CN110467624A - Adduct made of a kind of flavane and diphenylethylene compounds a pair of horses going side by side are closed - Google Patents

Adduct made of a kind of flavane and diphenylethylene compounds a pair of horses going side by side are closed Download PDF

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CN110467624A
CN110467624A CN201810445439.3A CN201810445439A CN110467624A CN 110467624 A CN110467624 A CN 110467624A CN 201810445439 A CN201810445439 A CN 201810445439A CN 110467624 A CN110467624 A CN 110467624A
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compound
substituent groups
flavane
pair
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CN110467624B (en
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张培成
叶菲
王序杰
田金英
杨桠楠
张晓琳
冯子明
姜建双
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/41—Crassulaceae (Stonecrop family)

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Abstract

Adduct made of being closed the invention discloses a kind of flavane and diphenylethylene compounds by pentamethylene [c] furans a pair of horses going side by side and preparation method thereof and anti-diabetic activity.The compound of the present invention has structure shown in general formula (I), and preparation method includes the following steps: (1) synthesizing the flavan derivatives of 4 connection thio groups；(2) synthesis flavane 4 and 2 intermediates connecting of talan；(3) a kind of flavane and diphenylethylene compounds are synthesized and pass through adduct made of the conjunction of pentamethylene [c] furans a pair of horses going side by side.The compound of the present invention preparation method is simple and has significant antidiabetic effect.

Description

Adduct made of a kind of flavane and diphenylethylene compounds a pair of horses going side by side are closed
Technical field
The present invention relates to Structures of Natural Products method of modifying and anti-diabetic activities in field of medicaments.
Background technique
Alpha-glucosidase is distributed widely in organism, and very important effect is played in the metabolic process of body. Polysaccharide in food can be degraded to monosaccharide by it, and it is made to be absorbed by organisms utilization, alpha-glucosidase in metabolism Biosynthesis and the catabolic process of internal glycolipid and glycoprotein are simultaneously participated in, the carbohydrate in food is in saliva Oligosaccharides phlorose, fructose are decomposed under the action of liquid, Pancreatic arnylase, then through glucosides at small intestinal cell brush border Enzyme is decomposed into monosaccharide and is absorbed into blood circulation by small intestine upper section epithelial cell.Alpha-glucosidase restrainer can reduce internal α- The activity of glucuroide, so that effectively absorption of the control body to monosaccharide, reduces blood glucose level.
PTP 1B (Protein tyrosine phosphatase 1B, PTP1B), is albumen junket ammonia One of Major Members in acid phosphoric acid enzyme family play important negative regulation effect in Insulin signaling pathway.Research It confirms, insulin receptor and its substrate phosphorylation level can be made to increase using PTP1B inhibitor in insulin responsive cells, PTP1B inhibitor plays the role of insulin analog and insulin sensitizer.It knocks out PTP1B gene or uses GEM 132 (ASO) inhibit internal PTP1B albumen and the expression of mRNA, can not only significantly improve test mice to the sensibility of insulin, And patient's probability of obesity can be substantially reduced.PTP1B is the new target for treating insulin resistance and correlated metabolism diseases Point.
Polyflavanostilbene A is that this seminar is isolated from Polygonum cuspidatum Sieb. et Zucc early period, and one has newly The compound of clever skeleton structure.Its design feature is that A ring is rearranged into α, and β-unsaturated ring hexanone ECG passes through hexamethylene [c] furan The polymer that ring plate of muttering section and polydatin are formed.This connection type between polydatin and ECG still belongs to the first time hair Existing, in order to illustrate its formation mechenism, we study its synthetic route, wherein flavane 4 and 2 phases of polydatin Polymer even is the important intermediate to form polyflavanostilbene A, which may be by 4 derivatives of flavane Object and polydatin are obtained by nucleophilic substitution.External pharmacological evaluation shows polyflavanostilbene A simultaneously There is stronger inhibiting effect, IC to alpha-glucosidase50It is 17.7 μM.To people's PTP1B (protein-tyrosine of genetic recombination Phosphatase 1 B) inhibiting rate be 95.3%, IC50It is 5.05 μM
Summary of the invention
The object of the present invention is to provide a kind of flavane to be closed with diphenylethylene compounds by pentamethylene [c] furans a pair of horses going side by side Adduct.
Another object of the present invention is to provide the methods of the preparation of such compound.
A further object of the present invention is to provide a kind of pharmaceutical compositions comprising a kind of flavane and hexichol of effective dose Adduct and pharmaceutical carrier and/or excipient made of ethylene compounds are closed by pentamethylene [c] furans a pair of horses going side by side.
