group C group D group E |
8 8 8 8 8 8 | 0.57±0.07 3.14±0.60 * 0.63±0.20 # 1.68±0.39 *# 2.12±0.38 **# 2.19±0.51 # | 1.86±0.46 3.00±0.54 ** 1.94±0.58 # 2.05±0.51 **# 2.20±0.28 **# 2.19±0.31 # |
*P＜0.01,
*Compare with normal control group (A) p＜0.05; Compare with model group (B group) #p＜0.05
By table 1-2 as seen; after rat gives high lipid food continuously; TC, TG, LDL-C (LDL-C) content obviously increase in the B group serum; highdensity lipoprotein-cholesterol (HDL-C) obviously reduces; illustrate that high blood lipid model forms, give formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-compare with the B group behind the sodium sulfonate, D, E group TC reduces (p＜0.01); HDL-C raises (p＜0.05), and LDL-C reduces (p＜0.05).Show formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate has tangible lipid-lowering effect to high fat rat fat.
(4) formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate is to the influence of rat blood serum AngII and ET
Rat blood serum Angiotensin (AngII) respectively organized by table 4 and endothelin (ET) measurement result compares
| Group | n | AngII | ET |
| A group B group C group D group E |
8 8 8 8 8 8 | 417.83±47.36 558.83±84.46 361.16±88.43 # 344.16±64.76 # 314.33±58.38 **# 453.64±36.10 # | 54.02±12.86 62.51±9.90 * 35.83±7.84 # 41.06±4.36 **# 44.55±6.70 **# 47.43±7.91 # |
*P＜0.01,
*Compare with normal control group (A) p＜0.05; ET is compared with model group (B group) in #p＜0.05 and AngII all is intensive vaso-excitor materials in the body, plays a significant role in the normal function of keeping blood vessel and arteriosclerosis process.There are the positive regeeration regulation mechanism of mutually promoting between the two in ET and AngII.AngII can stimulate vascular endothelial cell secretion ET to enter blood, makes ET content increase in the blood.Bibliographical information, high lipid diet rat plasma AngII obviously raises, and the hyperlipidemia model result is consistent with bibliographical information in the table 4.Formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-the sodium sulfonate effect after, D, E group and B group relatively, serum AngII and ET significantly reduce (p＜0.05).Show formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate can significantly reduce increasing of ET concentration that AngII causes, the vascular endothelial cell damage that AngII is caused has provide protection.
(5) formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate is to the influence of rats'liver enzymic activity
Table 5 is respectively organized rats'liver enzyme assay result relatively
| Group | n | ALT(U/L) | AST(U/L) | ALP(U/L) | GGT(U/L) |
| A group B group C group D group E |
8 8 8 8 8 8 | 70.00±24.54 113.66±40.65 **# 48.66±19.89 # 49.83±18.51 #** 46.00±18.93 #** 51.50±6.71 # | 136.16±33.16 148.66±29.20 ** 74.16±15.91 # 83.00±22.61 #** 83.17±14.00 #** 82.00±25.46 # | 95.16±19.12 162.83±33.55 ** 95.83±31.01 # 123.83±30.57 # 154.83±29.78 119.33±36.87 # | 1.00±0.63 2.00±0.89 1.17±0.75 1.33±0.95 1.55±0.50 1.67±0.81 |
*P＜0.01,
*P＜0.05, compare with normal control group (A): #p＜0.05, compare with model group (B group)
Increasing of gpt and glutamic-oxal(o)acetic transaminase is the indirect performance that liver function suffers damage, and also is one of index of tradition judgement hepatic disorder.The model group gpt and the glutamic-oxal(o)acetic transaminase of this experiment obviously increase, add formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate after with model group relatively, two groups of ALT of D, E and AST significantly reduce (p＜0.05), trend is normal.Illustrate formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate has liver protection effect preferably.
