CN109422786A - Benzo Zhuo phenol ketone derivatives and preparation method thereof and purposes - Google Patents

Benzo Zhuo phenol ketone derivatives and preparation method thereof and purposes Download PDF

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CN109422786A
CN109422786A CN201710724964.4A CN201710724964A CN109422786A CN 109422786 A CN109422786 A CN 109422786A CN 201710724964 A CN201710724964 A CN 201710724964A CN 109422786 A CN109422786 A CN 109422786A
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theaflavin
compound
preparation
formula
gallate
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温尧林
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SUZHOU KAIXIANG BIOTECHNOLOGY CO Ltd
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    • C07D311/28Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract

The invention belongs to drug or field of health care products, and in particular to benzo Zhuo phenol ketone derivatives and preparation method thereof and purposes.The benzo Zhuo phenol ketone derivatives have the following structure:

Description

Benzo Zhuo phenol ketone derivatives and preparation method thereof and purposes
Technical field
The invention belongs to drug or field of health care products, and in particular to benzo Zhuo phenol ketone derivatives and preparation method thereof with On the way.
Background technique
Obesity is a kind of chronic metabolic disease as caused by many factors, with the volume and cell of body fat cell Number, which increases, causes the percentage of body fat percentage of liveweight to increase extremely and with the characteristics of certain parts excessively deposit fat.Numerous studies table Bright, obesity can cause a variety of chronic diseases such as hypertension, diabetes, coronary heart disease, it has also become global serious public to defend Raw problem.According to statistics, 2015, population of being obese quantity was respectively 1.077 hundred million and 6.037 hundred million in global children and in adult, The same year whole world about cause of the death of 4,000,000 people is directly related with high BMI, accounts for the 7.1% of whole death tolls.
Current slimming drugs mainly include following two major classes: pancreatic lipase inhibitor and appetite inhibitor;Pancreatic lipase suppression Preparation is by inhibiting pancreatic lipase activity, inhibiting fatty decomposition absorption in food and lose weight, and appetite inhibitor is due to can Cause nervous system adverse reaction and is used by limitation.So far, the slimming drugs that can be used for a long time through FDA approval only have fat Enzyme inhibitor orlistat (orlistat), serotonin 2C receptor stimulating agent lorcaserin (lorcaserin) and compound slimming Medicine Qsymia (sustained release agent containing phentermine and Topiramate).However, above-mentioned slimming drugs can cause steatorrhea, liposoluble vitamin The adverse reactions such as shortage, and to brain centres and cardiovascular system etc., whether toxic side effect still has very big do not know Property.
Hyperlipidemia is that fat metabolism or operating exception make one or more lipid levels in blood plasma be higher than the complete of normal value Body disease is mainly characterized by triacylglycerol in serum (TG), total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) Level increases, and high-density lipoprotein cholesterol (HDL-C) is horizontal to be reduced.Hyperlipidemia be cause cardiovascular and cerebrovascular disease the reason of it One.According to statistics, there are about 12,000,000 people to die of cardiovascular and cerebrovascular disease every year in the whole world.Currently, the clinical first-line drug of reducing blood lipid is main It is curative for effect, rapid-action for statins, but have the shortcomings that easily rebound, high recurrence rate and need Long-term taking medicine. 2001, cerivastatin caused to quit listing because the lethal serious adverse reaction of rhabdomyolysis occurs for pill taker, while also causing It worry to the safety of other statins and discusses warmly.
Theaflavin (theaflavins, TFs) is found by Roberts E.A.H. in nineteen fifty-seven earliest, is polyphenols One kind that oxidation is formed has the general name of the compound of benzo Zhuo phenolic ketone structure, passes through C2-C4, C2-C6 key and 2 benzene a pair of horses going side by side dihydros Pyranoid ring is connected, and singly-bound is rotated freely by steric interference, to form specific space conformation.It has been reported that Theaflavin can reduce rat body weight and Fat Accumulation, can also improve lipid-metabolism with regulating blood lipoid level.
Therefore, the novel benzo Tropolones compound with fat-reducing and antihyperglycemic is studied to have great importance.
Summary of the invention
For this purpose, the present invention provides a kind of novel benzo Tropolones compound, and then provide preparation method and purposes.
In order to solve the above technical problems, the present invention is achieved through the following technical solutions:
The present invention provides the compound with structure shown in formula (I),
Wherein, R1、R2Be independently from each other H, by In At least one be formed by glycosyl residue.
