CN1944448A - Puerarin derivative and its medicinal use - Google Patents
Puerarin derivative and its medicinal use Download PDFInfo
- Publication number
- CN1944448A CN1944448A CN 200610000814 CN200610000814A CN1944448A CN 1944448 A CN1944448 A CN 1944448A CN 200610000814 CN200610000814 CN 200610000814 CN 200610000814 A CN200610000814 A CN 200610000814A CN 1944448 A CN1944448 A CN 1944448A
- Authority
- CN
- China
- Prior art keywords
- replacement
- alkyl
- amino
- cycloalkanes
- alkyloyl
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses the puerarin derivatives, and their preparation process, medicine compositions and application in preparing medicine for treating cardiac and cerebral vascular diseases, obstruction of retinal artery and vein, sudden hearing loss and other diseases, improving memory and lowering blood sugar.
Description
Technical field
The present invention relates to the new puerarin derivate shown in the general formula (I), its preparation method, the pharmaceutical composition that contains one or more these compound compositions, preparing and heart and brain circulation diseases associated with this compounds, and the retina arteriovenous is blocked, disease and improvement memories such as sudden deafness, the application in the medicine of lowering blood glucose.
Background technology
Puerarin (puerarin) is to extract from the dry root of legume pueraria lobata (Puerarialobata (Willd.) Ohwi) and sweet kudzu (P.thomaonii Benth), separate the isoflavones grape sugar charcoal glycosides that obtains, chemistry 74 '-dihydroxyl by name-8-β-D-glucone isoflavone, be one of main active ingredient in the Chinese medicine root of kudzu vine, have pharmacological action comparatively widely.Studies show that puerarin has dilating effect to coronary artery, can protect global ischemia cardiac muscle and myocardial ischemia-reperfusion injury, reduce the acute myocardial infarction area, reduce myocardial consumption of oxygen, stop platelet adhesion reaction, gathering and thrombosis; Effect with mediation retinal embolism; And acute cerebral ischemia there is significant protective effect; And the effect of improving memory and lowering blood glucose arranged.
Puerarin is mainly used in the treatment of diseases such as coronary heart disease, stenocardia, myocardial infarction, ischemic cerebrovascular disease and retina obstruction at present clinically.But the poly-hydroxy of puerarin chemistry structures shape it is fat-soluble poor, the defective that bioavailability is low at present mainly with the injection form administration, is not only made troubles to the patient for the cardiovascular and cerebrovascular chronic disease long term injections that the course of treatment is long, even cause local tissue necrosis or infection, increase patient's misery.Though some tablets, capsule, granule have appearred, puerarin oral administration absorption difference in gi tract, and bioavailability is low.And the poly-hydroxy structure of puerarin is unfavorable for passing through hemato encephalic barrier, and influence is to the curative effect of cerebrovascular disease.To fundamentally increase the fat-soluble of puerarin, improve the bioavailability of puerarin, improve drug effect, must carry out structural modification and transformation puerarin.So far, done partly about the structural modification China Medicine University of puerarin molecule and to have worked, only limit to 7, the 4 ' hydroxyl of position of molecule and the modification of 11 methylol, (Yang Ruolin, Li Na etc. China Medicine University's journal, 1999,30 (2): 81-85), Zhenping, Shaanxi pharmaceutical factory to wherein Hydroxyethylpuerarin as the new drug application of treatment cerebro-vascular diseases patent (CN1394603A).The present invention modifies respectively and transforms according to different reaction site on different each hydroxyl of reactive behavior in the puerarin molecule and the phenyl ring outside forefathers' work.
The objective of the invention is to improve its pharmacokinetic property, improve oral administration biaavailability, puerarin derivate that obtained performance is good and analogue by the puerarin molecule is carried out structural modification and transformation.
Summary of the invention
Another object of the present invention is to provide preparation novel puerarin derivate method;
A further object of the present invention is to provide a kind of pharmaceutical composition that contains one or more this compounds;
Another purpose of the present invention is to provide the purposes of novel puerarin derivate in the medicine of cardiovascular and cerebrovascular relative disease.
In order to finish the present invention's purpose, the present invention takes following technical scheme:
The present invention relates to have the novel puerarin derivate of general formula I:
Wherein,
R
1And R
2Be selected from hydrogen respectively, the C of replacement or non-replacement
1-18Alkyl, the C of replacement or non-replacement
3-9Cycloalkyl, the fragrant heterocycle of aromatic ring, replacement or the non-replacement of replacement or non-replacement, the C of replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
1-18(substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C to alkoxy acyl
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl);
Preferred R
1And R
2Be the alkyloyloxyethyl methylene radical, alkoxy acyl, amino low alkyl group, hydroxyl low-grade alkyl, carboxyl low-grade alkyl, alkyl ,-C (=O) (CH
2) nCOOH n=2,3,4,
R
3And R
4Be selected from hydrogen respectively; Halogen; Nitro; (substituting group is selected from the C of replacement or non-replacement to the amino of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
3-9Cycloalkyl or contain the C of fragrant heterocycle, replacement or non-replacement of aromatic ring, replacement or the non-replacement of one or both heteroatomic cycloalkyl, replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aroyl, replacement or non-replacement of aroyl, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyl groups, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aryl acyloxy, replacement or non-replacement of aryl acyloxy, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyloxy, replacement or non-replacement
1-18The C of alkoxy acyl, replacement or non-replacement
1-18The C of alkyl sulphonyl, replacement or non-replacement
3-9Cycloalkanes or contain the heterocyclic aryl alkylsulfonyl of aryl sulfonyl, replacement or non-replacement of one or both heteroatomic naphthene sulfamide bases, replacement or non-replacement (substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl), alkylsulfonyl); (substituting group is selected from the C of replacement or non-replacement to the hydroxyl of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
3-9Cycloalkyl or contain the C of fragrant heterocycle, replacement or non-replacement of aromatic ring, replacement or the non-replacement of one or both heteroatomic cycloalkyl, replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aroyl, replacement or non-replacement of aroyl, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyl groups, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aryl acyloxy, replacement or non-replacement of aryl acyloxy, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyloxy, replacement or non-replacement
1-18The C of alkoxy acyl, replacement or non-replacement
1-18The C of alkyl sulphonyl, replacement or non-replacement
3-9Cycloalkanes or contain the heterocyclic aryl alkylsulfonyl of aryl sulfonyl, replacement or non-replacement of one or both heteroatomic naphthene sulfamide bases, replacement or non-replacement (substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl));-OSO
