Polyhydroxy imine glycation compounds having alpha-glucosidase inhibitory activity and methods of making the same

Abstract

The application belongs to the field of organic chemistry and particularly relates to a kind of polyhydroxy imine sugar compounds with alpha-glucosidase inhibitory activity and a preparation method thereof.The specific technical scheme is: a kind of polyhydroxy imine sugar compounds, the structural general formula of the polyhydroxy imine sugar compounds is: the application provides a series of new polyhydroxy imine sugar compounds, has sugar analogue structure, can simulate the process of sugar hydrolysis, and is combined with enzyme competitively, so as to achieve the effect of inhibiting glucosidase.The application widens the selection range of alpha-glucosidase inhibitors, and has good pharmaceutical potential.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemistry, and particularly relates to a kind of polyhydroxy imine sugar compounds with α-glucosidase inhibitory activity and a preparation method thereof. BACKGROUND

[0002] In human body, the mixture produced after initial digestion of starch is hydrolyzed into glucose under the action of α-glucosidase on the brush border of small intestinal epithelial cells. By inhibiting the activity of α-glucosidase, the absorption of glucose by the intestine can be delayed or prevented, thereby effectively reducing blood glucose levels. Therefore, α-glucosidase is considered to be a key enzyme for regulating postprandial blood glucose and an effective target for treating type 2 diabetes. In clinical practice, commonly used α-glucosidase inhibitors include acarbose, voglibose and miglitol. However, the synthesis of these α-glucosidase inhibitors is difficult, and there are some side effects, such as gastrointestinal intolerance, diarrhea and flatulence, which limit their clinical application.

[0003] Therefore, if a new class of compounds can be provided to achieve the effect of inhibiting glucosidase by competitive binding with the enzyme, it is expected to broaden the selection range of α-glucosidase inhibitors. SUMMARY

[0004] The purpose of the present application is to provide a class of polyhydroxy imine sugar compounds with α-glucosidase inhibitory activity and a preparation method thereof.

[0005] To achieve the above-mentioned purpose of the application, the technical solution adopted by the present application is as follows: a class of polyhydroxy imine sugar compounds, the structural general formula of the polyhydroxy imine sugar compounds is:

[0006]

[0007] R1 is 1-α-allyl or 1-β-allyl; R2 is α-OBn or β-OBn; R3 is H or CH2OBn;

[0008] R4 is

[0009] Preferably, the polyhydroxy imine sugar compound is any one of the following compounds 5a-5k, 10a-10b:

[0010]

[0011] Correspondingly, the preparation method of compounds 5a-5k corresponds to the following reaction equation:

[0012]

[0013] Preferably, the method comprises the following steps:

[0014] (1) Benzyl protection reaction: L-arabinose is used as a starting material, and a methyl glycoside product is obtained by glycosylation reaction. The crude product of the methyl glycoside is subjected to benzyl protection on the exposed hydroxyl group under the condition of sodium hydride, tetrabutylammonium iodide and benzyl bromide. The crude product of the fully protected imino sugar is dissolved in ice acetic acid and sulfuric acid, and the reaction system is heated to reflux to obtain compound 2.

[0015] (2) Hydroxylamination reaction: compound 2 is subjected to hydroxylamination reaction with benzylamine compound under the action of p-toluenesulfonic acid, and compound 3 is separated.

[0016] (3) Sugar ring opening reaction: compound 3 is subjected to ring opening by allyl magnesium bromide Grignard reagent to obtain compound 4.

[0017] (4) Ring closure reaction: compound 4 is subjected to ring closure reaction under the action of pyridine and methanesulfonyl chloride to obtain compound 5.

[0018] Correspondingly, the preparation method of compounds 10a-10b corresponds to the following reaction equation:

[0019]

[0020] Preferably, the preparation method comprises the following steps:

[0021] (1) Benzyl protection reaction: D-glucose is used as a starting material, and a methyl glycoside product is obtained by glycosylation reaction. The crude product of the methyl glycoside is subjected to benzyl protection on the exposed hydroxyl group under the condition of sodium hydride, tetrabutylammonium iodide and benzyl bromide. The crude product of the fully protected imino sugar is dissolved in ice acetic acid and sulfuric acid, and the reaction system is heated to reflux to obtain compound 7.

[0022] (2) Hydroxylamination reaction: compound 7 is subjected to hydroxylamination reaction with benzylamine compound under the action of p-toluenesulfonic acid, and compound 8 is separated.

[0023] (3) Sugar ring opening reaction: compound 8 is subjected to ring opening by allyl magnesium bromide Grignard reagent to obtain compound 9.

[0024] (4) Ring closure reaction: compound 9 is subjected to ring closure reaction under the action of pyridine and methanesulfonyl chloride to obtain compound 10.

[0025] Correspondingly, the application of the polyhydroxyl imino sugar compound or the polyhydroxyl imino sugar compound prepared by the method in non-disease diagnosis or treatment for inhibiting the activity of α-glucosidase.

[0026] Correspondingly, the application of the polyhydroxyl imino sugar compound or the polyhydroxyl imino sugar compound prepared by the method in non-disease diagnosis or treatment for inhibiting the activity of α-glucosidase.

[0027] Correspondingly, the medicine prepared by using the polyhydroxy imine sugar compound or the polyhydroxy imine sugar compound prepared by using the method is used for inhibiting the activity of alpha-glucosidase.

