A coumarin-oxadiazole dual alpha-glucosidase and PTP1B inhibitor, preparation method and application

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a coumarin-oxadiazole alpha-glucosidase and PTP1B dual-target inhibitor, a preparation method and application. The chemical structure of the alpha-glucosidase and PTP1B dual-target inhibitor is: the coumarin-oxadiazole compound provided in the application has good activities of inhibiting alpha-glucosidase and PTP1B and reducing postprandial blood glucose, and can be used as a novel anti-diabetic research lead compound; the coumarin-oxadiazole compound has low toxicity to human normal HEK-293 cells and high safety; and the preparation method of the coumarin-oxadiazole compound provided in the application is simple, the synthesis route is short, the coumarin-oxadiazole compound is easy to mass-produce, low in price, and suitable for market promotion and application.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to a coumarin-oxadiazole alpha-glucosidase and PTP1B dual-target inhibitor, a preparation method and application. BACKGROUND

[0002] Diabetes is a lifelong disease caused by absolute or relative deficiency of insulin secretion and insulin utilization disorder. The main feature of the disease is long-term hyperglycemia, which often causes multiple system complications, such as cardiovascular disease, kidney disease, nerve damage and retinopathy. Its pathogenesis involves multiple aspects, including genetic factors, environmental factors and lifestyle.

[0003] In the treatment of diabetes, alpha-glucosidase inhibitors play a key role. It is mainly located in the brush border of the small intestine, which can hydrolyze carbohydrates into glucose to help the body absorb. Compared with other hypoglycemic drugs, alpha-glucosidase inhibitors have good effect on controlling postprandial blood glucose, low risk of hypoglycemia, and can also improve lipid metabolism and reduce the risk of cardiovascular complications in diabetic patients.

[0004] At the same time, protein tyrosine phosphatase 1B (PTP1B) is an emerging target for diabetes treatment and has attracted much attention. Insulin-dependent insulin signaling pathway is normally transduced to regulate blood glucose, while PTP1B can negatively regulate the pathway. It dephosphorylates tyrosine residues on the insulin receptor and substrate, interrupts signal transduction, and causes insulin resistance, which is an important pathogenesis of type II diabetes, manifested as decreased sensitivity of the body to insulin and decreased efficiency of insulin-promoted glucose uptake. Many studies have shown that knocking out the PTP1B gene or using its inhibitors in animal models can significantly enhance insulin sensitivity and improve abnormal glucose metabolism, providing a new idea for the treatment of diabetes.

[0005] Due to the complexity of the pathogenesis of diabetes, single-target treatment drugs are not easy to effectively control blood glucose, and multiple types of anti-diabetic drugs are often used in clinical practice to achieve effective hypoglycemic effect. Alpha-glucosidase and PTP1B dual-target inhibitors can act on two targets at the same time, fully exerting the synergistic effect. Compared with single-target inhibitors, dual-target inhibitors exhibit more outstanding effect in reducing blood glucose, and are expected to bring new breakthroughs and changes to the treatment of diabetes.

[0006] Therefore, it is of great significance to research and develop a new type of alpha-glucosidase and PTP1B dual-target inhibitor with high efficiency and safety. SUMMARY

[0007] Therefore, the present application provides a preparation method and application of a new coumarin-oxadiazole alpha-glucosidase and PTP1B dual-target inhibitor.

[0008] It needs to be explained that the application designs and synthesizes a group of novel coumarin-oxadiazole derivatives, and further studies the activities of alpha-glucosidase and PTP1B. The experimental results show that the compounds can effectively inhibit the activities of alpha-glucosidase and PTP1B, and then reduce postprandial blood glucose, so as to provide a more effective strategy for diabetes treatment.

[0009] Specifically, the coumarin compounds exist naturally in higher plants, the parent nucleus structure has good rigidity and planarity, is convenient for being combined with biological macromolecules through π-π stacking and hydrogen bond and the like; the oxadiazole is an important structural unit in medicinal chemistry research, and is also an effective strategy for rapid coupling and structural modification in medicinal chemistry, and the five-membered heterocyclic structure of the oxadiazole gives the oxadiazole compounds good electronic effect and space effect, so that the oxadiazole compounds can be accurately combined with the active sites of different targets. Based on the potential inhibitory activities of the coumarin and oxadiazole compounds on alpha-glucosidase and PTP1B, it is of great significance to design and construct a dual-target inhibitor by combining the two.

[0010] In order to achieve the above-mentioned purpose, the application adopts the following technical scheme:

[0011] The first technical purpose of the application is to provide a coumarin-oxadiazole alpha-glucosidase and PTP1B dual-target inhibitor, which has a structure as shown in formula (I):

[0012]

[0013] In formula I, the coumarin is 4- or 7-coumarin;

[0014] When the coumarin is 7-coumarin, R is at least one of H, 3-methyl, 2-hydroxy, 4-methyl, 4-fluoro, 4-butyl and 3-bromo;

[0015] When the coumarin is 4-coumarin, R is at least one of H, 2-hydroxy, 4-methyl, 4-biphenyl, 2-bromo, 2-amino, 3-methyl, 4-bromo, 2-chloro, 3-bromo, 4-butyl and 4-fluoro.

