CN112047993A

CN112047993A - Alpha-glucosidase inhibitor and application thereof

Info

Publication number: CN112047993A
Application number: CN202010628341.9A
Authority: CN
Inventors: 江成世; 谢洪旭; 葛永喜
Original assignee: University of Jinan
Current assignee: University of Jinan
Priority date: 2020-07-02
Filing date: 2020-07-02
Publication date: 2020-12-08

Abstract

The invention relates to the field of medicinal chemistry, in particular to an oleanolic acid derivative capable of inhibiting alpha-glucosidase activity, which has the following structural general formula:

Description

Alpha-glucosidase inhibitor and application thereof

Technical Field

The invention relates to an alpha-glycosidase inhibitor and application thereof, in particular to application of oleanolic acid derivatives as a novel alpha-glycosidase inhibitor.

Background

Diabetes Mellitus (DM) is a metabolic disease caused by dysfunction or insufficient secretion of insulin, mainly caused by metabolic disturbance of sugar, fat and protein substances, characterized by persistent rise of blood sugar and urine sugar, and accompanied by the occurrence of complications of multiple systems and multiple organs. There are 17 hundred million people worldwide suffering from diabetes, and diabetes, together with tumor and cardiovascular diseases, has become three major diseases threatening human health. The number of diabetic patients in China is increasing year by year, and the rapid onset speed of the diabetic patients in China makes China the second largest diabetic country.

In recent years, it has been found that postprandial hyperglycemia is the first symptom in the onset of diabetes, and can induce various complications and increase the mortality of diabetic patients. The carbohydrates in the food are the main source of blood sugar, and the carbohydrates in the food can be absorbed after being hydrolyzed by alpha-glucosidase to generate monosaccharide. Therefore, alpha-glucosidase is a key enzyme for regulating postprandial blood glucose and is another effective target for treating diabetes.

The alpha-glucosidase mainly comprises enzymes such as maltase, sucrase, maltase, lactase and the like, is widely distributed in brush borders of villous mucosa cells of small intestine of a human body, participates in digestion and absorption of carbohydrates, starch and glycoprotein by the human body, and is related to various diseases of metabolic disorder. The alpha-glucosidase inhibitor can inhibit the activity of alpha-glucosidase, reduce the generation of blood sugar and has clinical application value of reducing blood sugar. In view of the above, the development of novel α -glucosidase inhibitors has become a hot spot for new drug development in recent years.

Disclosure of Invention

The inventor carries out selective oxidation on the oleanolic acid, and then carries out a carboxyl amine reaction with different aminoalkane compounds to obtain a novel compound which has a similar structure and alpha-glycosidase inhibitory activity and is shown in a general formula I, so that the novel compound has a potential application in the field of preparing medicines for treating diabetes.

In a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

The structure of the compound is shown as a general formula I

General formula I

Wherein R is a different aminoalkane, includingN,N-diisopropylethane-1, 2-diamine, 2- (pyrrolidine)-1-yl) ethyl-1-amine, n-butylamine,N,N-a mixture of (a) and (b) dimethyl ethylene diamine,N,Ndiethyl ethylenediamine, cyclopropylamine, methyl 3-aminopropionate, 2, 2-dimethoxyethane-1-amine, N-tert-butoxycarbonyl-1, 4-butanediamine, 2- (methylsulfonyl) ethane-1-amine.

The preparation method of the oleanolic acid derivatives shown in the general formula I comprises the following steps:

a) reacting the compound shown in the formula 1 with 2-iodoxybenzoic acid (IBX) to obtain a compound shown in the formula 2, wherein the reaction solvent is at least one of N, N-dimethylformamide, acetone, dimethyl sulfoxide, 1, 4-dioxane, tetrahydrofuran, methanol, ethanol, pyridine and water; the reaction temperature is 0-140 ℃; the reaction time is 8-24 hours.