Preferably, above compound,
R1Selected from H, byAt least one of be formed by glycosyl residue, R2Choosing From H.
It is further preferred that above compound,
R1Selected from H,
It is further preferred that above compound, formula (I) compound represented is selected from:
The present invention also provides the pharmaceutically acceptable salt of above compound, ester, prodrug, solvate or its crystal forms.
The present invention also provides a kind of pharmaceutical preparations, with above compound, its pharmaceutically acceptable salt, ester, prodrug, solvent It closes object or its crystal form is active constituent, according to common process, customary adjuvant is added, clinically acceptable tablet, capsule is made Agent, powder, mixture, pill, granule, syrup, emplastrum, suppository, aerosol, ointment or injection.
The customary adjuvant are as follows: filler, disintegrating agent, lubricant, suspending agent, adhesive, sweetener, corrigent, anti-corrosion Agent, matrix etc..Filler includes: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose etc.;It collapses Solving agent includes: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low substitution hydroxyl Third cellulose, cross-linked carboxymethyl cellulose are received;Lubricant includes: magnesium stearate, lauryl sodium sulfate, talcum powder, dioxy SiClx etc.;Suspending agent includes: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose etc.;Bonding Agent includes starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose etc.;Sweetener includes: saccharin sodium, aspartame, sugarcane Sugar, honey element, enoxolone etc.;Corrigent includes: sweetener and various essence;Preservative include: parabens, benzoic acid, Sodium benzoate, sorbic acid and its esters, benzalkonium bromide, the fixed, eucalyptus oil of acetic acid chloroethene etc.;Matrix include: PEG6000, PEG4000, insect wax etc..
The present invention also provides a kind of method for preparing above compound, shown in formula (II) compound represented and formula (III) Compound is under the action of polyphenol oxidase by enzymatic reaction up to formula (I) compound represented;
Preferably, above-mentioned preparation method, formula (II) compound represented and the molar ratio of formula (III) compound represented are (1:2)~(2:1);
It is further preferred that the molar ratio of formula (II) compound represented and formula (III) compound represented is 1:1.
Preferably, above-mentioned preparation method is changed shown in formula (II) using citrate-phosphate disodium hydrogen buffer as reaction solution It closes object and total concentration of formula (III) compound represented in reaction solution is 1~2.7g/100mL.
It is further preferred that above-mentioned preparation method, pH value in reaction is 3.5~4.5, and reaction temperature is 25~35 DEG C, reaction Time is 0.75~2h, and the additional amount of the polyphenol oxidase is 1.5~2.5g/L, and minute ventilation volume is the reaction liquid 1~2 times of long-pending amount.
It is further preferred that above-mentioned preparation method, the source object of the polyphenol oxidase is selected from: fruit, plant, micro- life Object.
It is further preferred that above-mentioned preparation method, the source object of the polyphenol oxidase is selected from:
A, fruit: loquat, blue poison, apple, pears, peach, grape, lichee, apricot, pineapple;
B, plant: green tea, oolong tea, potato bud/root, spinach, semen viciae fabae, carrot, tomato;
C, microorganism: tea tree endophyte, Trametes trogii, hard Trametes trogii and Corilus versicolor Quel..
The present invention also provides above compounds or said medicine preparation to have the drug or health care product of antiobesity action in preparation In application.
The present invention also provides above compounds or said medicine preparation to have drug or the health care of effect for reducing blood fat in preparation Application in product.
The present invention also provides above compounds or said medicine preparation in preparation prevention or treats drug or the guarantor of fatty liver Application in strong product.
Technical solution of the present invention has the advantages that
(1) the compounds of this invention inhibits the increased significant effect of mouse weight to be better than theaflavin, theaflavin -3- gallic acid Ester, theaflavin-3'-gallate and theaflavin -3,3 '-digallic acid ester inhibit the increased effect of mouse weight;
(2) significant effect of the compounds of this invention reducing blood lipid is better than theaflavin, theaflavin-3-gallate, theaflavin- The effect of 3 '-gallates and theaflavin -3,3 '-digallic acid ester reducing blood lipid;
(3) the compounds of this invention is significantly better than theaflavin, theaflavin -3- to the therapeutic effect of nonalcoholic fatty liver and does not eat Sub- acid esters, theaflavin-3'-gallate and theaflavin -3,3 '-digallic acid ester imitate the treatment of nonalcoholic fatty liver Fruit.
