CN101613334B - Flavonoid derivative and medical application thereof - Google Patents
Flavonoid derivative and medical application thereof Download PDFInfo
- Publication number
- CN101613334B CN101613334B CN2008101271700A CN200810127170A CN101613334B CN 101613334 B CN101613334 B CN 101613334B CN 2008101271700 A CN2008101271700 A CN 2008101271700A CN 200810127170 A CN200810127170 A CN 200810127170A CN 101613334 B CN101613334 B CN 101613334B
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- China
- Prior art keywords
- methyl
- pharmaceutically acceptable
- ethoxycarbonylethoxy
- salt
- added
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims description 13
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
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- 125000001424 substituent group Chemical group 0.000 claims description 4
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
The invention relates to a flavonoid derivative of which an oxygen atom is substituted by alkyl-carboxylic acid or pharmaceutically acceptable salt thereof, a medicine composition containing the compounds as active components and an application of the flavonoid derivative or the pharmaceutically acceptable salt of the flavonoid derivative for preparing a lipid-lowering medicine.
Description
Technical Field
The invention relates to a novel flavonoid derivative with an oxygen atom substituted by carboxylic acid alkyl or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compounds as active ingredients, and application of the flavonoid derivative or the pharmaceutically acceptable salt thereof in preparing lipid-lowering medicines.
Background
Cardiovascular and cerebrovascular diseases are the first diseases threatening the life health of human beings, and hypercholesterolemia characterized by the rise of plasma low-density lipoprotein and very low-density lipoprotein levels is one of the main pathogenic factors of the cardiovascular and cerebrovascular diseases; the increased blood fat can also cause fatty liver and liver cirrhosis. The treatment of reducing blood fat becomes an important means for preventing and treating coronary heart disease and other cardiovascular and cerebrovascular diseases, and is also an effective measure for treating fatty liver, hepatic fibrosis and liver cirrhosis.
Currently, lipid-lowering drugs commonly used in clinical practice include phenoxyalkanoic acid compounds represented by fenofibrate, gemfibrozil and the like, and statins represented by simvastatin and atorvastatin. However, these lipid-lowering drugs often produce side effects of elevated transaminase in clinical applications. In addition, statins can cause side effects such as myositis, muscle lysis, liver and kidney damage; the fibrate drugs can increase the incidence of gallstones and also cause muscular disorders, manifested as muscle pain, muscle twitching, weakness, etc. These side effects limit the clinical use of lipid lowering drugs.
Flavonoids are the most common natural active substances. According to the structure type, the extract can be divided into flavone (such as apigenin and luteolin), isoflavone (such as daidzein and genistein), flavanone (such as hesperetin), chalcone and flavonol (such as quercetin).
The flavonoids have wide biological activity (Y.C.xu, S.W.S.Leung, D.K.Y.Yeung, et al.phytochemistry 2007, 68: 1179-1188.). These activities include: resisting oxidation, scavenging free radicals, inhibiting LDL oxidation, and preventing and treating arteriosclerosis; dilating coronary artery, reducing polar myocardial infarction area, reducing oxygen consumption of myocardium, and preventing platelet adhesion, aggregation and thrombosis; anti-liver injury effect and anti-tumor effect.
Disclosure of Invention
The invention discovers a new flavonoid derivative with lipid-lowering activity by introducing a pharmacophore with lipid-lowering effect into a flavonoid molecule; because the basic structural unit of flavone is reserved, the lipid-lowering lipid.
Accordingly, in a first aspect, the present invention provides a flavonoid derivative substituted by a carboxylic acid alkyl on an oxygen atom shown in formula I, or a pharmaceutically acceptable salt thereof:
wherein,
d represents a flavonoid derivative;
R1and R2Each independently is methyl or ethyl;
R3is H, or C1-5Alkyl optionally substituted with a substituent selected from methyl, ethyl or propyl;
n is 0 or an integer of 1 to 3.
A second aspect of the invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof.
A third aspect of the invention is directed to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
In a fourth aspect, the present invention relates to the use of a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for lowering lipid levels.
According to one embodiment of the present invention, the present invention relates to a flavonoid derivative represented by formula I, wherein the oxygen atom of the flavonoid derivative is substituted by a carboxylic acid alkyl group, or a pharmaceutically acceptable salt thereof:
wherein,
d represents a flavonoid derivative;
R1and R2Each independently is methyl or ethyl;
R3is H, or C1-5Alkyl optionally substituted with a substituent selected from methyl, ethyl or propyl;
n is 0 or an integer of 1 to 3.
The term "flavonoid derivative" as used herein includes flavonoids such as apigenin, luteolin; isoflavones such as daidzein, genistein; flavanones such as hesperetin; flavonols, such as quercetin; or chalcones and the like.
According to another embodiment of the invention, the alkyl side chain of the carboxylic acid may be attached to the 4' -OH group of the flavone or isoflavone molecule to form formula IaA compound shown in the specification:
wherein,
X1and X2Each independently of the other is H, OH OR OR4；R4Is C1-3An alkyl group; r1、R2、R3And n is as defined for formula I.
According toIn another embodiment of the present invention, the alkyl side chain of the carboxylic acid may also be linked to the 7-OH group of the flavone or isoflavone molecule to form formula IbA compound shown in the specification:
wherein,
X2and X3Each independently of the other is H, OH OR OR4；R4Is C1-3An alkyl group; r1、R2、R3And n is as defined in formula I.
According to another embodiment of the present invention, the alkyl side chain of the carboxylic acid may also be linked to the 7-OH group of the flavanone molecule to form formula IcA compound shown in the specification:
wherein,
X2and X3Each independently of the other is H, OH OR OR4；R4Is C1-3An alkyl group; r1、R2、R3And n is as defined in formula I.
According to another embodiment of the present invention, the alkyl side chain of the carboxylic acid may also be linked to the 7-OH group of the flavonol molecule to form formula IdA compound shown in the specification:
wherein,
X2and X3Each independently of the other is H, OH OR OR4；R4Is C1-3An alkyl group;R1、R2、R3and n is as defined in formula I.
