CN110818664B - Puerarin novel derivative and preparation method and application thereof - Google Patents

Puerarin novel derivative and preparation method and application thereof Download PDF

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CN110818664B
CN110818664B CN201910726765.6A CN201910726765A CN110818664B CN 110818664 B CN110818664 B CN 110818664B CN 201910726765 A CN201910726765 A CN 201910726765A CN 110818664 B CN110818664 B CN 110818664B
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袁崇均
陈帅
罗森
王笳
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Sichuan Academy of Chinese Medicine Sciences SACMS
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Abstract

The invention provides a compound, or a salt or a crystal form thereof, wherein the structure of the compound is shown as a formula I. The compound provided by the invention is a puerarin derivative with a novel structure, is easy to dissolve in water, and has the solubility 100 times that of puerarin in water; the puerarin also has obvious anti-anoxia activity, has better effect than puerarin, and can be widely used for preparing medicaments for preventing and/or treating cardiovascular and cerebrovascular diseases, diabetes, hypertension, cerebral infarction, viral myocarditis, glaucoma and other diseases clinically.
Figure DDA0002159179600000011

Description

Puerarin novel derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of medicine preparation, and particularly relates to a novel puerarin derivative, and a preparation method and application thereof.
Background art:
puerarin (Puerarin) is an isoflavone glycoside compound extracted and separated from dried root of Pueraria lobata (Willd.) Ohwi of Leguminosae, has chemical name of 8-beta-D-glucopyranose-4', 7-dihydroxyisoflavone, and has chemical structural formula:
Figure BDA0002159179580000011
puerarin is white to yellowish crystalline powder, which is dissolved in methanol, slightly soluble in ethanol, and slightly soluble in water.
Puerarin has wide pharmacological activity. Pharmacological research shows that the compound has beta-adrenoceptor blocking effect, can reduce vascular resistance, enlarge coronary artery, improve myocardial contraction function, reduce myocardial oxygen consumption, reduce acute myocardial infarction area and has protective effect on myocardial ischemia reperfusion injury. Is widely applied to the treatment of cardiovascular diseases such as coronary heart disease, angina pectoris, myocardial infarction, retinal artery and vein obstruction, sudden deafness, diabetes, hypertension, cerebral infarction, viral myocarditis, glaucoma and the like in clinic.
Puerarin has the characteristic of chemical structure of isoflavone substances, B ring is influenced by the stereo obstruction of pyran ring carbonyl, only a large conjugated system can be formed in space to form an approximate plane structure, the lattice arrangement is compact, the rigidity is strong, and two phenolic hydroxyl groups on 7, 4' positions can form intermolecular hydrogen bonds, so that the intermolecular force of puerarin is increased, the melting point is high, the fat solubility and the water solubility are poor, the absorption is poor, the elimination is fast, the biological activity and the drug effect performance of puerarin are influenced, and the wide application of puerarin in clinic is restricted. The clinical injection has low solubility of puerarin in water, propylene glycol, ethylene glycol or polyvinylpyrrolidone (PVP) and the like are usually added in the formula as a cosolvent solvent, and reports of relevant adverse reactions such as vascular irritation, fever, allergy, erythrolysis and the like caused by the cosolvent are increased year by year.
How to improve the solubility of puerarin derivatives by changing the structure of puerarin to optimize the pharmacokinetic properties of puerarin compounds, form safe, effective and durable drug effects, and improve the bioavailability of the puerarin derivatives is increasingly emphasized. The puerarin is subjected to a great amount of structural modification by the prior people, but the modification is focused on the 4 'and 7-position phenolic hydroxyl groups in the molecular structure of the puerarin, the hydrogen on the 3' and 5 'positions and the 6' position hydrogen in the molecular structure of the glucose, so that the water solubility and the lipid solubility of the puerarin are improved, the oil-water distribution coefficient of the puerarin in a body is improved, the drug effect is prolonged, the bioavailability of the puerarin is improved, and the pharmacological activity of the puerarin is enhanced. But no major breakthrough exists, and no reports on new puerarin derivative medicines or clinical tests are found.