Detailed description of the invention
In order to make the content of the present invention more clearly understood, it below according to specific embodiments of the present invention and combines Attached drawing, the present invention is described in further detail, in which:
Fig. 1 and Fig. 2 is the liver organization HE dye of 2 groups of rats of model control group and compound in experimental example 3 of the present invention respectively Color pathological examination result.
Specific embodiment
In following embodiment of the present invention and experimental example, myricetin, rutin, isoquercitrin, Quercetin are commercially available product, purity >=98% (HPLC detection).
Polyphenol oxidase extracts in accordance with the following methods: extracting the polyphenol oxidase in the object of enzyme source, tool using homogenate method Body is as follows: weighing 10kg apple, crushes in tissue mashing machine, smashed enzyme source object is taken out, is put into the lemon of 10L pre-cooling Acid-disodium hydrogen phosphate buffer (pH of buffer 5.5, crospovidone containing 100g PVPP, the EDTA of 20gVc, 1mmol/L), High-speed tissue mashing machine is homogenized 8min, extracts under 4 DEG C of low temperature 12 hours, leaching liquor obtained by 3 layers of filtered through gauze, by gained filtrate 4 DEG C low-temperature centrifugation 30 minutes, revolving speed 8000r/min, supernatant is apple polyphenol oxidase, and freeze-drying is stand-by.
The source object apple of polyphenol oxidase is replaced with into the kind of pear to get pears polyphenol oxidase;By polyphenol oxidase Source object apple replaces with fresh tea passes to get tea leaf polyphenols oxidizing ferment.
Embodiment 1The preparation of compound 1
Myricetin and each 150g of rutin are weighed respectively, are dissolved in the citrate-phosphate disodium hydrogen buffer that the pH of 15L is 4.5 In (concentration of substrate 2g/100mL), a certain amount of apple polyphenol oxidase (additive amount 2.5g/L) is added, ventilatory capacity is 15L/min reacts 2 hours at 25 DEG C, and temperature is increased to rapidly 100 DEG C by heating inactivates polyphenol oxidase, is kept for 5 points Clock.
Polyamide resin column on gained reaction solution is chromatographed, column chromatography diameter height compares for 1:10, applied sample amount and bed volume ratio It is successively eluted with water, 5% ethanol water, 95% ethanol water for 1:4, loading flow velocity 2BV/h, collects 95% second Alcohol elutes position, and 40 DEG C of reduced pressure dryings obtain crude extract, is further isolated and purified using suppressing in BUCHI, column chromatography Specification: crude extract is dissolved in 30% ethanol water (concentration 80mg/ by 15mm*310mm, filler C18, flow velocity 3mL/min ML it) is used as sample solution, gradient is that 15%-30% ethanol water elutes 3h, 30% ethanol water elutes 2h, 30%- 60% ethanol water elutes 3h, 60%-95% ethanol water and elutes 2h, collects 30% ethyl alcohol aqueous strip solution, 45 DEG C subtract Pressure is concentrated into no alcohol taste, is freeze-dried, obtains compound 1 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 897.2 [M+H]+1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-1:
Table 1-1 compound 11H NMR and13C NMR data
Note: in table 1-1, "-" indicate the position without H, it is same in table 1-2~table 1-3.
Embodiment 2The preparation of compound 2
Myricetin and each 200g of isoquercitrin are weighed respectively, and the citrate-phosphate disodium hydrogen that the pH for being dissolved in 15L is 3.5 is slow In fliud flushing, a certain amount of tea leaf polyphenols oxidizing ferment (additive amount 2.0g/L) is added, ventilatory capacity 25L/min is anti-at 35 DEG C It answers 45 minutes, temperature is increased to rapidly 100 DEG C by heating inactivates polyphenol oxidase, is kept for 5 minutes.
