CN109422714A - Benzo Tropolones compound and preparation method thereof and purposes - Google Patents

Benzo Tropolones compound and preparation method thereof and purposes Download PDF

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CN109422714A
CN109422714A CN201710725649.3A CN201710725649A CN109422714A CN 109422714 A CN109422714 A CN 109422714A CN 201710725649 A CN201710725649 A CN 201710725649A CN 109422714 A CN109422714 A CN 109422714A
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theaflavin
compound
preparation
formula
gallate
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夏增华
张小芸
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SUZHOU HEYAN BIOTECHNOLOGY Co Ltd
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SUZHOU HEYAN BIOTECHNOLOGY Co Ltd
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Abstract

The invention belongs to drug or field of health care products, and in particular to benzo Tropolones compound and preparation method thereof and purposes.The benzo Tropolones compound has the following structure:

Description

Benzo Tropolones compound and preparation method thereof and purposes
Technical field
The invention belongs to drug or field of health care products, and in particular to benzo Tropolones compound 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, X, Y are independently from each other: C=O, CH2, and X, Y are not simultaneously selected from CH2；Dotted line indicate selected from singly-bound or Double bond；
R1、R6Be independently from each other H, OH,By At least one of be formed by glycosyl residue；
R2、R3、R4、R5、R7、R8、R9、R10It is independently from each other H, OH, OCH3、CH3、ByAt least one of be formed by glycosyl residue.
Preferably, formula (I) compound represented is selected from:
Or
It is further preferred that above compound,
R1、R6Be independently from each other H, OH,By At least one of be formed by glycosyl residue；
R2Selected from H, OH；
R3Selected from H, CH3；
R4Selected from OH；
R5Selected from H；
R7、R8Be independently from each other H, OH, by In At least one be formed by glycosyl residue；
R9Selected from H, OH, OCH3, byIn at least one Kind is formed by glycosyl residue；
R10Selected from H, OH.
It is further preferred that
R1Selected from H, OH,The glycosyl residue of formation；
R6Selected from H, OH,By At least one of be formed by glycosyl residue.
It is further preferred that formula (I) compound represented is selected from:
Or
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, the molar ratio of formula (II) compound represented and formula (III) compound represented is (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.
It is further preferred that using citrate-phosphate disodium hydrogen buffer as reaction solution, formula (II) compound represented and formula (III) total concentration of the compound represented in reaction solution is 1~3g/100mL.
It is further preferred that pH value in reaction is 3.5~5.5, reaction temperature is 20-40 DEG C, and the reaction time is 0.75~2h, The additional amount of the polyphenol oxidase is 1~3g/L, and minute ventilation volume is 1~2 times of amount of the reaction solution volume.
It is further preferred that the source object of the polyphenol oxidase is selected from: fruit, plant, microorganism.
It is further preferred that 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, preparation have effect for reducing blood fat drug or health care product in application, prevent or treat fatty liver drug Or the application in health care 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 8 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, dihydromyricetin, epicatechin, L-Epicatechin gallate, two Hydrogen Quercetin, astilbin, myricetrin, dihydroquercetin 7-O- glucoside, eriodictyol, gossypetin, rhamnetin, Flavomarein, cedrin, robinetin, Quercetin, locust tree flavanone, eriocitrin, eriodictyol -6- glucoside, mountain balsam Phenol -8- glucoside, Epigallo-catechin gallate (EGCG), epicatechin, epigallocatechin, epicatechin galla turcica Acid esters is 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 the 10kg kind of pear, crushes in tissue mashing machine, smashed enzyme source object is taken out, is put into the lemon of 10L pre-cooling Lemon acid-disodium hydrogen phosphate buffer (pH of buffer 5.5, crospovidone containing 100g PVPP, 20gVc, 1mmol/L's EDTA), 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 institute 4 DEG C of filtrate low-temperature centrifugation 30 minutes is obtained, revolving speed 8000r/min, supernatant is pears polyphenol oxidase, and freeze-drying is stand-by.