Therefore, the research on a puerarin derivative with novel structure, good solubility and excellent pharmacological activity is very important for the development of new drugs for clinically treating cerebrovascular diseases, diabetes, hypertension, cerebral infarction, viral myocarditis, glaucoma and other diseases.
Disclosure of Invention
The invention aims to provide a novel puerarin derivative and a preparation method and application thereof.
The invention provides a compound, or a salt or a crystal form thereof, wherein the structure of the compound is shown as a formula I:
Figure BDA0002159179580000021
wherein glc has a structure of
Figure BDA0002159179580000022
R1、R2、R3Each independently selected from H, -OR4、C1-5Alkyl radical, R4Selected from H, C1-5Alkyl, -COR5，R5Is selected from C1-5An alkyl group.
Further, R1、R2、R3Each independently selected from H, -OR4、C1-3Alkyl radical, R4Selected from H, C1-3Alkyl, -COCH3。
Further, the structure of the compound is shown as formula II:
Figure BDA0002159179580000023
wherein glc has a structure of
Figure BDA0002159179580000024
The present invention also provides a process for preparing the above compound, comprising the steps of:
(1) reacting puerarin with an alkaline aqueous solution, and after the reaction is finished, adjusting the pH of the obtained system to 6-7 for later use;
(2) and (3) desalting the standby liquid obtained in the step (1) to obtain the compound.
Further, in the step (1), the alkaline aqueous solution is selected from NaOH aqueous solution, KOH aqueous solution or Na2CO3An aqueous solution; the solvent of the reaction is ethanol; the mass volume ratio of the puerarin to the alkaline aqueous solution to the solvent for reaction is 1.0 g: (0.5-2.0) ml: (10.0-30.0) ml; the reaction time is 5-60 min;
preferably, in the alkaline aqueous solution, NaOH, KOH or Na2CO3The mass volume ratio of the water to the water is 1 to 10 percent g/ml; the solvent of the reaction is ethanol with the volume concentration of 75 percent; the mass volume ratio of the puerarin to the alkaline aqueous solution to the solvent for reaction is 1.0 g: 1.0 ml: 20.0 ml.
Further, in the step (2), the desalting method comprises the following steps:
the method i comprises the steps of (1) concentrating the standby liquid, drying, dissolving with ethanol, filtering, taking the filtrate, concentrating and drying to obtain the compound I;
or, method ii, the standby liquid obtained in the step (1) is concentrated, then water with 10 times volume of the residual liquid is added, macroporous absorption resin column is used for absorption and elution, eluent is collected and filtered, filtrate is taken, and the concentrated solution is dried, so that the compound is obtained;
or, the method iii comprises the steps of concentrating the standby liquid obtained in the step (1), then utilizing a G3 vertical melting glass sand funnel for adsorption and elution, collecting eluent, concentrating and drying to obtain the compound preparation;
preferably, in the method i, the dissolving mode is ultrasonic dissolving, and the G3 vertical melting glass sand funnel is adopted for filtering;
in the method ii, the eluent adopted in the elution is water firstly, and when no chloride ion exists in the eluent, ethanol with the volume concentration of 70% is adopted as the eluent, and the eluent is collected; the filtration adopts a G3 vertical melting glass sand funnel;
in method iii, the eluent used in elution is ethanol.
Further, the method further comprises: recrystallizing a product obtained after desalting in the step (2) in a solvent;
preferably, the solvent is ethanol or water with a volume concentration of 70%; the mass volume ratio of the product obtained after desalting to the solvent is 1:1 g/ml; the recrystallization conditions are as follows: and standing for 10-14 hours at room temperature after heating and dissolving.
The invention also provides application of the compound, or the salt or the crystal form thereof in preparing an anti-hypoxic drug.