[0028] The present application has the following beneficial effects: the present application provides a series of new polyhydroxy imine sugar compounds, which have sugar analog structures and can simulate the process of sugar hydrolysis, compete with enzymes for binding, and thus achieve the effect of inhibiting glycosidase. The present application widens the selection range of alpha-glucosidase inhibitors and has good pharmaceutical potential. DETAILED DESCRIPTION

[0029] The present application provides a class of polyhydroxy imine sugar compounds, which have the following general structure:

[0030]

[0031] R1 is 1-alpha-allyl or 1-beta-allyl; R2 is alpha-OBn or beta-OBn; R3 is H or CH2OBn;

[0032] R4 is

[0033] The present application also provides a method for preparing the polyhydroxy imine sugar compound by using L-arabinose as a starting material, and the reaction equation of the preparation method is as follows:

[0034]

[0035] The numbers below the reaction equation are compound numbers, and the number 1 represents compound 1, which corresponds to the compound above the number, and the same applies here, and will not be repeated.

[0036] The specific preparation method includes the following steps, and the reaction basically does not proceed or the yield of the product is extremely low outside the following dosage relationship range:

[0037] First step: benzyl protection reaction (corresponding to step a in the reaction equation)

[0038] L-arabinose (compound 1) is used as a starting material to obtain a methyl glycoside product through a classic glycosylation reaction. The crude product is subjected to benzyl protection on the exposed hydroxyl group under the condition of sodium hydride, tetrabutylammonium iodide and benzyl bromide. The crude product of the fully protected imine sugar is dissolved in glacial acetic acid and 1M sulfuric acid, and the reaction system is heated to reflux to obtain a 1-position exposed hydroxyl compound 2.

[0039] The specific preparation method comprises the following steps: L-arabinose is dissolved in methanol, the reaction system is placed in an ice water bath, dichlorosulfide is slowly added dropwise, and the molar ratio of L-arabinose to dichlorosulfide is 1:0.35-1:0.47. After the addition is completed, the reaction system is heated to reflux. After the raw materials are completely reacted by thin layer chromatography, the reaction liquid is cooled to room temperature, sodium bicarbonate is slowly added for neutralization, filtration is performed, and the crude product is obtained by concentrating the filtrate.

[0040] The crude product is dissolved in N,N-dimethylformamide solvent, sodium hydride solid is added in batches under an ice water bath, after the addition is completed, the reaction is carried out at room temperature for 30-35 min, tetrabutylammonium iodide is added, and benzyl bromide is slowly added dropwise through a dropping funnel. The molar ratio of the crude product to sodium chloride, tetrabutylammonium iodide and benzyl bromide is 1:4:0.15:3.5-1:6:0.21:4.3. After the raw materials are completely reacted by thin layer chromatography, the reaction liquid is slowly poured into a cold saturated ammonium chloride solution for quenching, the reaction system is extracted with ethyl acetate and water, the organic phase is washed with saturated brine and dried with anhydrous sodium sulfate, and the yellow viscous slurry of the crude product is obtained by concentrating the filtrate.

[0041] The crude product is dissolved in 1,4-dioxane, 1M H2SO4-AcOH-dioxane is added to the reaction system, and the volume ratio of the three is 1:1:1-1:1.4:1.2. After the addition is completed, the reaction system is heated to reflux. After the raw materials are completely reacted by thin layer chromatography, the reaction system is naturally cooled to room temperature, n-hexane and water are added and stirred vigorously, and the volume ratio of n-hexane to water is 1:7-1:9. The white solid of compound 2 is collected by filtration.

[0042] The second step is a hydroxylamination reaction (corresponding to step b in the reaction equation).

[0043] Compound 2 reacts with different substituted benzylamine compounds under the action of p-toluenesulfonic acid to realize a hydroxylamination reaction, and compound 3 is separated.

[0044] The specific preparation method comprises the following steps: compound 2 (mmol) is dissolved in anhydrous dichloromethane (mL), p-toluenesulfonic acid (mmol) and benzylamine (mmol) are slowly added, and the amount ratio is 1:0.8:1:1.6-1:1.2:1.2:3.4. The reaction liquid is stirred at room temperature. After the raw materials are completely reacted by thin layer chromatography, dichloromethane is added, the organic phase is collected, washed with saturated sodium carbonate solution, dried with magnesium sulfate, and concentrated under vacuum to obtain compound 3.

[0045] The third step is a sugar ring opening reaction (corresponding to step c in the reaction equation).

[0046] Compound 3 is opened by allyl magnesium bromide Grignard reagent to obtain chain compound 4.

[0047] The specific preparation method comprises the following steps: compound 3 is dissolved in tetrahydrofuran, and allyl magnesium bromide Grignard reagent is slowly added dropwise under an ice water bath, and the volume ratio of compound 3 to allyl magnesium bromide Grignard reagent is 1:2.5-1:3.7. After the reaction system is left overnight, whether the raw material is completely reacted is judged by thin layer chromatography, the reaction is quenched by ice water, the filtrate is collected by filtration, and after concentration under reduced pressure, column chromatography is adopted to separate to obtain compound 4.

[0048] The fourth step is a ring closing reaction (corresponding to step d in the reaction equation)

[0049] Compound 4 is used to synthesize N-aryl substituted iminosugar product 5 under the action of pyridine and methanesulfonyl chloride. The synthesis route is shorter, and two kinds of iminosugar products with different stereoconfigurations can be obtained respectively. Compound 5 is the required polyhydroxyl iminosugar compound.

[0050] The specific preparation method comprises the following steps: compound 4 is dissolved in pyridine under anhydrous conditions. Methanesulfonyl chloride is slowly added dropwise into the reaction system under an ice water bath, and then Molecular sieves are added, and the molar ratio of compound 4 to methanesulfonyl chloride is 1:2-1:3. The whole reaction system is heated to 95-105 DEG C. After the raw material is completely consumed, the filtrate is collected by filtering through diatomite, and the filter cake is washed with ethyl acetate. The organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, the filtrate is concentrated under reduced pressure, and column chromatography is adopted to separate to obtain compound 5.