Another object of the present invention is to provide a kind of flavane and diphenylethylene compounds to pass through pentamethylene [c] furans a pair of horses going side by side Adduct made of conjunction is preparing the application in drug or health care product for treating and/or preventing diabetes.
The invention provides the following technical scheme:
First aspect present invention provides a kind of flavane and is closed with diphenylethylene compounds by pentamethylene [c] furans a pair of horses going side by side Dimer class compound, which is characterized in that have general formula (I) shown in structure.
Wherein, (1) RAAnd RBIt is on phenyl ring 1,2,3 arbitrary substituent groups,
The position of one substituent group are as follows:
The position of two substituent groups are as follows:
The position of three substituent groups are as follows:
Wherein R1、R2、R3It is independently selected from: hydrogen, hydroxyl, C1-5 alkoxy, amino, halogen；
(2)RCIt is selected from: hydrogen, hydroxyl or logical formula (II) and logical formula (III)
Wherein, R is 1,2,3 arbitrary substituent groups on phenyl ring,
The position of one substituent group are as follows:
The position of two substituent groups are as follows:
The position of three substituent groups are as follows:
Wherein R, R1、R2、R3It is independently selected from: hydrogen, hydroxyl, C1-5 alkoxy, amino, halogen.
(3)RDIt is selected from: hydrogen, hydroxyl, C1-5 alkoxy.
Most preferred compound is selected from:
Second aspect of the present invention provides a kind of flavane and is closed with diphenylethylene compounds by pentamethylene [c] furans a pair of horses going side by side Dimer class compound synthetic method, preparation method includes the following steps: (1) synthesize 4 connection thio group Huangs Alkane derivatives；(2) synthesis flavane 4 and 2 intermediates connecting of talan；(3) a kind of flavane and diphenylethylene are synthesized Adduct made of compound is closed by pentamethylene [c] furans a pair of horses going side by side.
It is further that preparation method includes the following steps:
Using dry rhodiola rhizome as crude drug in whole, with 80% alcohol reflux extraction 3 times after crushing, will extract Liquid filters after merging, and medicinal extract is concentrated under reduced pressure to obtain, and after the heavy processing of water, precipitating is filtered, carries out HP- after filtrate decompression concentration The separation of 20 macroporous absorbent resins, using pure water, 50% ethyl alcohol, 95% gradient of ethyl alcohol three is eluted, by washing for 50% ethyl alcohol De- liquid is concentrated under reduced pressure, obtained after freeze-dried rhodiola flavan polymers position (be detailed in Chinese patent, CN201010587820.7).The position is dissolved in anhydrous methanol, and corresponding thio reagents are added and HBr is water-soluble Liquid reacts 4h under the conditions of 60 DEG C, obtains intermediate 1.Intermediate 1 is dissolved in DMF, is sequentially added under the conditions of -10 DEG C Resveratrol (or derivative), AgOOCCF3It is stirred to react, obtains intermediate 2.It takes the dissolution of intermediate 2 in methyl alcohol and is added FeCl3.6H2The aqueous solution of O obtains target product after reaction.
Third aspect present invention be related to a kind of compound as described in general formula (I) each situation containing medicine effective dose and The pharmaceutical composition of pharmaceutically acceptable carrier.
The invention further relates to containing as the compounds of this invention and customary pharmaceutical excipients of active ingredient or the medicine of adjuvant Compositions.Usual pharmaceutical composition of the present invention contains the compounds of this invention of 0.1~95% weight.This hair in unit dosage form The bright general content of compound is 0.1~100mg, and preferred unit dosage form contains 4~50mg.
The pharmaceutical composition of the compounds of this invention can be prepared according to method well known in the art.When for this purpose, if It needs, can be by the compounds of this invention in conjunction with one or more solids or liquid pharmaceutical excipients and/or adjuvant, being made can be used as The administration form or dosage form appropriate that people's medicine or veterinary drug use.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum.
The compounds of this invention or administration route containing its pharmaceutical composition can be drug administration by injection.Injection includes that vein is infused It penetrates, intramuscular injection, subcutaneous injection, intracutaneous injection and acupoint injection therapy etc..
Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be true solution class, colloidal type, particle Dosage form, emulsion dosage form, mixed suspension form.Other dosage forms such as tablet, dripping pill, aerosol, pill, pulvis, solution, mixes capsule Suspension, emulsion, granule, suppository, freeze drying powder injection etc..
The compounds of this invention can be made ordinary preparation, be also possible to sustained release preparation, controlled release preparation, targeting preparation and various Particulate delivery system.