3H;-OC (=O) (CH
2) nCOOH n=2,3,4;-OP (=O) (OH)
2
Preferred R
3And R
4Be hydrogen, nitro, amino, N-alkylamino, N, N-dialkyl amido, alkyl amide, sulfonamido, alkyl sulfonyl amino, hydroxyl alkylamino, carboxyl alkylamino, halogen atom, hydroxyl, alkoxyl group, alkanoyloxy, alcoxyl acyloxy, aminoalkoxy, hydroxy alkoxy base, carboxyl alkoxyl group, the inferior methoxyl group of alkyloyloxyethyl, carbamyl alkoxyl group ,-OSO
3H ,-OC (=O) (CH
2) nCOOH n=2,3,4 ,-OP (=O) (OH)
2
R
5Be selected from hydrogen, the C of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
3-9Cycloalkyl or contain the C of fragrant heterocycle, replacement or non-replacement of aralkyl, replacement or the non-replacement of one or both heteroatomic cycloalkyl, replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aroyl, replacement or non-replacement of aroyl, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyl groups, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aryl acyloxy, replacement or non-replacement of aryl acyloxy, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyloxy, replacement or non-replacement
1-18The C of alkoxy acyl, replacement or non-replacement
1-18The C of alkyl sulphonyl, replacement or non-replacement
3-9Cycloalkanes or contain the heterocyclic aryl alkylsulfonyl of aryl sulfonyl, replacement or non-replacement of one or both heteroatomic naphthene sulfamide bases, replacement or non-replacement (substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl));-OSO
3H;-OC (=O) (CH
2) nCOOHn=2,3,4;-OP (=O) (OH)
2
R more preferably
5Be selected from hydrogen, alkyl, aralkyl, alkyloyl, alkoxyl formyl, alkyloyloxyethyl methylene radical ,-SO
3H ,-C (=O) (CH
2) nCOOH n=2,3,4 ,-P (=O) (OH)
2
R
6, R
7And R
8Be selected from hydrogen respectively, the C of replacement or non-replacement
1-18Alkyl, the C of replacement or non-replacement
3-9Cycloalkyl, the fragrant heterocycle of aralkyl, replacement or the non-replacement of replacement or non-replacement, the C of replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
1-18(substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C to alkoxy acyl
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl);-SO
3H ,-C (=O) (CH
2) nCOOH n=2,3,4 ,-P (=O) (OH)
2
R more preferably
6, R
7And R
8Be selected from hydrogen respectively, alkyl, aralkyl, alkyloyl, alkoxy acyl, alkyloyloxyethyl methylene radical ,-SO
3H ,-C (=O) (CH
2) nCOOH n=2,3,4 ,-P (=O) (OH)
2
Most preferably
R
1And R
2Be selected from hydrogen, ethanoyl, valeryl, benzoyl, methoxycarbonyl base, pivalyl oxygen methylene radical;
R
3And R
4Be selected from hydrogen, 3 '-nitro, 3 '-amino, N, the N-dimethylamino;
R
5, R
6, R
7And R
8Be selected from hydrogen, ethanoyl, valeryl, benzoyl, methoxycarbonyl base, pivalyl oxygen methylene radical, benzene methene, propylidene.
But
R
1, R
2, R
3, R
4, R
5, R
6,, R
7And R
8Can not be hydrogen simultaneously, can not be ethanoyl simultaneously.
R
3, R
4, R
5, R
6,, R
7And R
8When being hydrogen simultaneously, R
1And R
2Can not be simultaneously hydroxyethyl.
R
1, R
2, R
3, R
4, R
6, R
7And R
8When being hydrogen simultaneously, R
5Can not be trityl and benzoyl.
Among the present invention " alkane " and base generally comprises straight or branched or cyclic fatty alkyl, wherein can comprise one or two heteroatoms (N, O, S), halogen replaces or does not replace; Also comprise the fragrant alkane (aromatic ring or aromatic heterocycle) that replaces or do not replace, wherein substituting group (single replacement or polysubstituted) can be halogen, nitro, alkoxyl group, ester group, amido, alkyl, methylsulfonyl, amino methylsulfonyl).
The straight chained alkyl of 1～5 carbon that the low alkyl group among the present invention refers generally to replace or do not replace, substituting group can be fatty alkyl or fragrant alkane.
R of the present invention
33 ' position or 5 ' position is single replaces, wherein R
3Can with R
1Merge into a substituting group; R
3Also 3 ' position and 5 ' position, or 3 ' position and 6 ' position, or two replacements of 5 ' position and 2 ' position.R
4Single replacement of 6, also 5 with two replacements of 6.
R of the present invention
5, R
2, R
6, R
7, R
8In certain two can merge into a substituting group, as 12-O, 15-O-propylidene puerarin, 12-O, 15-O-benzene methene puerarin.Be the described compound of preparation general formula I of the present invention, the inventive method comprises:
In alkaline medium; optionally phenolic hydroxyl group is carried out acidylate or alkylation; and different according to the sterically hindered and reactivity worth of two phenolic hydroxyl groups, select suitable reaction conditions respectively 7 phenolic hydroxyl groups and a 4 ' phenolic hydroxyl group of puerarin molecule to be carried out acidylate and alkylation.Optionally mineral alkali comprises: anhydrous sodium carbonate, Anhydrous potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride etc.; Optional organic alkali comprises amine, nitrogen heterocyclic ring class, weak acid strong alkali salt class and alkali formula ion exchange resin etc.Optionally solvent comprises polar aprotic solvent and polar aprotic solvent, as acetone, and N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, Virahol, ethanol, the trimethyl carbinol, tetrahydrofuran (THF), pyridine, triethylamine etc.
In sour environment, optionally alcoholic extract hydroxyl group is carried out acidylate or alkylation, and different according to the reactive behavior of primary hydroxyl group and secondary hydroxyl group, select suitable reaction conditions respectively primary hydroxyl group and secondary hydroxyl group in the puerarin molecule to be carried out acidylate or alkylation.Optionally mineral acid comprises: boron trifluoride, aluminum chloride, lewis acids such as zinc dichloride, hydrochloric acid, sulfuric acid, phosphoric acid, strong acid weak base salt and acid salt such as protonic acid such as oxalic acid and ammonium chloride; Optional organic acid comprises: formic acid, acetate, carboxylic-acids such as phenylformic acid, methylsulfonic acid, sulfonic acid classes such as tosic acid, phenols and organic bases strong acid salt and acid amberlite lipid.Optionally solvent comprises polar aprotic solvent and polar aprotic solvent, as acetone, and N, dinethylformamide, methyl-sulphoxide, hexamethylphosphoramide, Virahol, ethanol, the trimethyl carbinol, tetrahydrofuran (THF), ethyl acetate, chloroform etc.
Can be respectively the phenolic hydroxyl group and the alcoholic extract hydroxyl group of puerarin molecule be carried out acidylate or alkylation by protection and deprotection strategy.As can under alkaline environment, protecting phenolic hydroxyl group with chloromethyl ether earlier, carry out the acidylate of alcoholic extract hydroxyl group again, under acidic conditions, slough the methyl ether protecting group then.
Also can carry out whole acidylates or alkylation to puerarin phenolic hydroxyl group and alcoholic extract hydroxyl group earlier, select appropriate reaction conditions optionally to remove then, thereby obtain needed structure modified outcome.
The modification of two phenyl ring can be by selecting suitable nitrating agent and controlling appropriate reaction conditions and carry out selectively nitrated in the puerarin molecule; further be reduced into amino; amino is carried out alkylation or acylations; and can further carry out nitrated to phenyl ring; amino is further diazotization also; thereby the substitution reaction of diazonium salt takes place, obtain a series of phenyl ring substitution product.Nitrating agent can be selected from: HNO
3/ AcOH, HNO
3/ Ac
2O, HNO
3/ BF
3, CH
3ONO
2/ BF
3, NH
4NO
3/ HNO
3/ Ac
2O, nitric acid benzoyl, nitric acid acetyl etc.