[0051] According to the selection of different R groups, the synthesized compound 5 is as follows:

[0052]

[0053] In order to obtain N-aryl substituted iminosugar compounds with different hydroxyl configurations, the application further provides a preparation method of polyhydroxyl iminosugar compounds taking D-glucose as a starting material, and the reaction equation of the preparation method is as follows:

[0054]

[0055] The specific preparation method is the same as the first preparation method, except that the starting material L-arabinose is replaced by D-glucose. Finally, the polyhydroxyl iminosugar compound 10 is prepared, and according to the different R groups, the synthesized compound 10 is as follows:

[0056]

[0057] The corresponding relationship between each polyhydroxyl iminosugar compound and the substituent group is shown in Table 1.

[0058] Table 1 is a relationship table of compounds and substituent groups.

[0059]

[0060]

[0061] The synthetic polyhydroxy imine sugar compounds (series compound 5, series compound 10) of the present application have α-glucosidase inhibitory activity.

[0062] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present application but not all the embodiments. If not specifically indicated, the technical means used in the embodiments are the conventional means familiar to those skilled in the art. The obtained data are all average values obtained after at least three repetitions, and the data obtained in each repetition are all valid data.

[0063] Embodiment one: preparation of polyhydroxy imine sugar compounds using L-arabinose as a starting material

[0064] L-arabinose (25 g, 0.17 mol) was dissolved in methanol (250 mL), the reaction system was placed in an ice water bath, and dichlorosulfoxide (5 mL, 0.069 mol) was slowly added dropwise. After the addition was completed, the reaction system was heated to reflux for 4 h. After the completion of the reaction of the raw material was determined by thin layer chromatography, the reaction solution was cooled to room temperature, sodium bicarbonate solid (17.5 g, 0.21 mol) was slowly added for neutralization, filtered, and the filtrate was concentrated to obtain a crude product.

[0065] The crude product was dissolved in N,N-dimethylformamide solvent, and sodium hydride solid (34 g, 0.85 mol) was added in batches (1 g per batch, with an interval of 2 min) under an ice water bath. After the addition was completed, the reaction was carried out at room temperature for 30 min, and tetrabutylammonium iodide (11 g, 0.03 mol) was added. Benzyl bromide (72.5 mL, 0.61 mol) was slowly added dropwise through a dropping funnel, and the reaction was carried out overnight. After the completion of the reaction of the raw material was determined by thin layer chromatography, the reaction solution was slowly poured into a cold saturated ammonium chloride solution for quenching, and the reaction system was extracted with ethyl acetate (400 mL) and water (400 mL). After the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, the filtrate was concentrated to obtain a yellow sticky slurry of a crude product.

[0066] The crude product was dissolved in 1,4-dioxane, 1M H2SO4(210 mL)-AcOH (240 mL)-dioxane (220 mL) was added to the reaction system, after the addition was completed, the reaction system was heated to reflux for 10 h. After the raw material was completely reacted by thin layer chromatography, the reaction system was naturally cooled to room temperature, then n-hexane (100 mL) and water (800 mL) were added and stirred vigorously, and white solid was collected by filtration. Compound 2 (50.7 g, 71%) was obtained.

[0067] Compound 2 (1.95 g, 4.64 mmol) was dissolved in anhydrous dichloromethane (4.7 mL), p-toluenesulfonic acid (0.81 g, 4.70 mmol) and benzylamine (1.04 mL, 9.48 mmol) were slowly added, and the reaction solution was stirred at room temperature for 20 h. After the raw material was completely reacted by thin layer chromatography, dichloromethane (100 mL) was added, the organic phase was collected, washed twice with saturated sodium carbonate solution (200 mL), dried over magnesium sulfate, and concentrated under vacuum to obtain the crude product of compound 3. The crude product of compound 3 was dissolved in tetrahydrofuran, and allyl magnesium bromide Grignard reagent (13.9 mL, 13.9 mmol) was slowly added dropwise under an ice water bath. After the reaction system was allowed to stand overnight, the raw material was completely reacted by thin layer chromatography, the reaction was quenched with ice water, the filtrate was collected by filtration, and concentrated under reduced pressure. Compound 4 was separated by column chromatography. Compound 4 (1.804 g, 3.0 mmol) was dissolved in pyridine (45 mL) under anhydrous conditions. Methylsulfonyl chloride (0.58 mL, 7.49 mmol) was slowly added dropwise to the reaction system under an ice water bath, followed by the addition of Molecular sieves (200 mg). The reaction system was heated to 100°C for 4 h. After the raw material was completely consumed by thin layer chromatography, the filtrate was collected by filtration with diatomite, and the filter cake was rinsed with ethyl acetate (200 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 5 was separated by silica gel column chromatography.

[0068] The structural formula of compound 5a is: The nuclear magnetic resonance hydrogen spectrum and carbon spectrum data are as follows.