[0016] Exemplarily, the structure formula of the coumarin-oxadiazole alpha-glucosidase and PTP1B dual-target inhibitor is as follows:

[0017]

[0018] The second technical purpose of the application is to provide a preparation method of the coumarin-oxadiazole alpha-glucosidase and PTP1B dual-target inhibitor, and the method specifically comprises the following steps:

[0019] Step 1: Dissolve benzhydrazide with different substituents and potassium hydroxide in an appropriate amount of absolute ethanol, slowly add carbon disulfide while stirring, then stir and reflux at 80°C for 2h; when the reaction is complete, filter and dry to obtain the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol with different substituents;

[0020]

[0021] Step 2: Dissolve 4-hydroxycoumarin or 7-hydroxycoumarin in absolute ethanol and add potassium hydroxide, slowly add epichlorohydrin while stirring, and reflux the reaction at 80°C for 5h; after the reaction is complete, terminate the reaction process, and cool the reaction mixture to room temperature, filter it, and then dry the obtained solid to obtain the intermediate 4-(oxirane-2-ylmethyl)-2H-chromen-2-one or 7-(oxirane-2-ylmethyl)-2H-chromen-2-one;

[0022]

[0023] Step 3: Dissolve the above-obtained product 4-(oxirane-2-ylmethyl)-2H-chromen-2-one or 7-(oxirane-2-ylmethyl)-2H-chromen-2-one and the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol with different substituents in an appropriate amount of absolute ethanol, reflux at 80°C for 5h, and after the reaction is complete, purify by column chromatography with petroleum ether: ethyl acetate = 5:1 to obtain the target compound I, i.e., the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor.

[0024]

[0025] Preferably, the ratio of the benzhydrazide with different substituents, carbon disulfide, KOH, and absolute ethanol is 2mmol:5mmol:2.2mmol:15mL.

[0026] Preferably, the ratio of the 4-hydroxy or 7-hydroxycoumarin, epichlorohydrin, KOH, and absolute ethanol is 37mmol:471.8mmol:41.4mmol:300mL.

[0027] Preferably, the ratio of the 4-(oxirane-2-ylmethyl)-2H-chromen-2-one or 7-(oxirane-2-ylmethyl)-2H-chromen-2-one, substituted 5-phenyl-1,3,4-oxadiazole-2-thiol, and absolute ethanol is 1mmol:1mmol:15mL.

[0028] The third technical objective of this invention is to request protection for the use of the aforementioned coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitors in pharmaceutical formulations.

[0029] Specifically, the application of the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor in the preparation of antidiabetic drugs.

[0030] Compared with the prior art, the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor disclosed in this invention, its preparation method and application, have the following advantages:

[0031] 1. The coumarin-oxadiazole dual-target inhibitor of α-glucosidase and PTP1B disclosed in this invention has a good effect on inhibiting the activity of α-glucosidase and PTP1B and reducing postprandial blood glucose, and can be used as a lead compound for novel anti-diabetic research.

[0032] 2. The preparation method of the coumarin-oxadiazole compounds disclosed in this invention is simple, has a short synthetic route, is easy to prepare in large quantities, and is inexpensive;

[0033] 3. The coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitors disclosed in this invention have low toxicity to normal human cells and high safety. Attached Figure Description

[0034] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0035] Figure 1 This is a preparation route diagram for the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor.

[0036] Figure 2 The effect of compound 11 on postprandial blood glucose in Kunming mice; (A) the inhibitory effect of compound 11 on blood glucose in Kunming mice after administration of sucrose; (B) the AUC of mice after administration of sucrose. 0-150min The increment, "*" indicates a significant difference, P<0.05.

[0037] Figure 3 This is the 1H NMR spectrum of compound 9.

[0038] Figure 4 This is the carbon NMR spectrum of compound 9.

[0039] Figure 5 is a high resolution mass spectrum of compound 9.

[0040] Figure 6 is a nuclear magnetic resonance hydrogen spectrum of compound 11.

[0041] Figure 7 is a nuclear magnetic resonance carbon spectrum of compound 11.

[0042] Figure 8 is a high resolution mass spectrum of compound 11.

[0043] Figure 9 is a nuclear magnetic resonance hydrogen spectrum of compound 13.

[0044] Figure 10 is a nuclear magnetic resonance carbon spectrum of compound 13.

[0045] Figure 11 is a high resolution mass spectrum of compound 13. DETAILED DESCRIPTION

[0046] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments of the present application, all the other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the present application.

[0047] The special word "embodiment" in this application is not necessarily interpreted as superior or better than other embodiments as explained by "exemplary". The performance index test in the embodiments of the present application adopts the conventional test method in the art, unless otherwise specified. It should be understood that the terms described in the present application are only for describing the specific embodiments, and are not used to limit the disclosure of the present application.