Polyamide resin column on gained reaction solution is chromatographed, column chromatography diameter height compares for 1:8, and applied sample amount is with bed volume ratio 1:5, loading flow velocity 2BV/h are successively eluted with water, 5% ethanol water, 95% ethanol water, and 95% ethyl alcohol is collected Position is eluted, 40 DEG C of reduced pressure dryings obtain crude extract, further isolate and purify using suppressing in BUCHI, column chromatography rule Lattice: crude extract is dissolved in 35% ethanol water (concentration 80mg/mL) by 15mm*310mm, filler C18, flow velocity 3mL/min As sample solution, gradient is that 15%-35% ethanol water elutes 3h, 35% ethanol water elutes 2h, 35%-60% Ethanol water elutes 3h, 60%-95% ethanol water and elutes 2h, collects 35% ethyl alcohol aqueous strip solution, and 45 DEG C of decompressions are dense It is reduced to no alcohol taste, is freeze-dried, obtains compound 2 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 751.1 [M+H]+1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-2:
Table 1-2 compound 21H NMR and13C NMR data
Embodiment 3The preparation of compound 3
Myricetin and each 75g of Quercetin are weighed respectively, are dissolved in the citrate-phosphate disodium hydrogen buffer that the pH of 15L is 4.0 In, a certain amount of pears polyphenol oxidase (additive amount 1.5g/L) is added, it is small to react 1.2 at 30 DEG C by ventilatory capacity 30L/min When, temperature is increased to rapidly 100 DEG C by heating inactivates polyphenol oxidase, is kept for 5 minutes.
Polyamide resin column on gained reaction solution is chromatographed, column chromatography diameter height compares for 1:10, applied sample amount and bed volume ratio It is successively eluted with water, 5% ethanol water, 95% ethanol water for 1:4, loading flow velocity 2BV/h, collects 95% second Alcohol elutes position, and 40 DEG C of reduced pressure dryings obtain crude extract, is further isolated and purified using suppressing in BUCHI, column chromatography Specification: crude extract is dissolved in 35% ethanol water (concentration 80mg/ by 15mm*310mm, filler C18, flow velocity 3mL/min ML it) is used as sample solution, gradient is that 15%-35% ethanol water elutes 3h, 35% ethanol water elutes 2h, 35%- 60% ethanol water elutes 3h, 60%-95% ethanol water and elutes 2h, collects 35% ethyl alcohol aqueous strip solution, 45 DEG C subtract Pressure is concentrated into no alcohol taste, is freeze-dried, obtains compound 3 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 589.2 [M+H]+1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-3:
Table 1-3 compound 31H NMR and13C NMR data
Embodiment 4The preparation of theaflavin
Theaflavin can be commercially available product, can be prepared according to method in the prior art, can also be according to this implementation Prepared by the following method of example: weighing epigallocatechin and each 150g of epicatechin respectively, the pH for being dissolved in 15L is 4 In citrate-phosphate disodium hydrogen buffer, a certain amount of tea leaf polyphenols oxidizing ferment (additive amount 1.5g/L) is added, ventilatory capacity is 20L/min reacts 1.5 hours at 25 DEG C, and temperature is increased to rapidly 100 DEG C by heating inactivates polyphenol oxidase, is kept for 5 points Clock.
Polyamide resin column on gained reaction solution is chromatographed, column chromatography diameter height compares for 1:10, applied sample amount and bed volume ratio It is successively eluted with water, 5% ethanol water, 95% ethanol water for 1:4, loading flow velocity 2BV/h, collects 95% second Alcohol elutes position, and 40 DEG C of reduced pressure dryings obtain crude extract, is further isolated and purified using suppressing in BUCHI, column chromatography Specification: crude extract is dissolved in 35% ethanol water (concentration 80mg/ by 15mm*310mm, filler C18, flow velocity 3mL/min ML it) is used as sample solution, gradient is that 15%-35% ethanol water elutes 3h, 35% ethanol water elutes 2h, 35%- 60% ethanol water elutes 3h, 60%-95% ethanol water and elutes 2h, collects 35% ethyl alcohol aqueous strip solution, 45 DEG C subtract Pressure is concentrated into no alcohol taste, is freeze-dried, obtains compound.It is compared by HPLC-MS and commercially available theaflavin reference substance, it is known that above-mentioned The above-mentioned compound being prepared is theaflavin.
Embodiment 5The bis- galla turcicas of theaflavin-3-gallate, theaflavin-3'-gallate, theaflavin -3,3 ' - The preparation of acid esters
Theaflavin-3-gallate, theaflavin-3'-gallate, theaflavin -3,3 '-digallic acid ester can be with For commercially available product, can be prepared according to method in the prior art, it can also be according to the following method system of the present embodiment It is standby:
Using Epigallo-catechin gallate (EGCG) and epicatechin as reaction raw materials, carried out according to the condition of embodiment 4 Reaction, can be prepared theaflavin-3-gallate;
Using L-Epicatechin gallate and epigallocatechin as reaction raw materials, carried out according to the condition of embodiment 4 Reaction, can be prepared theaflavin-3'-gallate;
Using Epigallo-catechin gallate (EGCG) and L-Epicatechin gallate as reaction raw materials, according to embodiment 4 Condition reacted, theaflavins-3,3'-bisgallate can be prepared.