According to another embodiment of the present invention, the alkyl side chain of the carboxylic acid may also be linked to an OH group in the chalcone molecule to form formula IeA compound shown in the specification:
wherein,
X2and X3Each independently of the other is H, OH OR OR4；R4Is C1-3An alkyl group; r1、R2、R3And n is as defined in formula I.
More preferred in the present invention are the following compounds:
4' - (1-methyl-1-ethoxycarbonylethoxy) -7-hydroxyisoflavone;
4' - (4-methyl-4-isobutoxycarbonylpentyloxy) -7-hydroxyisoflavone;
4' - (1-methyl-1-ethoxycarbonylethoxy) -5, 7-dihydroxyisoflavone;
4' - (1-methyl-1-carboxyethoxy) -5, 7-dihydroxyisoflavone;
4' - (4-methyl-4-isobutoxycarbonylpentyloxy) -5, 7-dihydroxyisoflavone;
4' - (1-methyl-1-ethoxycarbonylethoxy) -5, 7-dihydroxyflavone;
4' - (1-methyl-1-ethoxycarbonylethoxy) -7-methoxyisoflavone;
4' -methoxy-7- (1-methyl-1-ethoxycarbonylethoxy) isoflavone;
5-hydroxy-7- (1-methyl-1-ethoxycarbonylethoxy) flavone;
7- (1-methyl-1-ethoxycarbonylethoxy) isoflavone;
7- (1-methyl-1-ethoxycarbonylethoxy) flavone;
7- (1-methyl-1-ethoxycarbonylethoxy) flavanone;
7- (1-methyl-1-ethoxycarbonylethoxy) flavone; and
4- (1-methyl-1-ethoxycarbonylethoxy) chalcone;
or a pharmaceutically acceptable salt thereof.
When R is3When the compound is H, the invention also provides pharmaceutically acceptable salts of flavonoid derivatives which are shown in the formula I, Ia, Ib, Ic, Id or Ie and are substituted by carboxylic alkyl on the oxygen atom, and the salts can be formed by carboxyl in the molecule and various cations such as sodium ions, potassium ions, ammonium ions, calcium ions, zinc ions, magnesium ions and the like.
The flavonoid derivative represented by formula I of the present invention, wherein the oxygen atom is substituted by a carboxylic acid alkyl group, can be prepared by the following method.
When the flavonoid compound (D-OH) with only one hydroxyl in the molecule is adopted, the flavonoid compound can directly react with bromoalkanoate under the action of potassium carbonate to obtain an ester target compound, wherein the reaction solvent is DMF, the reaction temperature is 90-130 ℃, and the reaction time is 8-12 h; hydrolyzing the target ester compound to obtain the target compound of free carboxylic acid or carboxylate, wherein the solvent of the hydrolysis reaction is methanol or ethanol, the reaction reagent is 1-5N sodium hydroxide or potassium hydroxide, the reaction temperature is 0-50 ℃, and the reaction time is 8-20 hours.
The specific synthetic route is as follows:
in the reaction formula, D represents flavonoid derivative, R1、R2、R3And n is as defined for formula I.
When the molecule contains the flavonoid compound with two or more hydroxyl groups, the flavonoid compound can firstly react with methoxy methyl chloride (MOMCl) to obtain a part of hydroxyl-protected flavonoid derivative (MOM-O-D-OH), the reaction solvent is acetone, the catalyst is potassium carbonate, the reaction condition is heating reflux, and the reaction time is 10-14 hours; reacting MOM-O-D-OH with bromoalkanoate under the action of potassium carbonate to obtain an ester target compound protected by hydroxyl, wherein a reaction solvent is DMF, the reaction temperature is 90-130 ℃, and the reaction time is 8-12 h; finally, deprotection is carried out to obtain an ester target compound, the deprotection reaction solvent is methanol or ethanol, the deprotection reagent is 1-5N hydrochloric acid or sulfuric acid, and the reaction condition is heating reflux for 20-60 min; hydrolyzing the target ester compound to obtain the target compound of free carboxylic acid or carboxylate, wherein the solvent of the hydrolysis reaction is methanol or ethanol, the reaction reagent is 1-5N sodium hydroxide or potassium hydroxide, the reaction temperature is 0-50 ℃, and the reaction time is 8-20 hours.
The specific synthetic route is as follows:
in the reaction formula, D represents flavonoid derivative, R1、R2、R3And n is as defined for formula I.
The invention provides a pharmaceutical composition containing flavonoid derivative with carboxylic acid alkyl substituted on oxygen atom shown as formula I, Ia, Ib, Ic, Id or Ie or pharmaceutically acceptable salt thereof as an active ingredient and a suitable carrier or excipient. Such carriers or excipients include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin and the like. The pharmaceutical composition of the present invention can be prepared into solutions, tablets, capsules, injections, etc. according to conventional methods known to those skilled in the art, and is used for the treatment of hyperlipidemia and related disorders.
The flavonoid derivative substituted by a carboxylic acid alkyl on the oxygen atom shown in the formula I, Ia, Ib, Ic, Id or Ie, or the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the same can be administered by oral administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal and the like, or can be administered by means of an external reservoir. Among them, oral, intraperitoneal or intravenous administration is preferable.
It is further noted that the dosage and method of administration of the compounds of the present invention will depend upon a variety of factors including the age, weight, sex, physical condition, nutritional status, the strength of the compound's activity, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The preferable dosage is 0.01-100 mg/kg body weight/day, wherein the optimal dosage is 0.1-10 mg/kg body weight/day.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
Example 1.4' - (1-methyl-1-ethoxycarbonylethoxy) -7-hydroxyisoflavone (Compound I)1) Synthesis of (2)
The synthetic route is as follows:
the first step is as follows: 250mL of dry acetone was added to a 500mL round bottom flask, 10g (39.4mmol) of daidzein was added with mechanical stirring, and 4.35g of K was added with vigorous stirring2CO3(31.5mmol) was stirred at room temperature for 30min, 3.17mL (39.4mmol) of methoxymethyl chloride (MOMCl) was added, the mixture was refluxed for 12h, the reaction mixture was cooled to room temperature, then insoluble solid was filtered off, the mother liquor was concentrated under reduced pressure, and the mixture was stirred on silica gel and purified by silica gel column chromatography with eluent of V (petroleum ether)/V (ethyl acetate) ═ 85: 15 to give 3.2g of white solid as 4' -hydroxy-7-methoxymethyleneoxyisoflavone, the yield was 27.4%.