The invention still further relates to a kind of pharmaceutical composition that contains medicine effective dose as described compound of general formula I and pharmaceutically acceptable carrier.
In the compound of Formula I of the present invention, work as R
1, R
2, R
5, R
6, R
7, R
8For acyl group or part be acyl group all the other when being hydrogen; these compounds should be the prodrug of puerarin; in Biomedia, hydrolysis is transformed into former medicine puerarin easily under the effect of esterase or phosphoesterase, and fat-soluble, the bioavailability of the compound of these esterifications improve a lot.And the purposes of these esterification compounds should comprise the purposes of the puerarin of known and later discovery at present.
In compound of Formula I of the present invention, R
1, R
2, R
5, R
6, R
7, R
8For alkyl or part be alkyl all the other when being hydrogen, and R
3, R
4Be not hydrogen or part when the hydrogen, these puerarin derivates are better than or are equivalent to puerarin in some aspects as its biological activity of new activeconstituents.Pharmacological research finds, part of compounds is alleviating the activity that all demonstrates quite or be better than puerarin aspect cardiac muscular tissue's ischemic injuries in these puerarin derivates in the action model that isolated rat heart reperfusion injury and Pituitrin is brought out the rat heart muscle ischemic.
Compound of Formula I of the present invention; coronary artery there is dilating effect; can protect global ischemia cardiac muscle and myocardial ischemia-reperfusion injury; reduce the acute myocardial infarction area; reduce myocardial consumption of oxygen, stop platelet adhesion reaction, gathering and thrombosis, and have the effect of mediation retinal embolism; acute cerebral ischemia there is significant protective effect, and the effect of improving memory and lowering blood glucose is arranged.Clinically, can be used for the treatment of diseases such as coronary heart disease, stenocardia, myocardial infarction, ischemic cerebrovascular disease and retina obstruction.
The compounds of this invention can be with oral methods or the medication of parenteral road.Oral medication can be tablet, granule, capsule, soft capsule; Non-have injection and suppository etc. through the intestines drug formulation.These preparations are according to the known method preparation of those skilled in the art.For making tablet, granule, capsule, the used auxiliary material of soft capsule is the auxiliary agent of conventional usefulness, starch for example, lactose, gelatin, syrup, glycerine, beeswax, gum arabic, micropowder silica gel, talcum powder, polyoxyethylene glycol.The used solvent of liquid dosage form for example has water, ethanol, propylene glycol, plant oil such as Semen Maydis oil, peanut oil, olive wet goods.Containing in the preparation of The compounds of this invention also can have other auxiliary agents, tensio-active agent for example, lubricant, antioxidant, disintegrating agent, sanitas, correctives, pigment etc.
At tablet, granule, capsule, soft capsule, the dosage that contains formula I compound of the present invention in injection or the suppository is to calculate with the compound amount that exists in the unit dosage form.The general content of formula I compound of the present invention is 10-50mg in unit dosage form, and preferred unit dosage form contains 20-100mg.
Embodiment
Below with reference to embodiment invention is described further, but does not limit the scope of the invention.
Determining instrument: the fusing point micro-fusing point instrument of Yanaco, NMR (Nuclear Magnetic Resonance) spectrum VaariaanMercury 300 type nuclear magnetic resonance analyser.Mass spectrum ZAD-2F and VG300 mass spectrograph.
Embodiment 1.7-O-valeryl puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone, add Anhydrous potassium carbonate 0.414 gram (3 mmole), drip the pivalyl chloride of 1 mmole under the stirring at room in batches, TLC follows the tracks of reaction, stirring at room to raw material point disappears, add ethyl acetate extraction after revolving most of solvent, washing, anhydrous sodium sulfate drying, revolve and desolvate, column chromatography (ethyl acetate: methyl alcohol=10: 1) obtain white solid product 0.345 gram, fusing point: 216-218 ℃, productive rate 69%.
1H NMR(300MHZ，CD
3OD)，δ：8.261(S，3/7H，H2)，8.246(S，4/7H，H2)，8.17(d，1H，H5)，7.35(d，2H，H2′6′)，7.165(d，3/7H，H6)，7.095(d，4/7H，H6)，6.80(d，2H，H3′5′)，1.37(S，9H，-CH
3)，5.05(d，4/7H，H9)，4.66(d，3/7H，H9)，4.16(t，3/7H，H14)，3.94(t，4/7H，H14)，3.83(d，1H，H15)，3.64(dd，3/7H，H15)，3.54(dd，4/7H，H15)，3.22-3.52(m，3H，H11，H12，H13)。MS(FAB)：M+1＝501。
Embodiment 2.7-O-ethanoyl puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone, add Anhydrous potassium carbonate 0.414 gram (3 mmole), drip the Acetyl Chloride 98Min. of 1 mmole under the stirring at room in batches, TLC follows the tracks of reaction, and stirring at room to raw material point disappears, and adds ethyl acetate extraction after revolving most of solvent, washing, anhydrous sodium sulfate drying revolves and desolvates, column chromatography (ethyl acetate: methyl alcohol=10: 1) obtain white solid product 0.289 gram.Fusing point: 194-196 ℃, productive rate 63%.
1H NMR(300MHz，CD
3OD)，δ：8.278(S，2/5H，H2)，8.246(S，3/5H，H2)，8.18(d，1H，H5)，7.36(d，2H，H2′6′)，7.175(d，2/5H，H6)，7.15(d，3/5H，H6)，6.80(d，2H，H3′5′)，1.37(S，9H，-CH
3)，5.05(d，3/5H，H9)，4.67(d，2/5H，H9)，4.15(t，2/5H，H14)，3.93(t，3/5H，H14)，3.83(d，1H，H15)，3.64(dd，2/5H，H15)，3.54(dd，3/5H，H15)，3.3-3.5(m，3H，H11，H12，H13)。MS(FAB)：M+1＝459.3。
Embodiment 3.7-O, 4 '-O-two valeryl puerarins
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone, add Anhydrous potassium carbonate 0.414 gram (3 mmole), drip the pivalyl chloride of two mmoles under the stirring at room in batches, TLC follows the tracks of reaction, and stirring at room to raw material point disappears, and adds ethyl acetate extraction after revolving most of solvent, washing, anhydrous sodium sulfate drying revolves and desolvates, column chromatography (ethyl acetate: methyl alcohol=10: 1) obtain white solid product 0.42 gram.Fusing point: 163-165 ℃, productive rate 71%.
1H NMR(300MHz，CDCl
3)，δ：8.01(S，2/3H，H2)，7.99(S，1/3H，H2)，8.31(d，1H，H5)，7.41(d，2/3H，H2′6′)，7.39(d，4/3H，H2′6′)，7.11(d，1/3H，H6)，7.02(d，2/3H，H6)，6.85(d，2H，H3′5′)，5.28(d，2/3H，H9)，4.83(d，1/3H，H9)，5.62(dd，1/3H，H14)，5.39(dd，2/3H，H14)，3.40-4.20(m，5H，H11，H12，H13，H15).0.80-1.50(m，18H，CH
3)。
MS(FAB)：M+1＝585.2。
Embodiment 4.7-O, 4 '-O, 15-O-three valeryl puerarins
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone, add Anhydrous potassium carbonate 0.414 gram (3 mmole), drip the pivalyl chloride of 3 mmoles under the stirring at room in batches, TLC follows the tracks of reaction, and stirring at room to raw material point disappears, and adds ethyl acetate extraction after revolving most of solvent, washing, anhydrous sodium sulfate drying revolves and desolvates, column chromatography (ethyl acetate: methyl alcohol=10: 1) obtain white solid product 0.32 gram.Fusing point: 142-144 ℃, productive rate 47%.
1H NMR(300MHz，CDCl
3)，δ：8.10(S，4/9H，H2)，8.09(S，5/9H，H2)，8.27(d，5/9H，H5)，8.21(dd，4/9H，H5)，7.55(d，10/9H，H2′6′)，7.51(dd，8/9H，H2′6′)，7.05(dd，4/9H，H6)，7.00(d，5/9H，H6)，7.12(d，10/9H，H3′5′)，7.07(dd，8/9H，H3′5′)，5.18(d，4/9H，H9)，4.77(d，5/9H，J＝9.9Hz，H9)，5.64(dd，4/9H，H14)，5.44(dd，5/9H，H14)，3.38-3.93(m，5H，H11，H12，H13，H15)，0.82-1.42(m，27H，CH
3)。
MS(FAB)：M+1＝669.2。
Embodiment 5.7-O, 4 '-O-dibenzoyl puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone, add Anhydrous potassium carbonate 0.414 gram (3 mmole), drip the Benzoyl chloride of two mmoles under the stirring at room in batches, TLC follows the tracks of reaction, and stirring at room to raw material point disappears, and adds ethyl acetate extraction after revolving most of solvent, washing, anhydrous sodium sulfate drying revolves and desolvates, column chromatography (ethyl acetate: methyl alcohol=10: 1) obtain white solid product 0.18 gram.Fusing point: 169-171 ℃, productive rate 29%.
1H NMR(300MHZ，CD
3COCD
3)，δ：8.52(S，1H，H2)，8.17(d，1H，H5)，7.81(d，2H，H2′6′)，7.65(d，2H，H3′5′)，6.90(d，1H，H6)，8.31(m，2H，ArH)，7.3-7.9(m，8H，ArH)，5.87(dd，1H，H14)，5.43(d，1H，H9)，3.0-5.0(m，5H，H15，H11，H12，H13)。
MS(FAB)：M+1＝625.1。
Embodiment 6.12-O, 13-O, 14-O-triacetyl puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone; under the ice-water bath; drip 0.2 milliliter of boron trifluoride ether solution and acetic anhydride acylation agent 5 mmoles; TLC follows the tracks of reaction; stirring at room to raw material point disappears; added 5 milliliters of ethanol restir 1 hour; drip the saturated sodium bicarbonate solution termination reaction; revolve most of solvent, ethyl acetate extraction, saturated sodium bicarbonate solution washing; anhydrous sodium sulfate drying; revolve the back column chromatography that desolvates (ethyl acetate: methyl alcohol=10: 1) obtain yellow solid 0.17 gram, fusing point: 141-143 ℃, productive rate 31%.
1H NMR(300MHz，CD
3OD)，δ：8.24(S，1H，H2)，7.98(d，1H，H5)，7.34(d，2H)，6.90(d，1H，H6)，6.79(d，2H，H3′5′)，5.81(w，1H，H9)，5.28(w，1H，H14)，5.22(dd，1H，H13)，3.97(dd，1H，H12)，3.84(m，2H，H15)，3.54(m，1H，H11)，1.96(S，3H，COCH
3)，1,49(S，3H，COCH
3)，1.32(S，3H，COCH
3)。
MS(FAB)：M+1＝541。
Embodiment 7.12-O, 13-O, 14-O, 4 '-the O-tetra-acetylated puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone; under the ice-water bath; drip 0.2 milliliter of boron trifluoride ether solution and acetic anhydride acylation agent 5 mmoles; TLC follows the tracks of reaction; stirring at room to raw material point disappears; added 5 milliliters of ethanol restir 1 hour; drip the saturated sodium bicarbonate solution termination reaction; revolve most of solvent; ethyl acetate extraction; the saturated sodium bicarbonate solution washing, anhydrous sodium sulfate drying revolves the back column chromatography that desolvates (ethyl acetate: methyl alcohol=10: 1) obtain yellow solid 0.26 gram.Fusing point: 126-128 ℃, productive rate 45%.
1H NMR(300MHz，CD
3OD)，δ：8.34(S，1H，H2)，7.99(d，1H，H5)，7.55(d，2H，H2′6′)，6.92(d，1H，H6)，7.12(d，2H，H3′5′)，5.80(w，1H，H9)，5.31(w，1H，H14)，5.25(t，1H，H13)，3.98(t，1H，H12)，3.84(m，2H，H15)，3.54(m，1H，H11)，2.23(S，3H，COCH
3)，1.96(S，3H，COCH
3)，1，49(S，3H，COCH
3)，1.32(S，3H，COCH
3)。
MS(FAB)：M+1＝583。
Embodiment 8.14-O-methoxycarbonyl base puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone, add Anhydrous potassium carbonate 0.414 gram (3 mmole), drip the methoxy methyl acyl chlorides of two mmoles under the stirring at room in batches, TLC follows the tracks of reaction, and stirring at room to raw material point disappears, and adds ethyl acetate extraction after revolving most of solvent, washing, anhydrous sodium sulfate drying revolves and desolvates, column chromatography (ethyl acetate: methyl alcohol=10: 1) obtain white solid product 0.25 gram.Fusing point: 180-182 ℃, 59%.
1H NMR(300MHz，CD
3OD)，δ：8.16(S，1H，H2)，7.98(d，1H，H5)，7.33(d，2H，H2′6′)，6.89(d，1H，H6)，6.78(d，2H，H3′5′)，5.38(dd，1H，H14)，5.15(d，H，H9)，3.85(dd，1H，H15)，3.67(dd，1H，H15)，3.63(dd，1H，H13)，3.52(t，1H，H12)，3.42(dd，1H，H11)，3.39(S，3H，-OCH
3)。
MS(FAB)：M+1＝475.1
Embodiment 9.7-O, 4 '-O, 12-O, 14-O-tetra-acetylated puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone; under the ice-water bath; drip 0.2 milliliter of boron trifluoride ether solution and acetic anhydride acylation agent 5 mmoles; TLC follows the tracks of reaction; stirring at room to raw material point disappears; added 5 milliliters of ethanol restir 1 hour; drip the saturated sodium bicarbonate solution termination reaction; revolve most of solvent, ethyl acetate extraction, saturated sodium bicarbonate solution washing; anhydrous sodium sulfate drying; revolve the back column chromatography that desolvates (ethyl acetate: methyl alcohol=10: 1) obtain yellow solid 0.12 gram, fusing point: 134-136 ℃, productive rate 21%.