Experimental example 1The research of the compounds of this invention antiobesity action
1, experimental material
D12451 (45%) purifying feed high in fat and basal feed are purchased from Research Diets (U.S.).
4 week old male C 57 BL/6 J mouse of SPF grade 108 (is provided by Shanghai Ling Chang Biotechnology Co., Ltd;First initial body Weight is 11-13g;The sub-cage rearing in plastics cage tool freely ingests and drinks water 7 days, adapts it to environment and quarantine).
2, experimental method
2.1 experimental group
108 mouse are divided into 9 groups, and every group 12,4/cage, respectively blank control group, model control group, compound 1 Group, 2 groups of compound, 3 groups of compound, theaflavin group, theaflavin-3-gallate group, theaflavin-3'-gallate group With theaflavin -3,3 '-digallic acid ester group.
2.2 medication
Freely ingest drinking-water, blank control group feeding basal feed, model control group and each administration group feeding D12451 high Rouge purifies feed, and 1 group of compound, 2 groups of compound, 3 groups of compound, theaflavin group, theaflavin-3-gallate group, tea are yellow Plain -3 '-gallate groups and theaflavin -3,3 '-digallic acid ester group give the compound 1 of the preparation of embodiment 1, reality respectively It is yellow to apply theaflavin, the tea of the preparation of embodiment 5 prepared by the compound 2 of the preparation of example 2, compound 3 prepared by embodiment 3, embodiment 4 Element -3- gallate, theaflavin-3'-gallate and theaflavins-3,3'-bisgallate, each administration group are administered 1 times/day, dosage is 100mg/kg, and successive administration 8 weeks.
3, experimental data detection and processing
3.1 Testing index
Observe and record the weight and weight gain of each group.
3.2 statistical analysis
Data processing is carried out using 20.0 software of SPSS, group difference uses one-way analysis of variance.
4, experimental result
After being administered 8 weeks, the experimental data of the weight gain of each group mouse is as shown in table 2.
The weight gain of 2 each group mouse weight of table
Group number Weight gain weight (g)
Blank control group 10.16±1.50
Model control group 18.75±1.98##
1 group of compound 13.08±1.83**
2 groups of compound 13.21±1.75**
3 groups of compound 12.96±1.94**
Theaflavin group 15.16±1.88*
Theaflavin-3-gallate group 17.34±1.92
Theaflavin-3'-gallate group 16.57±1.86
Theaflavin -3,3 '-gallate group 17.19±1.97
P < 0.01 is compared in ## expression with blank control group, and P < 0.01 is compared in * * expression with model control group, and * is indicated and model Control group compares P < 0.05
As shown in Table 2: (1) after mouse is fed with 8 weeks, compared with blank control group, the weight gain of model control group rat body weight With extremely significant difference (P < 0.001);This shows obese model modeling success;
(2) compared with model control group, compound 1,2,3 being capable of extremely significant weight gain (the P < for reducing mouse 0.001);
(3) compared with model control group, theaflavin has the effect of certain reduction mouse weight gain, and theaflavin -3- is not eaten Sub- acid esters, theaflavin-3'-gallate and theaflavin -3,3 '-digallic acid ester, which all have, reduces becoming for mouse weight gain Gesture, but effect is not significant;
(4) compared with model control group, the compounds of this invention 1,2,3 can significantly inhibit the weight gain of mouse, and its The increased significant effect of mouse weight is inhibited to be better than theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate Inhibit the increased effect of mouse weight with theaflavin -3,3 '-digallic acid ester.
Experimental example 2The research of the compounds of this invention effect for reducing blood fat
1, experimental material
Cholesterol and sodium taurocholate are purchased from Great Wall pharmaceutcal corporation, Ltd (China, Shanghai).
Feed be it is commercially available, high lipid food include 75% basal feed, 2% cholesterol, 0.5% sodium taurocholate, 15% lard and 7.5% yolk.
4 week old male SD rat of cleaning grade 90 (is provided by Shanghai Ling Chang Biotechnology Co., Ltd;Original body mass is 150-180g;The sub-cage rearing in plastics cage tool freely ingests and drinks water 7 days, adapts it to environment and quarantine).