Such as in order to which tablet is made in unit dosage forms for administration, various carriers well known in the art can be widely used.About The example of carrier is, such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, Portugal Grape sugar, urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerol, poly- second two Alcohol, ethyl alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, carboxymethyl cellulose Sodium, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dry starch, alginate, agar Powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate, Methylcellulose, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；It inhales Receive promotor, such as quaternary ammonium salt, lauryl sodium sulfate etc.；Lubricant, such as talcum powder, silica, cornstarch, tristearin Hydrochlorate, boric acid, atoleine, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar coated tablet, film Coating tablet, enteric coated tablets or double-layer tablets and multilayer tablet.
Such as in order to which pill is made in administration unit, various carriers well known in the art can be widely used.About carrier Example be such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidine Ketone, single stearic acid glycerine lipoprotein, kaolin, talcum powder etc.；Adhesive, such as Arabic gum, bassora gum, gelatin, ethyl alcohol, honey, liquid Sugar, rice paste or batter etc.；Disintegrating agent, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, Ethyl cellulose etc..
Such as in order to which capsule is made in administration unit, effective component the compounds of this invention and above-mentioned various carriers are mixed It closes, and thus obtained mixture is placed in hard gelatine capsule or soft capsule.It can also be by effective component the compounds of this invention Microcapsules is made, is suspended in aqueous medium and forms suspension, also can be fitted into hard capsule or be made injection application.
For example, injection preparation is made in the compounds of this invention, such as solution, suspension solution, emulsion, freeze-dried powder Agent, this preparation can be aqueous or non-aqueous, can contain acceptable carrier in a kind of and/or a variety of pharmacodynamics, diluent, viscous Mixture, lubricant, preservative, surfactant or dispersing agent.As diluent can be selected from water, ethyl alcohol, polyethylene glycol, 1,3- the third two Alcohol, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol, polyoxyethylene sorbitol rouge, fat acid esters etc..In addition, in order to make Standby isotonic injection, can add suitable sodium chloride, glucose or glycerol, further, it is also possible to add into injection preparation Conventional cosolvent, buffer, pH adjusting agent etc..These auxiliary materials are commonly used in the art.
In addition, if desired, can also be added into pharmaceutical preparation colorant, preservative, fragrance, corrigent, sweetener or Other materials.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any The administration of prescription method.
The dosage of the compounds of this invention pharmaceutical composition depends on many factors, such as to be prevented or be treated disease Property and severity, gender, age, weight, personality and the individual reaction of patient or animal, administration route, administration number of times, Therapeutic purposes, therefore therapeutic dose of the invention can have large-scale variation.In general, Chinese pharmacology ingredient of the present invention makes It is well known to those skilled in the art with dosage.It can be according to the present invention contained in preparation last in compound composition Actual drug quantity is subject to adjustment appropriate, to reach the requirement of its therapeutically effective amount, completes prevention or treatment mesh of the invention 's.The daily Suitable dosage ranges of the compounds of this invention: the dosage of the compound of the present invention is 0.001~100mg/Kg body Weight, preferably 0.1~60mg/Kg weight, more preferably 1~30mg/Kg weight, most preferably 2~15mg/Kg weight.It is adult The compounds of this invention that patient takes is 10~500mg daily, preferably 20~100mg, can once take or divide 2~3 clothes With；The dosage of children taking is according to 5~30mg of every kg weight, preferably 10~20mg/kg weight.Above-mentioned dosage can be single dose Amount form is divided into several, such as two, three or four dosage forms for administration, this is limited to the clinical experience of administration doctor and controls The dosage regimen for the treatment of means.The compound of the present invention or composition can individually be taken, or with other treatment drug or symptomatic drugs Merge and uses.
Fourth aspect present invention is related to two made of flavane and diphenylethylene compounds are closed by pentamethylene [c] furans a pair of horses going side by side Aggressiveness class compound is preventing and/or is treating the application in diabetes medicament or health care product.
Experiments have shown that made of a kind of flavane of the invention and diphenylethylene compounds are closed by pentamethylene [c] furans a pair of horses going side by side Adduct shows apparent anti-sugar on the model for evaluating antidiabetic medicine curative effect, alpha-glucosaccharase enzyme inhibition activity model Urine disease activity, IC50Value is lower than positive control drug acarbose.
1. the compound of the present invention structure novel, is showed no document report, there is new drug in terms of being developed further into hypoglycemic Potentiality.
2. the compound of the present invention has preferable hypoglycemic activity, in terms of the inhibitory activity to alpha-glucosidase, this Class compound all has preferable pharmacological activity, and the IC50 of such compound is at 10 μM hereinafter, and the IC50 of positive control drug It is 500 μM.
Currently, having no report of such compound in terms of the inhibitory activity of alpha-glucosidase.
3. such compound synthesis route is mature, simple and easy to get.