[0069] 5a: Colorless syrup, yield 43%. 1H NMR (400 MHz, CDC13) δ 7.49 - 7.31 (m, 17 H), 7.06 (t, J = 8.7 Hz, 2 H), 6.08 - 5.95 (m, 1 H), 5.21 - 5.02 (m, 2 H), 4.81 - 4.51 (m, 6 H), 4.37 - 4.25 (m, 2 H), 3.97 (q, J = 14.1 Hz, 2 H), 3.76 (dd, J = 9.9, 4.4 Hz, 1 H), 3.63 - 3.35 (m, 3 H), 2.54 (dt, J = 14.1, 6.9 Hz, 1 H), 2.45 - 2.29 (m, 1 H). 13 CNMR (100 MHz, CDC13) δ 163.03, 160.60, 138.88, 138.69, 138.58, 137.65, 135.86, 135.83, 129.90, 129.82, 128.39, 128.37, 127.75, 127.57, 127.57, 127.54, 127.48, 115.97, 115.04, 114.83, 83.79, 83.54, 73.45, 72.74, 72.63, 67.71, 61.63, 59.88, 52.12, 32.82. HRMS (ESI): m / z calcd for C 36 H 38 FNO3, [M + Na] + : 574.2728; found 574.2721.

[0070] The structural formula of compound 5b is: The nuclear magnetic resonance hydrogen spectrum and carbon spectrum data are as follows.

[0071] 5b: Colorless syrup, yield 27%. 1 H NMR (400 MHz, CDC13) δ 7.48 - 7.20 (m, 17 H), 7.14 - 6.86 (m, 2 H), 6.11 - 6.02 (m, 1 H), 5.34 - 5.02 (m, 2 H), 5.05 - 4.90 (m, 1 H), 4.56 (dddd, J = 35.2, 27.6, 17.6, 8.3 Hz, 5 H), 4.15 (d, J = 13.3 Hz, 1 H), 4.04 - 3.73 (m, 3 H), 3.62 (dd, J = 7.6, 2.9 Hz, 1 H), 3.23 (d, J = 13.2 Hz, 1 H), 3.04 (dd, J = 12.8, 5.1 Hz, 1 H), 2.80 - 2.49 (m, 2 H), 2.33 - 1.94 (m, 1 H). 13C NMR (100 MHz, CDC13) δ 160.77, 138.90, 138.63, 138.59, 138.46, 135.36, 135.15, 135.12, 130.33, 130.26, 128.40, 128.34, 127.89, 127.79, 127.58, 127.54, 127.44, 116.91, 114.88, 114.76, 73.39, 71.72, 71.41, 71.28, 70.17, 69.04, 65.85, 56.18, 31.52. HRMS (ESI): m / z calcd for C 36 H 38 FNO3, [M + Na] + : 574.2728; found 574.2731.

[0072] The structural formula of compound 5c is: Nuclear magnetic resonance hydrogen spectrum and carbon spectrum data are as follows.

[0073] 5c: Colorless syrup, yield 31%. 1 H NMR (400 MHz, CDC13) δ 7.47-7.25 (m, 16H), 7.23-7.09 (m, 3H), 5.98-5.68 (m, 1H), 5.16-4.96 (m, 2H), 4.79-4.38 (m, 6H), 3.95 (d, J = 13.7 Hz, 2H), 3.84 (dd, J = 6.5, 3.1 Hz, 1H), 3.75 (dd, J = 6.7, 2.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 3.19-3.12 (m, 1H), 2.79-2.65 (m, 2H), 2.48-2.40 (m, 2H), 2.34 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 139.10, 139.00, 138.72, 137.78, 137.32, 130.21, 129.57, 128.31, 128.29, 128.26, 127.67, 127.60, 127.47, 127.43, 127.41, 126.77, 125.49, 115.88, 73.73, 72.70, 72.53, 70.91, 60.32, 19.33. HRMS (ESI): m / z calcd for C 37 H 41 NO3, [M + Na] + : 570.2979; found 570.2970.

[0074] The structural formula of compound 5d is: The nuclear magnetic resonance hydrogen spectrum and carbon spectrum data are as follows.

[0075] 5d: Colorless syrup, yield 39%. 1 H NMR (400 MHz, CDC13) δ 7.45 - 7.27 (m, 16 H), 7.16 (td, J = 8.9, 5.0 Hz, 3 H), 5.97 - 5.83 (m, 1 H), 5.00 (dd, J = 17.6, 14.0 Hz, 2 H), 4.69 - 4.56 (m, 4 H), 4.53 - 4.42 (m, 2 H), 4.24 (q, J = 6.3 Hz, 2 H), 3.95 (dd, J = 33.1, 14.5 Hz, 2 H), 3.71 (dd, J = 9.8, 4.7 Hz, 1 H), 3.44 (ddd, J = 17.4, 10.2, 4.8 Hz, 3 H), 2.43 (dt, J = 14.2, 7.1 Hz, 1 H), 2.36 - 2.24 (m, 4 H). 13 C NMR (100 MHz, CDC13) δ 138.82, 138.69, 138.57, 137.86, 137.59, 136.68, 130.08, 128.85, 128.30, 127.61, 127.50, 127.47, 127.41, 127.38, 126.53, 125.57, 115.80, 83.93, 83.47, 73.37, 72.73, 72.55, 68.05, 61.98, 60.45, 50.95, 32.22, 19.36. HRMS (ESI): m / z calcd for: C 37 H 41 NO3, [M + Na] + : 570.2979; found 570.2972.

[0076] The structural formula of compound 5e is: The nuclear magnetic resonance hydrogen spectrum and carbon spectrum data are as follows.

[0077] 5e: Colorless syrup, yield 46%. 1H NMR (400 MHz, CDC13) δ 7.65 - 7.28 (m, 18H), 7.06 (t, J = 8.6 Hz, 2H), 6.09 - 5.96 (m, 1H), 5.12 (dd, J = 19.9, 13.9 Hz, 2H), 4.88 - 4.42 (m, 6H), 4.31 (dt, J = 25.0, 6.5 Hz, 2H), 3.97 (q, J = 14.1 Hz, 2H), 3.76 (dd, J = 9.9, 4.4 Hz, 1H), 3.63 - 3.36 (m, 3H), 2.58 - 2.33 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 163.03, 160.61, 138.89, 138.69, 138.59, 137.65, 135.87, 135.84, 129.90, 129.83, 128.40, 128.37, 127.76, 127.58, 127.57, 127.54, 127.49, 115.97, 115.05, 114.84, 83.79, 83.55, 73.45, 72.75, 72.64, 67.72, 61.64, 59.89, 52.13, 32.83. HRMS (ESI): m / z calcd for: C 37 H 38 F3NO3, [M + Na] + : 624.2696; found 624.2699.