The second step is that: 50mL of redistilled DMF was taken in a 100mL round bottom flask, 3.2g (10.7mmol) of 4' -hydroxy-7-methoxymethyleneoxyisoflavone was added with mechanical stirring, and 9.5g K was added with vigorous stirring2CO3(68.8mmol) and 1g KI, stirring at room temperature for 30min, adding 10mL (68.2mmol) of ethyl 2-bromoisobutyrate, heating at 120 ℃ for reaction for 12h, cooling the reaction mixture to room temperature, filtering off insoluble solid, concentrating the mother liquor under reduced pressure to dryness, mixing the residue with silica gel, and purifying by silica gel column chromatography, wherein V (petroleum ether)/V (ethyl acetate) ═ 85: 15 is eluent, to obtain 2.6g of white solid, namely 4' - (1-methyl-1-ethoxycarbonylethoxy) -7-methoxymethyleneoxy isoflavone, and the yield is 60%.
The third step: 30mL of methanol is added into a 50mL round-bottom flask, 1g (2.4mmol) of 4 '- (1-methyl-1-ethoxycarbonylethoxy) -7-methoxymethyleneoxyisoflavone is added under magnetic stirring, 6mL of 3N hydrochloric acid aqueous solution is added after complete dissolution, heating reflux is carried out for 30min, after cooling, 40mL of water is added into reaction liquid, white flocculent precipitate is generated immediately, filtering, washing with water and infrared drying are carried out, and 0.75g of solid 4' - (1-methyl-1-ethoxycarbonylethoxy) -7-hydroxyisoflavone (I1) is obtained, wherein the yield is 85%.1H NMR(d6-DMSO)δppm 1.20(3H，m)，1.60(6H，m)，4.00(2H，m)，6.86(4H，m)，7.48(2H，d)，7.97(1H，d)，8.35(1H，s)，10.81(1H，s)。
Example 2.4' - (4-methyl-4-isobutoxycarbonylpentyloxy) -7-hydroxyIsoflavone (Compound I)2) Synthesis of (2)
The synthetic route is as follows:
the first step is as follows: in a 100mL round bottom flask was added 50mL of redistilled DMF and under mechanical stirring 1g (3.4mmol) of 4' -hydroxy-7-methoxymethyleneoxy isoflavone and under vigorous stirring 0.37g K2CO3(2.68mmol), stirring at room temperature for 30min, adding 2.22g (10.06mmol) of 5-chloro-2, 2-dimethylpentanoic acid isobutyl ester, heating at 120 ℃ for reaction for 12h, cooling the reaction mixture to room temperature, filtering off solid insoluble substances, concentrating the mother liquor under reduced pressure to dryness, mixing the residue with silica gel, purifying by silica gel column chromatography, and using eluent V (petroleum ether)/V (ethyl acetate) ═ 85: 15 to obtain 0.688g of white solid, namely 4' - (1-methyl-1-ethoxycarbonylpentoxy) -7-methoxymethyleneoxyisoflavone, wherein the yield is 43%.
The second step is that: adding 30mL of methanol into a 50mL round-bottom flask, adding 0.688g (1.43mmol) of 4 '- (1-methyl-1-ethoxycarbonylpentyloxy) -7-methoxymethyleneoxyisoflavone under magnetic stirring, completely dissolving, adding 6mL of 3N hydrochloric acid aqueous solution, heating and refluxing for 30min, cooling, adding 40mL of water into the reaction solution to generate white flocculent precipitate immediately, filtering, washing with water, and drying by infrared to obtain solid 4' - (4-methyl-4-isobutoxycarbonylpentyloxy) -7-hydroxyisoflavone (I)2)0.53g, yield 85%.1H NMR(d6-DMSO)δppm 0.90(6H，m)，1.16(6H，m)，1.65(4H，br)，1.86(H，m)，3.80(2H，d)，3.97(2H，br)，6.93(4H，m)，7.49(2H，d)，7.97(1H，d)，8.35(1H，s)，10.83(1H，s)。
Example 3.4' - (1-methyl-1-ethoxycarbonylethoxy) -5, 7-dihydroxyisoflavone (Compound I)3) Synthesis of (2)
The synthetic route is as follows:
the first step is as follows: 250mL of dry acetone was added to a 500mL round bottom flask, 5g (18.5mmol) of genistein was added with mechanical stirring, and 2.04g K was added with vigorous stirring2CO3(14.8mmol), stirring at room temperature for 30min, adding 1.49mL (18.5mmol) of methoxymethyl chloride, heating and refluxing for 12h, cooling the reaction mixture to room temperature, filtering off insoluble solid, concentrating the mother liquor under reduced pressure, purifying by silica gel column chromatography, and eluting with eluent V (petroleum ether)/V (ethyl acetate) ═ 8: 2 to obtain 2.6g of yellow solid 4' -hydroxy-5-hydroxy-7-methoxymethyleneoxy isoflavone, with the yield of 44.8%.
The second step is that: a250 mL round bottom flask was charged with 100mL redistilled DMF, 2.61g (8.3mmol) of 4', 5-dihydroxy-7-methoxymethyleneoxyisoflavone was added with mechanical stirring, and 6.89g (49.9mmol) of K was added with vigorous stirring2CO3And 1g of KI, stirring at room temperature for 30min, adding 3.66mL (25.0mmol) of ethyl 2-bromoisobutyrate, heating at 120 ℃ for reaction for 12h, cooling the reaction mixture to room temperature, filtering off solid insoluble substances, concentrating the mother liquor under reduced pressure to dryness, mixing the residue with silica gel, and purifying by silica gel column chromatography, wherein an eluent of V (petroleum ether)/V (ethyl acetate) ═ 8: 2 is used to obtain 1.79g of yellow solid 4' - (1-methyl-1-ethoxycarbonylethoxy) -5-hydroxy-7-methoxymethyleneoxyisoflavone, and the yield is 50.3%.