The source object kind of pear of polyphenol oxidase is replaced with into apple to get apple polyphenol oxidase；By polyphenol oxidase The source object kind of pear replace with tealeaves to get tea leaf polyphenols oxidizing ferment.
Embodiment 1The preparation of compound 1
Dihydromyricetin and each 150g of epicatechin are weighed respectively, are dissolved in the citrate-phosphate hydrogen two that the pH of 15L is 5.5 In sodium buffer, a certain amount of pears polyphenol oxidase (additive amount 1.5g/L), ventilatory capacity 18L/min, at 20 DEG C is added Reaction 2 hours, temperature is increased to rapidly 100 DEG C by reheating inactivates polyphenol oxidase, is kept for 5 minutes, terminates reaction.
Polyamide resin column on gained reaction solution is chromatographed, column chromatography diameter height compares for 1:11, 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 followed successively by 15%-30% ethanol water elution 3h, 30% ethanol water elutes 2h, 30%-60% ethanol water elution 3h, 60%-95% ethanol water elution 2h, 30% ethyl alcohol aqueous strip solution of collection, 45 DEG C it is concentrated under reduced pressure into no alcohol taste, is freeze-dried, obtains compound 1 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 579.1 [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
Position δH δC Position δH δC Position δH δC
2 4.55(d) 72.9 2’ 5.5(d) 76.9 a — 186
3 5.05(d) 87.9 3’ 4.4(m) 65.8 b — 155
4 — 197 4’ 2.7,3.1 (dd) 30.0 c 7.4(s) 116
5 — 168.7 5’ — 158.2 d — 122.3
6 5.96(d) 97.0 6’ 5.83(d) 96.5 e 7.9(s) 124.7
7 — 165.2 7’ — 157.6 f — 131.9
8 6.00(d) 96.3 8’ 5.91(d) 97.8 g 7.6(s) 129
9 — 163.8 9’ — 157.2 h — 147
10 — 101.7 10’ — 100.3 i — 151
j — 128.6
k — 129.6
Note: in table 1-1, "-" indicate the position without H, it is same in table 1-2~table 1-11.
Embodiment 2The preparation of compound 2
Dihydromyricetin and each 75g of L-Epicatechin gallate are weighed respectively, are dissolved in the citric acid-that the pH of 15L is 3.5 In disodium hydrogen phosphate buffer, it is added a certain amount of tea leaf polyphenols oxidizing ferment (additive amount 2g/L), ventilatory capacity 30L/min, It is reacted 45 minutes at 30 DEG C, temperature is increased to rapidly 100 DEG C by reheating inactivates polyphenol oxidase, is kept for 5 minutes, terminates Reaction.
Polyamide resin column on gained reaction solution is chromatographed, it is 1: 8 that column chromatography diameter height, which compares, 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 25% ethanol water (concentration 80mg/mL) by 15mm*310mm, filler C18, flow velocity 3mL/min As sample solution, gradient is that 15%-25% ethanol water elutes 3h, 25% ethanol water elutes 2h, 25%-60% Ethanol water elutes 3h, 60%-95% ethanol water and elutes 2h, collects 25% 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 731.2 [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
Position δH δC Position δH δC Position δH δC
2 4.51(d) 72.9 2’ 5.51(d) 77.1 a - 186.2
3 5.04(d) 87.6 3’ 5.47(m) 70.9 b - 153.7
4 -- 197.1 4’ 3.04,2.89 (dd) 27.3 c 7.41(s) 116.2
5 -- 169.9 5’ - 156.8 d - 122.3
6 5.92(d) 97.4 6’ 5.97(d) 95.9 e 7.90(s) 124.7
7 - 164.7 7’ - 157.3 f - 131.5
8 5.99(d) 95.3 8’ 6.01(d) 95.9 g 7.62(s) 129.2
9 - 161.8 9’ - 156.7 h - 145.6
10 - 101.7 10’ - 99.3 i - 150.7
11’ - 121.6 j - 127.9
12’ 7.03(s) 109.5 k - 129.1
13’ - 146.1 1 - 167.7
14’ - 138.7
15’ - 146.1
16’ 7.03(s) 109.5
Embodiment 3The preparation of compound 3
Epigallocatechin and each 100g of dihydroquercetin are weighed respectively, are dissolved in citric acid-phosphorus that the pH of 15L is 4.0 In sour disodium hydrogen buffer, it is added a certain amount of apple polyphenol oxidase (additive amount 3g/L), ventilatory capacity 30L/min, It is reacted 1 hour at 35 DEG C, temperature is increased to rapidly 100 DEG C by reheating inactivates polyphenol oxidase, is kept for 5 minutes, terminates anti- It answers.
