WO2023165382A1 - Use of acyltadine compound having glycosidase inhibitory activity - Google Patents

Abstract

The present invention provides an acyltadine compound having α-glycosidase and/or β-glycosidase inhibitory activity and a preparation method, and use of the α-glycosidase and/or β-glycosidase inhibitor in preventing and treating diseases such as diabetes.

Description

Application of acyltadine compounds with glycosidase inhibitory activity technical field

The invention belongs to the field of biomedicine, and more specifically, the invention relates to acyltadine compounds having glycosidase inhibitory activity and a preparation method, as well as the application of the glycosidase inhibitors in the prevention and treatment of diabetes and other diseases.

Background technique

Diabetes is a metabolic disease caused by insufficient insulin secretion or the inability of the human body to effectively use insulin, resulting in high blood sugar. It is mainly divided into type I diabetes, type II diabetes and gestational diabetes, especially type II diabetes is the most common. Excessive blood sugar concentration in diabetic patients will increase the prevalence of cardiovascular disease, induce chronic kidney disease, damage nerves or blood vessels, cause eye diseases or oral health problems, etc., which will greatly reduce the quality of life of patients. In recent years, the prevalence of diabetes has risen rapidly due to unhealthy diet and sedentary lifestyle. According to statistics from the International Diabetes Federation (IDF), there were 463 million diabetic patients in the world in 2019, of which 116.4 million were from China, making China the largest country with diabetes. With the age of onset of diabetes becoming younger and life-threatening complications becoming more frequent, diabetes has become a public health problem that cannot be ignored. Therefore, it is of strategic significance to intensify efforts to carry out basic research on diabetes.

At present, the main categories of clinical treatment drugs for type II diabetes include: ① insulin and its analogues (insulin lispro); ② biguanide diabetes drugs (metformin, or phenformin); Benuret, glipizide, glipizide, glibouride, glimepiride, or gliquidone); ④ α-glucosidase inhibitors (acarbose, voglibose or miglitol); ⑤ insulin sensitizers (ciglitazone, troglitazone, rosiglitazone, or pioglitazone); ⑥ aldose reductase inhibitors (aldose reductase inhibitors (aldose He, Bolastat, or Torrestat); ⑦ insulin-releasing drugs (repaglinide or nateglinide).

Although many types of diabetes treatment drugs have been developed, there are many negative factors restricting the application of some drugs. For example, studies have found that glucagon receptor antagonists are mainly vanadium compounds, which tend to accumulate in bones, kidneys and liver, and cause adverse reactions such as vomiting and dehydration. Biguanide oral hypoglycemic agents (phenformin and buformin) were discontinued because of their association with lactic acidosis.

Amino-oligosaccharide compound—acarbose is the most commonly used α-glucosidase inhibitor in clinical practice, and its adverse reactions are mainly abdominal distension and borborygmus. Although some amino-oligosaccharide compounds with α-glucosidase inhibitory activity have been reported successively, such as isovalertatins and acarviostatins, their curative effect in vivo still needs to be improved.

Therefore, this field also needs to find new drugs with higher biological safety to meet the needs of clinical medication.

Contents of the invention

The object of the present invention is to provide acyltadine compounds with glycosidase inhibitory activity and a preparation method, as well as the application of the glycosidase inhibitors in the treatment of diabetes and related metabolic diseases.

In the first aspect of the present invention, there is provided a compound represented by formula (I) or its pharmaceutically or food-acceptable salt, isomer, racemate, solvate, hydrate or precursor,

Wherein, n is 2, 3 or 4;

m is 2, 3 or 4;

Each R ₁ , R ₂ , R ₃ , R ₄ , R ₅ is each independently selected from the following group: hydrogen, C ₁ -C ₄ alkyl or -OZ; wherein each Z is independently selected from the following group: hydrogen, C ₃ -C ₆ acyl; and, at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ is -OZ;

Each R ₁ ′, R _{2 ′} , R ₃ ′, R ₄ ′, R ₁ ″, R ₂ ″, R ₃ ″, R ₄ ″, Ra are each independently selected from the following group: hydrogen, hydroxyl, C ₁ -C ₄ alkyl, halogen;

Each Y ₂ and Y ₃ are independently selected from the following group: -O-, -NH-;

When m is 3 and n is 2, R is _not hydroxyl or

In one or more embodiments, each R ₃ is independently -OZ; and each Z is independently C ₃ -C ₆ acyl.

In another preference, said _R is selected from the following group:

In one or more embodiments, each of R ₁ , R ₂ , R ₄ , R 1 ′, R ₂ ′, _{R 4} ′, R _{1 ″, R 2 ″} , R ₄ ″, Ra is independently selected from Subgroup: hydrogen, C ₁ -C ₂ alkyl or hydroxy.

In another preferred example, each R ₂ is independently C ₁ -C ₂ alkyl.

In one or more embodiments, the compound of formula (I) has the structure shown in formula (I-1) or formula (I-2),

Wherein, R ₃ is as defined above.

In one or more embodiments, the compound of formula (I) is selected from:

In the second aspect of the present invention, there is provided the compound of formula (I) described herein or its pharmaceutically or food acceptable salt or ester, isomer, racemate, solvate, hydrate or precursor Use in the preparation of products for inhibiting glycosidase activity, delaying the hydrolysis and absorption of carbohydrates in the gastrointestinal tract, reducing postprandial blood sugar concentration, or preventing, alleviating or treating diseases or conditions benefiting from blood sugar reduction.

In one or more embodiments, diseases or conditions that would benefit from lowering blood glucose include: hyperglycemia, diabetes and its complications, hyperinsulinemia, cardiovascular disease, or disorders of glucose metabolism. The diabetes is preferably type II diabetes.

In one or more embodiments, the glycosidase is an α-glucosidase, such as α-amylase; the carbohydrate is a carbohydrate containing an α-glycosidic bond, such as a carbohydrate containing an α-1,4 glycosidic bond compound.

In one or more embodiments, the glycosidase is a β-glucosidase, such as sucrase; the carbohydrate is a carbohydrate containing a β-glycosidic bond, such as sucrose.

In one or more embodiments, the product includes daily chemical products, food, health products, pharmaceutical compositions or kits.

In one or more embodiments, the product inhibits the activity of α-glucosidase, and inhibits the activity of α-glucosidase (such as α-glucosidase on the brush border of the small intestine) to carbohydrates containing α-1,4 glycosidic bonds. Hydrolysis, reducing the production and absorption of glucose, reducing postprandial blood sugar concentration, or preventing, relieving or treating diseases or diseases benefiting from blood sugar reduction, in the compound of formula (I), Z is selected from formyl, isobutyryl , unsubstituted n-butyryl, substituted 2-butyryl, the substituents are selected from hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen. Preferably, the compound of formula (I) is selected from the group described herein: alcaftadine II 02,2; propionyl alcaftadine II 02,3; Tadine II 03, 5; Propionyl alcatadine II 03, 6; Butyryl alcatadine II 03, 7 and 2-methylbutyryl alcatadine 03, 8;

In one or more embodiments, the product inhibits the activity of β-glucosidase (such as β-glucosidase on the small intestine), slows down the rate of producing glucose and fructose from sucrose, reduces the occurrence of postprandial hyperglycemia, or prevents, ease Or a product for the treatment of a disease or condition benefiting from lowering of blood sugar, said compound of formula (I) as described in the first aspect herein. Preferably, the compound of formula (I) is selected from the group described herein: alcaftadine II 03,1; alcaftadine II 02,2; propionyl alcatadine II 02,3; butyryl alcatadine II 02 , 4; Isovaleryl alcatadine II03, 5; Tadine Ⅰ 03,9; butyryl akatadine Ⅰ 03,10;

In a third aspect of the present invention, a method for inhibiting glycosidase activity is provided, comprising: making the compound of formula (I) described herein or its pharmaceutically or food acceptable salt, isomer, racemate , solvate, hydrate or precursor contact with the sample containing glycosidase, thereby inhibiting the activity of glycosidase.

In one or more embodiments, the method of inhibiting glycosidase activity is a non-diagnostic or therapeutic method.

In one or more embodiments, the glycosidase is α-glucosidase, preferably α-amylase, and in the compound of formula (I), Z is selected from formyl, isobutyryl, unsubstituted n-butyl Acyl, substituted 2-butyryl, the substituents are selected from hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen. Preferably, the compound of formula (I) is selected from the group described herein: alcaftadine II 02,2; propionyl alcaftadine II 02,3; Tadine II 03, 5; Propionyl alcatadine II 03, 6; Butyryl alcatadine II 03, 7 and 2-methylbutyryl alcatadine 03, 8;

In one or more embodiments, the glycosidase is β-glucosidase, preferably sucrase, and the compound of formula (I) is as described in the first aspect herein. Preferably, the compound of formula (I) is selected from the group described herein: alcaftadine II 03,1; alcaftadine II 02,2; propionyl alcatadine II 02,3; butyryl alcatadine II 02 , 4; Isovaleryl alcatadine II03, 5; Tadine Ⅰ 03,9; butyryl akatadine Ⅰ 03,10;

In the fourth aspect of the present invention, there is provided a method for inhibiting the hydrolysis of carbohydrates containing α-1,4 glycosidic bonds by α-glucosidase (such as α-glucosidase on the small intestine), reducing the production and absorption of glucose, reducing the Post-blood glucose concentration, or the method for preventing, alleviating or treating a disease or condition benefiting from blood glucose reduction, comprising: administering an effective amount of the compound represented by formula (I) described herein or its pharmaceutical or food acceptable to a subject in need Salt or ester, isomer, racemate, solvate, hydrate or precursor, in the compound of formula (I), Z is selected from formyl, isobutyryl, unsubstituted n-butyryl, Substituted 2-butyryl, the substituent is selected from hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen. Preferably, the compound of formula (I) is selected from the group described herein: alcaftadine II 02,2; propionyl alcaftadine II 02,3; Tadine II 03, 5; Propionyl alcatadine II 03, 6; Butyryl alcatadine II 03, 7 and 2-methylbutyryl alcatadine 03, 8;

In the fifth aspect of the present invention, there is provided a method for inhibiting the activity of β-glucosidase (such as β-glucosidase on the small intestine), slowing down the rate of glucose and fructose from sucrose, reducing the occurrence of postprandial hyperglycemia, or preventing and alleviating Or a method for treating a disease or condition benefiting from blood sugar reduction, comprising: administering an effective amount of a compound represented by formula (I) described herein or a pharmaceutically or food-acceptable salt or ester, isomer thereof to a subject in need , racemate, solvate, hydrate or precursor, the compound of formula (I) is as described in the first aspect herein. Preferably, the compound of formula (I) is selected from the group described herein: alcaftadine II 03,1; alcaftadine II 02,2; propionyl alcatadine II 02,3; butyryl alcatadine II 02 , 4; Isovaleryl alcatadine II03, 5; Tadine Ⅰ 03,9; butyryl akatadine Ⅰ 03,10;

In the sixth aspect of the present invention, a method for improving the inhibitory activity of amino oligosaccharides on glycosidases is provided, comprising: adding at least one acyl group to the amino oligosaccharides.

In one or more embodiments, the glycosidase is an alpha-glucosidase or a beta-glucosidase. Preferably, the glycosidase is alpha-amylase or sucrase.

Description of drawings

Figure 1A, a diagram of the cleavage pattern of acyltadine compounds 2-5.

Figure 1B, HRESIMS/MS spectrum of compound 2.

Figure 1C, HRESIMS/MS spectrum of compound 3.

Figure 1D, HRESIMS/MS spectrum of compound 4.

Figure 1E, HRESIMS/MS spectrum of compound 5.

Fig. 2A, a schematic diagram of the cleavage mode of acyltadine compounds 6-8.

Figure 2B, HRESIMS/MS spectrum of compound 6.

Figure 2C, HRESIMS/MS spectrum of compound 7.

Figure 2D, HRESIMS/MS spectrum of compound 8.

Figure 3, the inhibitory effect of acyltadine compounds on α-amylase

Figure 4, the inhibitory effect of acyltadine compounds on sucrase

Figure 5. The general structural formula of the alcatrazidine family compounds in Streptomyces sp.HO1518. (A) Aca-glu type; (B) glu-Aca-glu type; (C) incAca-glu type.

Detailed ways

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a preferred technical solution.

The present invention finds that a class of acyltadine compounds has high-efficiency glycosidase inhibitory activity.

The above-mentioned acyl hepatidine compound has a compound represented by formula (I),

Wherein, n is 2, 3 or 4;

m is 2, 3 or 4;

Each R ₁ , R ₂ , R ₃ , R ₄ , R ₅ is each independently selected from the following group: hydrogen, C ₁ -C ₄ alkyl or -OZ; wherein each Z is independently selected from the following group: hydrogen, C ₃ -C ₆ acyl; and, at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ is -OZ;

Each R ₁ ′, R _{2 ′} , R ₃ ′, R ₄ ′, R ₁ ″, R ₂ ″, R ₃ ″, R ₄ ″, Ra are each independently selected from the following group: hydrogen, hydroxyl, C ₁ -C ₄ alkyl, halogen;

Each of Y ₂ and Y ₃ is independently selected from the following group: -O-, -NH-.

In the study of the compounds in the Streptomyces strain HO 1518 Streptomyces sp. HO1518, the inventors predicted and discovered a series of Aka The structure of hedine family compound (compound shown in formula (I)), and it has been carried out in-depth research, finds unexpectedly, it has efficient α-glucosidase and β-glucosidase inhibitory activity, on this basis , completed the present invention.

The present invention also includes pharmaceutically acceptable salts, isomers, racemates, solvates, hydrates or precursors of the above-mentioned formula (I) compound, as long as they also have the same properties as the formula (I) compound have the same or substantially the same function.

As used herein, the term "alkyl" alone or in combination with other terms refers to a saturated aliphatic alkyl group, including straight or branched chain alkyl groups of 1-20 carbon atoms. Preferably, the alkyl group refers to a medium alkyl group containing 1-10 carbon atoms, such as methyl, ethyl, propyl, 2-isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and Similar to alkyl. More preferably, it refers to a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-isopropyl, n-butyl, isobutyl, t-butyl and the like. Alkyl groups may be substituted or unsubstituted. When substituted, the number of substituents is 1 or more, preferably 1-3, more preferably 1 or 2, and the substituents are independently selected from halogen, hydroxyl, lower alkoxy and aryl.

The term "alkenyl" as used herein includes straight and branched chain hydrocarbon groups containing at least one carbon-carbon double bond and 2-4 carbon atoms, preferably 2-3 carbon atoms.

The term "alkynyl" as used herein includes straight and branched chain hydrocarbon groups containing at least one carbon-carbon triple bond and 2-4 carbon atoms, preferably 2-3 carbon atoms.

The term "halogen" as used herein refers to F, Cl, Br, or I.

As used herein, the term "substituted" refers to a compound having a substituent comprising at least one carbon atom, nitrogen atom, oxygen atom or sulfur atom with one or more hydrogen atoms. If a substituent is described Reference to being "substituted" means that a non-hydrogen substituent occupies the position of a hydrogen on a carbon, nitrogen, oxygen, or sulfur. In the present invention, the alkyl, alkenyl and alkynyl groups may be substituted; for example, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl. Unless otherwise defined, a substituted group has a substituent at one or more appropriate positions, and when more than one position is substituted, the substituents at each substituted position may be the same or different. The substituents of the substituted acyl include: hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and halogen.

The term "isomer" as used herein includes: geometric isomers, enantiomers, diastereomers (such as cis-trans isomers, conformational isomers). The compounds disclosed in the present invention or their salts may contain one or more asymmetric centers, so there will be enantiomers, diastereoisomers and other stereoisomeric forms that can be defined, and can be divided according to stereochemistry. is (R)- or (S)-, (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be prepared by chiral synthons or chiral reagents, or by conventional techniques Such as the use of high performance liquid phase chiral column to separate the preparation. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise stated, it is meant that the compounds include both E and Z geometric isomers. Likewise, all tautomers are included.

In the present invention, "food or pharmaceutically acceptable" ingredients are substances that are suitable for humans and/or animals without excessive adverse side effects (such as toxicity, irritation and allergic reactions), that is, substances with a reasonable benefit/risk ratio.

The "food or pharmaceutically acceptable salts" mentioned herein include acid salts and basic salts.

"Pharmaceutically acceptable acid salt" refers to a salt that can maintain the biological activity and properties of the free base, and such salts will not have undesired biological activity or other changes. Such salts may be formed from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like. Such salts may also be formed from organic acids such as, but not limited to, acetic acid, dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, Camphorsulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, isethionic acid , formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphate , glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-di Sulfonic acid, 2-naphthalenesulfonic acid, 1-naphthol-2-carboxylic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, water Cylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and similar acids.

"Pharmaceutically acceptable basic salt" refers to a salt that can maintain the biological activity and properties of the free acid, and such salts will not have undesired biological activity or other changes. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary ammonium salts, and substituted amines include Naturally substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, tannol, 2-dimethylaminoethanol, 2-Diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, halamine, choline, betaine, phenethylbenzylamine, N,N' - Bisbenzylethylenediamine, ethylenediamine, glucosamine, meglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamide resin and similar structures. Preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Often crystallization will result in solvated products of the disclosed compounds. As used herein, the term "solvate" refers to a polymer comprising one or more molecules of a compound disclosed herein and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may also be an organic solvent. Therefore, the compounds disclosed in this patent can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates and similar structures, and can also be used as corresponding solvated products exist. The compounds disclosed herein may be true solvates, while in other cases, the compounds disclosed herein may retain some water only, or a mixture of water and some solvent.

The "precursor of the compound" refers to that when taken in an appropriate way, the precursor of the compound undergoes metabolism or chemical reaction in the patient's body and converts into a compound of structural formula (I), or a compound of chemical structural formula (I). A salt or solution of a compound.

In the present invention, the term "comprising" means that various components can be used together in the mixture or composition of the present invention. Accordingly, the terms "consisting essentially of" and "consisting of" are included in the term "comprising".

Preparation

Those skilled in the art will understand that, after knowing the structure of the compound of the present invention, the compound of the present invention can be obtained by various methods well known in the art, using known raw materials, such as chemical synthesis or from organisms (such as microorganisms, especially is the method for extracting in Streptomyces), and these methods are all included in the present invention.

As a preferred mode of the present invention, a method for preparing the compound shown in formula (I) of the present invention is provided, said method comprising: cultivating Streptomyces HO 1518 Streptomyces sp.HO1518, obtaining a culture product (such as a culture supernatant ), from which the compound of formula (I) is isolated. Afterwards, the culture product is purified, and different compounds of formula (I) are separated from different eluents. Collection and purification of products are well known in the art, for example, resin adsorption and elution methods such as gradient elution can be used.

Other methods of preparing compounds of formula (I) are also included in the present invention, such as linking sugar units by chemical synthesis. The synthesized compound can be further purified by column chromatography, high performance liquid chromatography and the like.

combination

The present invention also provides a composition comprising the compound of formula (I) described herein or its pharmaceutically or food-acceptable salt, isomer, racemate, solvate, hydrate or precursor, and pharmaceutically or food-acceptable excipients. The composition can be a food, a health care product, or a pharmaceutical composition.

In the present invention, "food or pharmaceutically acceptable excipients" are used to use the compound of formula (I) of the present invention or its A pharmaceutically or food-acceptable carrier, solvent, suspending agent or excipient for delivering pharmaceutically or food-acceptable salts, isomers, racemates, solvates, hydrates or precursors to animals or humans Forming agent. Excipients can be liquid or solid and include but are not limited to: pH adjusters, surfactants, carbohydrates, adjuvants, antioxidants, chelating agents, ionic strength enhancers, preservatives, carriers, glidants, sweeteners , dye/colorant, flavor enhancer, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier. In some embodiments, pharmaceutically acceptable excipients may include one or more inactive ingredients, including but not limited to: stabilizers, preservatives, additives, adjuvants, sprays, compressed air or other suitable gases, Or other suitable inactive ingredients used in combination with medicinal compounds. More specifically, suitable excipients may be excipients commonly used in the art for administration of plant extract components or nucleic acids.

Typically, the composition will contain a therapeutically effective amount of an agent described herein. A therapeutically effective amount refers to a dose that can achieve treatment, prevention, alleviation and/or alleviation of a disease or condition in a subject. The therapeutically effective dose can be determined according to factors such as the patient's age, sex, disease and its severity, and other physical conditions of the patient. A therapeutically effective amount may be administered as a single dose, or may be administered in multiple doses in accordance with an effective treatment regimen. Herein, a subject or a patient generally refers to a mammal, especially a human. Exemplarily, the composition contains, for example, 0.001-50% by weight, preferably 0.01-30%, more preferably 0.05-10% of the compound represented by formula (I) or its pharmaceutically or food-acceptable Salts, isomers, racemates, solvates, hydrates or precursors.

Compositions described herein may be used in combination with other agents for weight management or therapeutic benefit from reduced fat absorption. Dosages of other agents to be administered can be determined by those skilled in the art.

In one or more embodiments, the composition may also contain protein, lipid, carbohydrate, dietary fiber, vitamins and the like. Proteins such as milk protein (whole milk protein, sodium caseinate, calcium caseinate, etc.) and their hydrolysates, other animal proteins (egg protein, gelatin, etc.) thing. The composition of the present invention may contain protein as a main component. The total protein content can be appropriately determined, but if the purpose is to ingest 1/3 of the daily required intake, it is preferably about 13 to 30 g/400 ml. Vitamins can also be added vitamins A, B1, B2, B6, B12, C, D, E, K2, niacin, pantothenic acid, folic acid, etc., which can be added alone or mixed. The composition of the present invention may also contain dry yeast (eg brewer's yeast, baker's yeast, etc.).

The dosage form of the composition of the present invention can be varied, as long as the active ingredient can effectively reach the mammalian body, it can be made into a unit dosage form. Dosage forms can be selected from, for example, gels, aerosols, tablets, capsules, powders, granules, syrups, solutions, suspensions, injections, powders, pills, controlled immediate releases, infusions, suspensions, and the like. According to the type of disease to be treated by the compound of the present invention, those skilled in the art can choose a convenient dosage form. From the standpoint of ease of preparation and storage, preferred compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules. The compounds of the present invention or compositions thereof may also be stored in sterile devices suitable for injection or infusion. The compounds of the present invention or compositions thereof may also be stored in suitable containers and placed in kits or kits.

The composition can also be a daily chemical product, such as shampoo, shower gel, cosmetics, washing powder and the like.

method and use

The present inventors found in research that the compound represented by formula (I) has efficient inhibitory effect on α-glucosidase and β-glucosidase, so it is a good inhibitor of α-glucosidase and β-glucosidase. As an α-glucosidase and β-glucosidase inhibitor, the compound can delay the hydrolysis and absorption of carbohydrates in the gastrointestinal tract, reduce postprandial blood glucose concentration, or prevent, alleviate or treat diseases or conditions that benefit from blood glucose reduction. Diseases or conditions described herein that benefit from lowering blood sugar include: hyperglycemia, diabetes and its complications, hyperinsulinemia, cardiovascular disease, or disorders of glucose metabolism. In particular, the compound represented by formula (I) can efficiently inhibit the activity of α-glucosidase, and inhibit the activity of α-glucosidase (such as α-glucosidase on the brush border of the small intestine) on carbohydrates containing α-1,4 glycosidic bonds. The hydrolysis of glucose reduces the generation and absorption of glucose, and reduces the postprandial blood glucose concentration; moreover, the compound shown in formula (I) can efficiently inhibit the activity of β-glucosidase (such as β-glucosidase on the small intestine), and slow down the generation of glucose by sucrose and fructose, reducing the occurrence of postprandial hyperglycemia.

"Glycosidase" as used herein is an enzyme that hydrolyzes glycosidic bonds, including α-glucosidase and β-glucosidase, which hydrolyze α-glycosidic bonds (such as α-1,4 glycosidic bonds) and β-glycosidic bonds (such as β-glycosidic bonds) respectively. D-fructofuranosidic bond). Compounds containing glycosidic bonds can be proteins, nucleic acids, carbohydrates, such as disaccharides, including but not limited to maltose, sucrose.

Therefore, in a non-diagnostic or therapeutic aspect, the present invention provides a method of inhibiting α-glucosidase and/or β-glucosidase activity, comprising: making the compound of formula (I) described herein or pharmaceutically or food-available Accepted salts, isomers, racemates, solvates, hydrates or precursors come into contact with samples containing α-glucosidase and/or β-glucosidase, thereby inhibiting α-glucosidase and/or β-glucosidase Glycosidase activity. In addition, the present invention also provides a method for delaying the hydrolysis and absorption of carbohydrates in the gastrointestinal tract, reducing postprandial blood sugar concentration, or preventing, alleviating or treating diseases or conditions benefiting from blood sugar reduction, especially a method for inhibiting α- Glycosidase activity, inhibiting the hydrolysis of carbohydrates containing α-1,4 glycosidic bonds by α-glucosidase (such as α-glucosidase on the brush border of the small intestine), reducing the production and absorption of glucose, and reducing postprandial blood glucose concentration or a method for inhibiting the activity of β-glucosidase (such as β-glucosidase on the small intestine), slowing down the rate of producing glucose and fructose from sucrose, and reducing the occurrence of postprandial hyperglycemia, comprising: giving an effective dose to a subject in need The compound represented by formula (I) described herein or its pharmaceutically or food acceptable salt, isomer, racemate, solvate, hydrate or precursor.

Specifically, "effective amount" refers to the injection amount that can produce therapeutic functions for humans or animals and can be accepted by animals and humans. For example, in a liquid combination drug, the concentration of the polypeptide may be above 20 ng/mL, above 50 ng/mL, above 100 ng/mL, etc. The effective amount will vary with the mode of administration and the severity of the disease being treated. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as the exigencies of the therapeutic situation dictate.

The administration methods of the compounds of the present invention may include, but are not limited to, subcutaneous injection, transdermal injection, implantation, topical administration, intramuscular injection, sustained release administration, oral administration, and the like. Those skilled in the art are aware of other agents needed to administer the drug to a subject under different modes of administration, doses, sites of administration, and the like. Such as dressings, solvents (such as water), etc.

The kit for implementing the above method comprises the compound represented by formula (I) described herein or its pharmaceutically or food-acceptable salt, isomer, racemate, solvate, hydrate or precursor, or the composition, and any Optional other items required for their administration, and optional instructions. Such other items are, for example, measuring instruments, containers such as syringes, etc. required for using or administering the composition in various dosage forms. The instructions are for directing the use or administration process. Therefore, the present invention also provides the compound of formula (I) described herein or its pharmaceutically or food acceptable salt, isomer, racemate, solvate, hydrate or precursor in the production of inhibitory α-glucoside Enzyme and/or β-glucosidase activity, delaying the hydrolysis and absorption of carbohydrates in the gastrointestinal tract, reducing postprandial blood glucose concentration, or the use in products for the prevention, alleviation or treatment of diseases or conditions that benefit from blood glucose reduction. The product can be daily chemical products, food, health products, pharmaceutical compositions or kits.

In specific embodiments, the present invention includes compounds of formula (I) described herein or pharmaceutically or food acceptable salts, isomers, racemates, solvates, hydrates or precursors thereof in the preparation of inhibitory α-glucosidase activity, inhibits the hydrolysis of carbohydrates containing α-1,4 glycosidic bonds by α-glucosidase (such as α-glucosidase on the brush border of the small intestine), reduces the production and absorption of glucose, and reduces postprandial blood glucose concentration , or the prevention, alleviation or treatment of diseases or disorders benefiting from blood sugar reduction, wherein Z is selected from formyl, isobutyryl, unsubstituted n-butyryl, substituted 2-butyryl, said substituted The group is selected from hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen. Preferably, the compound of formula (I) is selected from the group described herein: alcaftadine II 02,2; propionyl alcaftadine II 02,3; Hetidine II03, 5; Propionyl akatadine II 03, 6; Butyryl akatadine II 03, 7; 2-methyl butyryl akatadine 03, 8; The glycosidase is preferably an alpha-amylase.

In another specific embodiment, the present invention includes the compound of formula (I) described herein or its pharmaceutically or food acceptable salt, isomer, racemate, solvate, hydrate or precursor in The preparation inhibits the activity of β-glucosidase (such as β-glucosidase on the small intestine), slows down the rate of producing glucose and fructose from sucrose, reduces the occurrence of postprandial hyperglycemia, or prevents, alleviates or treats diseases or conditions benefited from the reduction of blood sugar Use in a product, wherein the compound of formula (I) is as described herein. Preferably, the compound of formula (I) is selected from the group described herein: alcaftadine II 03,1; alcaftadine II 02,2; propionyl alcatadine II 02,3; butyryl alcatadine II 02 , 4; Isovaleryl alcatadine II03, 5; Tadine Ⅰ 03,9; butyryl akatadine Ⅰ 03,10; The β-glucosidase is preferably sucrase.

The present invention is described in further detail by referring to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified. Accordingly, the invention should in no way be construed as limited to the following examples, but rather should be construed to encompass any and all variations that become apparent as a result of the teaching presented herein. The methods and reagents used in the examples, unless otherwise stated, are conventional methods and reagents in the art.

Example

Example 1, Global Prediction of Alcaftadine Family Compounds in Streptomyces strain HO 1518 Streptomyces sp.HO1518 Using High Resolution Liquid Mass Spectrometry (LC-MS/MS)

Inoculate an appropriate amount of HO 1518 seed liquid into 10ml Pharmamedia liquid medium (3 parallels), ferment and cultivate at 28°C and 200rpm for 7 days, centrifuge and discard the bacteria, and collect the supernatant; the supernatant is passed through the macroporous resin XAD-16 adsorption column Chromatography, eluting with 95% ethanol, obtained the total extract of HO1518. Using LC-MS/MS liquid-mass spectrometry, the metabolomics analysis of the HO 1518 strain was carried out. According to the mass spectrometry fragmentation rules of the alcaftadine family compounds, 98 alcaftidine family compounds were finally predicted. The structures are detailed in Figure 5 and Table 6.

Table 6 Prediction of alcatathidine family compounds from Streptomyces sp.HO1518

Aca, acarviostatin; Ac, acetyl; Hac, hydroxyacetyl; Pr, propionyl; Hpr, hydroxypropionyl; Bu, butyryl; isoBu, isobutyryl; Hbu, hydroxybutyryl; Mbu, 2-methyl-butyryl; hexanoyl; Hhe, hydroxyhexanoyl; diHva, dihydroxyvaleryl. Acarviostatins, marked with “-” in Ref.column, are potential new compounds.

Embodiment 2, the fermentation culture of bacterial strain and the preparation of compound

Streptomyces strain HO 1518 Streptomyces sp.HO1518 was collected from marine sediments in the 50-100m deep sea area near Rizhao, Shandong, China in 2010, and its preservation number in the China Center for Type Culture Collection is CCTCC NO:M 2018176.

Add 100mL 3% TSB solution (purchased from BD Company, USA) to a 500mL Erlenmeyer flask, sterilize with high pressure steam at 121°C for 20min, cool to room temperature, inoculate Streptomyces HO 1518 Streptomyces sp.HO1518 slant spores, place at 28°C, 250rpm Cultivate for 48 hours in a constant temperature shaker as a seed solution.

Accurately weigh the following inorganic salts (g/L): NaCl 24.4770, Na ₂ SO ₄ 3.9170, KCl 0.664, SrCl ₂ ^. 6H ₂ O 0.0404, MgCl ₂ ^. 6H ₂ O 4.981, CaCl ₂ 0.9482, NaHCO ₃ 0.192, H ₃ BO ₃ 0.026, NaF 0.004, dissolved in tap water and fixed to a certain volume to prepare artificial seawater; accurately weigh trace element metal salts (g/L): MnCl ₂ 0.389, NiSO ₄ ^. 6H ₂ O 0.056, LiCl 0.028, K ₂ Cr ₂ O ₇ 0.15, Na ₂ EDTA 1.00, FeCl ₃ ^. 6H ₂ O 2.00, AlCl ₃ 0.05, CuCl ₂ 0.02, CoCl ₂ ^. 6H ₂ O 0.005, ZnCl ₂ 0.06, Na ₂ MoO ₄ ^. 2H ₂ O 0.074, KI 0.08, BaCl ₂ ^. 2H ₂ O 0.05, dilute to the corresponding volume with tap water, and prepare trace element solution. Use artificial seawater to prepare PH medium (Pharmamedia powder 1%, soluble starch 1%, glucose 1.2%, corn steep liquor dry powder 0.5%), adjust the pH to 7.2, add 400mL PH medium (containing 400μL trace element solution), sterilized by autoclaving at 121°C for 20 minutes, inoculated with HO 1518 seed solution after cooling, and cultured in a fermenter at 28°C and 200 rpm for 7 days, with a total of 35 L fermented.

Centrifuge the fermentation broth of strain HO1518 at high speed and collect the supernatant; use macroporous resin XAD-16 to absorb the supernatant The metabolites in the solution were obtained to obtain the crude extract of HO1518. The crude extract was subjected to C ₁₈ reversed-phase silica gel column chromatography, and was eluted with different concentrations of methanol/water (5:95→100:0) gradient, and was divided into 6 fractions (Fr.1-Fr.6).

We performed targeted separation of the target compounds in fractions Fr.1 and Fr.2. Fraction Fr.1 was subjected to ODS-C ₁₈ reverse phase silica gel column chromatography, methanol/water gradient elution (5:95→100:0), and was divided into 6 subcomponents (Fr.1-1～Fr.1- 6). Subfraction Fr.1-1 was subjected to MCI column chromatography, and then purified by full preparative HPLC (MeCN/H ₂ O, 6:94, 8mL/min), and the known compound 1 (alcaftadine II03, Aca II03, 10.0 mg, t _R 10.5 min) and new compound 2 (alcaftadine II02, Aca II02, 1.6 mg, t _R 9.6 min). Subfraction Fr.1-3 was passed through the MCI column, and then purified by full preparative HPLC (MeCN/H ₂ O, 10:90, 8mL/min) to obtain the known compound 11 (β-hydroxybutyrylalcaftadine II03 , Hbu-Aca II03, 4.5 mg, t _R 15.1 min). Subcomponents Fr.1-4 were subdivided by MCI and ODS-C ₁₈ column chromatography, and then purified by HPLC (MeCN/H ₂ O, 10:90, 6mL/min) to obtain a new compound 6 (propionyl Alcaftadine II03, Pr-Aca II03, 13.2mg, t _R 40.5min). Subfractions Fr.1-5 were purified by reverse-phase silica gel and MCI column chromatography, followed by two HPLC preparative purifications (MeCN/H ₂ O, 10:90, 6 mL/min; MeCN/H ₂ O, 16:84 , 8mL/min); Obtain known compound 9 (alcastatine I03, Aca I03, 2.2mg, t _R 6.0min) and 10 (butyryl alcastatine I03, Bu-Aca I03, 10.2mg, t _R 14.3min). Subfraction Fr.1-6 was purified by MCI column chromatography, and then purified by HPLC twice (MeCN/H ₂ O, 10:90, 6mL/min; MeCN/H ₂ O, 18:82, 8mL/min ); Obtain new compound 8 (2-methylbutyryl alcatadine II03, Mbu-Aca II03, 4.2 mg, t _R 12.2min) and known compound 12 (isovaleryl alcatadine II03, isoVa-Aca II03, 6.2 mg, _tR 12.8 min).

Fraction Fr.2 was subjected to gradient elution (MeOH/H ₂ O, 5:95→100:0) using an MCI column, and was subdivided into 4 subcomponents. Subfraction Fr.2-2 was purified by reverse-phase silica gel column chromatography, and then purified by HPLC twice (MeCN/H ₂ O, 10:90, 6mL/min; MeCN/H ₂ O, 16:84, 8mL /min), obtain new compound 7 (butyryl alcastatine II03, Bu-Aca II03, 5.9mg, t _R 11.9min) and 4 (isobutyryl alcastatine II02, isoBu-Aca II02, 1.9mg, t _R 10.4min). The subfraction Fr.2-3 was purified by HPLC twice (MeCN/H ₂ O, 10:90, 6mL/min; MeCN/H ₂ O, 12:88, 8mL/min) to obtain the new compound 3 ( Propionylalcatadine II02, Pr-Aca II02, 2.2mg, _tR 17.0min). Subfraction Fr.2-4 was purified by full preparative HPLC (MeCN/H ₂ O, 6:94, 8mL/min) to obtain a new compound 5 (isovalerylalcastatine II02, isoVa-Aca II02, 2.0mg , t _R 44.3min).

The full preparative column is SilGreen C ₁₈ , 250×20mm; semi-preparative column is TSK-gel 100V C ₁₈ , 250×10mm; the analytical detection column is Phenomenex/Luna C ₁₈ (2) 100A, 4.6×250mm; UV detection wavelength is 210nm.

Embodiment 3, the chemical structure of the new compound of acyl hepatidine family

The three new compounds obtained above are all colorless transparent solids, easily soluble in water, and the ultraviolet absorption is terminal absorption.

Alcaftadine II 02 (corresponding to compound 2) has a molecular formula of C ₅₀ H ₈₄ N ₂ O ₃₅ and a molecular weight of 1273.4927.

Propionatadine II 02 (corresponding to compound 3) has a molecular formula of C ₅₃ H ₈₈ N ₂ O ₃₆ and a molecular weight of 1329.5190.

Isobutyrate II 02 (corresponding to compound 4) has a molecular formula of C ₅₄ H ₉₀ N ₂ O ₃₆ and a molecular weight of 1343.5346.

Isovaleratadine II02 (corresponding to compound 5) has a molecular formula of C ₅₅ H ₉₂ N ₂ O ₃₆ and a molecular weight of 1357.5503.

Propionatadine II 03 (corresponding to compound 6) has a molecular formula of C ₅₉ H ₉₈ N ₂ O ₄₁ and a molecular weight of 1491.5718.

Butyrastatidine II 03 (corresponding to compound 7) has a molecular formula of C ₆₀ H ₁₀₀ N ₂ O ₄₁ and a molecular weight of 1505.5872.

2-Methylbutyrazidine II 03 (corresponding to compound 8) has a molecular formula of C ₆₁ H ₁₀₂ N ₂ O ₄₁ and a molecular weight of 1519.6031.

Table 1 Hydrogen spectrum and carbon spectrum data of compounds 2 and 3.

Table 2 Hydrogen spectrum and carbon spectrum data of compounds 4 and 5.

Table 3 Hydrogen spectrum and carbon spectrum data of compounds 6-8.

Example 4, Mass Spectrometry Fragmentation Rules of New Compounds of Acyl Hepatidine Family

1. Alcaftadine family Ⅱ 02 skeleton type

The new compounds 1-4 of acyltadine belong to the skeleton type of alcaftadine family Ⅱ 02, and they form common fragment ion peaks m/z 304(b2), 466(b3), 624(b4) in the fragmentation mode of positive ion mass spectrometry and 769(b5). Compared with the precursor compound 1 (alcaftadine Ⅱ 02), the fragment ion peaks and molecular ion peaks of compound 2-4 at m/z y5 and b3-b5 are 56, 70 and 84 degrees different from alcaftadine Ⅱ 02, respectively unit of mass. The above shows that the acyl substitution positions of acyltadine compounds 1-4 are all on the D ring. The detailed fragmentation modes of the four compounds are shown in Figure 1A, and their HRESIMS/MS spectra are shown in Figures 1B-1E.

2. Alcaftadine family II03 skeleton type

The new compound 6-8 of acyltadine belongs to the skeleton type II03 of the alcaftadine family, and in the fragmentation mode of positive ion mass spectrometry, it forms common fragment ion peaks m/z 304(b2), 466(b3), 624(b4) and 769(b5), which are the same as the mass fragmentation fragments of the precursor compound—alcaftadine II03; while the fragment ion peaks and molecular ion peaks at m/z y5-y8 and b6-b8 are the same as the fragments of alcaftadine II03 The difference is 56, 70 and 84 mass units. As explained above, the acyl substitution position of the acyltadine compound M-1b is also on the D ring. The detailed fragmentation mode of compound M-1b is shown in Figure 2A, and its HRESIMS/MS spectra are shown in Figures 2B-2D.

Example 5. Inhibition of α-glucosidase activity by new compounds of the acyltadine family at the enzymatic level

The new compound obtained above belongs to the amino-oligosaccharide compound, and has similarities with the compound acarbose in part of the structure. Acarbose is a clinical drug for type II diabetes, and its mechanism of action is to inhibit the hydrolysis of starch by α-amylase (a typical glycosidase) in the intestine, reduce the production of glucose, and thereby achieve the purpose of lowering blood sugar. In view of this, the inventors used acarbose as a positive control to test the activity of the new compound obtained.

First, establish a standard curve for the starch solution:

Take 0, 10, 20, 30, 40, 45, 50, 55, 60, 70, 80, 90 and 100 μL of 0.2% starch solution respectively, add them into 96-well plate, add 150, 140, 130, 120, 110 , 105, 100, 95, 90, 80, 70, 60 and 50 μL of phosphate buffer solution (pH=6.9), incubated at 20° C. for 30 min, and then added 20 μL of 1M hydrochloric acid. Accurately measure 100 μL of the reaction solution, transfer it to a 96-well plate, add 25 μL of Lugol’s iodine solution, and mix well. The absorbance value of each concentration was read at 630nm, and measured in parallel three times.

Mix 5 μL porcine pancreatic α-amylase solution (50U/ml) and 45 μL test sample solutions of different concentrations or Aka Wave sugar solution (inhibitor, dissolved in distilled water) was mixed, placed in a shaker at 20°C and 100 rpm for 10 min, and then 100 μL of 0.2% soluble starch solution (substrate, dissolved in 100 mM phosphate buffer at pH 6.9) was added ), mix well, react for 30 min, and add 20 μL of 1M hydrochloric acid to terminate the reaction. The rest of the operations are the same as above.

[Corrected 26.06.2023 under Rule 91]
According to the absorbance values of the starch solutions with a series of concentration gradients, the standard curve was drawn, as shown in Figure 3; the absorbance values of the acarbose and test sample solutions were substituted to calculate the inhibition rate of the test compound on starch. The _IC50 values of each sample were calculated using GraphPad Prism 5.0, see Figure 3 and Table 4.

The inhibitory activity of table 4 acyl hepatidine compounds to α-amylase

As can be seen from Table 4, the 7 new compounds of the present invention all exhibit significant α-amylase inhibitory activity, and are all better than the positive control drug—acarbose; among them, compound 6 has the strongest inhibitory activity (IC ₅₀ = 0.035±0.001μM), about 243 times the inhibitory activity of acarbose; the IC ₅₀ values of the other six new oligosaccharides were between 0.052-0.092μM, and their inhibitory activity was far better than that of acarbose.

Example 6, Inhibition of Sucrase Activity by Acyl Hepatidine Family Compounds at the Enzymatic Level

The 12 compounds obtained above belong to amino-oligosaccharide compounds, and have partial structural similarities with the compound acarbose. According to literature reports, acarbose has sucrase inhibitory activity. In view of this, the present inventors used acarbose as a positive control to test the sucrase inhibitory activity of 12 compounds.

Mix 10 μL sucrase solution (100 U/ml) and 30 μL test sample solution (inhibitor, dissolved in distilled water) of different concentrations, and incubate at 37 °C for 10 min; then add 100 μL 60 mM sucrose solution (substrate, dissolved in pH 6.0 phosphate buffer), mix well, and incubate at 37°C for 30min. Then, add 200 μL of 3,5-dinitrosalicylic acid, inactivate in boiling water for 5 minutes, and cool to room temperature. Place the reaction solution under a microplate reader, read the absorbance value of each sample solution (sample A) at 540 nm, and try three times in parallel. Replace the test sample solution with the same volume of distilled water as a negative control group, and test its absorbance value (A sample space) according to the same operation. According to the absorbance values of different concentrations of sample solutions and blank solutions, the invertase inhibition rate was calculated according to the following formula. Next, use GraphPad Prism 5.0 to calculate the IC ₅₀ value of each sample, see Figure 4 and Table 5.

Inhibition rate of sucrase activity/%=(A sample-A sample empty)/A sample empty×100

The inhibitory activity of table 5 acyl hepatidine compound to sucrase

It can be seen from Table 5 that all the compounds of the present invention have significant sucrase inhibitory activity, and their IC ₅₀ values are between 2.56-17.24 μM. Among them, compounds 6 and 10 have the best sucrase inhibitory activity, which is equivalent to that of acarbose. Through structure-effect relationship analysis, it was found that the compounds (1 and 2) containing two pseudotrioses (i.e., nine structural units) were inferior to the compounds containing one pseudotriose (i.e., six structural units) against invertase 10. The above shows that the increase of the pseudotriose structural unit is not conducive to the sucrase inhibitory activity of the compound. In addition, by comparing the inhibitory activities of compounds 2-5, it was found that substituting side chains can improve their activities, and the sucrase inhibitory activity of propionyl group is the best.

Claims (10)

1. The use of the compound of formula (I) or its pharmaceutically or food-acceptable salt or ester, isomer, racemate, solvate, hydrate or precursor is characterized in that it is used to prepare glycosidase-inhibiting Active, products that delay the hydrolysis and absorption of carbohydrates by the gastrointestinal tract, lower postprandial blood glucose concentrations, or prevent, alleviate or treat diseases or conditions that benefit from lowering blood glucose,
   

   Wherein, n is 2, 3 or 4;

   m is 2, 3 or 4;

   Each R ₁ , R ₂ , R ₃ , R ₄ , R ₅ is each independently selected from the following group: hydrogen, C ₁ -C ₄ alkyl or -OZ; wherein each Z is independently selected from the following group: hydrogen, C ₃ -C ₆ acyl; and, at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ is -OZ;

   Each R ₁ ′, R _{2 ′} , R ₃ ′, R ₄ ′, R ₁ ″, R ₂ ″, R ₃ ″, R ₄ ″, Ra are each independently selected from the following group: hydrogen, hydroxyl, C ₁ -C ₄ alkyl, halogen;

   Each Y ₂ and Y ₃ are independently selected from the following group: -O-, -NH-;

   X ₂ , X ₃ , X ₄ are oxygen;

   When m is 3 and n is 2, _R is not hydroxyl or
2. The use according to claim 1, wherein each R ₃ is independently -OZ; and each Z is independently a C ₃ -C ₆ acyl group.

   In another preference, said _R is selected from the following group:
3. purposes as claimed in claim 1, is characterized in that, n is 2.
4. The use according to claim 1, characterized in that each R ₁ , R ₂ , R ₄ , R 1 ′, R ₂ ′, R ₄ ′, R ₁ ″, R _{2 ″} , R ₄ ″, and Ra are each independently is selected from the group consisting of hydrogen, C ₁ -C ₂ alkyl or hydroxy.

   In another preferred example, each R ₂ is independently C ₁ -C ₂ alkyl.
5. The use according to claim 1, wherein the compound has a structure selected from the group consisting of:
   
6. The use according to any one of claims 1-5, wherein the glycosidase is a β-glucosidase, and the product inhibits the activity of the β-glucosidase to slow down the rate of glucose and fructose from sucrose, Products that reduce the occurrence of postprandial hyperglycemia.
7. The use according to any one of claims 1-5, wherein the glycosidase is α-glucosidase, and the product inhibits the activity of α-glucosidase, and inhibits α-glucosidase to contain α-1 , The hydrolysis of carbohydrates with 4 glycosidic bonds, reducing the production and absorption of glucose, and reducing the concentration of blood sugar after meals.
8. The use according to any one of claims 1-5, wherein the disease or condition benefiting from lowering of blood sugar is selected from hyperglycemia, diabetes and its complications, hyperinsulinemia, cardiovascular disease or glucose metabolism disease.
9. A non-diagnostic, non-therapeutic method for inhibiting glycosidase activity, comprising: making the compound of formula (I) or its pharmaceutically acceptable salt or ester, isomer, racemate, solvate , hydrates or precursors are in contact with samples containing α-glucosidase and/or β-glucosidase, thereby inhibiting the activity of α-glucosidase and/or β-glucosidase,
   

   Wherein, n is 2, 3 or 4;

   m is 2, 3 or 4;

   Each R ₁ , R ₂ , R ₃ , R ₄ , R ₅ is each independently selected from the following group: hydrogen, C ₁ -C ₄ alkyl or -OZ; wherein each Z is independently selected from the following group: hydrogen, C ₃ -C ₆ acyl; and, at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ is -OZ;

   Each R ₁ ′, R _{2 ′} , R ₃ ′, R ₄ ′, R ₁ ″, R ₂ ″, R ₃ ″, R ₄ ″, Ra are each independently selected from the following group: hydrogen, hydroxyl, C ₁ -C ₄ alkyl, halogen;

   Each Y ₂ and Y ₃ are independently selected from the following group: -O-, -NH-;

   X ₂ , X ₃ , X ₄ are oxygen;

   When m is 3 and n is 2, R is _not hydroxyl or

   In another preferred embodiment, the compound of formula (I) is selected from the following group:
   
   
10. A method for improving the inhibitory activity of amino oligosaccharides on β-glucosidase, comprising: adding at least one acyl group to the amino oligosaccharides.