The third step: adding 45mL of methanol into a 100mL round-bottom flask, adding 1.5g (3.51mmol) of 4 '- (1-methyl-1-ethoxycarbonylethoxy) -5-hydroxy-7-methoxymethyleneoxyisoflavone under magnetic stirring, adding 9mL of 3N hydrochloric acid aqueous solution after complete dissolution, heating and refluxing for 30min, cooling, pouring the reaction solution into 60mL of ice water, stirring, standing at 4 ℃ overnight, filtering, washing with water, and drying to obtain yellow solid 4' - (1-methyl-1-ethoxycarbonylethoxy) -5, 7-dihydroxyisoflavone (I)3)1.2g, yield 90%.1H NMR(d6-DMSO)δppm 1.20(3H，m)，1.55(6H，m)，3.72(1H，m)，4.20(1H，m)，6.23(H，s)，6.40(H，s)，6.84(2H，m)，7.47(2H，d)，8.38(1H，s)，10.90(1H，s)，12.89(1H，s)。
Example 4.4' - (1-methyl-1-carboxyethoxy) -5, 7-dihydroxyisoflavone (Compound I)4) Synthesis of (2)
The synthetic route is as follows:
0.5g (1.3mmol) of the compound from example 3 was taken and 50mL CH was added2Cl2Dissolving in mixed solvent of 9: 1/MeOH, adding 10mL of 2N NaOH MeOH solution, stirring at room temperature for 12h to hydrolyze completely to form a large amount of white precipitate, evaporating the reaction solution under reduced pressure, adding 30mL of water to dissolve, extracting with ethyl acetate for 3 times (3X 20mL), adjusting pH of the water layer with 3N hydrochloric acid to 2-3 to immediately form white precipitate, extracting with ethyl acetate for 3 times (3X 20mL), combining ethyl acetate layers, and evaporating the reaction solution under reduced pressure to obtain solid I40.4g, yield 87%.1H NMR(d6-DMSO)δppm1.60(6H，m)，6.23(1H，d)，6.40(1H，d)，6.87(2H，d)，7.46(2H，d)，8.39(1H，s)，10.94(1H，s)，12.91(1H，s)，13.14(1H，s)。
Example 5.4' - (4-methyl-4-isobutoxycarbonylpentyloxy) -5, 7-dihydroxyisoflavone (Compound I)5) Synthesis of (2)
The synthetic route is as follows:
the first step is as follows: 40mL of redistilled DMF was taken in a 100mL round bottom flask, 1.2g (3.82mmol) of 4', 5-dihydroxy-7-methoxymethyleneoxyisoflavone was added with mechanical stirring, and 0.422g (3.06mmol) of K was added with vigorous stirring2CO3Stirring at room temperature for 30min, adding 2.53g (11.46mmol) of 5-chloro-2, 2-dimethylIsobutyl pivalate, heating at 120 deg.c for 5 hr, cooling the reaction mixture to room temperature, filtering out insoluble solid, vacuum concentrating the mother liquid, mixing the residue with silica gel, silica gel column chromatographic purification with eluent V (petroleum ether)/V (ethyl acetate) of 9: 1 to obtain yellow solid 0.84g, i.e. 4' - (1-methyl-1-ethoxycarbonylpentoxy) -5-hydroxy-7-methoxy methyleneoxy isoflavone in 44.2% yield.
The second step is that: adding 30mL of methanol into a 50mL round-bottom flask, adding 0.84g (1.68mmol) of 4 '- (1-methyl-1-ethoxycarbonylpentyloxy) -5-hydroxy-7-methoxymethyleneoxy isoflavone under magnetic stirring, completely dissolving, adding 6mL of 3N hydrochloric acid aqueous solution, heating and refluxing for 30min, cooling, pouring the reaction solution into 40mL of ice water, stirring, standing at 4 ℃ overnight, filtering, washing with water, and drying to obtain yellow solid 4' - (4-methyl-4-isobutoxycarbonylpentyloxy) -5, 7-dihydroxyisoflavone (I)5)0.687g, yield 90%.1H NMR(d6-DMSO)δppm 0.90(6H，m)，1.16(6H，m)，1.65(4H，br)，1.87(1H，m)，3.80(2H，d)，3.97(2H，br)，6.23(1H，s)，6.39(1H，s)，6.96(2H，d)，7.48(2H，d)，8.37(1H，s)，10.89(1H，s)，12.93(1H，s)。
Example 6.4' - (1-methyl-1-ethoxycarbonylethoxy) -5, 7-dihydroxyflavone (Compound I)6) Synthesis of (2)
The synthetic route is as follows:
the first step is as follows: 250mL of dry acetone was added to a 500mL round bottom flask, 5g (18.5mmol) of apigenin (5, 7, 4' -trihydroxyflavone) was added with stirring, and 2.04g K was added with vigorous stirring2CO3(14.8mmol), stirring at room temperature for 30min, adding 1.49mL (18.5mmol) of methoxymethyl chloride, heating and refluxing for 12h, cooling the reaction mixture to room temperature, filtering off insoluble solid, concentrating the mother liquor under reduced pressure, purifying by silica gel column chromatography, and purifying with V (petroleum ether)/V (ethyl acetate)Ester) ═ 8: 2 as eluent, to give 3.0g of yellow solid, i.e., 4' -hydroxy-5-hydroxy-7-methoxymethyleneoxy flavone, in 51.7% yield.
The second step is that: a250 mL round bottom flask was charged with 100mL redistilled DMF, 3.0g (9.55mmol) of 4', 5-dihydroxy-7-methoxymethyleneoxy flavone was added with mechanical stirring, and 7.91g (57.3mmol) of K was added with vigorous stirring2CO3And 1g of KI, stirring at room temperature for 30min, adding 4.19mL (28.65mmol) of ethyl 2-bromoisobutyrate, heating at 120 ℃ for reaction for 12h, cooling the reaction mixture to room temperature, filtering off solid insoluble substances, concentrating the mother liquor under reduced pressure to dryness, mixing the residue with silica gel, and purifying by silica gel column chromatography, wherein an eluent of V (petroleum ether)/V (ethyl acetate) ═ 8: 2 is used to obtain 2.45g of yellow solid, namely 4' - (1-methyl-1-ethoxycarbonylethoxy) -5-hydroxy-7-methoxymethyleneoxyflavone, and the yield is 60%.