Adduct pair made of a kind of flavane and diphenylethylene compounds of the invention is closed by pentamethylene [c] furans a pair of horses going side by side The inhibiting rate of the people PTP1B (PTP 1B) of genetic recombination is 95.3%, IC50It is 5.05 μM, it is prompted to have The preferable pharmacological action for promoting body glycometabolism can be clinically used for reducing blood glucose level, treat diabetes and relevant Metabolic disease.
Effective technology effect
Adduct made of 1. a kind of flavane of the invention and diphenylethylene compounds are closed by pentamethylene [c] furans a pair of horses going side by side Structure novel is showed no document report, has the potentiality of new drug in terms of being developed further into anti-diabetic.
Adduct made of 2. a kind of flavane of the invention and diphenylethylene compounds are closed by pentamethylene [c] furans a pair of horses going side by side Preparation method route is novel, and separation is easy.
Dimer class made of 3. flavane of the invention and diphenylethylene compounds are closed by pentamethylene [c] furans a pair of horses going side by side Closing object has preferable anti-diabetic activity, can obviously inhibit alpha-glucosidase and the activity of PTP1B, to pass through blocking Body reduces machine blood sugar level to the metabolism of sugar to the absorption of sugar and promotion body.The anti-diabetic activity of such compound Relevant report is had no at present.
Specific embodiment
The synthesis of 1 compound S4 of embodiment
The preparation and detection of compound S4 is as follows:
1. the acquisition at rhodiola flavan polymers position
Using dry rhodiola rhizome as crude drug in whole, with 80% alcohol reflux extraction 3 times after crushing, will extract Liquid filters after merging, and medicinal extract is concentrated under reduced pressure to obtain, and after the heavy processing of water, precipitating is filtered, carries out HP- after filtrate decompression concentration The separation of 20 macroporous absorbent resins, using pure water, 50% ethyl alcohol, 95% gradient of ethyl alcohol three is eluted, by washing for 50% ethyl alcohol De- liquid is concentrated under reduced pressure, obtained after freeze-dried rhodiola flavan polymers position (be detailed in Chinese patent, CN201010587820.7)。
2. the synthesis of midbody compound S1
A certain amount of rhodiola flavan polymers position is taken to be dissolved in anhydrous methanol according to the mass ratio of 1:30, and HBr aqueous solution (the matter of corresponding thio reagents and the ratio addition 48% of 1:0.5 is added in the ratio (mass ratio) of 1:0.5 Measure ratio), 4h is reacted under the conditions of 60 DEG C, is added into reaction solution after being suspended with the distilled water of reaction solution mass ratio 3:1, with acetic acid Ethyl ester extracts 3 times, merges organic layer, and organic layer is concentrated under reduced pressure after being dried over anhydrous sodium sulfate, and then successively carries out reverse phase silica gel Post separation efficiently prepares 65% (MeOH/H of liquid phase2O volume ratio) obtain 4- (S)-(benzylthio)-L-Epicatechin gallate (S1), white powder, yield 41.5%.
UVλmax(MeOH)nm:278,216；Mp.135.6~138.1 DEG C；ESI-MS:(m/z 563.1[M–H]-,599.0 [M+Cl]-)；1H NMR(400MHz,DMSO-d6)δH:7.45(2H,m,2″′,6″′-H),7.33(2H,m,3″′,5″′-H), 7.23(1H,m,4″′-H),6.83(1H,brs,2′-H),6.78(2H,s,2″,6″-H),6.67(2H,s,5′,6′-H),5.92 (1H, d, J=2.0Hz, 8-H), 5.82 (1H, d, J=2.0Hz, 6-H), 5.43 (1H, brs, 3-H), 5.25 (1H, brs, 2- ), H 4.07 (1H, d, J=2.0Hz, 4-H), 4.05 (1H, dd, J=27.0,13.0Hz, S-C-H)
3. the synthesis of midbody compound S2
Synthetic method 1
4- benzylthio L-Epicatechin gallate (S1) 564mg (1mmol) is weighed in 100mL eggplant-shape bottle, then plus Enter 30mL THF, sequentially adds resveratrol 630mg (5mmol), silver tetrafluoroborate after stirring and dissolving under the conditions of -10 DEG C 990mg (5mmol), after -10 DEG C are stirred to react 10h, HPLC monitors end of reaction.After filtering out precipitating, it is added into reaction solution 50mL distilled water terminates reaction, and ethyl acetate extracts (30mL × 3 time), merges organic layer, and organic layer is dry through anhydrous sodium sulfate column Dry, evaporated under reduced pressure, high pressure preparation liquid phase prepares (MeOH/H2O=45%), product 54.7mg, yield 8.2% are obtained.