Polyamide resin column on gained reaction solution is chromatographed, column chromatography diameter height compares for 1:10, applied sample amount and bed volume ratio For 1:5, loading flow velocity 2BV/h, water, 5% ethanol water are successively used, 95% ethanol water is eluted, and 95% second is collected 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, and 30% ethanol water elutes 2h, 30%- 60% ethanol water elutes 3h, and 60%-95% ethanol water 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 3 (HPLC purity >=98%).Structure confirmation data is as follows: ESI:m/z 579.2[M+H]+。
Embodiment 4The preparation of compound 4
Epigallo-catechin gallate (EGCG) and each 80g of dihydroquercetin are weighed respectively, and the pH for being dissolved in 15L is 4.5 In citrate-phosphate disodium hydrogen buffer, a certain amount of apple polyphenol oxidase (additive amount 2.0g/L) is added, ventilatory capacity is 30L/min reacts 45min at 40 DEG C, and temperature is increased to rapidly 100 DEG C by reheating inactivates polyphenol oxidase, is kept for 5 points Clock terminates reaction.
Polyamide resin column on gained reaction solution is chromatographed, column chromatography diameter height compares for 1:10, applied sample amount and bed volume ratio For 1:5, loading flow velocity 2BV/h, water, 5% ethanol water are successively used, 95% ethanol water is eluted, and 95% second is collected 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, and 30% ethanol water elutes 2h, 30%- 60% ethanol water elutes 3h, and 60%-95% ethanol water 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 4 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 731.2 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-3:
Table 1-3 compound 41H NMR and13C NMR data
Position δH δC Position δH δC Position δH δC
2 5.00(d) 79.5 2’ 4.85(d) 85.1 a — 185.9
3 5.49(m) 71.4 3’ 4.43(d) 73.6 b 154.2
4 3.00,2.91(dd) 26.5 4’ — 198.4 c 7.56(s) 116.0
5 — 156.3 5’ — 164.5 d — 125.3
6 5.92(d) 95.6 6’ 5.92(d) 97.3 e 7.84(s) 124.9
7 — 157.2 7’ — 168.7 f — 129.8
8 5.98(d) 95.9 8’ 6.02(d) 96.3 g 7.62(s) 128.7
9 — 155.8 9’ — 165.3 h — 144.9
10 — 98.7 10’ — 101.8 i — 150.6
11 — 120.8 j — 125.6
12 7.01(s) 107.9 k — 128.8
13 — 146.5 l — 167.9
14 — 137.4
15 — 145.1
16 7.01(s) 105.7
Embodiment 5The preparation of compound 5
Using epigallocatechin and astilbin as reaction raw materials, reacted under the following conditions: pH3.5-5.5, Concentration of substrate 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, reaction temperature 20- It 40 DEG C, reaction time 0.75-2 hour, can prepare compound 5 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 725.2 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) is as shown in table 1-4:
Table 1-4 compound 51H NMR and13C NMR data
Embodiment 6The preparation of compound 6
It using myricetrin and Quercetin as reaction raw materials, is reacted under the following conditions: pH3.5-5.5, concentration of substrate 1- 3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, 20-40 DEG C of reaction temperature, are reacted It time 0.75-2 hour, can prepare compound 6 (HPLC purity >=98%).Structure confirmation data is as follows: ESI:m/z 735.1 [M+H]+。
Embodiment 7The preparation of compound 7
Using epigallocatechin and dihydroquercetin -7-O glucoside as reaction raw materials, carry out under the following conditions anti- Answer: pH3.5-5.5, concentration of substrate 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the body of 1-2 times of quantitative response liquid Product, 20-40 DEG C of reaction temperature, reaction time 0.75-2 hour, can prepare compound 7 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 741.2 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in tables 1 to 5:
Table 1-5 compound 71H NMR and13C NMR data
Embodiment 8The preparation of compound 8
Using dihydromyricetin and dihydroquercetin -7-O glucoside as reaction raw materials, reacted under the following conditions: PH3.5-5.5, concentration of substrate 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, It 20-40 DEG C of reaction temperature, reaction time 0.75-2 hour, can prepare compound 8 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 755.1 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-6:
Table 1-6 compound 81H NMR and13C NMR data
Embodiment 9The preparation of compound 9
Using Epigallo-catechin gallate (EGCG) and eriodictyol as reaction raw materials, reacted under the following conditions: PH3.5-5.5, concentration of substrate 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, It 20-40 DEG C of reaction temperature, reaction time 0.75-2 hour, can prepare compound 9 (HPLC purity >=98%).Structural confirmation number According to as follows: ESI:m/z 715.1 [M+H]+。
Embodiment 10The preparation of compound 10
Using dihydromyricetin and gossypetin as reaction raw materials, reacted under the following conditions: pH3.5-5.5, substrate are dense Spend 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume be 1-2 times of quantitative response liquid volume, 20-40 DEG C of reaction temperature, It reaction time 0.75-2 hour, can prepare compound 10 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 607.1 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-7:
Table 1-7 compound 101H NMR and13C NMR data
Embodiment 11The preparation of compound 11
Using Epigallo-catechin gallate (EGCG) and rhamnetin as reaction raw materials, reacted under the following conditions: PH3.5-5.5, concentration of substrate 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, It 20-40 DEG C of reaction temperature, reaction time 0.75-2 hour, can prepare compound 11 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 743.1 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-8:
Table 1-8 compound 111H NMR and13C NMR data
Embodiment 12The preparation of compound 12
With dihydromyricetin and Flavomarein (No. CAS for 577-38-8, structural formula are as follows:) it is reaction raw materials, it is reacted under the following conditions: pH3.5-5.5, bottom Object concentration 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, reaction temperature 20-40 DEG C, it reaction time 0.75-2 hour, can prepare compound 12 (HPLC purity >=98%).Structure confirmation data is as follows: ESI: m/z 739.1[M+H]+。
Embodiment 13The preparation of compound 13
It using cedrin and rutin as reaction raw materials, is reacted under the following conditions: pH3.5-5.5, concentration of substrate 1- 3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, 20-40 DEG C of reaction temperature, are reacted It time 0.75-2 hour, can prepare compound 13 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 913.2 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-9:
Table 1-9 compound 131H NMR and13C NMR data
Embodiment 14The preparation of compound 14
It using robinetin and Quercetin as reaction raw materials, is reacted under the following conditions: pH3.5-5.5, concentration of substrate 1- 3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, 20-40 DEG C of reaction temperature, are reacted It time 0.75-2 hour, can prepare compound 14 (HPLC purity >=98%).Structure confirmation data is as follows: ESI:m/z 575.1[M+H]+。
Embodiment 15The preparation of compound 15
It using locust tree flavanone and catechin as reaction raw materials, is reacted under the following conditions: pH3.5-5.5, substrate Concentration 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, reaction temperature 20-40 DEG C, it reaction time 0.75-2 hour, can prepare compound 15 (HPLC purity >=98%).Structure confirmation data is as follows: ESI: m/z 547.1[M+H]+。
Embodiment 16The preparation of compound 16
Using dihydromyricetin and holy careless glycosides as reaction raw materials, reacted under the following conditions: pH3.5-5.5, substrate Concentration 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, reaction temperature 20-40 DEG C, it reaction time 0.75-2 hour, can prepare compound 16 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 885.3 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) is as shown in table 1-10:
Table 1-10 compound 161H NMR and13C NMR data
Embodiment 17The preparation of compound 17
Using myricetin and eriodictyol -6- glucoside as reaction raw materials, reacted under the following conditions: pH3.5-5.5, Concentration of substrate 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, reaction temperature 20- It 40 DEG C, reaction time 0.75-2 hour, can prepare compound 17 (HPLC purity >=98%).