The third step: adding 30mL of methanol into a 50mL round-bottom flask, adding 1g (2.34mmol) of 4 '- (1-methyl-1-ethoxycarbonylethoxy) -5-hydroxy-7-methoxymethyleneoxy flavone under magnetic stirring, completely dissolving, adding 6mL of 3N hydrochloric acid aqueous solution, heating and refluxing for 30min, cooling, pouring the reaction solution into 40mL of ice water, stirring, standing at 4 ℃ overnight, filtering, washing with water, and drying to obtain a yellow solid, namely 4' - (1-methyl-1-ethoxycarbonylethoxy) -5, 7-dihydroxyflavone (I)6)0.79g, yield 88%.1H NMR(d6-DMSO)δppm1.20(3H，m)，1.65(6H，m)，4.22(2H，m)，6.23(1H，d)，6.40(1H，d)，7.02(1H，s)，7.60(3H，m)，，8.38(1H，s)，10.87(1H，s)，12.92(1H，s)。
Example 7.4' - (1-methyl-1-ethoxycarbonylethoxy) -7-methoxyisoflavone (Compound I)7) Synthesis of (2)
The synthetic route is as follows:
get I10.2g(0.5mmol), anhydrous potassium carbonate 0.055g (0.4mmol), tetrabutylammonium bromide 0.242g (0.75mmol), dimethyl carbonate 20mL as solvent, heating and refluxing for 12h, cooling the reaction solution, filtering to obtain filtrate, washing the filtrate with 3M hydrochloric acid aqueous solution, extracting with methyl tert-butyl ether for 3 times (3 × 20mL), combining the extracts, evaporating to dryness under reduced pressure, mixing with silica gel, purifying by silica gel column chromatography, eluting with V (petroleum ether)/V (ethyl acetate) ═ 9: 1 to obtain 4' - (1-methyl-1-ethoxycarbonylethoxy) -7-methoxyisoflavone (I)7)0.17g, yield 90%.1H NMR(d6-DMSO)δppm1.23(2H，m)，1.56(6H，m)，3.73(3H，s)，3.91(3H，s)，6.83(2H，m)，7.09(1H，dd)，7.19(1H，d)，7.50(2H，m)，8.03(1H，d)，8.46(1H，s)。
Example 8.4' -methoxy-7- (1-methyl-1-ethoxycarbonylethoxy) isoflavone (Compound I)8) Synthesis of (2)
The synthetic route is as follows:
a100 mL round bottom flask was charged with 40mL redistilled DMF, 2.07g (7.5mmol) of formononetin was added with stirring, and 3.14g K was added with vigorous stirring2CO3(22.5mmol) and 0.267g KI (1mmol) were stirred at room temperature for 30min, 2.21mL (15mmol) ethyl 2-bromoisobutyrate was added, the reaction was heated at 120 ℃ for 12h, the reaction mixture was cooled to room temperature, the insoluble solid was filtered off, the mother liquor was concentrated to dryness under reduced pressure, the residue was stirred on silica gel and purified by silica gel column chromatography, eluent was V (petroleum ether)/V (ethyl acetate) ═ 85: 15 to give 1.95g solid, i.e., 4' -methoxy-7- (1-methyl-1-ethoxycarbonylethoxy) isoflavone, in 68% yield.1H NMR(d6-DMSO)δppm1.17(3H，m)，1.65(6H，s)，3.79(3H，s)，4.20(2H，m)，6.85(1H，d)，6.99(3H，m)，7.52(2H，d)，8.05(1H，d)，8.41(1H，s)。
Example 9.5-hydroxy-7- (1-methyl-1-ethoxycarbonylethoxy) flavone (Compound I)9) Synthesis of (2)
The synthetic route is as follows:
40mL of redistilled DMF was charged in a 100mL round bottom flask, 1.905g (7.5mmol) of 5, 7-dihydroxyflavone was added with mechanical stirring, and 3.14g of K was added with vigorous stirring2CO3(22.5mmol) and 0.254g KI (1mmol) were stirred at room temperature for 30min, 2.21mL (15mmol) ethyl 2-bromoisobutyrate was added, the reaction was heated at 120 ℃ for 12h, the reaction mixture was cooled to room temperature, the insoluble solid was filtered off, the mother liquor was concentrated to dryness under reduced pressure, the residue was stirred on silica gel and purified by silica gel column chromatography, eluent was V (petroleum ether)/V (ethyl acetate) ═ 85: 15 to give 2.07g of solid, i.e., 5-hydroxy-7- (1-methyl-1-ethoxycarbonylethoxy) flavone, yield was 75%.1HNMR(d6-DMSO)δppm1.18(3H，m)，1.65(6H，s)，4.22(2H，m)，6.16(1H，d)，6.51(1H，d)，7.02(1H，s)，7.60(3，m)，8.10(2，m)，12.71(H，br)。
Example 10.7- (1-methyl-1-ethoxycarbonylethoxy) isoflavone (Compound I)10) Synthesis of (2)
The synthetic route is as follows:
in the first step, 100mL of phenylacetonitrile and 250mL of 20% NaOH aqueous solution are added into a 500mL round-bottom flask, the mixture is heated and refluxed for reaction for 15h, the reaction solution is cooled to room temperature, the pH value is adjusted to 1 by concentrated hydrochloric acid, the reaction solution is stirred and cooled, solid is obtained by suction filtration, and the solid is washed by water to obtain 99.96g of white flaky solid, namely phenylacetic acid, wherein the yield is 86%.
And secondly, taking a 250mL round-bottom flask, installing a reflux condenser with an anhydrous calcium chloride drying tube, adding 24.586g (0.18mol) of phenylacetic acid and 16.341g (0.16mol) of anhydrous zinc chloride, heating the flask to 120 ℃ in an oil bath, adding 8.889g (0.081mol) of resorcinol, continuing stirring and reacting for 3 hours, cooling the flask at room temperature, freezing and solidifying the flask to 0 ℃, washing the flask with 10% sodium acetate, and decoloring the flask with activated carbon to obtain 10.16g of 2, 4-dihydroxy phenyl benzyl ketone with the yield of 55%.