Synthetic method 2
4- benzylthio L-Epicatechin gallate (S1) 564mg (1mmol) is weighed in 100mL eggplant-shape bottle, then plus Enter 30mL DMF, sequentially adds resveratrol 630mg (5mmol), silver tetrafluoroborate after stirring and dissolving under the conditions of -10 DEG C 990mg (5mmol), after -10 DEG C are stirred to react 10h, HPLC monitors end of reaction.After filtering out precipitating, it is added into reaction solution 50mL distilled water terminates reaction, and ethyl acetate extracts (30mL × 3 time), merges organic layer, and organic layer is dry through anhydrous sodium sulfate column Dry, evaporated under reduced pressure, high pressure preparation liquid phase prepares (MeOH/H2O=45%), product 362.7mg, yield 54.3% are obtained.
Synthetic method 3
4- benzylthio L-Epicatechin gallate (S1) 564mg (1mmol) is weighed in 100mL eggplant-shape bottle, then plus Enter 30mL DMF, sequentially adds resveratrol 630mg (5mmol), AgOOCCF after stirring and dissolving under the conditions of -10 DEG C31100mg (5mmol), after -10 DEG C are stirred to react 10h, HPLC monitors end of reaction.After filtering out precipitating, 50mL distillation is added into reaction solution Water terminates reaction, and ethyl acetate extracts (30mL × 3 time), merges organic layer, and organic layer is dry through anhydrous sodium sulfate column, and decompression is steamed Dry, high pressure preparation liquid phase prepares (MeOH/H2O=45%), product 422.2mg, yield 63.2% are obtained.
HRESIMS(m/z 669.1609[M+H]+,calcd,669.1603)；1,1H NMR(500MHz,acetone-d6) δH: 5.68 (1H, brs, 2-H), 5.55 (1H, brs, 3-H), 4.57 (1H, brs, 4-H), 5.95 (1H, d, J=2.0Hz, 6- ), H 6.10 (1H, d, J=2.0Hz, 8-H), the 7.02 (- H of 1H, d, J=2.0Hz, 2 '), the 6.67 (- H of 1H, overlap, 5 '), The 6.73 (- H of 1H, overlap, 6 '), 7.15 (2H, brs, 2 ", 6 "-H), 6.27 (1H, d, J=2.5Hz, 4 " '-H), 6.73 (1H, Overlap, 6 " '-H), 7.97 (1H, d, J=16.0Hz, 7 " '-H), 6.58 (1H, d, J=16.0Hz, 8 " '-H), 7.08 (2H, D, J=8.5Hz, 10 " ', 14 " '-H), 6.72 (2H, d, J=8.5Hz, 11 " ', 13 " '-H)；13C NMR(125MHz, acetone-d6)δC:76.1(C-2),75.2(C-3),38.7(C-4),158.6(C-5),96.8(C-6),158.5(C-7), 96.1(C-8),158.1(C-9),102.5(C-10),132.4(C-1′),115.5(C-2′),146.0(C-3′),146.2(C- 4′),116.4(C-5′),119.7(C-6′),122.3(C-1″),110.8(C-2″,6″),146.7(C-3″,5″),139.7 (C-4 "), 167.0 (C=O), 142.5 (C-1 " '), 117.7 (C-2 " '), 158.7 (C-3 " '), 104.8 (C-4 " '), 158.4 (C-5″′),107.1(C-6″′),126.7(C-7″′),131.5(C-8″′),129.5(C-9″′),129.5(C-10″′, 14″′),116.7(C-11″′,13″′),158.4(C-12″′).
4. the synthesis of compound S4
Then 50mL CH is added in 100mL eggplant-shape bottle in Weigh Compound S2 334mg (0.5mmol)3OH is stirred molten FeCl is added dropwise to after solution3.6H2The aqueous solution of O, [67.5mg (0.25mmol) is dissolved in 10mL H2In O], it stirs under normal temperature condition anti- After answering 22h, HPLC monitors end of reaction.Evaporated under reduced pressure, high pressure preparation liquid phase prepare (MeOH/H2O=53%), product is obtained 124.8mg yield 36.5%.