[0078] The structural formula of compound 5f is: NMR data of hydrogen and carbon are as follows.

[0079] 5f: Colorless syrup, yield 61%. 1H NMR (400 MHz, CDC13) δ 7.48 - 7.20 (m, 17 H), 7.06 - 6.98 (m, 2 H), 6.03 (ddt, J = 13.6, 10.8, 6.7 Hz, 1 H), 5.34 - 5.06 (m, 2 H), 4.95 (d, J = 11.1 Hz, 1 H), 4.72 - 4.53 (m, 4 H), 4.37 (d, J = 12.5 Hz, 1 H), 4.13 (d, J = 13.3 Hz, 1 H), 3.92 (t, J = 7.7 Hz, 1 H), 3.78 - 3.73 (m, 1 H), 3.59 (dd, J = 7.9, 3.2 Hz, 1 H), 3.20 (d, J = 13.3 Hz, 1 H), 3.01 (dd, J = 12.8, 5.2 Hz, 1 H), 2.85 - 2.58 (m, 2 H), 2.53 (dt, J = 8.9, 4.6 Hz, 1 H), 2.00 (d, J = 12.5 Hz, 1 H). 13 C NMR (100 MHz, CDC13) δ 163.16, 160.73, 138.86, 138.59, 138.56, 135.32, 135.12, 135.09, 130.30, 130.22, 128.37, 128.31, 128.23, 127.85, 127.75, 127.62, 127.55, 127.51, 127.41, 116.88, 115.06, 114.85, 81.92, 74.40, 71.69, 71.38, 70.14, 63.41, 56.15, 49.86, 31.49. HRMS (ESI): m / z calcd for: C 37 H 38 F3NO3, [M + Na] + : 624.2696; found 624.2691.

[0080] The structural formula of compound 5g is: Nuclear magnetic resonance hydrogen spectrum and carbon spectrum data are as follows.

[0081] 5g: Colorless syrup, yield 38%. 1H NMR (400 MHz, CDC13) δ 7.49 - 7.05 (m, 19 H), 5.95 (ddd, J = 17.1, 7.0, 3.2 Hz, 1 H), 5.21 - 4.90 (m, 2 H), 4.74 - 4.41 (m, 6 H), 4.24 (dt, J = 23.2, 6.5 Hz, 2 H), 3.90 (q, J = 14.4 Hz, 2 H), 3.69 (dd, J = 9.9, 4.4 Hz, 1 H), 3.56 - 3.27 (m, 3 H), 2.46 (dd, J = 14.3, 7.1 Hz, 1 H), 2.39 - 2.18 (m, 1 H). 13 C NMR (100 MHz, CDC13) δ 139.31, 138.76, 138.56, 138.45, 137.49, 131.20, 130.08, 128.34, 128.33, 128.31, 127.70, 127.52, 127.48, 127.43, 120.24, 115.97, 83.66, 83.42, 73.40, 72.69, 72.58, 67.66, 61.58, 59.84, 52.18, 32.77. HRMS (ESI): m / z calcd for: C 36 H 38 BrNO3, [M + Na] + : 612.2108; found 612.2101.

[0082] The structure of compound 5h is: The nuclear magnetic resonance hydrogen spectrum and carbon spectrum data are as follows.

[0083] 5h: Colorless syrup, yield 24%. 1 H NMR (400 MHz, CDC13) δ 7.48 - 7.18 (m, 19 H), 6.06 - 5.67 (m, 1 H), 5.25 - 5.10 (m, 1 H), 4.99 - 4.90 (m, 1 H), 4.69 - 4.40 (m, 5 H), 4.15 - 3.95 (m, 1 H), 3.94 - 3.70 (m, 3 H), 3.53 (ddd, J = 14.2, 8.5, 4.1 Hz, 1 H), 3.27 (ddd, J = 38.6, 20.2, 9.3 Hz, 1 H), 3.05 - 2.79 (m, 1 H), 2.60 (ddd, J = 11.9, 10.3, 4.9 Hz, 2 H), 2.38 - 1.76 (m, 2 H). 13CNMR (100 MHz, CDC13) δ 138.82, 138.60, 138.40, 138.24, 135.72, 131.29, 130.47, 128.36, 128.32, 127.85, 127.74, 127.63, 127.52, 120.61, 116.92, 82.33, 73.37, 71.74, 71.26, 70.35, 69.26, 66.01, 57.86, 56.27, 31.50. HRMS (ESI): m / z calcd for: C 36 H 38 BrNO3, [M + Na] + : 612.2108; found 612.2101.

[0084] The structure of compound 5i is: NMR data of hydrogen and carbon are as follows.