Thirdly, a 50mL three-neck flask is provided with a reflux condenser with a drying tube and a constant pressure dropping funnel, 1.823g (8mmol) of 2, 4-dihydroxy phenyl benzyl ketone and 20mLDMF are added, the heating temperature is controlled below 70 ℃, and POCl is slowly dropped36mL, after the dropwise addition, heating to 70 ℃ for reaction for 2h, pouring the reaction solution into 100mL of ice water under stirring, cooling and filtering, washing the solid with 10mL of 60% ethanol for 3 times to obtain a brown solid, and then washing with absolute ethanol to obtain 1.102g of light pink solid, namely 7-hydroxyisoflavone, wherein the yield is 58%.
Fourth step in 50mL round bottom flask was added 12mL redistilled DMF, 0.370g (1.55mmol) 7-hydroxyisoflavone was added with stirring, and 1.300g K was added with vigorous stirring2CO3(9.3mmol) and 0.06g KI were stirred at room temperature for 30min, 1.364mL (9.3mmol) of ethyl 2-bromoisobutyrate was added, the reaction was heated at 120 ℃ for 12h, the reaction mixture was cooled to room temperature, insoluble solids were filtered off, the mother liquor was concentrated to dryness under reduced pressure, and the residue was recrystallized from anhydrous ethanol to give 0.296g of 7- (1-methyl-1-ethoxycarbonylethoxy) isoflavone in 52% yield.1H NMR(d6-DMSO)δppm1.17(3H，m)，1.65(6H，s)，4.20(2H，m)，6.87(1H，d)，6.99(1H，d)，7.50(5H，m)，8.05(1H，d)，7.96(1H，d)，8.48(1H，s)。
Example 11.7- (1-methyl-1-ethoxycarbonylethoxy) flavone (Compound I)11) Synthesis of (2)
The synthetic route is as follows:
in the first step, 100mL of dry acetone is added into a 250mL round-bottom flask, 1.530g (10mmol) of 2, 4-dihydroxy acetophenone and 10.107g (73mmol) of anhydrous potassium carbonate are added under stirring, 2.3mL (19.8mmol) of benzoyl chloride is added dropwise, after the addition is finished, the mixture is heated and refluxed for 15 hours, cooled to room temperature, filtered, washed by a small amount of acetone, 180mL of 10% acetic acid solution is added into a filter cake, the mixture is stirred fully and acidified, filtered, washed by water and dried to obtain 1.918g of solid, namely 2-hydroxy-4- (benzoyloxy) dibenzoylmethane, and the yield is 53.3%.
Secondly, 1.461g of 2-hydroxy-4- (benzoyloxy) dibenzoylmethane (4mmol), 3.650g of sodium acetate and 17mL of glacial acetic acid are added into a 50mL round-bottom flask, heated and refluxed for 12h, cooled to room temperature, filtered, washed by 5 percent of NaHCO3 and boiling water in sequence, and dried to obtain 0.781g of light pink powder, namely 7-hydroxyflavone, with the yield of 80.8 percent.1H NMR(d6-DMSO)δppm6.972(3H，m)，7.58(3H，m)，7.90(1H，d)，8.07(2H，m)，10.86(1H，s).
Third step 23mL of redistilled DMF was taken in a 50mL round bottom flask, 0.732g (3mmol) of 7-hydroxyflavone was added with mechanical stirring, and 2.488g K was added with vigorous stirring2CO3(18mmol) and 0.06g KI, stirring at room temperature for 30min, adding 2.64mL (18mmol) of ethyl 2-bromoisobutyrate, heating at 120 ℃ for reaction for 12h, cooling the reaction mixture to room temperature, filtering off solid insoluble substances, concentrating the mother liquor under reduced pressure to dryness, and recrystallizing the residue with anhydrous ethanol to obtain 0.76g of 7- (1-methyl-1-ethoxycarbonylethoxy) flavone with a yield of 69%.1H NMR(d6-DMSO)δppm1.17(3H，m)，1.67(6H，s)，4.21(2，dd)，7.02(3H，m)，7.59(3H，m)，7.96(1H，d)，8.11(2H，dd)。
Example 12.7- (1-methyl-1-ethoxycarbonylethoxy) flavanone (Compound I)12) Synthesis of (2)
The synthetic route is as follows:
firstly, adding 12.164g (80mmol) of 2, 4-dihydroxy acetophenone and 100mL of dry acetone into a 250mL round-bottom flask, mixing and dissolving, adding 33.12g (240mmol) of anhydrous potassium carbonate, heating and refluxing for 1h, dropwise adding 8mL (100mmol) of chloromethyl methyl ether, heating and refluxing for 15h, concentrating under reduced pressure and evaporating to dryness, adding ethyl acetate for dissolving, filtering, washing precipitate with ethyl acetate, merging filtrate and washing liquid, mixing the filtrate with the washing liquid, purifying by silica gel column chromatography, and using eluent V (petroleum ether)/V (ethyl acetate) ═ 9.5: 0.5 to obtain 4.706g of solid 4.706g, namely 2-hydroxy-4-methoxy acetophenone with the yield of 30%.
In the second step, 4.706g (24mmol) of 2-hydroxy-4-methoxy methoxyidene acetophenone and 3mL (28mmol) of benzaldehyde are mixed in 7mL of absolute ethyl alcohol, cooling to 0 deg.C, cooling 8mL of 60% ethanol aqueous solution containing 4g KOH to 0 deg.C, adding dropwise into the mixed solution, the reaction solution is changed into yellow from colorless immediately, the stirring reaction is continued, the color is gradually deepened, under the protection of nitrogen, the reaction solution is cooled in an ice bath and stirred for reaction for 3 hours, then stirring for 38h at room temperature, pouring the reaction solution into 50mL of ice water, adjusting the pH value to 2-3 by using dilute hydrochloric acid, extracting by using ethyl ether, backwashing an ethyl ether layer by using water, drying, stirring the sample by using silica gel, and purifying by using silica gel column chromatography, wherein an eluent is 9.5: 0.5 of V (petroleum ether)/V (ethyl acetate), so as to obtain 6.13g of solid, i.e. 2-hydroxy-4-methoxymethyleneoxychalcone, in 90% yield.