1H NMR(300MHz，CD
3OD)，δ：8.35(S，1H，H2)，8.14(d，1H，H5)，7.57(d，2H，H2′6′)，7.07(d，1H，H6)，7.15(d，2H，H3′5′)，4.81(d，1H，H9)，4.39(dd，1H，H14)，5.11(dd，1H，H12)，3.85(dd，1H，H15)，3.63(m，3H，H11，H13，H15)，2.24(S，3H，COCH
3)，2.10(S，3H，COCH
3)，1.54(S，3H，COCH
3).1.20(S，3H，COCH
3)。
MS(FAB)：M+1＝585
Embodiment 10.12-O, 15-O-benzene methene puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone, adds two tosic acid, ice-water bath drips 1.2 mmole phenyl aldehydes down, TLC follows the tracks of reaction, and stirring at room to raw material point disappears, and adds several saturated sodium carbonate solution termination reactions, revolve most of solvent, ethyl acetate extraction, washing, saturated sodium bicarbonate solution washing, anhydrous sodium sulfate drying, revolve and desolvate, column chromatography (ethyl acetate: methyl alcohol=10: 1) separate, obtain white solid product 0.24 gram.Fusing point: 199-201 ℃, productive rate 48%.
1H NMR(300MHZ，CD
3OD)，δ：8.16(S，1H，H2)，8.00(d，1H，H5)，7.48(m，2H，H17)，7.31(d，2H，H2′6′)，6.95(d，1H，H6)，7.29(m，3H，H18)，6.79(d，2H，H3′5′)，5.59(S，1H，H16)，4.32(dd，1H，H14)，5.15(d，1H，H9)，4.22(dd，1H，H15)，3.76(dd，1H，H15)，3.69(dd，1H，H13)，3.63(dd，1H，H12)，3.57(m，1H，H11)。
MS(FAB)：M+1＝505。
Embodiment 11.12-O, 15-O-propylidene puerarin
Puerarin 0.416 gram (1 mmole) is dissolved in 50 milliliters of acetone, adds two tosic acid, ice-water bath drips 1.2 mmole 2-methoxyl group propylene down, TLC follows the tracks of reaction, is stirred to raw material point and disappears, and adds several saturated sodium carbonate solution termination reactions, revolve most of solvent, ethyl acetate extraction, washing, saturated sodium bicarbonate solution washing, anhydrous sodium sulfate drying, revolve and desolvate, column chromatography (ethyl acetate: methyl alcohol=10: 1) separate, obtain white solid product 0.27 gram.Fusing point: 230-232 ℃, productive rate 59%.
1H NMR(300MHZ，CD
3OD)，δ：8.16(S，1H，H2)，8.01(d，1H，H5)，7.33(d，2H，H2′6′)，6.94(d，1H，H6)，6.79(d，2H，H3′5′)，4.26(t，1H，H14)，5.06(d，1H，H9)，3.80(m，2H，H15)，3.69(dd，1H，H13)，3.54(dd，1H，H12)，3.39(m，1H，H11)，1.51(S，3H，CH
3)，1.36(S，3H，CH
3)。MS(FAB)，M+1＝457。
Embodiment 12.7-O-pivalyl oxygen methylene radical puerarin
Pivalyl oxygen METHYLENE CHLORIDE (6.8 mmole) and anhydrous sodium iodide 1.02 grams (6.8 mmole) are dissolved in sealing in 15 milliliters of anhydrous propanones spend the night, joining Anhydrous potassium carbonate 1.9 gram (13.6 mmole) and puerarin 1.4 then restrains in 150 milliliters of acetone solns of (6.8 mmole) and stirs, TLC follows the tracks of reaction to reacting completely, add 150 milliliters of ethyl acetate dilutions after revolving most of solvent, filter, column chromatography for separation obtains white solid 0.19 gram behind the concentrating under reduced pressure, fusing point: 183-185 ℃, productive rate 37%.
1H NMR(300MHZ，CD
3OD)，δ：8.17(S，1H，H2)，8.21(d，1H，H5)，7.34(d，2H，H2′6′)，5.90(dd，2H，-OCH2O-)，7.34(d，1H，H6)，6.80(d，2H，H3’5’)，1.16(S，9H，-CH3)，5.02(d，2/5H，H9)，4.96(d，3/5H，H9)，4.17(t，1H，H14)，3.82(dd，1H，H15)，3.64(dd，1H，H15)，3.25-3.45(m，3H，H11，H12，H13)。
MS(FAB)：M+1＝531
Embodiment 13.7-O, 4 '-O-two pivalyl oxygen methylene radical puerarins
Pivalyl oxygen METHYLENE CHLORIDE 2.04 gram (13.6 mmole) and anhydrous sodium iodide 2.04 are restrained (13.6 mmole) to be dissolved in sealing in 30 milliliters of anhydrous propanones and to spend the night, joining Anhydrous potassium carbonate 1.9 gram (13.6 mmole) and puerarin 1.4 then restrains in 150 milliliters of acetone solns of (6.8 mmole) and stirs, TLC follows the tracks of reaction to reacting completely, add 150 milliliters of ethyl acetate dilutions after revolving most of solvent, filter, (ethyl acetate: methyl alcohol=10: 1) separation obtains white solid 0.37 gram to column chromatography behind the concentrating under reduced pressure.Fusing point: 176-178 ℃, productive rate 58%.
1H NMR(300MHZ，CD
3OD)，δ：8.19(S，1H，H2)，8.21(d，1H，H5)，7.36(d，2H，H2′6′)，6.01(S，2H，-OCH2O-)，7.38(d，1H，H6)，5.90(dd，2H，-OCH2O-)，6.80(d，2H，H3′5′)，1.10(S，9H，-CH
3)，1.16(S，9H，-CH
3)，5.02(d，2/5H，H9)，4.96(d，3/5H，H9)，4.17(t，1H，H14)，3.82(dd，1H，H15)，3.64(dd，1H，H15)，3.25-3.45(m，3H，H11，H12，H13)。
MS(FAB)：M+1＝645
Embodiment 14.3 '-nitro puerarin
Puerarin 3 grams are dissolved in the mixed solution of 30 ml waters and 30 milliliters of acetate, ice-water bath slowly drips the mixing solutions of 36 milliliters of acetate and 24 milliliters of concentrated nitric acids down, TLC follows the tracks of reaction, after being stirred to the disappearance of raw material point, filter, washing, oven dry obtain product yellow solid 2.18 grams, fusing point 237-239 ℃, productive rate 65%.
1H NMR(300MHz，CD
3OD)，δ：8.33(S，1H，H2)，8.02(d，1H，H5)，8.31(d，1H，H6′)，7.78(dd，1H，H2′)，6.96(d，1H，H6)，7.17(d，1H，H3′)，5.04(d，1H，H9)，4.06(t，1H，H14)，3.84(dd，1H，H15)，3.69(dd，1H，H15)，3.45(m，3H，H11，H13，H12)。
MS(FAB)：M+1＝462
Embodiment 15.3 '-amino puerarin
Gained nitro-compound above 0.5 gram is dissolved in 20 milliliters of solvents, adds the Raney-Ni0.05 gram, normal pressure hydrogenation to raw material point disappears, and leaches Raney-Ni, is spin-dried for filtrate, and ethyl alcohol recrystallization obtains product white solid 0.5 gram, 260 ℃ of carbonizations, productive rate 95%.
1H NMR(300MHz，CD
3OD)，δ：8.08(S，1H，H2)，7.99(d，1H，H5)，8.31(d，1H，H6′)，6.70(S，2H，H2′，H6′)，6.92(d，1H，H6)，6.88(S，1H，H3′)，5.03(d，1H，H9)，4.05(w，1H，H14)，3.83(dd，1H，H15)，3.69(dd，1H，H15)，3.39-3.50(m，3H，H11，H13，H12)。
MS(FAB)：M+1＝432.2
Embodiment 16.3 '-N, N-dimethylamino puerarin
The formalin of gained nitro-compound and 0.07 milliliter 36% above 0.5 gram is dissolved in 50 milliliters of solvents, adds 0.05 gram Raney-Ni, normal pressure hydrogenation to raw material point disappears, and leaches Raney-Ni, is spin-dried for filtrate, and ethyl alcohol recrystallization obtains product 0.51 and restrains.Fusing point: 180-182 ℃, productive rate 95%.
1H NMR(300MHz，CD
3COCD
3)，δ：8.19(S，1H，H2)，8.03(d，1H，J＝9，H5)，7.41(S，1H，H2’)，7.11(d，H，J＝7.8，H6’)6.94(d，1H，J＝9，H6)，6.85(d，1H，J＝7.8，H5’)，5.18(d，1H，J＝9.9，H9)，3.89(w，1H，H14)，3.81(dd，1H，H15)，3.69(dd，1H，H15)，3.39-3.50(m，3H，H11，H13，H12)，2.69(S，6H，2N-CH
3).
MS(FAB)：M+1＝460.2.
Embodiment 17.7-O, 4 '-O, 12-O, 13-O, 14-O, 15-O-six ethanoyl-3 '-N, N dimethylamine base puerarin
With 3 '-N, N dimethylamine base puerarin 0.23 gram (0.5 mmole) places 30 milliliters of round-bottomed flasks, add 2 milliliters of aceticanhydrides and 2 milliliters of pyridines, stirring at room is after 2 hours in impouring 20 ml waters, use ethyl acetate extraction, wash 3 times after anhydrous sodium sulfate drying, obtain white solid 0.35 gram after the removal of solvent under reduced pressure, fusing point 78-80 ℃, productive rate 98%.
1H NMR(300MHz，CD
3COCD
3)，δ：8.66(S，1H，H2)，8.24(d，1H，J＝9，H5)，7.38(S，1H，H2’)，7.28(d，H，J＝8.1，H6’)，7.28(d，1H，J＝9，H6)，7.07(d，1H，J＝8.1，H5’)，5.8～4.0(m，7H，H9，H11，H13，H12，2H15，H14)，2.79(S，6H，2N-CH
3)，1，68～2.44(6S，18H，COCH
3).
MS(FAB)：M+1＝712.2
Embodiment 18.7-O, 4 '-O-two valeryls-3 '-N, N dimethylamine base puerarin,
With 3 '-N, N dimethylamine base puerarin 0.23 gram (0.5 mmole) is dissolved in 60 milliliters of acetone, add Anhydrous potassium carbonate 0.414 gram (3 mmole), drip the pivaloyl chloride of two mmoles under the stirring at room, stirring at room to raw material point disappears in batches, adds ethyl acetate extraction after revolving most of solvent, washing, anhydrous sodium sulfate drying revolves and desolvates, and column chromatography obtains white solid product 0.21 gram.Fusing point: 136～138 ℃, productive rate 66%.
1H NMR(300MHz，CD
3COCD
3)，δ：8.49(S，2/3H，H2)，8.39(S，1/3H，H2)，8.26(d，2/3H，J＝9，H5)，8.24(d，1/3H，J＝9，H5)，7.25～7.44(m，3H，H2′H6′H6)，7.16(d，2/3H，J＝8.1，H5′)，6.90(d，1/3H，J＝8.1，H5′)，5.20～5.38(m，1H，H9)，2.80(S，6H，2N-CH
3)，2.0～4.0(6S，18H，CH
3)，3.4～3.9(m，5H，H14，H11，H12，H13，H15).
MS(FAB)：M+1＝628.2.
Active appraisal experiment
Experimental example 1. puerarin derivates are to the influence of isolated rat heart reperfusion injury model
The SD rat is adopted in the model preparation, preparation Langendorff isolated heart.Experiment is divided into model group, blank group and administration group.Observation index is to measure LDH activity in the perfusion heart effluent liquid.Statistical method is that each administration group is compared with model group respectively, adopts studentt test to carry out test of significance.The results are shown in following table:
Table 1. puerarin derivate is to the influence of isolated rat heart reperfusion injury model
| Group | Concentration μ g/ml | n | LDH activity (U/L/g wet wt) | Before the active ratio of LDH is irritated back/ischemic again | |
| Before the ischemic | After multiple the filling | ||||
| Blank ischemia model embodiment 1 embodiment 15 positive controls | 100 100 100 | 5 12 5 5 5 | 273±77 222±69 256±120 295±95 298±67 | 216±68 638±164 428±174 475±119 463±78 | 0.80±0.13 3.04±0.83 1.74±0.89 * 1.73±0.61 ** 1.95±0.20 * |
*P＜0.05,
*P＜0.01vs ischemia model.Positive control---root of kudzu vine hitch really shows: given the test agent embodiment 1 and embodiment 15 can make the active ratio of the preceding LDH of the multiple filling back/ischemic of Langendorff isolated heart ischemical reperfusion injury model significantly reduce, and obviously alleviate myocardial cell injury.
Experimental example 2. puerarin derivate Pituitrins bring out the influence of SD rat heart muscle ischemia model
The SD rat is adopted in the model preparation, and in advance with rat anesthesia, record rat normal ECG II leads the rat of intravenous injection Pituitrin, and continuous recording then electrocardiogram(ECG 5 minutes.Observe the variation of rat ECG ST section.Given the test agent group rat is distinguished subcutaneous injection given the test agent 20mg/kg and 40mg/kg in advance, and be administered once every day, and continuous 7 days, 30 minutes intravenous injection Pituitrin 0.5U/kg brought out myocardial infarction and ischemia model after the last administration.Observation index is the degree of raising of measuring the ECG ST ripple.Experimental result sees the following form:
Table 2. puerarin derivate (20mg/kg subcutaneous injection 7 days) brings out the influence of SD rat heart muscle ischemia model ECG ST section to Pituitrin
*P＜0.05,
*P＜0.01VS blank group
| Sample number into spectrum | N | Sample dose 20mg/kg | ||
| Control | Pituitrin (0.5U/kg) | ST section changing value (mv) | ||
| Model control group embodiment 1 embodiment 12 embodiment 15 | 15 5 5 5 | 0.091±0.015 0.1±0 0.1±0 0.1±0 | 0.26±0.05 0.206±0.017 0.17±0.04 0.198±0.04 | 0.167±0.053 0.106±0.017 * 0.072±0.036 ** 0.098±0.04 * |
Table 3. puerarin derivate (40mg/kg subcutaneous injection 7 days) brings out the influence of SD rat heart muscle ischemia model ECG ST section to Pituitrin
| Sample number into spectrum | N | Sample dose 40mg/kg | ||
| Control | Pituitrin (0.5U/kg) | ST section changing value (mv) | ||
| Model control group embodiment 1 embodiment 12 embodiment 15 | 15 5 5 5 | 0.091±0.015 0.1±0.004 0.089±0.017 0.1±0 | 0.26±0.05 0.19±0.028 0.178±0.018 0.21±0.017 | 0.167±0.053 0.092±0.028 * 0.092±0.015 ** 0.114±0.017 * |
*P＜0.05,
*P＜0.01VS blank group result shows: given the test agent embodiment 1, embodiment 12 and embodiment 15, no matter the rising degree of ECG ST section significantly reduces than model group behind 20mg/kg dosage group or the 40mg/kg dosage group rat injection of pituitrin, illustrate that given the test agent can obviously alleviate cardiac muscular tissue's ischemic and decrease.