[0085] 5i: Colorless syrup, yield 46%. 1 H NMR (400 MHz, CDC13) δ 7.49 - 7.22 (m, 19H), 6.00 - 5.85 (m, 1H), 5.04 - 4.95 (m, 2H), 4.74 - 4.39 (m, 6H), 4.23 (dt, J = 22.7, 6.5 Hz, 2H), 3.90 (q, J = 14.3 Hz, 2H), 3.74 - 3.66 (m, 1H), 3.54 - 3.30 (m, 3H), 2.51 - 2.39 (m, 1H), 2.35 - 2.22 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 138.77, 138.58, 138.47, 137.51, 132.16, 129.68, 128.34, 128.33, 128.30, 128.24, 127.70, 127.51, 127.47, 127.43, 115.94, 83.67, 83.43, 73.40, 72.68, 72.57, 67.67, 61.57, 59.85, 52.13, 32.75. HRMS (ESI): m / z calcd for: C 36 H 38 ClNO3, [M + Na] + : 590.2432; found 590.2429.

[0086] The structure of compound 5j is: NMR data of hydrogen and carbon are as follows.

[0087] 5j: Colorless syrup, yield 19%. 1 H NMR (400 MHz, CDC13) δ 7.38 - 7.31 (m, 19H), 6.18 - 5.89 (m, 1H), 5.16 (d, J = 12.4 Hz, 2H), 4.72 - 4.58 (m, 5H), 4.17 (d, J = 13.6 Hz, 1H), 3.92 (dd, J = 16.4, 8.9 Hz, 2H), 3.79 (dd, J = 14.2, 4.9 Hz, 2H), 3.61 (dd, J = 7.9, 3.1 Hz, 1H), 3.03 (dd, J = 12.8, 5.1 Hz, 1H), 2.76 - 2.66 (m, 2H), 2.45 (t, J = 6.6 Hz, 1H), 2.03 (d, J = 12.5 Hz, 1H). 13 CNMR (100 MHz, CDC13) δ 141.84, 138.85, 138.59, 135.24, 134.23, 129.50, 128.75, 128.41, 128.34, 128.28, 127.89, 127.76, 127.67, 127.13, 117.01, 84.27, 74.47, 72.84, 72.18, 71.69, 71.33, 70.26, 63.46, 56.37, 31.62. HRMS (ESI): m / z calcd for C 36 H 38 ClNO3, [M + Na] + : 590.2432; found 590.2431.

[0088] The structure of compound 5k is: The hydrogen and carbon magnetic resonance spectral data are as follows.

[0089] 5k: Colorless syrup, yield 62%. 1H NMR (400 MHz, CDC13) δ 7.39 - 7.27 (m, 19H), 6.01 (td, J = 16.7, 6.8 Hz, 1H), 5.24 - 5.08 (m, 2H), 4.94 (d, J = 11.1 Hz, 1H), 4.62 (ddd, J = 29.5, 14.7, 9.3 Hz, 4H), 4.39 (d, J = 12.4 Hz, 1H), 4.12 (d, J = 13.5 Hz, 1H), 3.91 (t, J = 7.5 Hz, 1H), 3.76 (s, 1H), 3.66 - 3.50 (m, 1H), 3.22 (d, J = 13.4 Hz, 1H), 3.00 (dd, J = 12.7, 5.2 Hz, 1H), 2.70 (s, 2H), 2.54 (d, J = 6.4 Hz, 1H), 2.03 (d, J = 12.4 Hz, 1H). 13 C NMR (100 MHz, CDC13) δ 138.82, 138.58, 138.07, 135.30, 132.53, 130.09, 128.38, 128.32, 128.25, 127.85, 127.75, 127.62, 127.55, 127.42, 127.18, 116.90, 109.49, 81.81, 74.36, 71.73, 71.52, 70.31, 63.35, 56.22, 49.95, 42.62, 31.51. HRMS (ESI): m / z calcd for C 36 H 38 ClNO3, [M + Na] + : 590.2432; found 590.2431.

[0090] Example Two: Preparation of polyhydroxyl imine saccharide compound using D-glucose as starting material

[0091] Compound 10 was prepared according to the procedure of Example One, except that the starting material was changed to D-glucose.

[0092] D-glucose (compound 6, 31 g, 0.17 mol) was dissolved in methanol (250 mL), the reaction system was placed in an ice water bath, and dichlorosulfoxide (5 mL, 0.069 mol) was slowly added dropwise. After the addition was completed, the reaction system was heated to reflux for 4 h. After the reaction was completed as judged by thin layer chromatography, the reaction solution was cooled to room temperature, sodium bicarbonate solid (17.5 g, 0.21 mol) was slowly added to neutralize the reaction solution, filtered, and the filtrate was concentrated to obtain the crude product.

[0093] The crude product was dissolved in N,N-dimethylformamide solvent, sodium hydride solid (34 g, 0.85 mol) was added in batches (1 g each batch, interval time 2 min) under ice water bath, after the addition was completed, the reaction was carried out at room temperature for 30 min, then tetrabutylammonium iodide (11 g, 0.03 mol) was added, benzyl bromide (72.5 mL, 0.61 mol) was slowly added dropwise through a dropping funnel, after the addition was completed, the reaction was carried out overnight. After the raw material was completely reacted by thin layer chromatography, the reaction solution was slowly poured into a cold saturated ammonium chloride solution for quenching, and the reaction system was extracted with ethyl acetate (400 mL) and water (400 mL), then the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain a yellow sticky slurry of the crude product.

[0094] The crude product was dissolved in 1,4-dioxane, 1M H2SO4 (210 mL)-AcOH (240 mL)-dioxane (220 mL) was added to the reaction system, after the addition was completed, the reaction system was heated to reflux state for 10 h. After the raw material was completely reacted by thin layer chromatography, the reaction system was naturally cooled to room temperature, then n-hexane (100 mL) and water (800 mL) were added and stirred vigorously, and a white solid was collected by filtration, which was compound 7 (67.1 g, 73%).