6 conclusions
Onocol and prunusetin belong to isoflavonoid on chemical structure.Flavonoid substances extensively is present in nature, the color and luster that many tools are gorgeous, and major part is combined into glycosides with sugar in plant materials, and a part exists with free form.Modern medicine study is found, much is used for the treatment of the active drug of heart trouble, cerebral thrombosis and prostatosis, all contains abundant flavonoids in the medicine of promoting blood circulation and removing blood stasis, heat-clearing, detoxifcation, anti-inflammatory.Flavonoid compound has varied physiologically active, comprising anti-oxidant, remove functions such as free radical, anticancer, antibiotic, antiviral, reducing blood-fat, hypoglycemic and immunomodulatory.More to the reducing blood lipid mechanism and the action effect research of Flavonoid substances both at home and abroad at present.This experimental model is a hypercholesterolemia; result of study shows; formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate has following function: (1) reduces the hypercholesterolemia effect preferably, and formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate between decreasing cholesterol effect no significant difference.(2) reduce liver homogenate lipid (TC and TG) and liver enzyme (ALT and AST) activity, make it be tending towards normal.(3) reduce serum AngII and ET level, blood vessel endothelium injury and cardiovascular disorder that protection is raise and caused by AngII.Therefore think, formononetin-3 '-'-sodium sulfonate and prunusetin-3 '-sodium sulfonate has the function of lowering fat and protecting liver effect preferably and protection blood vessel endothelium.
Claims (6)
1. following formula (1) or formula (2) compound.
Formula (1): R
1=R
2=H R
3=CH
3
Formula (2): R
1=CH3 R
2=OH R
3=H
2. the preparation method of claim 1 Chinese style (1) or formula (2) compound, this method may further comprise the steps:
(1) add solvent and following formula (3) onocol or formula (4) prunusetin in the reactor, onocol or prunusetin are molten
Formula (3): R
1=R
2=H R
3=CH
3
Formula (4): R
1=CH
3R
2=OH R
3=H
Separate in solvent, add sulphonating agent again, onocol or prunusetin and sulphonating agent carry out chemical reaction, the mol ratio of used onocol or prunusetin and sulphonating agent is 1: 1～1: 10, making the temperature of reaction solution with register is 20～100 ℃, reacted 5 minutes～10 hours, formononetin-3 '-'-sulfonic acid or prunusetin-3 '-mixture of sulfonic acid and unreacted reactant;
(2) (1) post reaction mixture 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, the compound separation of claim 1 Chinese style (1) or formula (2) is come out, obtain crude product, 1～5 times of amount 10～20% sodium chloride solution that adds the crude product amount again make its purifying, obtain the pure product of compound of claim 1 Chinese style (1) or formula (2).
Formula (3): R
1=R
2=H R
3=CH
3Formula (1): R
1=R
2=H R
3=CH
3
Formula (4): R
1=CH
3R
2=OH R
3=H formula (2): R
1=CH
3R
2=OH R
3=H
3. according to the preparation method of described claim 1 Chinese style of claim 2 (1) or formula (2) compound, its Chinese style (3) or formula (4) are 40 ℃ and 50 ℃ with the temperature of reaction of sulphonating agent respectively, and chemical time was respectively 2 hours and 2.5 hours.
4. according to the preparation method of described claim 1 Chinese style of claim 2 (1) or formula (2) compound, it is characterized in that: said solvent is 70～98% sulfuric acid; Said sulphonating agent is the vitriol oil or chlorsulfonic acid or oleum or sulphur trioxide.
5. a pharmaceutical composition for the treatment of hyperlipidaemia and fatty liver disease wherein has claim 1 Chinese style (1) or formula (2) compound and the pharmaceutically acceptable carrier for the treatment of significant quantity.