[0048] Unless otherwise specified, the technical and scientific terms used in this application have the same meanings as commonly understood by those skilled in the art to which the present application belongs; the test methods and technical means not specially noted in the present application refer to the experimental methods and technical means commonly used by those skilled in the art.

[0049] In order to better illustrate the content of the present application, a large number of specific details are given in the specific embodiments below. Those skilled in the art should understand that the present application can also be implemented without some specific details. In the embodiments, some methods, means, instruments, equipment and the like which are well known to those skilled in the art are not described in detail, in order to highlight the main idea of the present application.

[0050] The technical features disclosed in the embodiments of the present application can be combined in any way without conflict, and the technical solutions obtained by the combination belong to the disclosure of the embodiments of the present application.

[0051] The application discloses a coumarin-oxadiazole alpha-glucosidase and PTP1B dual-target inhibitor and a preparation method thereof.

[0052] In order to better understand the present application, the following examples are further specifically described, but it should not be understood as limiting the present application, and some non-essential improvements and adjustments made by those skilled in the art according to the above application content are also regarded as falling within the protection scope of the present application.

[0053] Example 1

[0054] Preparation of 7-(2-hydroxy-3-((5-phenyl-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H-chromen-2-one (compound 1)

[0055] The structural formula of compound 1 is as follows:

[0056]

[0057] The specific preparation steps are as follows:

[0058] Step 1: 2 mmol of benzoyl hydrazine and 2.2 mmol of potassium hydroxide are completely dissolved in 15 mL of anhydrous ethanol, 5 mmol of carbon disulfide is slowly added under stirring, and then stirring and refluxing at 80 DEG C for 2 h; when the reaction is completed, filtration is performed, and then the obtained solid is dried to obtain an intermediate 5-phenyl-1,3,4-oxadiazol-2-thiol;

[0059] Step 2: 37 mmol of 7-hydroxycoumarin is dissolved in 300 mL of anhydrous ethanol, and 41.4 mmol of potassium hydroxide is added, 471.8 mmol of epichlorohydrin is slowly added under stirring, and then refluxing reaction at 80 DEG C for 5 h; after the reaction is completed, the reaction process is terminated, and the reaction mixture is cooled to room temperature, filtered, and then the obtained solid is dried to obtain an intermediate 7-(oxirane-2-ylmethyl)-2H-chromen-2-one;

[0060] Step 3: 1 mmol of the obtained product 7-(oxirane-2-ylmethyl)-2H-chromen-2-one and 1 mmol of the intermediate 5-phenyl-1,3,4-oxadiazol-2-thiol are dissolved in 15 mL of anhydrous ethanol, 80 DEG C refluxing is performed for 5 h, after the reaction is completed, petroleum ether: ethyl acetate = 5:1 column chromatography purification is performed to obtain the target compound 1.

[0061] The compound 1 is a white solid, the yield is 68.00%, and the melting point is 146.0-147.0 DEG C; and the data of the nuclear magnetic hydrogen spectrum, the nuclear magnetic carbon spectrum and the high resolution mass spectrum of the compound 1 are as follows:

[0062] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.43-3.65 (m, 2H), 4.10-4.25 (m, 3H), 5.78 (d, 1H, J = 5.2 Hz), 6.29 (d, 1H, J = 8.0 Hz), 6.94-6.99 (m, 2H), 7.55-7.63 (m, 4H), 7.93-7.98 (m, 3H).

[0063] 13 CNMR (DMSO-d6, 100 MHz) δ: 36.18, 67.18, 71.03, 101.35, 112.56, 112.67, 112.75, 123.08, 126.40, 129.46, 129.59, 132.03, 144.39, 155.36, 160.35, 161.54, 164.02, 165.13.

[0064] HRMS (ESI) calcd for [M+H] + C20H16N2O5S+: 397.0853 found 397.0861.

[0065] The following examples were prepared in a similar manner to Example 1, using the same ratios of starting materials as in Example 1, except that the 7-hydroxycoumarin in Example 1 was unchanged or changed to 4-hydroxycoumarin, and the benzhydrazide was replaced by another corresponding benzhydrazide.

[0066] Example 2:

[0067] 7-(2-hydroxy-3-((5-(m-tolyl)-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H-chromen-2-one (Compound 2) was prepared in a similar manner to Example 1, except that only the benzhydrazide was replaced by 3-methylbenzhydrazide.

[0068] The structural formula of Compound 2 is shown below:

[0069]

[0070] Compound 2 was a white solid with a yield of 70% and a melting point of 140-141 °C. The nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, and high resolution mass spectrum data of Compound 2 are shown below:

[0071] 1HNMR (DMSO-d6, 400 MHz) δ: 2.38 (s, 1H), 3.64 (d, 2H, J = 18.4 Hz), 4.24-4.12 (m, 3H), 5.78 (s, 1H), 6.29-6.27 (d, 1H, J = 7.6 Hz), 6.93-6.99 (m, 2H), 7.40-7.47 (m, 2H), 7.61 (d, 1H, J = 9.6 Hz), 7.73 (t, 2H, J = 6.4 Hz), 7.98 (d, 1H, J = 7.6 Hz).