Thirdly, 0.697g (2.45mmol) of 2-hydroxy-4-methoxy methyleneoxy chalcone and 0.704g of anhydrous sodium acetate are mixed in 7mL of ethanol, 3 drops of water are added to dissolve the sodium acetate, heating and refluxing are carried out for 72h, after cooling, silica gel is used for sample mixing, silica gel column chromatography is carried out for purification, and eluent V (petroleum ether)/V (ethyl acetate) ═ 9.5: 0.5 is used to obtain 0.592g of solid, namely 7-methoxy methyleneoxy flavanone, with the yield of 84.9%.
Fourthly, dissolving 0.592g (2.08mmol) of 7-methoxy methyleneoxy flavanone in 20mL of methanol, adding 4mL of 3M hydrochloric acid, heating and refluxing for 30min, cooling, adding 20mL of water into the reaction solution to generate white turbidity, performing suction filtration to obtain a solid, washing with water, and drying to obtain 0.459g of 7-methoxy methyleneoxy flavanone with the yield of 91.8%.
Fifthly, adding 25mL redistilled DMF into a 50mL round-bottom flask, adding 0.459g (1.9mmol) of 7-hydroxyflavanone under mechanical stirring, and then adding0.787gK was added with vigorous stirring2CO3(5.7mmol), stirring at room temperature for 30min, adding 0.836mL (5.7mmol) of ethyl 2-bromoisobutyrate, heating at 120 ℃ for reaction for 12h, cooling the reaction mixture to room temperature, filtering off insoluble solid, concentrating the mother liquor under reduced pressure to dryness, and recrystallizing the residue with absolute ethanol to obtain 0.427g of 7- (1-methyl-1-ethoxycarbonylethoxy) flavanone with a yield of 63%.1H NMR(d6-DMSO)δppm1.1.15(3H，m)，1.59(6H，m)，2.78(1H，d)，3.20(1H，t)，4.18(2H，m)，5.65(1H，d)，6.31(1H，s)，6.51(1H，d)，7.47(5H，m)，7.72(1H，d)。
Example 13.7- (1-methyl-1-ethoxycarbonylethoxy) flavonol (Compound I)13) Synthesis of (2)
The synthetic route is as follows:
first, 0.888g (3.13mmol) of 2-hydroxy-4-methoxymethyleneoxychalcone and 55mL of methanol were put into a 100mL round-bottomed flask and dissolved in 6mL of a 16% aqueous NaOH solution and 30% H2O21.5mL, reacted at room temperature for 14h, neutralized to pH7 with a few drops of hydrochloric acid, filtered to give a pale yellow solid, recrystallized from ethanol, and dried to give 0.408g of 7-methoxymethyleneoxy flavonol in 43.8% yield.
And secondly, dissolving 0.408g (1.37mmol) of 7-methoxy methyleneoxy flavonol in 20mL of methanol, adding 4mL of 3M hydrochloric acid, heating and refluxing for 30min, cooling, adding 20mL of water into the reaction solution to generate white turbidity, performing suction filtration to obtain a solid, washing with water, and drying to obtain 0.313g of 7-hydroxy flavonol with the yield of 90%.
Third step in 50mL round bottom flask was added 25mL redistilled DMF, 0.313g (1.23mmol) 7-hydroxyflavonol was added with mechanical stirring, and 0.509g K was added with vigorous stirring2CO3(3.69mmol), stirred at room temperature for 30min, added 0.54mL (3.69mmol) of ethyl 2-bromoisobutyrate and heated at 120 ℃ to reactAfter the reaction mixture is cooled to room temperature for 12 hours, solid insoluble substances are filtered, the mother liquor is concentrated to dryness under reduced pressure, and the residue is recrystallized by absolute ethyl alcohol to obtain 0.267g of 7- (1-methyl-1-ethoxycarbonylethoxy) flavonol with the yield of 59 percent.1H NMR(d6-DMSO)δppm1.17(3H，m)，1.65(6H，s)，4.20(2，dd)，6.93(2H，m)，7.57(3H，m)，7.98(3H，m)，8.95(1H，br)。
Example 14.4- (1-methyl-1-ethoxycarbonylethoxy) chalcone (Compound I)14) Synthesis of (2)
The synthetic route is as follows:
firstly, 5.446g (40mmol) of p-hydroxyacetophenone and 50mL of dry acetone are added into a 100 round-bottom flask for mixing and dissolving, then 16.56g (120mmol) of anhydrous potassium carbonate is added, heating reflux is carried out for 1h, 4mL (50mmol) of chloromethyl methyl ether is added dropwise, heating reflux is carried out for 15h, reduced pressure concentration and evaporation to dryness are carried out, ethyl acetate is added for dissolving, filtration is carried out, ethyl acetate is carried out for washing and precipitation, filtrate and washing liquid are combined, silica gel is used for sample mixing, silica gel column chromatography and purification are carried out, eluent is V (petroleum ether)/V (ethyl acetate) ═ 9.5: 0.5, 5.698g of white solid is obtained, namely 4-methoxy methoxyacetophenone is.
In the second step, 5.480g (30.4mmol) of 4-methoxy methoxyidene acetophenone and 3.9mL (36.5mmol) of benzaldehyde are mixed in 10mL of absolute ethyl alcohol, the mixture is cooled to 0 ℃, 10mL of 60% ethanol aqueous solution containing 5g of KOH is cooled to 0 ℃, then the mixture is dripped into the mixed solution, the reaction solution is changed into yellow from colorless immediately, the dripping speed is controlled, the mixture is continuously stirred for reaction, under the protection of nitrogen, the mixture is cooled in an ice bath and stirred for reaction for 2.5h, then the mixture is stirred for 40h at room temperature, the reaction solution is poured into 100mL of ice water, the pH value is adjusted to 2-3 by dilute hydrochloric acid, ether is extracted, the ether layer is backwashed by water, the mixture is dried, silica gel is used for sample mixing, and silica gel column chromatography is used for purification, and eluent is 9.5: 0.5 of V (petroleum ether)/V (ethyl acetate), 7.518g of white solid, namely 4-methoxy methyleneoxy.