Structure confirmation data is as follows: ESI:m/z 737.1 [M+H]+；1H NMR (600MHz, CD3OD) and13C NMR (150MHz, CD3OD) as shown in table 1-11:
Table 1-11 compound 171H NMR and13C NMR data
Embodiment 18The preparation of compound 18
Using nutgall catechin and eriodictyol -8- glucoside as reaction raw materials, reacted under the following conditions: PH3.5-5.5, concentration of substrate 1-3%, enzyme additive amount 1g/L-3g/L, minute ventilation volume are the volume of 1-2 times of quantitative response liquid, It 20-40 DEG C of reaction temperature, reaction time 0.75-2 hour, can prepare compound 18 (HPLC purity >=98%).Structural confirmation Data are as follows: ESI:m/z 725.1 [M+H]+。
Embodiment 19The 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 respectively, each 150g of epicatechin is dissolved in the lemon that the pH of 15L is 4 In lemon acid-disodium hydrogen phosphate 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 Freeze-drying obtains compound after pressure is concentrated into no alcohol.It is compared by HPLC-MS and commercially available theaflavin reference substance, it is known that above-mentioned system Standby obtained compound is theaflavin.
Embodiment 20Theaflavin-3-gallate, theaflavin-3'-gallate, theaflavin -3,3 '-are bis- not to be eaten The preparation of sub- 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 19 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 19 Reaction, can be prepared theaflavin-3'-gallate；
Using Epigallo-catechin gallate (EGCG) and L-Epicatechin gallate as reaction raw materials, according to embodiment 19 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 288 (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
288 mouse are divided into 24 groups, and every group 12,4/cage, respectively blank control group, model control group, compound 18 groups of 1- compound, theaflavin group, theaflavin-3-gallate group, theaflavin-3'-gallate group and theaflavin -3, 3 '-digallic acid ester groups.
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 18 groups of 1 group-compound of compound, theaflavin group, theaflavin-3-gallate group, theaflavin -3 '-are not eaten Sub- acid esters group and theaflavin -3,3 '-digallic acid ester group give respectively embodiment 1- embodiment 18 preparation compound 1-18, Embodiment 19 prepare theaflavin, embodiment 20 prepare theaflavin-3-gallate, theaflavin-3'-gallate and Theaflavins-3,3'-bisgallate, each administration group are administered once/day, and dosage is 100mg/kg, successive administration 8 Week.
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 (N=12)
P < 0.01 is compared in ## expression with blank control group, and * * indicates to compare P < 0.01 with model control group,
* it indicates to compare P < 0.05 with model control group
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- compound 18 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- compound 18 can significantly inhibit the weight gain of mouse, And it inhibits the increased significant effect of mouse weight to be better than theaflavin, theaflavin-3-gallate, theaflavin -3 '-galla turcica Acid esters and theaflavin -3,3 '-digallic acid ester inhibit the increased effect of mouse weight.
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 240 (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
240 rat stochastic averaginas are divided into 24 groups, every group 10, respectively 18 groups of compound 1- compound, theaflavin Group, theaflavin-3-gallate group, theaflavin-3'-gallate group and theaflavins-3,3'-bisgallate 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, 18 groups of 1 group-compound of compound, theaflavin group, theaflavin-3-gallate group, theaflavin-3'-gallate group and Theaflavin -3,3 '-digallic acid ester group is given the compound 1- compound 18 of the preparation of embodiment 1- embodiment 18 respectively, is implemented Theaflavin-3-gallate, theaflavin-3'-gallate and the tea Huang of theaflavin, the preparation of embodiment 20 prepared by example 19 Plain -3,3 '-digallic acid esters, each administration group are administered once/day, and dosage is 70mg/kg, are 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.