[0072] 13 CNMR (DMSO-d6, 100 MHz) δ: 20.82, 36.18, 67.17, 70.95, 101.34, 112.52, 112.61, 112.65, 122.95, 123.53, 126.64, 129.28, 129.52, 132.62, 138.90, 144.28, 155.30, 160.26, 161.49, 163.84, 165.18.

[0073] HRMS (ESI) calcd for [M+H] + C 21 H 18 N2O5S + : 411.0965 found 411.0977.

[0074] Example Three:

[0075] Preparation of 7-(2-hydroxy-3-((5-(2-hydroxyphenyl)-l,3,4-oxadiazol-2-yl)thio)propoxy)-2H-chromen-2-one (Compound 3), which differs from Example One in that only the benzhydrazide is replaced with 2-hydroxybenzhydrazide.

[0076] The structural formula of Compound 3 is shown below:

[0077]

[0078] Compound 3 is a white solid with a yield of 68% and a melting point of 146-147 °C. The data of the nuclear magnetic hydrogen spectrum, the nuclear magnetic carbon spectrum and the high resolution mass spectrum of Compound 3 are shown below:

[0079] 1HNMR (DMSO-d6, 400 MHz) δ: 3.43-3.65 (m, 2H), 4.10-4.25 (m, 3H), 5.78 (d, IH, J = 5.2 Hz), 6.29 (d, IH, J = 8.0 Hz), 6.94-6.99 (m, 2H), 7.55-7.63 (m, 4H), 7.93-7.98 (m, 3H).

[0080] 13 CNMR (DMSO-d6, 100 MHz) δ: 36.18, 67.18, 71.03, 101.35, 112.56, 112.67, 112.75, 123.08, 126.40, 129.46, 129.59, 132.03, 144.39, 155.36, 160.35, 161.54, 164.02, 165.13.

[0081] HRMS (ESI) calcd for [M+H] + C 20 H 16 N2O5S + 397.0853 found 397.0861.

[0082] Example Four:

[0083] 7-(2-Hydroxy-3-((5-(p-tolyl)-l,3,4-oxadiazol-2-yl)thio)propoxy)-2H-chromen-2- one (Compound 4) was prepared as in Example One, except that only the benzoyl hydrazide was replaced with 4-methylbenzoyl hydrazide.

[0084] The structural formula of Compound 4 is shown below:

[0085]

[0086] Compound 4 was a silver solid with a yield of 70% and a melting point of 125-126 °C. The H NMR, C NMR and high resolution mass spectrum data of Compound 4 are shown below:

[0087] 1HNMR (DMSO-d6, 400 MHz) δ: 2.39 (s, 3H), 3.43-3.63 (m, 2H), 4.12-4.25 (m, 3H), 5.66 (d, IH, J = 5.2 Hz), 6.28 (d, IH, J = 9.2 Hz), 6.92-6.97 (m, 2H), 7.38 (d, 2H, J = 8.0 Hz), 7.60 (d, IH, J = 8.4 Hz), 7.82 (d, 2H, J = 8.0 Hz), 7.96 (d, IH, J = 9.6 Hz).

[0088] 13 CNMR (DMSO-d6, 100 MHz) δ: 21.14, 36.19, 67.18, 70.94, 101.35, 112.52, 112.59, 112.63, 120.29, 126.30, 129.53, 129.91, 142.12, 144.29, 155.31, 160.26, 161.48, 163.55, 165.19.

[0089] HRMS (ESI) calcd for [M + H] C26H22FN4O5S 529.1419 found 529.1419. + C 21 H 18 N2O5S + : 411.1009 found 411.1021.

[0090] Example Five:

[0091] Preparation of 7-(3-((5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)thio)-2- hydroxypropoxy)-2H-chromen-2-one (Compound 5), which differs from Example One in that only the benzhydrazide is replaced with 4-fluorobenzhydrazide.

[0092] The structural formula of Compound 5 is shown below:

[0093]

[0094] Compound 5 is a white solid with a yield of 67%; melting point: 135-1360C; and the data of the nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum and high resolution mass spectrum of Compound 5 are shown below:

[0095] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.43-3.64 (m, 2H), 4.10-4.25 (m, 3H), 5.76 (d, IH, J = 5.2 Hz), 6.29 (

[0096] d, 1H, J = 9.6 Hz), 6.95 (t, 2H, J = 8.4 Hz), 7.41 (t, 2H, J = 8.8 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.95-8.00 (m, 3H).

[0097] 13 CNMR (DMSO-d6, 100 MHz) δ: 36.19, 67.17, 70.93, 101.32, 112.51, 112.60, 112.66 (d, 2C, J = 19.