Further, the anti-hypoxic drug is a drug for preventing and/or treating the following diseases: cardiovascular and cerebrovascular diseases, diabetes, hypertension, cerebral infarction, viral myocarditis, and glaucoma.
The invention also provides a pharmaceutical composition, which is a preparation prepared from the compound, or the salt or the crystal form thereof as an active ingredient and a pharmaceutically acceptable carrier.
Further, the preparation is selected from injection, freeze-dried powder injection, tablet, powder, granule, capsule, pill, oral solution and eye drop;
preferably, the tablet comprises: common compressed tablets, chewable tablets, effervescent tablets, multilayer tablets, sustained release tablets, controlled release tablets, coated tablets, dispersible tablets, buccal tablets, sublingual tablets; the pill comprises: dripping pill, buccal dripping pill, and pellet; the capsule comprises: hard capsule, soft capsule, enteric capsule, sustained release capsule, and microcapsule.
In conclusion, the puerarin isoflavone skeleton is structurally modified, and the puerarin forms a chain-shaped acetophenone glycosidase compound through C-ring opening, so that the plane structure of the puerarin is broken, and the puerarin derivative with a novel structure is prepared. The puerarin derivative is easy to dissolve in water, and the solubility of the puerarin derivative in water is 100 times of that of puerarin; the puerarin also has obvious anti-anoxia activity, has better effect than puerarin, and can be widely used for preparing medicaments for preventing and/or treating cardiovascular and cerebrovascular diseases, diabetes, hypertension, cerebral infarction, viral myocarditis, glaucoma and other diseases clinically.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. C1-5The alkyl group is a straight-chain or branched alkyl group having 1 to 5 carbon atoms.
As used herein, "pharmaceutically acceptable" means that the carrier, cargo, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and is physiologically compatible with the recipient.
The compound of the invention is added with pharmaceutically acceptable carriers to prepare different pharmaceutical preparations, such as injections, freeze-dried powder injections, tablets, powder, granules, capsules, pills, oral solutions, eye drops and the like, wherein the tablets comprise: common compressed tablets, chewable tablets, effervescent tablets, multilayer tablets, sustained release tablets, controlled release tablets, coated tablets, dispersible tablets, buccal tablets, sublingual tablets and the like; the pill includes dripping pill, buccal dripping pill, pellet, etc. The capsule comprises: hard capsule, soft capsule, enteric capsule, sustained release capsule, microcapsule, etc.
In the present invention, "positive reaction" means that a chemical reaction can occur; by "negative reaction" is meant that no chemical reaction can occur.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a UV spectrum of a compound of the present invention.
FIG. 2 is an infrared spectrum of a compound of the present invention.
FIG. 3 is a mass spectrum of a compound of the present invention.
FIG. 4 is a high resolution mass spectrum of a compound of the present invention.
FIG. 5 is a drawing of a compound of the present invention1HNRM hydrogen spectrum.
FIG. 6 is a drawing of a compound of the present invention13CNRM carbon spectrum.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
EXAMPLE 1 preparation of the Compounds of the invention
Chemical reaction
50g of puerarin is added into a 2L round bottom flask with 20 times of 75% V/V ethanol, heated and refluxed in a water bath, and then added with 1-10% W/V NaOH or KOH or Na2CO3Reacting 50ml of aqueous solution for 5-60 min, taking out reaction liquid, and adjusting the pH value to 6-7 by using hydrochloric acid for later use.
② desalting
The method comprises the following steps: recovering solvent from the liquid at 60 deg.c under reduced pressure, concentrating in evaporating dish in water bath to obtain extract, and drying at 60 deg.c under reduced pressure to obtain brown yellow dry powder. Ultrasonically dissolving with 500ml anhydrous ethanol for 5 times, filtering with G3 sintered glass sand funnel, mixing filtrates, recovering solvent, and drying at 60 deg.C under reduced pressure to obtain brown yellow dry powder.