2, experimental method
2.1 experimental group
90 rat stochastic averaginas are divided into 9 groups, every group 10, respectively 1 group of compound, 2 groups of compound, compound 3 Group, theaflavin group, theaflavin-3-gallate group, theaflavin-3'-gallate group and the bis- no foods of theaflavin -3,3 ' - Sub- acid esters group, model control group and blank control group.Blank control group is fed with basal feed, other each groups are fed with high lipid food Diet.
2.2 medication
It freely ingests drinking-water, blank control group is fed with basal feed, and model control group and each administration group are fed with high lipid food, 1 group of compound, 2 groups of compound, 3 groups of compound, theaflavin group, theaflavin-3-gallate group, theaflavin -3 '-galla turcica Acid esters group and theaflavin -3,3 '-digallic acid ester group give the compound 1 of the preparation of embodiment 1 respectively, prepared by embodiment 2 Theaflavin -3- the galla turcica of theaflavin, the preparation of embodiment 5 prepared by compound 2, the compound 3 of the preparation of embodiment 3, embodiment 4 Acid esters, theaflavin-3'-gallate and theaflavins-3,3'-bisgallate, each administration group are administered once/day, administration Dosage is 70mg/kg, is administered 7 weeks.
3, experimental data detection and processing
3.1 Testing index
After being administered 7 weeks, rat is taken a blood sample through retroorbital venous clump, is quantitatively examined on automatic biochemistry analyzer using enzymatic method It is solid to survey its serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein gallbladder Alcohol (LDL-C).
3.2 statistical analysis
Data processing is carried out using 20.0 software of SPSS, group difference uses one-way analysis of variance.
4, experimental result
After being administered 7 weeks, the experimental result of the biochemical blood parameters of each group rat is as shown in table 3.
The biochemical blood parameters of 3 each group rat of table
P < 0.01 is compared in ## expression with blank control group, and P < 0.01 is compared in * * expression with model control group, and * is indicated and model Control group compares P < 0.05
As shown in Table 3: (1) compared with model control group, TG, TC, LDL-C reduction of 1,2,3 pair of rat of compound have pole Significant difference (P < 0.01) shows that TG, TCLDL-C of 1,2,3 pair of hyperlipemia rat of the compounds of this invention all have significant drop Low effect;
(2) compared with model control group, theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate and There were significant differences (P < 0.05) or has reduction for TG, TC, LDL-C reduction of theaflavin-the 3,3 '-digallic acid ester to rat Trend;
(3) significant effect of 1,2,3 reducing blood lipid of the compounds of this invention is better than theaflavin, theaflavin-3-gallate, tea The effect of flavine -3 '-gallate and theaflavin -3,3 '-digallic acid ester reducing blood lipid.
Experimental example 3Research of the compounds of this invention to the preventive and therapeutic action of nonalcoholic fatty liver
1, experimental material
Experimental material of the experimental material of this experimental example with experimental example 2.
2, experimental method
With the experimental group and medication of experimental example 2, difference is only that the experimental group and medication of this experimental example: Successive administration 4 weeks.
3, experimental data detection and processing
3.1 Testing index
To experiment last day, after etherization, 10% formalin is fixed after taking rat liver to weigh, paraffin section, Microscopy after HE dyeing: (1) recording the weight and liver weight in wet base of each group, calculates liver index (liver weight/weight * 100%);(2) right Model control group and 2 groups of compound of pathology of hepar inspection.
3.2 statistical analysis
Data processing is carried out using 20.0 software of SPSS, group difference uses one-way analysis of variance.
4, experimental result
After being administered 4 weeks, each group rat body weight, liver weight in wet base, liver index are as shown in table 4, pathology of hepar inspection result As shown in Figs. 1-2.
4 each group rat body weight of table, liver weight in wet base and liver index variation
P < 0.05 is compared in # expression with blank control group, and P < 0.01 is compared in ## expression with blank control group, and * * is indicated and model Control group compares P < 0.01, and * indicates to compare P < 0.05 with model control group
As shown in Table 4: (1) with model control group compared with, 1,2,3 pair of rat body weight of compound, liver weight in wet base and liver index drop It is low to have extremely significant difference or significant difference (P < 0.01 or P < 0.05), show 1,2,3 pair of non-alcoholic rouge of the compounds of this invention Fat hepatomegaly mouse has certain therapeutic effect;
(2) compared with model control group, theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate and Theaflavin -3,3 '-digallic acid ester to rat body weight, liver weight in wet base and liver index reduce there were significant differences (P < 0.05) or Has the tendency that reduction, but effect is not significant;
(3) therapeutic effect of 1,2,3 pair of nonalcoholic fatty liver of the compounds of this invention is significantly better than theaflavin, theaflavin- 3- gallate, theaflavin-3'-gallate and theaflavin -3,3 '-digallic acid ester are to nonalcoholic fatty liver Therapeutic effect.
By Fig. 1-2 it is found that model control group rat liver is loose, color is partially light, and liver cell diffuses sex vesicle steatosis; 2 groups of liver fats of compound are steeped obvious number and are reduced, and scale mitigates.
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or It changes.There is no necessity and possibility to exhaust all the enbodiments.And it is extended from this it is obvious variation or It changes still within the protection scope of the invention.

Claims (10)

1. the compound with structure shown in formula (I),
Wherein, R1、R2Be independently from each other H, by In At least one is formed by glycosyl residue.
2. compound according to claim 1, which is characterized in that
R1Selected from H, byAt least one of be formed by glycosyl residue, R2Selected from H.
3. compound according to claim 1 or 2, which is characterized in that
R1Selected from H,
4. compound according to claim 1-3, which is characterized in that formula (I) compound represented is selected from:
5. the pharmaceutically acceptable salt of the described in any item compounds of claim 1-4, ester, prodrug, solvate or its crystalline substance Type.
6. a kind of pharmaceutical preparation, which is characterized in that with the described in any item compounds of claim 1-4, its is pharmaceutically acceptable Salt, ester, prodrug, solvate or its crystal form be active constituent, according to common process, customary adjuvant be added be made and clinically may be used Tablet, capsule, powder, mixture, pill, granule, syrup, emplastrum, suppository, aerosol, ointment or the note of receiving Penetrate agent.
7. a kind of method for preparing the described in any item compounds of claim 1-4, which is characterized in that chemical combination shown in formula (II) Object and formula (III) compound represented pass through enzymatic reaction under the action of polyphenol oxidase up to formula (I) compound represented;
8. preparation method according to claim 7, which is characterized in that shown in formula (II) compound represented and formula (III) The molar ratio of compound is (1:2)~(2:1);
Using citrate-phosphate disodium hydrogen buffer as reaction solution, formula (II) compound represented and formula (III) compound represented Total concentration in reaction solution is 1~2.7g/100mL.
9. preparation method according to claim 7 or 8, which is characterized in that pH value in reaction is 3.5~4.5, and reaction temperature is 25~35 DEG C, the reaction time is 0.75~2h, and the additional amount of the polyphenol oxidase is 1.5~2.5g/L, minute ventilation volume For 1~2 times of amount of the reaction solution volume.
10. the described in any item compounds of claim 1-5 or pharmaceutical preparation as claimed in claim 9 in preparation there is weight-reducing to make Application in drug or health care product;
Preferably, the application is the application in the drug or health care product that preparation has effect for reducing blood fat;
It is further preferred that the application is the application in the drug or health care product of preparation prevention or treatment fatty liver.
CN201710724964.4A 2017-08-22 2017-08-22 Benzo Zhuo phenol ketone derivatives and preparation method thereof and purposes Withdrawn CN109422786A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109422785A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Tropolones and preparation method thereof and purposes
CN109422787A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Tropolones are like object and preparation method thereof and purposes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102427807A (en) * 2009-05-21 2012-04-25 三得利控股株式会社 Anti-obesity agent comprising compound containing benzotropolone ring
CN109422714A (en) * 2017-08-22 2019-03-05 苏州禾研生物技术有限公司 Benzo Tropolones compound and preparation method thereof and purposes
CN109422785A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Tropolones and preparation method thereof and purposes
CN109422787A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Tropolones are like object and preparation method thereof and purposes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102427807A (en) * 2009-05-21 2012-04-25 三得利控股株式会社 Anti-obesity agent comprising compound containing benzotropolone ring
CN109422714A (en) * 2017-08-22 2019-03-05 苏州禾研生物技术有限公司 Benzo Tropolones compound and preparation method thereof and purposes
CN109422785A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Tropolones and preparation method thereof and purposes
CN109422787A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Tropolones are like object and preparation method thereof and purposes

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109422785A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Tropolones and preparation method thereof and purposes
CN109422787A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Tropolones are like object and preparation method thereof and purposes

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