[0098] 8 Hz, 2 J CF ), 116.53 (d, 1C, J = 3.5 Hz, 4 J CF ), 119.76, 129.03 (d, 2C, J = 9.0 Hz, 3 J CF ), 129.52, 144.28, 155.30, 1

[0099] 60.25, 161.47, 162.90 (d, 1C, J = 240.3 Hz, 1 J CF ) 163.97, 164.35.

[0100] HRMS (ESI) calcd for [M + H] + C 20 H 15 FN2O5S + : 415.0759 found 415.0779.

[0101] Example Six:

[0102] 7-(3-((5-(4-(tert-Butyl)phenyl)-1,3,4-oxadiazol-2-yl)sulfanyl)-2-hydroxypropoxy)-2H- chromen-2-one (Compound 6) was prepared according to Example One, except that only the benzhydrazide was replaced with 4-butylbenzhydrazide.

[0103] The structural formula of Compound 6 is shown below:

[0104]

[0105] Compound 6 was a white solid with a yield of 71% and a melting point of 153-155 °C. The1H NMR,13C NMR and high resolution mass spectrum data of Compound 6 are shown below:

[0106] 1HNMR (DMSO-d6, 400 MHz) δ: 1.30 (s, 9H), 3.42-3.64 (m, 2H), 4.10-4.25 (m, 3H), 5.78 (d, IH, J = 5.6 Hz), 6.29 (d, IH, J = 9.6 Hz), 6.93-6.99 (m, 2H), 7.56-7.62 (m, 3H), 7.86 (d, 2H, J = 8.8 Hz), 7.98 (d, IH, J = 9.6 Hz),

[0107] 13 CNMR (DMSO-d6, 100 MHz) δ: 30.80, 34.83, 36.21, 67.15, 70.97, 101.34, 112.52, 112.62, 112.67, 120.33, 126.21, 129.53, 144.29, 154.89, 155.32, 160.26, 161.50, 163.64, 165.10.

[0108] HRMS (ESI) calcd for [M + H] + C 24 H 24 N2O5S + : 453.1479 found 453.1486.

[0109] Example Seven:

[0110] 7-(3-((5-(3-bromophenyl)-l,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H- chromen-2-one (Compound 7) was prepared according to Example One, except that only the benzhydrazide was replaced with 3-bromobenzhydrazide.

[0111] The structural formula of Compound 7 is shown below:

[0112]

[0113] Compound 7 was a light purple solid in 76% yield; mp 166-167 °C; and the NMR, CNMR and HRMS data of Compound 7 are shown below:

[0114] 1HNMR (DMSO-d6, 400 MHz) δ: 3.42-3.65 (m, 2H), 4.10-4.38 (m, 3H), 5.76 (d, IH, J = 5.2 Hz), 6.29 (d, IH, J = 9.2 Hz), 6.95 (t, 2H, J = 8.8 Hz), 7.61 (d, IH, J = 8.4 Hz), 7.77 (d, 2H, J = 6.4 Hz), 7.84-7.87 (m, 2H), 7.97 (d, IH, J = 7.2 Hz).

[0115] 13 CNMR (DMSO-d6, 100 MHz) δ: 36.21, 67.15, 70.93, 101.32, 112.52, 112.61, 112.67, 122.24, 125.56, 128.24, 129.53, 132.46, 144.27, 155.30, 160.25, 161.47, 164.28, 164.45.

[0116] HRMS (ESI) calcd for [M+H] + C 20 H 15 BrN2O5S + : 474.9958 found 474.9979.

[0117] Example Eight:

[0118] Preparation of 4-(2-hydroxy-3-((5-phenyl-l,3,4-oxadiazol-2-yl)thio)propoxy)-2H- chromen-2-one (Compound 8), instead of 7-hydroxycoumarin in Example One, only 4-hydroxycoumarin was used.

[0119] The structural formula of Compound 8 is shown below:

[0120]

[0121] Compound 8 is a white solid with a yield of 48%, a melting point of 143-145 °C, and the following data for its nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, and high resolution mass spectrum:

[0122] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.44-3.66 (m, 2H), 4.11-4.27 (m, 3H), 5.76 (d, IH, J = 5.6 Hz), 6.26-6.30 (m, IH), 6.93-6.99 (m, 2H), 7.54-7.62 (m, 4H), 7.92-7.99 (m, 3H).

[0123] 13 CNMR (DMSO-d6, 100 MHz) δ: 36.17, 67.16, 71.00, 101.34, 112.53, 112.62, 112.68, 123.05, 126.35, 129.39, 129.53, 131.96, 144.30, 155.32, 160.27, 161.51, 163.97, 165.08.

[0124] HRMS (ESI) calcd for [M+H] + C 20 H 16 N2O5S + :397.0853 found397.0885.

[0125] Example Nine:

[0126] Preparation of (E)-2-((2-oxo-2H-chromen-7-yl)oxy)ethyl-3-(4- fluorophenyl)acrylate (Compound 9) was similar to Example One, except that 7- hydroxy coumarin was replaced by 4-hydroxy coumarin and benzhydrazide was replaced by 2-hydroxybenzhydrazide.

[0127] The structural formula of Compound 9 is shown below:

[0128]

[0129] Compound 9 was a white solid with a yield of 39% and a melting point of 204-206 °C. The H NMR, C NMR and HRMS data of Compound 9 are shown below:

[0130] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.48-3.69 (m, 2H), 4.24-4.36 (m, 3H), 5.86 (d, IH, J = 5.2 Hz), 5.90 (s, IH), 6.96 (t, IH, J = 7.6 Hz), 7.09 (d, IH, J = 8.4 Hz), 7.31-7.46 (m, 3H), 7.61-7.71 (m, 2H), 7.92-7.94 (m, IH), 10.19 (s, IH).

[0131] 13CNMR (DMSO-d6, 100 MHz) δ: 35.80, 66.83, 71.68, 90.59, 109.30, 115.07, 116.18, 116.93, 119.53, 123.07, 123.90, 128.48, 132.58, 133.21, 152.64, 155.96, 161.39, 163.20, 164.41, 164.75.

[0132] HRMS (ESI) calcd for [M+H] + C 20 H 16 N2O6S + : 413.0802 found 413.0812.

[0133] Example Ten:

[0134] Preparation of 4-(2-hydroxy-3-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H- chromen-2-one (Compound 10), which differs from Example One in that 7-hydroxy coumarin is replaced with 4-hydroxy coumarin and benzhydrazide is replaced with 4-methyl benzhydrazide.

[0135] The structural formula of Compound 10 is shown below:

[0136]

[0137] Compound 10 is a white solid with a yield of 47%; melting point: 176-177 °C; and the data of the nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum and high resolution mass spectrum of Compound 10 are as follows:

[0138] 1 HNMR (DMSO-d6, 400 MHz) δ: 2.38 (s, 3H), 3.48-3.67 (m, 2H), 4.23-4.31 (m, 3H), 5.89-5.92 (m, 2H), 7.32-7.39 (m, 4H), 7.64 (t, 1H, J = 7.2 Hz), 7.80-7.83 (m, 2H), 7.95 (d, 1H, J = 7.6 Hz).

[0139] 13CNMR (DMSO-d6, 100 MHz) δ: 21.00, 35.78, 66.87, 71.65, 90.60, 115.09, 116.23, 120.23, 123.10, 123.96, 126.20, 129.79, 132.64, 142.01, 152.66, 161.43, 163.40, 164.77, 165.16.

[0140] HRMS (ESI) calcd for [M+H] + C 21 H 18 N2O5S + : 411.1009 found 411.1013.

[0141] Example Eleven:

[0142] Preparation of 4-(3-((5-([1,1'-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)thio)-2- hydroxypropoxy)-2H-chromen-2-one (Compound 11), which is different from Example One in that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin and benzhydrazide is replaced by 4-biphenylbenzhydrazide.

[0143] The structural formula of Compound 11 is shown below:

[0144]

[0145] Compound 11 is a white powder with a yield of 50%, a melting point of 197-199°C, and the data of its nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, and high resolution mass spectrum are shown below:

[0146] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.51-3.71 (m, 2H), 4.24-4.36 (m, 3H), 5.90 (t, 2H, J = 5.6 Hz), 7.32-7.38 (m, 2H), 7.44 (t, 1H, J = 7.2 Hz), 7.52 (t, 2H, J = 7.2 Hz), 7.63 (t, 1H, J = 7.2 Hz), 7.76 (d, 2H, J = 6.8 Hz), 7.87 (d, 2H, J = 8.8 Hz), 7.93-8.01 (m, 3H).

[0147] 13CNMR (DMSO-d6, 100 MHz) δ: 35.84, 66.93, 71.74, 90.72, 115.15, 116.36, 121.90, 123.24, 124.12, 126.87, 126.95, 127.52, 128.39, 129.16, 132.78, 138.76, 143.33, 152.74, 161.60, 163.92, 164.87, 165.01.

[0148] HRMS (ESI) calcd for [M+H] + C 26 H 20 N2O5S + : 473.1166 found 473.1191.

[0149] Example Twelve:

[0150] Preparation of 4-(3-((5-(2-bromophenyl)-l,3,4-oxadiazol-2-yl)thio)-2- hydroxypropoxy)-2H-chromen-2-one (Compound 12), which differs from Example One in that 7-hydroxy coumarin is replaced with 4-hydroxy coumarin and benzhydrazide is replaced with 2-bromobenzhydrazide.

[0151] The structural formula of Compound 12 is shown below:

[0152]

[0153] Compound 12 is a light yellow solid with a yield of 35%; melting point: 144-145 °C; and the data of the nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum and high resolution mass spectrum of Compound 12 are as follows:

[0154] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.49-3.68 (m, 2H), 4.21-4.33 (m, 3H), 5.90-6.01 (m, 2H), 7.32-7.38 (m, 4H), 7.62-7.66 (m, IH), 7.82 (d, 2H, J = 8.4 Hz), 7.92-7.94 (m, IH).