b) Reacting the compound of the formula 2 with a corresponding amine compound under the catalysis of a condensing agent to obtain a compound of a target general formula I; the condensing agent used isN,N'-dicyclohexylcarbodiimide,N,N'Diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1-hydroxy-7-azobenzotriazol, 1-hydroxybenzotriazole, O- (7-azobenzotriazol) -N,N,N',N'Tetramethyluronium hexafluorophosphate and benzotriazole-N,N,N',N'One or a combination of two or more of tetramethylurea hexafluorophosphate; the solvent is selected from methanol, ethanol, propanol, isopropanol, acetonitrile, 1, 4-dioxane, dichloroethane, methanol, ethanol, isopropanol, ethanol,N,N-dimethylformamide,N,N-diisopropylethylamine, one or a combination of two or more of water; the reaction temperature is 0-130 ℃; the reaction time is 6-24 hours; the amine compound isN,NDiisopropylethane-1, 2-diamine, 2- (pyrrolidin-1-yl) ethyl-1-amine, n-butylamine,N,N-a mixture of (a) and (b) dimethyl ethylene diamine,N,Ndiethylethylenediamine, cyclopropylamine, methyl 3-aminopropionate, 2, 2-dimethoxyethane-1-amine,N-Boc-1, 4-butanediamine, 2- (methylsulfonyl) amideYl) ethan-1-amine.

Wherein R isN,NDiisopropylethane-1, 2-diamine, 2- (pyrrolidin-1-yl) ethyl-1-amine, n-butylamine,N, Ndimethylethylenediamine, N, N-diethylethylenediamine, cyclopropylamine, methyl 3-aminopropionate, 2, 2-dimethoxyethane-1-amine,N-tert-butyloxycarbonyl-1, 4-butanediamine, amino corresponding to 2- (methylsulfonyl) ethan-1-amine.

In a second aspect of the present invention, a pharmaceutical composition comprises a compound represented by formula I in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

In a third aspect of the present invention, there is provided a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for use in:

(i) preparing an alpha-glycosidase inhibitor;

(ii) preparing the medicine for preventing and/or treating diabetes related diseases.

Pharmaceutically acceptable carriers must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof, and generally suitable carriers, diluents and excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the mode and purpose of administration of the compounds of the invention. The solvent is generally selected based on the solvents (GRAS) that one of skill in the art would consider safe for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents (such as water) and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400 or PEG300), and the like, and mixtures thereof. One or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, slip agents, processing aids, colorants, sweeteners, flavorants, flavoring agents and other known additives that provide a tailored appearance to the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) or aid in the manufacture of the drug product (i.e., for use in the preparation of a medicament) may also be included.

Advantageous effects

The compound can inhibit alpha-glycosidase and can be used for preparing medicaments for preventing and/or treating diabetes and other related diseases.

Detailed Description

The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.

The inventor conducts selective oxidation on the oleanolic acid, and then conducts a carboxyl amine reaction on different aminoalkane compounds to obtain a novel compound which has a similar structure and alpha-glycosidase inhibitory activity and is shown in a general formula I, and the novel compound can effectively inhibit the alpha-glycosidase activity. On the basis of this, the present invention has been completed.

Detailed description of the preferred embodiments

The present invention will be described in further detail with reference to specific examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention.

EXAMPLE 1 preparation of the Compound of formula 2

Oleanolic acid (456.7 mg,1 mmol,1 eq) was dissolved in 15 mL of dimethyl sulfoxide, 2-iodoxybenzoic acid (IBX, 1.2g, 3.5mmol, 3.5 eq) was added, and the reaction was carried out at 85 ℃ for 8 hours. The reaction solution was diluted with two times the volume of ether, extracted with water, an aqueous sodium hydrogencarbonate solution and saturated brine several times, and the ether phase was retained and dried over anhydrous magnesium sulfate for two hours. Finally, the compound of the formula 2 is obtained by column chromatography separation.

The compound of formula 2 was obtained as a pale yellow solid in 81% yield.¹H NMR (600 MHz, Chloroform-d) 7.02 (d, J = 10.1 Hz, 1H), 5.79 (d, J = 10.1 Hz, 1H), 5.33 (t, J = 3.7 Hz, 1H), 2.84 (dd, J = 13.9, 4.6 Hz, 1H), 1.19 – 1.11 (m, 12H), 1.06 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.83 (s, 3H).¹³C NMR (151 MHz, CDCl₃) 205.43, 184.42, 159.17, 144.18, 125.21, 122.03, 77.19, 53.49, 46.75, 45.76, 44.66, 42.07, 41.86, 41.27, 40.18, 39.62, 33.91, 33.20, 32.52, 32.48, 30.81, 27.90, 27.76, 25.98, 23.69, 23.43, 22.95, 21.72, 18.96, 18.82, 17.67. ESI-MS m/z 452.3[M-H]^-。