The method 2 comprises the following steps: recovering solvent from the solution at 60 deg.C under reduced pressure, concentrating to 100ml in water bath pot, adding 1000ml water, shaking, and adding D101Macroporous adsorbent resin column (column specification: diameter 10cm × length 65cm), washing with water until no chloride ion exists in effluent, eluting with 70% V/V ethanol, filtering with G3 sintered glass sand funnel, recovering solvent, and drying at 60 deg.C under reduced pressure to obtain brown yellow dry powder.
The method 3 comprises the following steps: recovering the solvent from the standby liquid in the step I under reduced pressure at 60 ℃, concentrating the standby liquid in a water bath kettle to 100ml by using an evaporation dish, adding 100g of 80-100-mesh silica gel, adsorbing, uniformly stirring, drying at 60 ℃, putting the standby liquid in a 500ml G3 vertical melting glass sand funnel, then stirring and eluting by using 500ml of absolute ethyl alcohol, combining the eluents, recovering the solvent, and drying under reduced pressure at 60 ℃ to obtain brown yellow dry powder for standby.
③ crystallization
Recrystallizing the standby powder in the step II with 70% V/V ethanol or water (the ratio of the solvent to the powder is 1: 1V/W) (standing for 10-14 hours at room temperature after heating and dissolving) to obtain the compound of the invention, wherein the compound is colorless to reddish crystalline powder, and the yield is 80% (calculated by the amount of the puerarin added).
The melting point mp of the compound is 108-110 ℃, and the UV lambda ismax281nm, ultraviolet spectrum, infrared spectrum (IR), Mass Spectrum (MS), high-resolution mass spectrum,1HNRM、13The CNRM is shown in the figures 1-6 in sequence and is identified as 4,6,4' -trihydroxy diphenylethanone-5-beta-D-glucopyranoside, and the chemical structural formula is as follows:
Figure BDA0002159179580000051
the following is the preparation of the compound formulations of the present invention.
EXAMPLE 2 preparation of an injection of a Compound of the invention
Taking 1000ml of injection for preparing the compound of the invention as an example, the raw and auxiliary materials are as follows:
Figure BDA0002159179580000052
the preparation method adopts the preparation process of a conventional injection, and the pH of the injection is adjusted to 4-6 by 1% hydrochloric acid, wherein each injection contains 2ml of the compound 50 mg. The product is colorless clear liquid.
EXAMPLE 3 preparation of tablets of the Compound of the invention
Taking 1000 tablets of the compound of the invention as an example, the raw and auxiliary materials used are as follows:
compound of the invention 25g
Starch 160g
Magnesium stearate 15g
The traditional Chinese medicine composition is prepared by adopting a conventional preparation process of tablets, each tablet weighs 0.2g, and each tablet contains 25mg of the compound.
EXAMPLE 4 preparation of capsules of Compounds of the invention
Taking 1000 capsules of the compound of the invention as an example, the raw materials and auxiliary materials are as follows:
compound of the invention 25g
260g of starch
Magnesium stearate 15g
The traditional Chinese medicine composition is prepared by adopting a preparation process of a conventional capsule, wherein each capsule is 0.3g in weight, and each capsule contains 25mg of the compound.
EXAMPLE 5 preparation of oral solutions of Compounds of the invention
Taking 1000 samples for preparing the compound oral solution of the invention as an example, the raw and auxiliary materials are as follows:
Figure BDA0002159179580000061
the traditional Chinese medicine composition is prepared by adopting a preparation process of a conventional oral solution, and the pH of the oral solution is adjusted to 4-6 by using 1% hydrochloric acid, wherein each oral solution is 10ml, and each oral solution contains 50mg of the compound. The product is colorless clear liquid.
EXAMPLE 6 preparation of eye drops of the Compound of the present invention
Taking 1000 times for preparing the compound eye drops of the invention as an example, the raw and auxiliary materials are as follows:
Figure BDA0002159179580000062
the traditional Chinese medicine composition is prepared by adopting the preparation process of conventional oral solutions, wherein each oral solution contains 5ml of compound 50 mg. The product is colorless clear liquid.