HRESIMS(m/z 685.1538[M+H]+,calcd,685.1552)；1H NMR(500MHz,DMSO-d6)δH: 4.89 (1H, brs, 2-H), 5.48 (1H, brs, 3-H), 3.82 (1H, brs, 4-H), 2.62 (1H, d, J=15.5Hz, 6a-H), 2.70 (1H, d, J=15.5Hz, 6b-H), 5.80 (1H, brs, 8-H), 6.52 (1H, d, J=2.0Hz, 12-H), 6.54 (1H, D, J=8.5Hz, 15-H), 6.46 (1H, dd, J=8.5,2.0Hz, 16-H), 6.83 (2H, s, 19,23-H), 6.10 (1H, Brs, 12 '-H), the 4.74 (- H of 1H, d, J=1.5Hz, 14 '), the 4.44 (- H of 1H, d, J=8.0Hz, 8 '), 5.28 (1H, d, J= 7.5Hz, 7 '-H), 7.08 (2H, d, J=8.5Hz, 2 ', 6 '-H), 6.63 (2H, d, J=8.5Hz, 3 ', 5 '-H)；13C NMR (125MHz,DMSO-d6)δC:76.8(C-2),72.5(C-3),48.6(C-4),103.8(C-5),47.4(C-6),194.2(C- 7),104.5(C-8),175.0(C-9),61.4(C-10),128.9(C-11),113.9(C-12),145.1(C-13),144.9 (C-14),115.2(C-15),117.3(C-16),164.1(C-17),118.2(C-18),108.7(C-19,23),145.5 (C-20,22),143.3(C-21),143.3(C-9′),105.9(C-10′),153.5(C-11′),101.4(C-12′), 157.5(C-13′),103.8(C-14′),61.4(C-8′),81.8(C-7′),128.8(C-1′),127.6(C-2′,6′), 114.3(C-3′,5′),156.5(C-4′).
The synthesis of 2 compound S7 of embodiment
1. the synthesis of midbody compound S5
A certain amount of Ledum palustre flavan polymers position is taken to be dissolved in anhydrous methanol according to the mass ratio of 1:30, and HBr aqueous solution (the matter of corresponding thio reagents and the ratio addition 48% of 1:0.5 is added in the ratio (mass ratio) of 1:0.5 Measure ratio), 4h is reacted under the conditions of 60 DEG C, is added into reaction solution after being suspended with the distilled water of reaction solution mass ratio 3:1, with acetic acid Ethyl ester extracts 3 times, merges organic layer, and organic layer is concentrated under reduced pressure after being dried over anhydrous sodium sulfate, and then successively carries out reverse phase silica gel Post separation efficiently prepares liquid phase (MeOH/H2O=65% 4- (S)-(benzylthio)-epigallocatechin gallic acid) is obtained Ester (S5), white powder, yield 44.6%.
UVλmax(MeOH)nm:278,216；Mp.146.3~147.4 DEG C；ESI-MS:(m/z 579.2[M–H]-,615.0 [M+Cl]-)；1H NMR(400MHz,DMSO-d6)δ:7.44(2H,m,2″′,6″′-H),7.33(2H,m,3″′,5″′-H), 7.24 (1H, m, 4 " '-H), 6.78 (2H, s, 2 ", 6 "-H), 6.38 (2H, s, 2 ', 6 '-H), 5.92 (1H, d, J=2.0Hz, 8- ), H 5.82 (1H, d, J=2.0Hz, 6-H), 5.36 (1H, brs, 3-H), 5.29 (1H, brs, 2-H), 4.05 (1H, dd, J= 27.0,13.0Hz, S-C-H), 4.04 (1H, d, J=2.0Hz, 4-H)
2. the synthesis of midbody compound S6
4- (S)-(benzylthio)-Epigallo-catechin gallate (EGCG) (S5) 580mg (1mmol) is weighed in 100mL eggplant In shape bottle, 30mL DMF is then added, sequentially adds resveratrol 1140mg (5mmol) under the conditions of -10 DEG C after stirring and dissolving, AgOOCCF31100mg (5mmol), after -10 DEG C are stirred to react 10h, HPLC monitors end of reaction.After filtering out precipitating, to reaction solution Middle addition 50mL distilled water terminates reaction, and ethyl acetate extracts (30mL × 3 time), merges organic layer, organic layer is through anhydrous slufuric acid Sodium column is dry, evaporated under reduced pressure, and high pressure preparation liquid phase prepares (MeOH/H2O=45%), product S6, yield 65.4% are obtained.
HRESIMS(m/z 685.1553[M+H]+,calcd,685.1552)；1,1H NMR(500MHz,acetone-d6) δH: 5.60 (1H, brs, 2-H), 5.53 (1H, brs, 3-H), 4.54 (1H, brs, 4-H), 5.93 (1H, d, J=2.5Hz, 6- ), H 6.08 (1H, d, J=2.0Hz, 8-H), 6.54 (1H, brs, 2 ', 6 '-H), 7.12 (2H, brs, 2 ", 6 "-H), 6.25 (1H, D, J=2.5Hz, 4 " '-H), 6.71 (1H, overlap, 6 " '-H), 7.96 (1H, d, J=16.0Hz, 7 " '-H), 6.57 (1H, D, J=16.0Hz, 8 " '-H), 7.06 (2H, d, J=8.5Hz, 10 " ', 14 " '-H), 6.71 (2H, d, J=8.5Hz, 11 " ', 13″′-H)；13C NMR(125MHz,acetone-d6)δC:76.0(C-2),75.1(C-3),38.7(C-4),158.6(C-5), 96.8(C-6),158.5(C-7),96.2(C-8),158.1(C-9),102.6(C-10),131.7(C-1′),107.2(C-2′, 6′),146.9(C-3′,5′),133.6(C-4′),122.4(C-1″),110.8(C-2″,6″),146.9(C-3″,5″), 139.6 (C-4 "), 167.1 (C=O), 142.5 (C-1 " '), 117.7 (C-2 " '), 158.3 (C-3 " '), 104.8 (C-4 " '), 158.2(C-5″′),107.1(C-6″′),126.7(C-7″′),131.4(C-8″′),131.3(C-9″′),129.5(C- 10″′,14″′),116.7(C-11″′,13″′),158.3(C-12″′).