EXAMPLE 2 preparation of Compounds of formula I

The compound of formula 2 (0.2 mmol,1 equiv.) is dissolved in 5mL of dichloromethane, and O- (7-azobenzotriazole) is addedN,N, N',N'Tetramethyluronium hexafluorophosphate (83.7mg,0.22mmol,1.1 equiv.), the corresponding amino compound (0.22 mmol,1.1 equiv.), and N, N-diisopropylethylamine (661. mu.L, 0.8 mmol, 4 equiv.). The reaction mixture was stirred at room temperature overnight, 15 mL of water was added, and the mixture was extracted with ethyl acetate (3X 15 mL). And combining organic phases, drying the organic phases by anhydrous magnesium sulfate, filtering the organic phases, concentrating the organic phases to obtain residues, and separating and purifying the residues by silica gel chromatography to obtain the corresponding compounds in the general formula I. The compound number, the specific structural formula and the raw materials are shown in the following table 1.

Table 1 specific structural formula of compound of general formula I, raw materials used

The compound of formula I-1 was obtained as a yellow solid in 58.8% yield.¹H NMR (600 MHz, DMSO-d6) 7.15 (d, J = 10.1 Hz, 1H), 5.71 (d, J = 10.1 Hz, 1H), 5.28 (t, J = 3.7 Hz, 1H), 2.17 (dt, J = 18.0, 5.1 Hz, 1H), 1.75 (dd, J = 11.5, 6.0 Hz, 1H), 1.10 (d, J = 2.9 Hz, 6H), 1.05 (s, 3H), 0.99 (s, 3H), 0.87 (d, J = 5.7 Hz, 6H), 0.78 (s, 3H). ¹³C NMR (151 MHz, DMSO) 204.21, 176.70, 159.87, 144.76, 124.87, 121.56, 54.87, 54.00, 53.24, 46.25, 45.80, 44.30, 42.06, 41.72, 41.31, 38.70, 38.17, 34.06, 33.33, 33.05, 32.49, 30.88, 27.96, 27.30, 25.94, 23.93, 23.55, 23.20, 22.83, 21.84, 18.86, 17.63. ESI-MS m/z 548.4[M-H]^-。

The compound of formula I-2 was obtained as a white solid in 69.3% yield.¹H NMR (600 MHz, CDCl₃) 7.01 (d, J = 10.1 Hz, 1H), 5.90 – 5.83 (m, 1H), 5.80 (d, J = 10.1 Hz, 1H), 5.43 (t, J = 3.6 Hz, 1H), 3.39 – 3.31 (m, 1H), 3.04 (dtd, J = 13.4, 7.2, 4.6 Hz, 1H), 2.58 – 2.52 (m, 1H), 1.97 (td, J = 13.7, 3.8 Hz, 1H), 1.86 (dd, J = 11.3, 6.2 Hz, 1H), 1.76 (t, J = 13.4 Hz, 1H), 1.67 (d, J = 1.5 Hz, 2H), 1.45 (p, J = 7.3 Hz, 2H), 1.18 – 1.14 (m, 9H), 1.09 (s, 3H), 0.94 (s, 1H), 0.92 (s, 1H), 0.91 (d, J = 3.1 Hz, 6H), 0.86 (s, 3H). 1H NMR (600 MHz, CDCl₃) 7.01 (d, J = 10.2 Hz, 1H), 5.90 – 5.83 (m, 1H), 5.80 (d, J = 10.1 Hz, 1H), 5.43 (t, J = 3.6 Hz, 1H), 3.39 – 3.31 (m, 1H), 3.04 (dtd, J = 13.4, 7.2, 4.6 Hz, 1H), 2.58 – 2.52 (m, 1H), 1.97 (td, J = 13.7, 3.8 Hz, 1H), 1.86 (dd, J = 11.3, 6.2 Hz, 1H), 1.76 (t, J = 13.4 Hz, 1H), 1.67 (d, J = 1.5 Hz, 2H), 1.45 (p, J = 7.3 Hz, 2H), 1.18 – 1.14 (m, 9H), 1.09 (s, 3H), 0.94 (s, 1H), 0.92 (s, 1H), 0.91 (d, J = 3.1 Hz, 6H), 0.86 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) 205.33, 177.94, 158.80, 145.82, 125.32, 121.94, 53.46, 46.70, 46.46, 44.70, 42.64, 42.59, 41.86, 40.27, 39.51, 39.33, 34.27, 33.14, 32.72, 32.35, 31.65, 30.88, 27.91, 27.42, 25.81, 23.85, 23.71, 23.58, 21.77, 20.41, 18.99, 18.81, 17.51, 13.95. ESI-MS m/z 507.4[M-H]^-。