And thirdly, dissolving 1.5g (5.6mmol) of 4-methoxy methyleneoxy chalcone in 50mL of methanol, adding 12mL of 3M hydrochloric acid, heating and refluxing for 30min, cooling, adding 50mL of water into the reaction solution to generate white turbidity, performing suction filtration to obtain a solid, washing with water, and drying to obtain a white solid, namely 1.111g of 4-hydroxy chalcone, wherein the yield is 88.6%.
Fourth step 50mL of redistilled DMF was taken in a 100mL round bottom flask, 1.051g (4.69mmol) of 4-hydroxychalcone was added with mechanical stirring, and 3.906g K was added with vigorous stirring2CO3(28.15mmol), stirring at room temperature for 30min, adding 4mL (28.15mmol) of ethyl 2-bromoisobutyrate, heating at 120 ℃ for reaction for 12h, cooling the reaction mixture to room temperature, filtering off insoluble solid substances, concentrating the mother liquor under reduced pressure to dryness, mixing the residue with silica gel, and purifying by silica gel column chromatography with eluent V (petroleum ether)/V (ethyl acetate) ═ 7: 3 to obtain 0.952g of 4- (1-methyl-1-ethoxycarbonylethoxy) chalcone with the yield of 60%.1H NMR(d6-DMSO)δppm1.16(3H，m)，1.60(6H，s)，4.18(2H，m)，6.90(2H，m)，7.46(3H，m)，7.74(1H，d)，7.91(3H，m)，8.14(2H，d)。
Example 15 evaluation of lipid-lowering Effect in a model of hyperlipemia caused by egg yolk emulsion
20 +/-2 g of female and male parent of Kunming mouse, and randomly divided into a model control group and 100mg/kg of daidzein-1Groups and test compound groups (tween-80 boost), 10 animals per group. Except for the normal control group, the other groups were administered by intragastric administration, and 75% egg yolk emulsion was intraperitoneally injected 2h after administration. After 22h (fasting for 12h), the eyeball was removed and blood was collected, and the contents of Triglyceride (TG) and Total Cholesterol (TC) in the serum were measured by the kit method, and the results are shown in Table 1.
TABLE 1 Effect of Compounds on TC, TG in 75% egg yolk emulsion in hyperlipidemic mice
P < 0.05 compared to control.
Example 16 evaluation of lipid lowering Effect in Triton WR-1339-induced hyperlipidemic mouse model
30 +/-2 g of Kunming mouse is divided into a model control group and 300 mg/kg of daidzein-1Group and test compound group (tween-80 hydrotrope). Triton WR-1339400 mg/kg of caudal vein iv-1Immediately after the administration, the drugs were administered by gavage, and 24 hours later (fasting for 12 hours), the eyeballs were removed and blood was collected, and the contents of TG and TC in the serum were measured by a kit method, and the results are shown in table 2. TABLE 2 Effect of the Compounds on TC and TG in Triton WR-1339-induced hyperlipidemic mice
P < 0.05 compared to control.
As can be seen from tables 1 and 2, the target compound had a significant lipid-lowering effect, and the daidzein lipid-lowering effect was not significant.
Claims (9)
1. A flavonoid derivative, or a pharmaceutically acceptable salt thereof, having the formula Ia：
Wherein,
X1and X2Each independently of the other is H, OH OR OR4；R4Is C1-3An alkyl group;
R1and R2Each independently is methyl or ethyl;
R3is H, or C1-5Alkyl optionally substituted with a substituent selected from methyl, ethyl or propyl;
n is 0 or an integer of 1 to 3.
2. A flavonoid derivative, or a pharmaceutically acceptable salt thereof, having the formula Ie：
Wherein,
X2and X3Each independently of the other is H, OH OR OR4；R4Is C1-3An alkyl group;
R1and R2Each independently is methyl or ethyl;
R3is H, or C1-5Alkyl optionally substituted with a substituent selected from methyl, ethyl or propyl;
n is 0 or an integer of 1 to 3.
3. A flavonoid derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:
4' - (1-methyl-1-ethoxycarbonylethoxy) -7-hydroxyisoflavone;
4' - (4-methyl-4-isobutoxycarbonylpentyloxy) -7-hydroxyisoflavone;
4' - (1-methyl-1-ethoxycarbonylethoxy) -5, 7-dihydroxyisoflavone;
4' - (1-methyl-1-carboxyethoxy) -5, 7-dihydroxyisoflavone;
4' - (4-methyl-4-isobutoxycarbonylpentyloxy) -5, 7-dihydroxyisoflavone;
4' - (1-methyl-1-ethoxycarbonylethoxy) -5, 7-dihydroxyflavone;
4' - (1-methyl-1-ethoxycarbonylethoxy) -7-methoxyisoflavone; and
4- (1-methyl-1-ethoxycarbonylethoxy) chalcone.
4. The flavonoid derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt is a sodium salt, a potassium salt, an ammonium salt, a calcium salt, a zinc salt or a magnesium salt.
5. The flavonoid derivative according to claim 3, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt is a sodium salt, a potassium salt, an ammonium salt, a calcium salt, a zinc salt or a magnesium salt.
6. A pharmaceutical composition comprising a flavonoid derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
7. A pharmaceutical composition comprising a flavonoid derivative according to claim 3 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
8. Use of a flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of a medicament for the treatment of hyperlipidemia.
9. The use of a flavonoid derivative or a pharmaceutically acceptable salt thereof according to claim 3 for the preparation of a medicament for the treatment of hyperlipidemia.
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| KR102393639B1 (en) * | 2019-09-27 | 2022-05-04 | 중앙대학교 산학협력단 | Dimethylchalcone derivatives and preparation method thereof |
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| 邵国贤 等.葛根有效成分黄豆甙元及其衍生物的合成及结构与抗缺氧作用关系.《药学学报》.1980,第15卷(第9期),第538-547页. * |
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