[0155] 13CNMR (DMSO-d6, 100 MHz) δ: 35.82, 66.85, 71.80, 90.75, 115.14, 116.40, 120.77, 123.25, 124.10, 124.37, 128.28, 131.64, 132.82, 133.38, 134.31, 152.75, 161.63, 163.87, 164.62, 164.88.

[0156] HRMS (ESI) calcd for [M+H] + C 20 H 15 BrN2O5S + : 474.9958 found 474.9969.

[0157] Example XIII:

[0158] Preparation of 4-(3-((5-(2-aminophenyl)-l,3,4-oxadiazol-2-yl)thio)-2- hydroxypropoxy)-2H-chromen-2-one (Compound 13), which is different from Example I in that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin and benzhydrazide is replaced by 2-aminobenzhydrazide.

[0159] The structural formula of Compound 13 is shown below:

[0160]

[0161] Compound 13 is a light yellow solid with a yield of 56% and a melting point of 198-199 °C. The data of the hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high resolution mass spectrum of Compound 13 are shown below:

[0162] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.48-3.69 (m, 2H), 4.24-4.36 (m, 3H), 5.82 (d, IH, J = 5.2 Hz), 5.90 (s, IH), 6.62 (t, 3H, J = 7.2 Hz), 6.89 (s, IH), 7.24 (t, IH, J = 6.8 Hz), 7.31-7.38 (m, 2H), 7.57-7.66 (m, 2H), 7.94 (d, IH, J = 6.4 Hz).

[0163] 13CNMR (DMSO-d6, 100 MHz) δ: 35.77, 66.89, 71.70, 90.61, 101.71, 115.09, 115.41, 115.80, 116.22, 123.09, 123.92, 127.28, 132.30, 132.62, 147.38, 152.67, 161.43, 161.75, 164.78, 165.25.

[0164] HRMS (ESI) calcd for [M+H] + C 20 H 17 N3O5S + : 412.0962 found 412.0970.

[0165] Example Fourteen:

[0166] Preparation of 4-(2-hydroxy-3-((5-(m-tolyl)-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H- chromen-2-one (Compound 14), which differs from Example One in that 7-hydroxy coumarin is replaced by 4-hydroxy coumarin and benzhydrazide is replaced by 3-methylbenzhydrazide.

[0167] The structural formula of Compound 14 is shown below:

[0168]

[0169] Compound 14 is a white solid with a yield of 42% and a melting point of 168-169 °C. The data of the hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high resolution mass spectrum of Compound 14 are shown below:

[0170] 1 HNMR (DMSO-d6, 400 MHz) δ: 2.38 (s, 3H), 3.49-3.69 (m, 2H), 4.24-4.36 (m, 3H), 5.83 (d, 1H, J = 5.6 Hz), 5.89 (s, 1H), 7.31-7.46 (m, 4H), 7.61-7.74 (m, 3H), 7.93 (d, 1H, J = 7.6 Hz).

[0171] 13CNMR (DMSO-d6, 100 MHz) δ: 20.67, 35.81, 66.87, 71.63, 90.60, 115.07, 116.20, 122.87, 123.08, 123.42, 123.92, 126.54, 129.13, 132.48, 132.61, 138.77, 152.64, 161.41, 163.67, 164.74, 165.14.

[0172] HRMS (ESI) calcd for [M+H] + C 21 H 18 N2O5S + : 411.1009 found 411.1004.

[0173] Example Fifteen:

[0174] Preparation of 4-(3-((5-(4-bromophenyl)-l,3,4-oxadiazol-2-yl)thio)-2- hydroxypropoxy)-2H-chromen-2-one (Compound 15), which differs from Example One in that 7-hydroxycoumarin is replaced with 4-hydroxycoumarin and benzhydrazide is replaced with 4-bromobenzhydrazide.

[0175] The structural formula of Compound 15 is shown below:

[0176]

[0177] Compound 15 is a white solid with a yield of 50% and a melting point of 167-168 °C. The data of the nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum and high resolution mass spectrum of Compound 15 are shown below:

[0178] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.49-3.70 (m, 2H), 4.22-4.34 (m, 3H), 5.89 (t, 2H, J = 5.2 Hz), 7.32-7.38 (m, 2H), 7.64 (t, IH, J = 6.8 Hz), 7.78 (d, 2H, J = 8.8 Hz), 7.87 (d, 2H, J = 8.8 Hz), 7.94 (d, IH, J = 6.0 Hz).

[0179] 13CNMR (DMSO-d6, 100 MHz) δ: 35.80, 66.89, 71.71, 90.71, 115.13, 116.36, 122.23, 123.23, 124.11, 125.56, 128.25, 132.46, 132.78, 152.72, 161.58, 164.23, 164.50, 164.85.