The beneficial effects of the compounds of the present invention are demonstrated by the following experimental examples.
EXAMPLE 1 determination of physicochemical constants and chemical reaction of Compound of the present invention (compared with Puerarin)
(1) Ultraviolet spectroscopy was performed according to the method described in the four parts 0401 of the Chinese pharmacopoeia 2015 edition, and the results showed that the compound of the present invention, lambdamax280.6nm, puerarin lambdamax250.7nm (literature report lambda)max250nm)。
(2) The melting point of the compound is measured according to the method of the first method of the four parts 0612 of the Chinese pharmacopoeia 2015 edition, and the results show that the compound of the invention has mp.108-110 ℃ and the puerarin has mp.186-189 ℃ (the literature reports mp.187-189 ℃).
(3) Solubility determination is carried out according to the method described in the fourth page X of the Chinese pharmacopoeia 2015 edition, and the result shows that the solubility of the compound of the invention in water is 0.48g/ml, and the solubility of puerarin in water is 4.6mg/ml (the literature reports 4-6 mg/ml).
(4) Reaction with hydrochloric acid-magnesium powder: puerarin is in positive reaction, reaction liquid is bright yellow to dark brown, and the compound of the invention is in negative reaction.
(5) Reaction with alkaline reagent (1% NaOH): both the reactions are positive reactions, the puerarin reaction liquid is bright yellow, and the compound reaction liquid of the invention is dark brown.
The above experiments show that the compound of the present invention has reduced melting point, red shift of ultraviolet absorption and increased solubility in water compared with puerarin. The compound of the invention does not have the structural characteristics of isoflavone, the phenolic hydroxyl is increased, and the activity is enhanced.
Experimental example 2 Normal pressure hypoxia tolerance test of the drug of the invention on mice
1. The experimental method comprises the following steps: 36 mice, 20-22 g in weight, half male and female, are randomly divided into 3 groups, namely a blank group, a puerarin group (puerarin is purchased from Shanxi Lvqing bioengineering Co., Ltd., batch number 181203, content is more than 99 percent), the compound group of the invention, and 12 mice in each group. The blank group was administered by intragastric administration with an equal volume of vehicle (tragacanth suspension) daily, and the puerarin group and the compound group of the present invention were suspended in tragacanth at a dose of 100 mg/kg-1·d-1. Gavage administration, treatment of animals after 7 consecutive days of administration. Starting an anoxia test 1h after the last administration, putting a mouse into a closed wide-mouth bottle, smearing Vaseline on the bottle mouth, tightly covering, and recording survival of the mouse from bottle entering to deathTime.
2. The experimental results are as follows: the results are shown in Table 1. The result shows that the medicine can obviously prolong the survival time of mice with hypoxia tolerance, has obvious difference (P is less than 0.05) compared with a blank group, and has better effect than puerarin, thereby proving that the medicine can obviously enhance the hypoxia tolerance of organisms.
TABLE 1 Normal pressure hypoxia tolerance test of the Compounds of the invention on mice: (
Figure BDA0002159179580000071
n＝12)
Group of Dosage (mg/kg) Survival time(s)
Blank group / 13.05±1.78
Puerarin group 100 18.25±2.08*
Compounds of the invention 100 23.17±3.52**
Note: compared with the blank control group, the composition of the composition,*P<0.05，**P<0.01
experimental example 3 test of the Compound of the present invention for acute cerebral ischemia in mice
1. The experimental method comprises the following steps: 36 mice, weighing 20-22 g, with half male and female, were randomly divided into 3 groups, namely blank group, puerarin group, and compound group of the invention, and each group had 12 mice. The blank group was administered by intragastric administration with an equal volume of vehicle (tragacanth suspension) daily, and the puerarin group and the compound group of the present invention were suspended in tragacanth at a dose of 100 mg/kg-1·d-1. Gavage administration, treatment of animals after 7 consecutive days of administration. That is, 1h after the last administration, the mouse rapidly broke its head from the back of the ear, and the time from the beginning of the head break to the last gasping of the mouse was recorded.