The compound of formula I-3 was obtained as a pale yellow solid in 43.2% yield.¹H NMR (600 MHz, CDCl₃) 7.01 (d, J = 10.1 Hz, 1H), 6.55 (t, J = 4.6 Hz, 1H), 5.79 (dd, J = 10.1, 1.4 Hz, 1H), 5.40 (t, J = 3.6 Hz, 1H), 3.39 – 3.31 (m, 1H), 3.17 (ddd, J = 11.4, 5.8, 2.9 Hz, 1H), 2.57 (dd, J = 13.3, 4.3 Hz, 1H), 2.41 (t, J = 6.0 Hz, 2H), 1.84 (dd, J = 11.4, 6.0 Hz, 1H), 1.17 – 1.13 (m, 10H), 1.08 (d, J = 1.5 Hz, 3H), 0.90 (d, J = 5.2 Hz, 6H), 0.87 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) 205.31, 178.20, 158.89, 145.01, 125.25, 122.16, 57.81, 53.55, 53.44, 46.52, 46.49, 45.30, 44.66, 42.57, 42.46, 41.81, 40.28, 39.45, 36.91, 34.27, 33.14, 32.75, 32.44, 30.83, 27.89, 27.44, 25.70, 23.69, 23.67, 23.57, 21.73, 18.97, 18.79, 17.51. ESI-MS m/z 522.4[M-H]^-。

The compound of formula I-4 was obtained as a yellow oil in 43.8% yield.¹H NMR (600 MHz, CDCl₃) 7.01 (d, J = 10.1 Hz, 1H), 5.79 (d, J = 10.1 Hz, 1H), 5.41 (t, J = 3.7 Hz, 1H), 3.47 (dd, J = 13.7, 5.9 Hz, 1H), 3.12 (s, 1H), 1.96 (td, J = 13.7, 3.9 Hz, 1H), 1.85 (dd, J = 11.2, 6.4 Hz, 1H), 1.73 (t, J = 13.4 Hz, 1H), 1.38 – 1.32 (m, 2H), 1.17 – 1.12 (m, 10H), 1.07 (s, 9H), 0.90 (d, J = 4.5 Hz, 6H), 0.83 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) 205.34, 177.90, 158.90, 145.13, 125.24, 121.96, 53.45, 51.68, 46.98, 46.63, 46.45, 44.66, 42.36, 42.24, 41.86, 40.25, 39.53, 36.52, 34.26, 33.15, 32.83, 32.31, 30.85, 27.86, 27.46, 25.85, 23.58, 23.49, 21.74, 18.98, 18.75, 17.42. ESI-MS m/z 550.8[M-H]^-。

The compound of formula I-5 was obtained as a white solid in 58.9% yield.¹H NMR (600 MHz, CDCl₃) 7.01 (d, J = 9.3 Hz, 1H), 5.96 (s, 1H), 5.80 (d, J = 9.3 Hz, 1H), 5.40 (s, 1H), 2.64 (d, J = 3.8 Hz, 1H), 2.54 – 2.46 (m, 1H), 1.97 (td, J = 13.7, 3.8 Hz, 1H), 1.55 (t, J = 12.9 Hz, 6H), 1.22 – 1.04 (m, 15H), 0.94 – 0.85 (m, 9H), 0.50 – 0.34 (m, 2H). ¹³C NMR (151 MHz, CDCl₃) 205.17, 179.42, 158.65, 145.48, 125.18, 121.89, 77.23, 77.02, 76.81, 53.31, 46.50, 46.14, 44.55, 42.42, 42.36, 41.71, 40.16, 39.36, 34.07, 32.98, 32.44, 32.21, 30.72, 27.76, 27.25, 25.65, 23.71, 23.56, 23.42, 22.65, 21.63, 18.84, 18.68, 17.36, 6.71, 6.08. ESI-MS m/z 491.3[M-H]^-。

The compound of formula I-6 was obtained as a pale yellow solid in 66.5% yield.¹H NMR (600 MHz, CDCl₃) 7.01 (d, J = 10.1 Hz, 1H), 6.46 (t, J = 6.0 Hz, 1H), 5.80 (d, J = 10.1 Hz, 1H), 5.43 (t, J = 3.6 Hz, 1H), 3.70 (s, 3H), 3.58 (dd, J = 12.9, 6.0 Hz, 1H), 3.40 (dd, J = 13.5, 7.7 Hz, 1H), 2.56 (dt, J = 13.1, 3.1 Hz, 1H), 2.51 (dt, J = 6.6, 5.0 Hz, 2H), 2.14 (dd, J = 6.3, 4.2 Hz, 1H), 2.10 (dd, J = 11.3, 3.1 Hz, 1H), 1.97 (td, J = 13.7, 3.9 Hz, 1H), 1.87 – 1.83 (m, 1H), 1.17 – 1.13 (m, 9H), 1.08 (s, 3H), 0.90 (d, J = 2.4 Hz, 6H), 0.83 (s, 3H).¹³C NMR (151 MHz, CDCl₃) 205.33, 177.98, 173.39, 158.87, 144.88, 125.29, 122.33, 53.45, 51.86, 46.55, 44.68, 42.45, 42.39, 41.84, 40.29, 39.50, 34.77, 34.23, 33.89, 33.14, 32.86, 32.39, 30.85, 27.90, 27.41, 25.81, 23.69, 23.67, 23.54, 21.76, 18.98, 18.80, 17.52. ESI-MS m/z 537.4[M-H]^-。

The compound of formula I-7 was a dark green solid in 28.7% yield.¹H NMR (600 MHz, Chloroform-d) 7.01 (d, J = 10.1 Hz, 1H), 6.12 – 6.06 (m, 1H), 5.80 (d, J = 10.1 Hz, 1H), 5.43 (t, J = 3.5 Hz, 1H), 4.37 – 4.32 (m, 1H), 3.53 (ddd, J = 13.6, 6.4, 4.8 Hz, 1H), 3.39 (d, J = 8.3 Hz, 6H), 3.18 (ddd, J = 13.6, 6.2, 4.9 Hz, 1H), 2.58 (dd, J = 13.2, 4.9 Hz, 1H), 1.18 – 1.14 (m, 9H), 1.09 (s, 3H), 0.91 (d, J = 2.2 Hz, 6H), 0.86 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) 205.32, 178.21, 158.84, 145.25, 125.29, 122.17, 102.96, 77.37, 77.16, 76.95, 54.70, 54.65, 53.47, 46.61, 46.55, 44.69, 42.53, 42.51, 41.85, 41.19, 40.29, 39.48, 34.25, 33.13, 32.77, 32.41, 30.86, 27.89, 27.42, 25.77, 23.84, 23.68, 23.58, 21.76, 18.98, 18.81, 17.47. ESI-MS m/z 539.4[M-H]^-。

The compound of formulae 1-8 was obtained as a white solid in 71.3% yield.¹H NMR (600 MHz, Chloroform-d) 8.69 (d, J = 4.5 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.4, 4.4 Hz, 1H), 7.02 (d, J = 10.0 Hz, 1H), 5.80 (d, J = 10.0 Hz, 1H), 5.42 (q, J = 5.0, 3.8 Hz, 1H), 2.98 (dd, J = 13.9, 4.8 Hz, 1H), 1.85 (dd, J = 10.9, 6.3 Hz, 1H), 1.16 (d, J = 8.1 Hz, 6H), 1.10 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) 205.42, 173.46, 159.17, 151.71, 142.79, 140.97, 135.17, 129.42, 125.19, 123.22, 120.82, 53.62, 47.69, 45.51, 44.71, 42.43, 42.02, 41.89, 40.43, 39.56, 33.83, 33.09, 32.73, 32.23, 30.79, 28.19, 27.93, 25.79, 23.66, 23.53, 23.40, 21.79, 19.06, 18.86, 17.62。

The compound of formula I-9 was obtained as a pale yellow solid in 72.6% yield.¹H NMR (600 MHz, CDCl₃) 7.01 (d, J = 10.1 Hz, 1H), 5.96 (t, J = 5.5 Hz, 1H), 5.80 (d, J = 10.1 Hz, 1H), 5.44 (d, J = 3.5 Hz, 1H), 4.68 – 4.55 (m, 1H), 3.37 (dq, J = 13.0, 6.6 Hz, 1H), 3.12 (d, J = 6.6 Hz, 2H), 2.57 (dd, J = 13.1, 4.3 Hz, 1H), 1.43 (s, 9H), 1.18 – 1.13 (m, 9H), 1.08 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) 205.31, 178.11, 158.80, 156.12, 145.69, 125.30, 121.99, 79.28, 53.44, 46.65, 46.45, 44.68, 42.53, 42.46, 41.84, 40.26, 39.51, 39.25, 34.24, 33.13, 32.76, 32.32, 30.87, 28.55, 27.89, 27.84, 27.40, 26.88, 25.81, 23.81, 23.73, 23.55, 21.75, 18.97, 18.81, 17.53. ESI-MS m/z 622.5[M-H]^-。