3. the synthesis of compound S7
Then 40mL CH is added in 100mL eggplant-shape bottle in Weigh Compound S5 342mg (0.5mmol)3OH is stirred molten It is added dropwise to after solution silver tetrafluoroborate 48.5mg (0.25mmol), after being stirred to react 10h under normal temperature condition, HPLC monitoring has been reacted Finish.Evaporated under reduced pressure, high pressure preparation liquid phase prepare (MeOH/H2O=48%), product S7, yield 6.3% are obtained.
HRESIMS(m/z 701.1484[M+H]+,calcd,701.1501)；1H NMR(500MHz,DMSO-d6)δ: 7.10 (2H, d, J=9.0,10 " ', 14 " '-H), 6.85 (2H, s, 2 ", 6 "-H), 6.64 (2H, d, J=9.0,11 " ', 13 " '- ), H 6.11 (3H, s, 2 ', 6 ', 6 " '-H), 5.70 (1H, s, 8-H), 5.50 (1H, s, 3-H), 5.29 (1H, d, J=8.0,8 " '- ), H 4.81 (1H, s, 2-H), 4.77 (1H, s, 4 " '-H), 4.44 (1H, d, J=8.0,7 " '-H), 3.84 (1H, s, 4H), 2.68 (2H,m,6H)；13C NMR(125MHz,DMSO-d6)δ:194.1(C-7),175.0(C-9),164.0(O-C-O-),157.5 (C-5″′),156.5(C-12″′),153.5(C-3″′),145.7(C-3′,5′),145.5(C-3″,5″),143.3(C-4″, 1″′),132.6(C-1′,4′),128.9(C-9″′),128.8(C-10″′,14″′),118.2(C-1″),114.2(C-11″′, 13″′),108.8(C-2″,6″),105.8(C-2″′),105.1(C-2′,6′),104.5(C-8),103.7(C-5,6″′), 101.4(C-4″′),81.8(C-8″′),76.8(C-2),72.5(C-3),61.5(C-10,7″′),47.5(C-4),47.4(C- 6).
1 in-vitro screening model of experimental example: PTP 1B (PTP1B) inhibitory activity screening
Insulin is to play its biological effect by insulin signal transduction system.In insulin signal transduction system, Many important cytokines such as IRS-1 are acidified by tyrosine phosphatase and are activated, then again through Protein-tyrosine-phosphatase 1B (PTP1B) loses phosphorylation and inactivates.Therefore, PTP1B inhibitor can be enhanced by extending insulin signaling pathways The effect of body insulin.Currently, PTP1B has become one of important target spot of insulin sensitizer.
1 materials and methods
1.1 material
Cell culture medium and glutamine are GIBCO Products；Fetal calf serum (FCS) is Japan Biofluids, Inc Product；Glutamate dehydrogenase (GDH) is purchased from Japan Oriental Yeast CO., LTD company；Genetic recombination People GFAT (hGFAT, EC2.6,1.16), various viruses and cell are provided by Shiga, Japan medical university close friend.PTP1B specifically resists Body is BioLabs Products；RL2 polyclonal antibody is Affinity Bioreagents, Inc product；Genetic recombination PTP1B For Biomol Research Labortiories, Inc product.With Bio-Red protein assay reagents, UV-265W spectrophotometric It counts (Shimadzu) and measures protein concentration.DNA is extracted with Bio-Red DNA purification kit；With III analyzer of Ultrospec (Pharmacia, LKB) measures DNA concentration；It is marked with Bea BESTTM Labeling Kit kit (Takapa, Japan) DNA prepares probe.Other reagents are purchased from Sigma company.
1.2 method
Using molecular biology method, the hGST-PTP1B-BL21E.Coli engineering bacteria mistake recombinated with IPTG induced gene Mankind PTP1B albumen is expressed, obtains hGST-PTP1B protease by GST affinity chromatography column purification.With Bio-Rad analysis of protein Reagent measures protein content.Using external Enzymology method, using polypeptide para-NitroPhenyl Phosphate as substrate, observation Influence of the drug to hGST-PTP1B proteinase activity.
2 results
External pharmacological evaluation shows inhibition of the compound S4 to the people PTP1B (PTP 1B) of genetic recombination Rate is 95.3%, IC50It is 5.05 μM
2 in-vitro screening model of experimental example: alpha-glucosaccharase enzyme inhibition activity screening
Alpha-glucosidase is located in small intestine endothelium brush border, main function be promote enteron aisle to amylodextrin, polysaccharide, The decomposition and absorption of sucrose and maltose, and other oligosaccharide are decomposed into D-glucose, galactolipin and dextrorotation fructose etc..α- Glucosidase inhibitor by reversible inhibition brush border alpha-glucosidase (including amylase, maltose, invertase, Isomaltase etc.) delay polysaccharide, disaccharide is converted to absorbable monosaccharide, mitigate the raising of postprandial blood sugar.In addition, normal condition Lower lower intestines are without food ingredients, after taking alpha-glucosidase inhibition class medicine, enteral carbohydrate, fat, protein Equal chymes can enter ileum distal end, which is the most abundant position of small intestine glucagon like peptide -1 (GLP-1) reserves, can be pierced Swash GLP-1 secretion to increase, insulin releasing is stimulated, to reduce postprandial blood sugar concentration.
1 method
0.1M PBS buffer solution 50 μ L and 80 μ L are separately added into experimental group and blank group；It is each that 10 μ L of sample is added, 30 μ L of alpha-glucosidase, reacts 5min in 37 DEG C of waters bath with thermostatic control, 90rpm centrifugation, then it is each PNPG (1mM) 20 μ L is added, Then 15min is reacted in 37 DEG C of waters bath with thermostatic control, 0.4M Na is finally used in 90rpm centrifugation2CO350 μ L terminate reaction.Spectrophotometric OD value is surveyed at instrument 400nm.
2 results
External pharmacological evaluation shows that compound S4 has stronger inhibiting effect, IC to alpha-glucosidase50For 17.7 μ M。

Claims (7)

1. the compound that one kind has structure shown in general formula (I), which is characterized in that
RAAnd RBIt is on phenyl ring 1,2,3 arbitrary substituent groups,
The position of one substituent group are as follows:
The position of two substituent groups are as follows:
The position of three substituent groups are as follows:
Wherein R1、R2、R3It is independently selected from: hydrogen, hydroxyl, C1-5 alkoxy, amino, halogen；RCIt is selected from: hydrogen, hydroxyl, or it is logical Formula (II) and logical formula (III)
Wherein, R is 1,2,3 arbitrary substituent groups on phenyl ring,
The position of one substituent group are as follows:
The position of two substituent groups are as follows:
The position of three substituent groups are as follows:
Wherein R, R1、R2、R3It is independently selected from: hydrogen, hydroxyl, C1-5 alkoxy, amino, halogen；
RDIt is selected from: hydrogen, hydroxyl, C1-5 alkoxy.
2. compound according to claim 1, which is characterized in that RAAnd RBIt is on phenyl ring 1,2,3 arbitrary substituent groups are described The structure feature of one substituent group are as follows:
The structure feature of two substituent groups are as follows:
The structure feature of three substituent groups are as follows:
RCIt is selected from:
H,OH,
RDSelected from H, OH, OCH3, OCH2CH3。
3. compound according to claim 1, which is characterized in that the compound is selected from:
4. a kind of pharmaceutical composition, which is characterized in that the described in any item compounds of claim 1-3 containing effective dose and Pharmaceutically acceptable carrier.
5. pharmaceutical composition according to claim 4, which is characterized in that the dosage form of the composition is selected from tablet, capsule, ball Agent, granule, oral solution and suspension.
6. application of the described in any item compounds of claim 1-3 in the product of preparation treatment and/or prevention diabetes.
7. application according to claim 6, which is characterized in that the product is selected from drug, health care product.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102526165A (en) * 2010-12-07 2012-07-04 中国医学科学院药物研究所 Rhodiola effective fractions, preparation method, drug composition and uses thereof
CN105085461A (en) * 2014-05-21 2015-11-25 中国医学科学院药物研究所 Flavane compound, preparation method thereof and hypoglycemic activity

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Publication number Priority date Publication date Assignee Title
CN102526165A (en) * 2010-12-07 2012-07-04 中国医学科学院药物研究所 Rhodiola effective fractions, preparation method, drug composition and uses thereof
CN105085461A (en) * 2014-05-21 2015-11-25 中国医学科学院药物研究所 Flavane compound, preparation method thereof and hypoglycemic activity

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