2. The experimental results are as follows: the results are shown in Table 2. The results show that the compound can obviously prolong the survival time of acute cerebral ischemia of mice, has obvious difference (P is less than 0.01) compared with a blank group, has better effect than puerarin, and proves that the medicine can be used for treating ischemic cerebrovascular diseases.
Table 2 test of the compounds of the invention on acute cerebral ischemia in mice: (
Figure BDA0002159179580000081
n＝12)
Group of Dosage (mg/kg) Survival time(s)
Blank group / 14.48±2.15
Puerarin group 100 22.95±2.21**
Compounds of the invention 100 25.37±2.68***
Note: compared with the blank control group, the composition of the composition,**P<0.01，***P<0.001
experimental example 4 chemical hypoxia assay of the Compound of the present invention in mice
1. The experimental method comprises the following steps: 36 mice, weighing 20-22 g, with half male and female, were randomly divided into 3 groups, namely blank group, puerarin group, and compound group of the invention, and each group had 12 mice. The blank group was administered by intragastric administration with an equal volume of vehicle (tragacanth suspension) daily, and the puerarin group and the compound group of the present invention were suspended in tragacanth at a dose of 100 mg/kg-1·d-1. Gavage administration, treatment of animals after 7 consecutive days of administration. That is, NaNO was intraperitoneally injected 1h after the last administration2200mg·kg-1Immediately, the recording of mouse survival time was started.
2. The experimental results are as follows: the results are shown in Table 3. The result shows that the compound can obviously prolong the survival time of the chemical hypoxia of the mouse, has obvious difference (P is less than 0.01) compared with a blank group, has better effect than puerarin, and proves that the medicine can obviously improve the hypoxia tolerance of the body.
TABLE 3 chemical hypoxia assay of the Compounds of the invention in mice: (
Figure BDA0002159179580000082
n＝12)
Group of Dosage (mg/kg) Survival time(s)
Blank group / 9.72±1.17
Puerarin group 100 12.53±2.81**
Compounds of the invention 100 15.85±2.57***
Note: compared with the blank control group, the composition of the composition,**P<0.01，***P<0.001
in conclusion, the puerarin isoflavone skeleton is structurally modified, and the puerarin forms a chain-shaped acetophenone glycosidase compound through C-ring opening, so that the plane structure of the puerarin is broken, and the puerarin derivative with a novel structure is prepared. The puerarin derivative is easy to dissolve in water, and the solubility of the puerarin derivative in water is 100 times of that of puerarin; the puerarin also has obvious anti-anoxia activity, has better effect than puerarin, and can be widely used for preparing medicaments for preventing and/or treating cardiovascular and cerebrovascular diseases, diabetes, hypertension, cerebral infarction, viral myocarditis, glaucoma and other diseases clinically.

Claims (2)

1. The application of the compound shown in the formula II, or the salt or the crystal form thereof in preparing anti-hypoxic drugs; the structure of the compound shown in the formula II is as follows:
Figure DEST_PATH_IMAGE001
whereinThe structure of glc is
Figure 863934DEST_PATH_IMAGE002
(ii) a The anti-hypoxic drug is a drug for preventing and/or treating cardiovascular and cerebrovascular diseases.
2. Use according to claim 1, characterized in that: the cardiovascular and cerebrovascular diseases are cerebral infarction or viral myocarditis.
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CN104876951A (en) * 2015-05-26 2015-09-02 西安交通大学 Preparation method for puerarin morphine
CN107216243A (en) * 2017-06-07 2017-09-29 四川省中医药科学院 A kind of chalcone analog and its production and use

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