6. claim 1 Chinese style (1) or formula (2) the compound application in the medicine of preparation treatment hyperlipidaemia and fatty liver disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100173265A CN100462361C (en) | 2007-01-31 | 2007-01-31 | Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100173265A CN100462361C (en) | 2007-01-31 | 2007-01-31 | Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101020684A true CN101020684A (en) | 2007-08-22 |
| CN100462361C CN100462361C (en) | 2009-02-18 |
Family
ID=38708571
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2007100173265A Active CN100462361C (en) | 2007-01-31 | 2007-01-31 | Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100462361C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101904836A (en) * | 2009-06-08 | 2010-12-08 | 山东绿叶天然药物研究开发有限公司 | New usage of formononetin-3'-sodium sulfonate |
| CN102552241A (en) * | 2012-01-06 | 2012-07-11 | 南京中医药大学 | Application of formononetin in preparing medicine for preventing and treating airway inflammation and asthma |
| CN104208058A (en) * | 2014-08-18 | 2014-12-17 | 周玉梅 | Application of sodium prunusetin-3'-sulfonate to prepare medicines for treating male infertility |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1199964C (en) * | 2001-03-14 | 2005-05-04 | 陕西师范大学 | Soya aglycone-3'-sodium sulfonate and its preparing method and medicinal use |
| CN1275958C (en) * | 2004-06-25 | 2006-09-20 | 陕西师范大学 | Genistein-3'-sodium sulfonate, dimethylation daidzein-3'-sodium sulfonate, their preparing process and pharmaceutical use |
| CN1594307A (en) * | 2004-06-25 | 2005-03-16 | 陕西师范大学 | Extraction separation for Nepal irid isoflavone from kudzu, process for preparing sulfonated compounds thereof , and their pharmaceutical uses |
| CN100351248C (en) * | 2004-07-05 | 2007-11-28 | 南京大学 | Genistein derivatives and their preparation process and use |
-
2007
- 2007-01-31 CN CNB2007100173265A patent/CN100462361C/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101904836A (en) * | 2009-06-08 | 2010-12-08 | 山东绿叶天然药物研究开发有限公司 | New usage of formononetin-3'-sodium sulfonate |
| CN102552241A (en) * | 2012-01-06 | 2012-07-11 | 南京中医药大学 | Application of formononetin in preparing medicine for preventing and treating airway inflammation and asthma |
| CN104208058A (en) * | 2014-08-18 | 2014-12-17 | 周玉梅 | Application of sodium prunusetin-3'-sulfonate to prepare medicines for treating male infertility |
| CN104208058B (en) * | 2014-08-18 | 2016-05-11 | 李健 | The application of prunetin-3 '-sodium sulfonate in the medicine of preparation treatment male sterility |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100462361C (en) | 2009-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101380390B (en) | Preparation method of Pu-Er ripe tea standard extract PRC-001 and preparation method and use thereof | |
| CN105982884B (en) | A kind of purposes of Corylifolin methyl ether and the like | |
| CN101406513B (en) | Malaytea scurfpea fruit extract, pharmaceutical composition containing the same, and preparation method and application thereof | |
| CN101172102A (en) | Water-solubility cozymase Q* supermolecule composition and method for preparing the same | |
| CN100462361C (en) | Formononetin-3'-sodium sulfonate, prunetin-3'-sodium sulfonate and their prepn process and medicinal use | |
| CN101455750B (en) | Extraction method of coptis detoxifcation decoction active site and use thereof | |
| CN102030796A (en) | Several cardiac glycoside compounds separated from rosebay and applications thereof | |
| CN106008446A (en) | Xanthone derivatives, and preparation methods and use of xanthone and derivatives thereof | |
| CN106554339B (en) | A kind of isoflavone derivative and its preparation method and application | |
| CN101817827A (en) | Method for preparing sesamin from sesame | |
| CN108752404B (en) | A kind of berberine salt derivative and its preparation method and application that triazole is sugar-modified | |
| CN111410643A (en) | Preparation and application of novel cinnamoyl ester catechin and four novel phenylpropanoid flavane alkaloids | |
| CN100475804C (en) | Isochromanone 4 derivate, preparation process and therapeutic use thereof | |
| CN102731459B (en) | Scutellarin aglycone Mannich derivatives, and preparation method and application thereof | |
| CN110857295A (en) | Flavone-ligustrazine compound CH-X with selective anti-liver cancer effect and preparation method and application thereof | |
| CN101633652B (en) | Baicalein-8-sodium sulfonate and preparation method thereof and pharmaceutical use thereof | |
| WO2005003146A1 (en) | The c-glycosylisoflavones having alkylaminoalkoxyl substituent, the preparation and the use of the same | |
| CN111393277B (en) | 4-butyl polyhydroxy benzophenone compound derivative and application thereof | |
| CN1594307A (en) | Extraction separation for Nepal irid isoflavone from kudzu, process for preparing sulfonated compounds thereof , and their pharmaceutical uses | |
| CN110143902B (en) | Selenium-containing chalcone derivative Compound1, synthesis method and application in non-alcoholic steatohepatitis resisting medicine | |
| CN1059444C (en) | Composition for curing angicardiopathy and its production and usage | |
| CN1275958C (en) | Genistein-3'-sodium sulfonate, dimethylation daidzein-3'-sodium sulfonate, their preparing process and pharmaceutical use | |
| JP2004508282A (en) | Novel Torarakuton and its derivatives, and their use for hypolipidemic and weight loss | |
| CN1095669C (en) | Medicine composition of saponin containing protopanaxyndiol component and preparing process and application thereof | |
| CN108210454A (en) | A kind of Orally taken emulsion of Pabuk former times profit cloth and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |