阅读说明：本技术 杨梅素衍生物及在制备治疗降血糖和降血脂药物中的应用 (Myricetin derivative and the application in the hypoglycemic and blood lipid-lowering medicine of preparation treatment ) 是由 李文保 杨冲 李峰 张良 管华诗 于 2018-05-24 设计创作，主要内容包括：本发明提供了如式(I)所示的杨梅素衍生物、其药学上可接受的盐及其制备方法,还提供了所述杨梅素衍生物在用于制备降血糖和/或降血脂的药物中的用途。本发明所述的杨梅素衍生物可以显著抑制α-葡萄糖苷酶的活性,效果显著优于临床上广泛应用的阿卡波糖,具有良好的应用前景。(The present invention provides myricetin derivative, its pharmaceutically acceptable salts as shown in formula (I) and preparation method thereof, additionally provide the myricetin derivative in the purposes being used to prepare in hypoglycemic and/or reducing blood lipid drug.Myricetin derivative of the present invention can significantly inhibit the activity of alpha-glucosidase, and significant effect has a good application prospect better than clinically widely applied acarbose.)

1. a kind of myricetin derivative and its pharmaceutically acceptable salt, the myricetin derivant structure general formula such as formula (I) institute Show:

In formula:

1)R¹Selected from replacing or non-substituted glucosyl group, substituted or non-substituted galactosyl and substituted or non-substituted Xylosyl；

2)R²Selected from substitution or non-substituted glucosyl group, substituted or non-substituted galactosyl, substituted or non-substituted wood Glycosyl, substituted or non-substituted ribosyl and substituted or non-substituted mannose group；

3)R¹And R²Between with glucosides key connection, R¹With glucosides key connection between the myricetin 3 upper oxygen atoms connected.

2. myricetin derivative according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that: the R¹With R²Combination are as follows:

1)R¹To replace or non-substituted glucosyl group, and R²For substitution or non-substituted galactosyl；Or

2)R¹To replace or non-substituted galactosyl, and R²For substitution or non-substituted galactosyl；Or

3)R¹To replace or non-substituted galactosyl, and R²For substitution or non-substituted glucosyl group；Or

4)R¹To replace or non-substituted xylosyl, and R²For substitution or non-substituted galactosyl；Or

5)R¹To replace or non-substituted galactosyl, and R²For substitution or non-substituted mannose group；Or

6)R¹To replace or non-substituted galactosyl, and R²For substitution or non-substituted xylosyl；Or

7)R¹To replace or non-substituted glucosyl group, and R²For substitution or non-substituted glucosyl group.

3. myricetin derivative according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that: the R¹With R²Between with β-type glucosides key connection, R¹Also with β-type glucosides key connection between the myricetin 3 upper oxygen atoms connected.

4. myricetin derivative according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that: the R¹With R²It is D type monosaccharide groups.

5. myricetin derivative according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that: the red bayberry Plain derivative is N1, N2, N3, N4, N5, N6, N7 or N8, and structural formula is as follows:

6. myricetin derivative according to claim 1 and its pharmaceutically acceptable salt, it is characterised in that: the pharmacy Upper acceptable salt is sylvite, sodium salt or calcium salt.

7. myricetin derivative according to claim 1-6 and its pharmaceutically acceptable salt are being used to prepare drop Purposes in blood glucose and/or the drug of reducing blood lipid.

8. a kind of myricetin derivative and its pharmaceutically acceptable salt are in being used to prepare hypoglycemic and/or reducing blood lipid drug Purposes, it is characterised in that: the myricetin derivative be N1, N2, N3, N4, N5, N6, N7, N8, N9 or N10, structural formula It is as follows:

9. a kind of pharmaceutical composition, includes:

1) myricetin derivative or its pharmaceutically acceptable salt as claimed in any one of claims 1 to 6, and

2) pharmaceutically acceptable carrier.

10. pharmaceutical composition according to claim 9, it is characterised in that: the pharmaceutically acceptable carrier is alkalinity Substance, the carrier include the auxiliary material or solvent of alkalinity, and the auxiliary material of the alkalinity is sodium bicarbonate, saleratus or hydroxide Sodium, the solvent of the alkalinity are sodium bicarbonate solution.

Technical field

The invention belongs to drug field, it is related to a kind of myricetin derivative and preparation method, and its in treatment colitis, anti- Application in terms of controlling the conversion of colitis cancer and treating colon cancer.The invention belongs to drug fields, are related to a kind of myricetin derivative And preparation method thereof and its application in the drug of the hypoglycemic and reducing blood lipid disease of preparation treatment.

Background technique

Myricetin is also known as myricetrin, arbutin, belongs to flavone compound, chemical name 3,5,7- trihydroxy -2- (3,4, 5- trihydroxy phenyl) -4H-1- benzofuran -4- ketone, it is the main chemical compositions of Myruca ceas plant red bayberry leaf, skin, root, It is present in onion, berries and other plant.Studies have shown that myricetin has a variety of pharmacological activities: (1) antiplatelet is living Change the factor (PAF) effect, has that antithrombotic, various cardiovascular pharmacological activities such as resist myocardial ischemia, improve microcirculation；(2) Hypoglycemic effect；(3) antioxidation；(4) liver protection function；(5) anti-inflammatory effect；(6) antitumor action etc..

Although myricetin has a variety of pharmacology blood activity, poor, the shadow such as water-soluble, stability and bioavilability The development and application of myricetin are rung.It is chemically modified and is transformed in myricetin structure basis, increase its water-soluble and biology Availability can increase its pharmacological activity, thus enhance its druggability, this is for developing novel therapeutic agent with important Meaning.

Summary of the invention

Object of the present invention is in view of the deficiencies of the prior art, provide a kind of myricetin derivative and preparation method thereof and Application in the hypoglycemic drug with reducing blood lipid disease of preparation treatment.The present invention proved by pharmacological experiment, above-mentioned myricetin Derivative has significant hypoglycemic and effect for reducing blood fat.

For achieving the above object, technical scheme is as follows:

A kind of myricetin derivative and its pharmaceutically acceptable salt, shown in general structure such as formula (I):

In formula:

R¹Selected from replacing or non-substituted glucosyl group, substituted or non-substituted galactosyl and substituted or non-substituted Xylosyl；R²Selected from replacing or non-substituted glucosyl group, substituted or non-substituted galactosyl, substituted or non-substituted Xylosyl, substituted or non-substituted ribosyl and substituted or non-substituted mannose group.

R¹And R²Between with glucosides key connection, R¹With glucosides key connection between the myricetin 3 upper oxygen atoms connected.

The glycosidic bond refers to, sugared hemiacetal type is reacted with hydroxyl and the covalent bond that is formed, glucosides key connection anomeric carbon With pure oxygen atom.Glycosidic bond is to can be α-type or β-type.In a preferred embodiment, the R¹And R²Between with β-type glucosides Key connection, R¹Also with β-type glucosides key connection between the myricetin 3 upper oxygen atoms connected.

In other embodiments, R¹It is also selected from other substitutions or non-substituted monosaccharide groups (such as erythrose base, Su Li Glycosyl, ribosyl, deoxyribosyl, aralino, lysol glycosyl, rhamnopyranosyl, mannose group, altrose base, gulose Base, sorb glycosyl, talose base, allose base, idose base etc.)；R²It is also selected from other substitutions or non-substituted list Glycosyl (such as erythrose base, Su Li glycosyl, deoxyribosyl, aralino, lysol glycosyl, rhamnopyranosyl, altrose base, Gu Lip river glycosyl, sorb glycosyl, talose base, allose base, idose base etc.).

The monosaccharide is the carbohydrate that cannot be hydrolyzed again, is the basic unit for constituting various disaccharides and polysaccharide molecule.It is natural Monosaccharide existing for boundary is mostly D configuration, and also having a small number of is L-configuration.In a preferred embodiment, the above-mentioned R of the present invention¹And R²It is D type Monosaccharide groups.

In another preferred example, the combination of the R1 and R2 are as follows:

1) R1 is that perhaps non-substituted glucosyl group and R2 is replaced to be substitution or non-substituted galactosyl；Or

2) R1 is that perhaps non-substituted galactosyl and R2 is replaced to be substitution or non-substituted galactosyl；Or

3) R1 is that perhaps non-substituted galactosyl and R2 is replaced to be substitution or non-substituted glucosyl group；Or

4) R1 is that perhaps non-substituted xylosyl and R2 is replaced to be substitution or non-substituted galactosyl；Or

5) R1 is that perhaps non-substituted galactosyl and R2 is replaced to be substitution or non-substituted mannose group；Or

6) R1 is that perhaps non-substituted galactosyl and R2 is replaced to be substitution or non-substituted xylosyl；Or

7) R1 is that perhaps non-substituted glucosyl group and R2 is replaced to be substitution or non-substituted glucosyl group.

In another preferred example, the myricetin derivative is N1, N2, N3, N4, N5, N6, N7 or N8, and structural formula is such as Shown in lower:

Further, the isomers of the various compounds for including the invention also includes above-mentioned general formula, racemic modification, pharmaceutically Acceptable salt, hydrate, precursor, derivative or the like；As long as the isomers, racemic modification, pharmaceutically acceptable Salt, hydrate, derivative or the like also have the function of similar (hypoglycemic or reducing blood lipid).

The isomers includes: conformer, and optical isomer (such as enantiomter and diastereoisomer) is several What isomers (such as cis-trans-isomer).It is different that these isomers or combinations thereof can be used as racemic mixture, individual mapping Structure body, individual diastereoisomer, non-enantiomer mixture, cis or trans isomers exist.

Described derivative or the like refers to the similar structural formula with the included compound of above-mentioned general formula, especially It is mother nucleus structure having the same, but some compound groups compound replaced similar group, the compound is still So remain with similar function (hypoglycemic or reducing blood lipid).

The precursor of the compound refers to after being taken with method appropriate, the precursor of the compound in patient body into Row metabolism or chemical reaction and myricetin derivative and myricetin derivative that transition cost invention general formula is included are formed Salt or solution.The precursor of compound include but is not limited to the carboxylate of the compound, carbonic ester, phosphate, nitrate, Sulfuric ester, sulfone ester, sulfoxide esters, amino-compound, carbaminate, azo-compound, phosphamide, glucoside, ether, acetal Etc. forms.

The pharmaceutically acceptable salt refers to above compound and inorganic acid, Organic Acid and Base metal or alkaline-earth metal The salt that equal reactions generate.These salt include but is not limited to: (1) salt formed with following inorganic acid: such as hydrochloric acid, hydrobromic acid, hydrogen Acid iodide, sulfuric acid, nitric acid, phosphoric acid；(2) salt formed with following organic acid, such as acetic acid, lactic acid, citric acid, succinic acid, rhizoma corydalis Acid, gluconic acid, benzoic acid, Loprazolam, ethane sulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, oxalic acid, succinic acid, tartaric acid, Maleic acid or the other salt of arginine (3), including the salt formed with alkali or alkaline earth metal (such as sodium, potassium, calcium or magnesium), ammonium Salt or water-soluble amine salt (such as N-METHYL-ALPHA-L-GLUCOSAMINE salt), rudimentary alkanol ammonium salt and other pharmaceutically acceptable amine salt (such as methylamine salt, ethylamine salt, propylamine salt, dimethyl amine salt, trismethylamine salt, diethyl amine salt, triethyl amine salt, tert-butyl Amine salt, ethylenediamine salt, oxyethylamine salt, dihydroxy ethylamine salt, three oxyethylamine salt, and formed respectively by morpholine, piperazine, lysine Amine salt) or other conventional " pro-drugs " form.

Further, the pharmaceutically acceptable salt is sylvite, sodium salt or calcium salt.

The present invention also provides the preparation method of the myricetin derivative (I), the preparation method includes following step It is rapid:

(1) using myricetrin M1 as starting material, 7 of myricetrin, 3 ' positions, 4 ' positions, 5 ' position phenolic hydroxyl groups are protected, shape At the myricetrin M2 of benzyl protection；

(2) 3 rhamnoses for removing the myricetrin M2 of benzyl protection, form the myricetin M3 of benzyl protection；

(3) the myricetin M3 of benzyl protection and the various sugared bromine glycosides of acetyl group protection carry out condensation reaction system under alkali effect Obtain the various sugar derivatives M5-X of the acetyl group protection of the myricetin of benzyl protection；

(4) the various sugar derivatives M6- of the myricetin of benzyl protection are made in M5-X removing acetyl group under sodium methoxide effect X；

(5) M6-X removes benzyl under palladium carbon catalytic action and myricetin derivative (I) is made；

Wherein, the structural formula of M1-M6 is as follows, and wherein R is glycosyl, and R (Ac) n is the glycosyl of acetyl group protection:

In another preferred example, alkali described in step (3) is potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diisopropyl One or more of ethamine or 4-dimethylaminopyridine.

Preferably, alkali described in step (3) selects potassium carbonate.

The present invention provides above-mentioned myricetin derivatives or its pharmaceutically acceptable salt to prepare hypoglycemic or drop blood Purposes in the drug of rouge.

The present invention provides additionally provide a kind of myricetin derivative and its pharmaceutically acceptable salt to be used to prepare drop Purposes in blood glucose and/or the drug of reducing blood lipid, the myricetin derivative be N1, N2, N3, N4, N5, N6, N7, N8, N9 or N10, structural formula are as follows:

The present invention also provides a kind of pharmaceutical compositions, include: 1) myricetin derivative described above and its pharmaceutically Acceptable salt and 2) pharmaceutically acceptable carrier.The pharmaceutically acceptable carrier is alkaline matter, the carrier Auxiliary material or solvent including alkalinity, the auxiliary material of the alkalinity are sodium bicarbonate, saleratus or sodium hydroxide, described alkaline molten Matchmaker is sodium bicarbonate solution.

In another preferred example, the pharmaceutically acceptable carrier is alkaline matter, and the carrier includes the auxiliary of alkalinity Material or solvent, the auxiliary material of the alkalinity is sodium bicarbonate, saleratus, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, pungent One of sour sodium, sodium iso-octoate, Chinese holly edge acid sodium, sodium tartrate are a variety of；The solvent of the alkalinity be sodium bicarbonate solution or Injection, Chinese holly edge acid sodium solution or injection, sodium lactate solution or injection, compound sodium lactate and glucose solution or injection, One of injection sodium hydroxybutyrate solution or injection, monosodium glutamate solution or injection, potassium glutamate solution or injection Or it is a variety of.

Preferably, the auxiliary material of the alkalinity is sodium bicarbonate, saleratus or sodium hydroxide, and the solvent of the alkalinity is carbon Sour hydrogen sodium solution or injection.

Beneficial effects of the present invention:

(1) the present invention provides the myricetin derivatives with logical formula (I) structure；Pharmacological experiment proves, this hair Myricetin derivative provided by bright has the function of being capable of significant hypoglycemic and reducing blood lipid.

(2) the present invention provides the preparation methods of the myricetin derivative, are that starting is former with myricetrin cheap and easy to get Material, it is not only at low cost, and also yield is high, and product purity is high, and large-scale industrial production may be implemented, have great market price Value and wide economic prospect.

Specific embodiment

The present invention will be further explained with reference to the examples below.