Claims (10)
1, the puerarin derivate shown in the general formula (I):
Wherein,
R
1And R
2Be selected from hydrogen respectively, the C of replacement or non-replacement
1-18Alkyl, the C of replacement or non-replacement
3-9Cycloalkyl, the fragrant heterocycle of aromatic ring, replacement or the non-replacement of replacement or non-replacement, the C of replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
1-18(substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C to alkoxy acyl
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl);
R
3And R
4Be selected from hydrogen respectively; Halogen; Nitro; (substituting group is selected from the C of replacement or non-replacement to the amino of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
3-9Cycloalkyl or contain the C of fragrant heterocycle, replacement or non-replacement of aromatic ring, replacement or the non-replacement of one or both heteroatomic cycloalkyl, replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aroyl, replacement or non-replacement of aroyl, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyl groups, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aryl acyloxy, replacement or non-replacement of aryl acyloxy, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyloxy, replacement or non-replacement
1-18The C of alkoxy acyl, replacement or non-replacement
1-18The C of alkyl sulphonyl, replacement or non-replacement
3-9Cycloalkanes or contain the heterocyclic aryl alkylsulfonyl of aryl sulfonyl, replacement or non-replacement of one or both heteroatomic naphthene sulfamide bases, replacement or non-replacement (substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl), alkylsulfonyl); (substituting group is selected from the C of replacement or non-replacement to the hydroxyl of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
3-9Cycloalkyl or contain the C of fragrant heterocycle, replacement or non-replacement of aromatic ring, replacement or the non-replacement of one or both heteroatomic cycloalkyl, replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aroyl, replacement or non-replacement of aroyl, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyl groups, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aryl acyloxy, replacement or non-replacement of aryl acyloxy, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyloxy, replacement or non-replacement
1-18The C of alkoxy acyl, replacement or non-replacement
1-18The C of alkyl sulphonyl, replacement or non-replacement
3-9Cycloalkanes or contain the heterocyclic aryl alkylsulfonyl of aryl sulfonyl, replacement or non-replacement of one or both heteroatomic naphthene sulfamide bases, replacement or non-replacement (substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl));-OSO
3H;-OC (=O) (CH
2) nCOOH n=2,3,4;-OP (=O) (OH)
2
R
5Be selected from hydrogen, the C of replacement or non-replacement
1-18The C of alkyl, replacement or non-replacement
3-9Cycloalkyl or contain the C of fragrant heterocycle, replacement or non-replacement of aralkyl, replacement or the non-replacement of one or both heteroatomic cycloalkyl, replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aroyl, replacement or non-replacement of aroyl, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyl groups, replacement or non-replacement
3-9Cycloalkanes or contain the C of heterocycle aryl acyloxy, replacement or non-replacement of aryl acyloxy, replacement or the non-replacement of one or both heteroatomic cycloalkanes acyloxy, replacement or non-replacement
1-18The C of alkoxy acyl, replacement or non-replacement
1-18The C of alkyl sulphonyl, replacement or non-replacement
3-9Cycloalkanes or contain the heterocyclic aryl alkylsulfonyl of aryl sulfonyl, replacement or non-replacement of one or both heteroatomic naphthene sulfamide bases, replacement or non-replacement (substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl));-OSO
3H;-OC (=O) (CH
2) nCOOHn=2,3,4;-OP (=O) (OH)
2
R
6, R
7And R
8Be selected from hydrogen respectively, the C of replacement or non-replacement
1-18Alkyl, the C of replacement or non-replacement
3-9Cycloalkyl, the fragrant heterocycle of aralkyl, replacement or the non-replacement of replacement or non-replacement, the C of replacement or non-replacement
1-18The C of alkyloyl, replacement or non-replacement
1-18(substituting group is selected from halogen, nitro, hydroxyl, sulfydryl, carboxyl, ester group, amino, amido, C to alkoxy acyl
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyloyl, C
1-6Alkanoyloxy, methylsulfonyl, amino methylsulfonyl);-SO
3H ,-C (=O) (CH
2) nCOOH n=2,3,4 ,-P (=O) (OH)
2
But
R
1, R
2, R
3, R
4, R
5, R
6,, R
7And R
8Can not be hydrogen simultaneously, can not be ethanoyl simultaneously.
R
3, R
4, R
5, R
6,, R
7And R
8When being hydrogen simultaneously, R
1And R
2Can not be simultaneously hydroxyethyl.
R
1, R
2, R
3, R
4, R
6, R
7And R
8When being hydrogen simultaneously, R
5Can not be trityl and benzoyl.
2, according to the compound of claim 1, it is characterized in that,
R
1And R
2Be selected from the alkyloyloxyethyl methylene radical, alkoxy acyl, amino low alkyl group, hydroxyl low-grade alkyl, carboxyl low-grade alkyl, alkyl ,-C (=O) (CH
2) nCOOH n=2,3,4.
R
3And R
4Be selected from hydrogen, nitro, amino, N-alkylamino, N, N-dialkyl amido, alkyl amide, sulfonamido, alkyl sulfonyl amino, hydroxyl alkylamino, carboxyl alkylamino, halogen atom, hydroxyl, alkoxyl group, alkanoyloxy, alcoxyl acyloxy, aminoalkoxy, hydroxy alkoxy base, carboxyl alkoxyl group, the inferior methoxyl group of alkyloyloxyethyl, carbamyl alkoxyl group ,-OSO
3H ,-OC (=O) (CH
2) nCOOH n=2,3,4 ,-OP (=O) (OH)
2
R
5Be selected from hydrogen, alkyl, aralkyl, alkyloyl, alkoxyl formyl, alkyloyloxyethyl methylene radical ,-SO
3H ,-C (=O) (CH
2) nCOOH n=2,3,4 ,-P (=O) (OH)
2
R
6, R
7And R
8Be selected from hydrogen respectively, alkyl, aralkyl, alkyloyl, alkoxy acyl, alkyloyloxyethyl methylene radical ,-SO
3H ,-C (=O) (CH
2) nCOOH n=2,3,4 ,-P (=O) (OH)
2
3, according to the compound of claim 2, it is characterized in that,
R
1And R
2Be selected from hydrogen, ethanoyl, valeryl, benzoyl, methoxycarbonyl base, pivalyl oxygen methylene radical;
R
3And R
4Be selected from hydrogen, 3 '-nitro, 3 '-amino, N, the N-dimethylamino;
R
5, R
6, R
7And R
8Be selected from hydrogen, ethanoyl, valeryl, benzoyl, methoxycarbonyl base, pivalyl oxygen methylene radical, benzene methene, propylidene.
According to the compound of claim 3, it is characterized in that 4, compound is selected from
5, a kind of pharmaceutical composition is characterized in that, contains described arbitrary compound of claim 1-4 and pharmaceutical carrier.
6, treat the application of heart and brain circulation diseases related medicine as the described compound of claim 1-4.
7, the application of blocking medicine as the described compound treatment of claim 1-4 retina arteriovenous.
8, treat the application of sudden deafness medicine as the described compound of claim 1-4.
9, improve the application of memory medicine as the described compound of claim 1-4.
10, treat the application of the medicine of lowering blood glucose as the described compound of claim 1-4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100008140A CN1944448B (en) | 2005-01-11 | 2006-01-11 | Puerarin derivative and its medicinal use |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510000423.4 | 2005-01-11 | ||
| CN200510000423 | 2005-01-11 | ||
| CN2006100008140A CN1944448B (en) | 2005-01-11 | 2006-01-11 | Puerarin derivative and its medicinal use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1944448A true CN1944448A (en) | 2007-04-11 |
| CN1944448B CN1944448B (en) | 2011-07-20 |
Family
ID=38044119
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006100008140A Expired - Fee Related CN1944448B (en) | 2005-01-11 | 2006-01-11 | Puerarin derivative and its medicinal use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1944448B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009019721A3 (en) * | 2007-08-09 | 2009-04-02 | Dabur Pharma Ltd | Quercetin derivatives as anti-cancer agents |
| CN101805332A (en) * | 2010-04-30 | 2010-08-18 | 西安力邦制药有限公司 | Preparation method and application of puerarin derivatives |
| CN101712676B (en) * | 2008-10-06 | 2013-02-13 | 深圳市健元医药科技有限公司 | Water soluble puerarin derivatives and preparation method and application thereof |
| CN103694229A (en) * | 2013-12-31 | 2014-04-02 | 深圳市健元医药科技有限公司 | Puerarin derivatives and preparation methods thereof |
| CN108017624A (en) * | 2016-11-01 | 2018-05-11 | 潘嘉慧 | The structure and its synthetic method of puerarin derivate |
| CN109134445A (en) * | 2018-09-30 | 2019-01-04 | 福州热方健康科技有限公司 | A kind of puerarin derivate B and preparation method thereof and application |
| CN110840880A (en) * | 2019-12-02 | 2020-02-28 | 陕西中医药大学 | Application of puerarin derivative in preparing anticancer medicine and medicine for treating cancer |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100441589C (en) * | 2002-12-31 | 2008-12-10 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Puerarin compound containing water soluble group and its preparation and use |
-
2006
- 2006-01-11 CN CN2006100008140A patent/CN1944448B/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009019721A3 (en) * | 2007-08-09 | 2009-04-02 | Dabur Pharma Ltd | Quercetin derivatives as anti-cancer agents |
| CN101712676B (en) * | 2008-10-06 | 2013-02-13 | 深圳市健元医药科技有限公司 | Water soluble puerarin derivatives and preparation method and application thereof |
| CN101805332A (en) * | 2010-04-30 | 2010-08-18 | 西安力邦制药有限公司 | Preparation method and application of puerarin derivatives |
| CN103694229A (en) * | 2013-12-31 | 2014-04-02 | 深圳市健元医药科技有限公司 | Puerarin derivatives and preparation methods thereof |
| CN103694229B (en) * | 2013-12-31 | 2016-03-23 | 深圳市健元医药科技有限公司 | Puerarin derivate and preparation method thereof |
| CN108017624A (en) * | 2016-11-01 | 2018-05-11 | 潘嘉慧 | The structure and its synthetic method of puerarin derivate |
| CN109134445A (en) * | 2018-09-30 | 2019-01-04 | 福州热方健康科技有限公司 | A kind of puerarin derivate B and preparation method thereof and application |
| CN109134445B (en) * | 2018-09-30 | 2020-07-28 | 福州热方健康科技有限公司 | Puerarin derivative B and preparation method and application thereof |
| CN110840880A (en) * | 2019-12-02 | 2020-02-28 | 陕西中医药大学 | Application of puerarin derivative in preparing anticancer medicine and medicine for treating cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1944448B (en) | 2011-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1022566C (en) | Process for preparing novel substituted 1-piperidinoalkylene-pyridopyrimidones or thiazolopyrimidinones | |
| CN1944448A (en) | Puerarin derivative and its medicinal use | |
| CN1821212A (en) | Synthetic method for dapoxetine | |
| CN1793132A (en) | Derivative of cyclo membranousol kind and application thereof | |
| CN1929829A (en) | (S)-2-N-propylamino-5-hydroxytetralin as a D3-agonist | |
| CN1708495A (en) | Heterocyclic compounds and antitumor drugs containing the same as the active ingredient | |
| CN1384827A (en) | Indeno-, naphtho-, and benzocyclohepta-dihydrothiazole derivatives, the production thereof and their use as anorectic medicaments | |
| CN1035821C (en) | 4-deoxy-4-epipodophyllotoxin derivatives or pharmaceutically acceptable salt thereof | |
| CN111662294A (en) | Compound with activity of degrading Btk | |
| CN101074189A (en) | Styrene acid derivative and use in preparation of various blood-vessels target agent medicine | |
| CN1009826B (en) | The method for preparing quinoline compound | |
| CN1638756A (en) | R-bambuterol, its preparation and therapeutic uses | |
| CN1148362C (en) | Polycyclic 2-aimino-thiazole systems, method for prodn. thereof and medicament contg. said compounds | |
| JPH01294670A (en) | 2-(piperadinyl)-2-oxoethylene-substituted flavonoid derivative, its production and pharmaceutical composition containing said derivative | |
| CN1847240A (en) | Prazole derivative and its salt and use | |
| CN1141940C (en) | Use of polycyclic thiazole systems for producing medicaments for preventing of treating obesity | |
| CN1850820A (en) | Coumarin derivatives, and their preparing method and use as alpha, receptor agonist | |
| CN1144801C (en) | Vitreous form of know bradykinin antagonist | |
| CN1037266C (en) | Quinoline derivative fumarates | |
| CN1712408A (en) | Dicycloalcohol glucoside compound its production and use | |
| CN1301996C (en) | Novel anticancer conjugates of camptothecin and unsaturated fatty acids | |
| CN1146573C (en) | Novel arabinosyladenine derivatives | |
| CN1566128A (en) | Sugar charcoal glycoside isoflavone compound containing alkane amine group and alkoxy substitution, process and uses thereof | |
| CN103159649B (en) | The preparation of sulfamide compound and application thereof | |
| CN1303085C (en) | C6- and C9-substituted isoxazoline derivatives and their use as anti-depressants |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110720 Termination date: 20150111 |
|
| EXPY | Termination of patent right or utility model |