[0095] Compound 7 (2.51 g, 4.64 mmol) was dissolved in anhydrous dichloromethane (4.7 mL), p-toluenesulfonic acid (0.81 g, 4.70 mmol) and benzylamine (1.04 mL, 9.48 mmol) were slowly added, and the reaction solution was stirred at room temperature for 20 h. After the raw material was completely reacted by thin layer chromatography, dichloromethane (100 mL) was added, the organic phase was collected, washed twice with saturated sodium carbonate solution (200 mL), dried over magnesium sulfate, and concentrated under vacuum to obtain the crude product of compound 8.

[0096] The crude product of compound 8 was dissolved in tetrahydrofuran, and allyl magnesium bromide Grignard reagent (13.9 mL, 13.9 mmol) was slowly added dropwise under ice water bath. After the raw material was completely reacted by thin layer chromatography after the reaction system was overnight, the reaction was quenched with ice water, the filtrate was collected by filtration, and concentrated under reduced pressure, and then separated by column chromatography to obtain compound 9. Compound 9 (1.622 g, 3.0 mmol) was dissolved in pyridine (45 mL) under anhydrous conditions. Methylsulfonyl chloride (0.58 mL, 7.49 mmol) was slowly added dropwise to the reaction system under ice water bath, followed by the addition of Molecular sieves (200 mg). The reaction system was heated to 100 °C for 4 h. After the starting material was completely consumed as judged by thin layer chromatography, the filtrate was collected by filtration through celite and the filter cake was rinsed with ethyl acetate (200 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 10 was isolated by silica gel column chromatography.

[0097] wherein the structural formula of compound 10a is: NMR hydrogen spectrum and carbon spectrum data are as follows.

[0098] 6a: Colorless syrup, yield 36%. 1 H NMR (400 MHz, CDC13) δ 7.46 - 7.15 (m, 24H), 5.76 - 5.44 (m, 1H), 5.10 - 4.95 (m, 2H), 4.92 (d, J = 11.4 Hz, 1H), 4.85 (d, J = 11.3 Hz, 1H), 4.74 (d, J = 11.3 Hz, 1H), 4.67 - 4.50 (m, 4H), 4.42 (d, J = 11.4 Hz, 1H), 4.34 (dd, J = 7.7, 2.7 Hz, 1H), 4.22 - 4.03 (m, 1H), 3.95 - 3.84 (m, 2H), 3.75 - 3.56 (m, 3H), 3.54 (dd, J = 7.0, 2.7 Hz, 1H), 2.61 (t, J = 5.3 Hz, 1H), 2.43 (dt, J = 11.8, 5.7 Hz, 1H), 2.32 - 2.21 (m, 1H). 13 CNMR (100 MHz, CDC13) δ 143.00, 138.89, 138.39, 138.11, 138.05, 136.00, 134.12, 129.55, 128.45, 128.42, 128.38, 128.33, 128.13, 127.93, 127.78, 127.74, 127.72, 127.69, 127.51, 127.05, 126.48, 117.32, 80.15, 79.39, 77.65, 74.67, 74.61, 73.45, 72.77, 71.51, 70.42, 57.06, 50.38, 35.16. HRMS (ESI): m / z calcd for C 44 H 46 ClNO4, [M + Na] + : 710.3008; found 710.3001.

[0099] The structural formula of compound 10b is: NMR hydrogen spectrum and carbon spectrum data are as follows.

[0100] 6b: Colorless syrup, 42%. 1 H NMR (400 MHz, CDC13) δ 7.56 - 6.96 (m, 24H), 5.69 - 5.52 (m, 1H), 5.06 - 4.93 (m, 2H), 4.90 (d, J = 11.4 Hz, 1H), 4.82 (d, J = 11.3 Hz, 1H), 4.72 (d, J = 11.4 Hz, 1H), 4.64 - 4.49 (m, 4H), 4.42 (d, J = 11.4 Hz, 1H), 4.30 (d, J = 5.3 Hz, 1H), 4.14 - 4.06 (m, 1H), 3.95 - 3.80 (m, 2H), 3.72 - 3.48 (m, 4H), 2.63 - 2.54 (m, 1H), 2.50 - 2.35 (m, 1H), 2.34 - 2.17 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 138.85, 138.37, 138.06, 136.01, 129.72, 128.43, 128.39, 128.37, 128.34, 128.30, 128.09, 127.90, 127.75, 127.70, 127.49, 117.29, 99.99, 80.11, 79.35, 74.61, 74.54, 73.47, 72.78, 71.52, 70.43, 56.98, 50.19, 35.09. HRMS (ESI): m / z calcd for C 44 H 46 ClNO4, [M + Na] + : 710.3008; found 710.3001.

[0101] Example Three: Polyhydroxy Iminium Sugar Compounds Inhibit Alpha-Glucosidase Activity

[0102] The pNPG (p-nitrophenyl-β-D-glucopyranoside) method is used to investigate the inhibitory activity of each compound on α-glucosidase. The main principle is that the α-D glucoside of p-nitrophenol is used as a substrate, which is colorless and has no absorption at 405 nm. After hydrolysis by α-glucosidase, the substrate releases p-nitrophenol, which has an absorption value at 405 nm. Na2CO3 is used as a reaction terminator to terminate the combination of enzyme and substrate. The polyhydroxy iminosugar compound prepared in the application can be combined with the enzyme after being added to the system, thereby inhibiting the action of enzyme and glycosidic bond, and reducing the release of p-nitrophenol. After the reaction is completed, 200 μL of the reaction solution is taken to read the corresponding absorbance value at 405 nm, and the IC 阴 -A 样 ) / (A 阴 -A 空 ) is calculated. 50 .

[0103] The specific experimental method is as follows: 20 μL of α-glucosidase (yeast) (2 U / mL), 50 μL of glutathione (1 mg / mL), and 180 μL of iminosugar solution are mixed, preheated at 37°C in a constant temperature water bath for 20 min, 150 μL of 4-nitrophenyl-α-D-pyranoglucoside (α-pNPG) (1 mg / mL) is added to the preheated reaction solution, preheated at 37°C in a constant temperature water bath for 20 min, and then terminated by an equal volume of 1M sodium carbonate solution. Shake the whole reaction solution system appropriately to make it uniform, take 200 μL of the reaction solution in the system and directly measure the absorbance at 405 nm in the enzyme marker. Acarbose is used as a positive control for enzyme activity test, and blank control (using pH=6.8 phosphate buffer instead of enzyme solution and sample solution) and negative control (using pH=6.8 phosphate buffer instead of iminosugar sample solution) are designed. The specific grouping is shown in Table 2, and three repeats are set for each group.

[0104] Table 2 Control group design

[0105]

[0106]

[0107] The results are shown in Table 3. In the table, "-" represents no inhibitory activity.

[0108] Table 3 IC 50 values of inhibiting α-glucosidase activity

[0109] Compound No. IC 50 (μM) Compound No. IC 50 (μM) 5a 7.11±0.06 5h 11.80±0.13 5b 58.23±0.57 5i 17.09±0.14 5c 6.89±0.06 5j 5.55±0.09 5d - 5k 16.83±0.04 5e 4.48±0.05 10a 13.49±0.21 5f 158.77±0.98 10b 8.72±0.17 5g 5.13±0.12 Acarbose 6.32±0.08

[0110] The results show that acarbose has good inhibitory effect on alpha-glucosidase, and most of the newly synthesized polyhydroxy imine sugar compounds have good inhibitory effect on alpha-glucosidase, even better than acarbose.

[0111] Comparing the activity data of compounds 5a and 5b, 5c and 5d, 5e and 5f, 5g and 5h, 5i and 5j respectively, it can be seen that the stereochemical configuration of the functional groups on the imine sugar ring has a very great influence on the enzyme inhibitory activity of the compound. Among them, the inhibitory activity of 1-alpha-allyl compounds is better than that of 1-beta-allyl compounds. It can be seen from the activity comparison of the products synthesized by L-arabinose and D-glucose that the configuration of different hydroxyl groups on the imine sugar ring will affect the inhibitory activity of the compound on glucosidase.

[0112] The above-described embodiments are only used to describe the preferred modes of the present application, and do not limit the scope of the present application. Without departing from the design spirit of the present application, various modifications, variations, modifications and replacements of the technical solutions of the present application made by those skilled in the art shall fall within the protection scope determined by the claims of the present application.

Claims

1. A polyhydroxyimino sugar compound characterized by: The general structural formula of the polyhydroxyimino sugar compound is: R1 is 1-α-allyl or 1-β-allyl; R2 is α-OBn or β-OBn; R3 is H or CH2OBn; R4 is 2. The polyhydroxyimino sugar compound according to claim 1, wherein: The polyhydroxyimino sugar compound is any one of the following compounds 5a-5c, 5e-5k, 10a-10b:

3. The method for preparing the polyhydroxyimino sugar compound according to claim 2, wherein: The corresponding reaction equations for the preparation of compounds 5a-5c, 5e-5k are as follows: The method comprises the following steps: (1) Benzyl protection reaction: L-arabinose is used as the starting material to obtain a glycoside product through glycosidation reaction. The exposed hydroxyl groups of the crude glycoside product are benzyl protected under the conditions of sodium hydride, tetrabutylammonium iodide and benzyl bromide. The crude product of the fully protected iminosugar is dissolved in glacial acetic acid and sulfuric acid, and the reaction system is heated to reflux to obtain compound 2; (2) Hydroxyamination reaction: Compound 2 reacts with benzylamine in the presence of p-toluenesulfonic acid to obtain compound 3; (3) Sugar ring opening reaction: Compound 3 is subjected to ring opening with allyl magnesium bromide Grignard reagent to obtain compound 4; (4) Ring-closure reaction: Compound 4 is synthesized into compound 5 under the action of pyridine and methanesulfonyl chloride.

4. The method for preparing the polyhydroxyimino sugar compound according to claim 2, wherein: The corresponding reaction equations for the preparation of compounds 10a-10b are as follows: The preparation method comprises the following steps: (1) Benzyl protection reaction: Using D-glucose as the starting material, a glycoside product is obtained by glycosidation reaction. The exposed hydroxyl groups of the crude glycoside product are benzyl-protected under the conditions of sodium hydride, tetrabutylammonium iodide and benzyl bromide. The crude fully protected iminosugar product is dissolved in glacial acetic acid and sulfuric acid, and the reaction system is heated to reflux to obtain compound 7; (2) Hydroxyamination reaction: Compound 7 reacts with benzylamine in the presence of p-toluenesulfonic acid to obtain compound 8; (3) Sugar ring opening reaction: Compound 8 is subjected to ring opening with allyl magnesium bromide Grignard reagent to obtain compound 9; (4) Ring-closure reaction: Compound 9 is reacted with pyridine and methanesulfonyl chloride to synthesize compound 10.

5. Use of the polyhydroxyimino sugar compound according to claim 1 or 2 or the polyhydroxyimino sugar compound prepared by the method according to claim 3 or 4 in the preparation of a drug for inhibiting α-glucosidase activity.

6. A medicament comprising the polyhydroxyimino sugar compound according to claim 1 or 2 or the polyhydroxyimino sugar compound prepared by the method according to claim 3 or 4, characterized in that: The drug is used to inhibit α-glucosidase activity.

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