3 each group rat of table biochemical blood parameters (N=10)
P < 0.01 is compared in ## expression with blank control group, and * * indicates to compare P < 0.01 with model control group,
* it indicates to compare P < 0.05 with model control group
As shown in Table 3: (1) compared with model control group, compound 1- compound 18 reduces TG, TC, LDL-C of rat There is extremely significant difference (P < 0.01), shows that the compounds of this invention 1- compound 18 has TG, TCLDL-C of hyperlipemia rat It is significantly reduced 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 18 reducing blood lipid of the compounds of this invention 1- compound is better than theaflavin, theaflavin -3- gallic acid The effect of ester, theaflavin-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 8 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 (N=10)
P < 0.05 is compared in # expression with blank control group, and ## indicates to compare P < 0.01 with blank control group,
P < 0.01 is compared in * expression with model control group, and * indicates to compare P < 0.05 with model control group
As shown in Table 4: (1) compared with model control group, compound 1- compound 18 refers to rat body weight, liver weight in wet base and liver Number, which reduces, extremely significant difference or significant difference (P < 0.01 or P < 0.05), shows that the compounds of this invention 1- compound 18 is right Rats with nonalcoholic fatty liver disease 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) the compounds of this invention 1- compound 18 is significantly better than theaflavin, tea to the therapeutic effect of nonalcoholic fatty liver Flavine -3- gallate, theaflavin-3'-gallate and theaflavin -3,3 '-digallic acid ester are to non-alcoholic rouge The therapeutic effect of fat liver.
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； 8 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, X, Y are independently from each other: C=O, CH2, and X, Y are not simultaneously selected from CH2；Dotted line indicates to be selected from singly-bound or double bond；
R1、R6Be independently from each other H, OH,By At least one of be formed by glycosyl residue；
R2、R3、R4、R5、R7、R8、R9、R10It is independently from each other H, OH, OCH3、CH3、ByAt least one of be formed by glycosyl residue.
2. compound according to claim 1, which is characterized in that
R1、R6Be independently from each other H, OH,By At least one of be formed by glycosyl residue；
R2Selected from H, OH；
R3Selected from H, CH3；
R4Selected from OH；
R5Selected from H；
R7、R8Be independently from each other H, OH, by In extremely Few one kind is formed by glycosyl residue；
R9Selected from H, OH, OCH3, byAt least one of institute The glycosyl residue of formation；
R10Selected from H, OH.
3. compound according to claim 2, which is characterized in that
R1Selected from H, OH,The glycosyl residue of formation；
R6Selected from H, OH,By In At least one be formed by glycosyl residue.
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 1~3g/100mL.
9. preparation method according to claim 7 or 8, which is characterized in that pH value in reaction is 3.5~5.5, and reaction temperature is 20-40 DEG C, the reaction time is 0.75~2h, and the additional amount of the polyphenol oxidase is 1~3g/L, and minute ventilation volume is described 1~2 times of amount of 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.
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Cited By (3)

* 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
CN109422786A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Zhuo phenol ketone derivatives 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 (1)

* 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

Patent Citations (1)

* 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOSUKE MATSUO，等: "Nonenzymatic Biomimetic Synthesis of Black Tea Pigment Theaflavins", 《SYNLETT》 *

Cited By (3)

* 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
CN109422786A (en) * 2017-08-22 2019-03-05 苏州凯祥生物科技有限公司 Benzo Zhuo phenol ketone derivatives 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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Application publication date: 20190305