The compound of formula I-10 was obtained as a white solid in 64.2% yield.¹H NMR (600 MHz, CDCl₃) 7.01 (d, J = 10.2 Hz, 1H), 6.60 (t, J = 5.8 Hz, 1H), 5.80 (d, J = 10.2 Hz, 1H), 5.45 (t, J = 3.7 Hz, 1H), 4.11 (q, J = 7.1 Hz, 1H), 3.89 (dtd, J = 14.7, 6.4, 4.8 Hz, 1H), 3.58 (ddt, J = 14.7, 8.2, 4.8 Hz, 1H), 3.25 (ddd, J = 13.4, 8.2, 4.9 Hz, 1H), 3.17 (ddd, J = 14.2, 6.4, 4.7 Hz, 1H), 2.95 (s, 3H), 2.03 (s, 1H), 1.85 (dd, J = 10.8, 6.7 Hz, 1H), 1.25 (t, J = 7.1 Hz, 2H), 1.16 (d, J = 5.3 Hz, 6H), 1.14 (s, 3H), 1.08 (s, 3H), 0.91 (d, J = 4.5 Hz, 5H), 0.85 (s, 2H). ¹³C NMR (151 MHz, CDCl₃) 205.29, 178.63, 158.82, 144.50, 125.26, 122.80, 54.00, 53.44, 46.57, 46.46, 44.66, 42.35, 42.11, 41.84, 41.59, 40.34, 39.50, 34.17, 33.23, 33.10, 32.68, 32.30, 30.83, 27.84, 27.38, 25.86, 23.74, 23.64, 23.49, 21.75, 18.96, 18.77, 17.54. ESI-MS m/z 557.4[M-H]^-。

EXAMPLE 3 inhibition Rate and inhibitory Activity of Compounds on alpha-glycosidase

Alpha-glucosidase was purchased from Sigma, p-nitrophenyl-alpha-D-glucoside (PNPG) as substrate was purchased from Aladdin, and sodium salt and phosphate salt required for buffer preparation and quencher were purchased from Shanghai Michelin Biotech, Inc. The alpha-glycosidase inhibitory activity is determined by reference to published reported methods. After 99. mu.L of PBS phosphate buffer (pH 6.8) was added to each well of the 96-well plate, 20 mmol of 1. mu.L of the test compound solution or a blank was added to the corresponding well, 25. mu.L of the alpha-glucosidase solution was added thereto, and the plate was incubated at 37 ℃ for 15 min with shaking. Adding 25 mu L of PNPG solution, placing the PNPG solution in a shaking table at 37 ℃ for incubation for 15 min, then adding 50 mu L of 0.2M sodium carbonate solution, measuring the absorbance at 405nm by using an enzyme-labeling instrument, and calculating the inhibition rate of the compound to be detected on alpha-glycosidase. The concentration of part of the compound was measured again at different gradients in 10, and the IC of the compound was determined from the inhibition curve₅₀Value (concentration of inhibitor at 50% inhibition of enzyme activity).

Experimental results show that the synthetic compound has good inhibitory activity on alpha-glycosidase. Wherein the compound of formula 2 has the strongest alpha-glucosidase inhibitory activity, IC₅₀The value was 13.35. + -. 0.77. mu.M.

The preparation steps, identification process and screening for α -glucosidase inhibitory activity of the compounds of the present invention are illustrated in the specific examples above, but those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims

1. An oleanolic acid derivative characterized by having a structure represented by the following general formula I:

wherein R isN,NDiisopropylethane-1, 2-diamine, 2- (pyrrolidin-1-yl) ethyl-1-amine, n-butylamine,N,N-a mixture of (a) and (b) dimethyl ethylene diamine,N,Ndiethyl ethylenediamine, cyclopropylamine, methyl 3-aminopropionate, 2, 2-dimethoxyethane-1-amine, N-tert-butoxycarbonyl-1, 4-butanediamine, 2- (methylsulfonyl) ethane-1-amine.

2. Use of the oleanolic acid derivative of claim 1 for the preparation of an antidiabetic agent.

3. A medicament for preventing and/or treating diabetes, characterized in that it is prepared from the derivative as claimed in claim 1 as an active ingredient or a main active ingredient, together with pharmaceutically acceptable adjuvants.