[0180] HRMS (ESI) calcd for [M+H] + C 20 H 15 BrN2O5S + : 474.9958 found 474.9980.

[0181] Example Six:

[0182] Preparation of 4-(3-((5-(2-chlorophenyl)-l,3,4-oxadiazol-2-yl)thio)-2- hydroxypropoxy)-2H-chromen-2-one (Compound 16), which differs from Example One in that 7-hydroxy coumarin is replaced with 4-hydroxy coumarin and benzhydrazide is replaced with 2-chlorobenzhydrazide.

[0183] The structural formula of Compound 16 is shown below:

[0184]

[0185] Compound 16 is a white solid with a yield of 53%; melting point: 144-146 °C; and the data of the nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum and high resolution mass spectrum of Compound 16 are shown below:

[0186] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.50-3.70 (m, 2H), 4.24-4.31 (m, 3H), 5.88-5.92 (m, 2H), 7.31-7.38 (m, 2H), 7.50-7.55 (m, IH), 7.63 (t, IH, J = 6.8 Hz), 7.83 (d, IH, J = 8.0 Hz), 7.94 (d, 2H, J = 6.4 Hz), 8.06 (d, IH, J = 6.0 Hz).

[0187] 13CNMR (DMSO-d6, 100 MHz) δ: 35.83, 66.91, 71.69, 90.71, 115.10, 116.33, 122.38, 123.21, 124.07, 125.12, 125.37, 128.64, 131.57, 132.77, 134.65, 152.71, 161.56, 163.89 164.47, 164.83.

[0188] HRMS (ESI) calcd for [M+H] + C 20 H 15 ClN2O5S + : 431.0463 found 431.0474.

[0189] Example Seventeen:

[0190] Preparation of 4-(3-((5-(3-bromophenyl)-l,3,4-oxadiazol-2-yl)thio)-2- hydroxypropoxy)-2H-chromen-2-one (Compound 17), which differs from Example One in that 7-hydroxy coumarin is replaced with 4-hydroxy coumarin and benzhydrazide is replaced with 3-bromobenzhydrazide

[0191] The structural formula of Compound 17 is shown below:

[0192]

[0193] Compound 17 is a white powder with a yield of 43% and a melting point of 132-133 °C. The data for the nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum and high resolution mass spectrum of Compound 17 are shown below:

[0194] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.44-3.66 (m, 2H), 4.12-4.24 (m, 3H), 5.71 (d, IH, J = 5.6 Hz), 6.28 (d, IH, J = 6.4 Hz), 6.92-6.97 (m, 2H), 7.52-7.69 (m, 4H), 7.91-7.97 (m, 2H).

[0195] 13 CNMR (DMSO-d6, 100 MHz) δ: 36.13, 67.09, 70.95, 79.82, 101.31, 112.46, 112.54, 122.14, 127.71, 129.40, 130.98, 131.01, 131.57 133.08, 144.12, 155.22, 160.09, 161.42, 163.06, 164.49.

[0196] HRMS (ESI) calcd for [M+H] + C 20 H 15 BrN2O5S + : 474.9958 found 474.9974.

[0197] Example Eighteen:

[0198] Preparation of 4-(3-((5-(4-(tert-butyl)phenyl)-l,3,4-oxadiazol-2-yl)thio)-2- hydroxypropoxy)-2H-chromen-2-one (Compound 18), which differs from Example One in that 7-hydroxycoumarin is replaced with 4-hydroxycoumarin and benzhydrazide is replaced with 4-butylbenzhydrazide.

[0199] The structural formula of Compound 18 is shown below:

[0200]

[0201] Compound 18 is a white solid with a yield of 38% and a melting point of 172-173 °C. The data of the nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum and high resolution mass spectrum of Compound 18 are shown below:

[0202] 1 HNMR (DMSO-d6, 400 MHz) δ: 1.31 (s, 9H), 3.48-3.69 (m, 2H), 4.22-4.33 (m, 3H), 5.89 (t, 2H, J = 5.6 Hz), 7.31-7.38 (m, 2H), 7.55-7.65 (m, 3H), 7.85 (d, 2H, J = 8.4 Hz), 7.94 (d, 1H, J = 9.6 Hz).

[0203] 13 CNMR (DMSO-d6, 100 MHz) δ: 30.68, 34.67, 35.82, 66.88, 71.58, 90.59, 115.07, 116.19, 120.21, 123.07, 123.92, 126.02, 126.09, 132.60, 152.64, 154.82, 161.39, 163.41, 164.74, 165.08.

[0204] HRMS (ESI) calcd for [M+H] + C 24 H 24 N2O5S + : 453.1479 found 453.1494.

[0205] Example Nineteen:

[0206] 4-(3-((5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H- chromen-2-one (Compound 19) was prepared according to the procedures of Example One, except that 7-hydroxycoumarin was replaced by 4-hydroxycoumarin and benzhydrazide was replaced by 2-bromobenzhydrazide.

[0207] The structural formula of Compound 19 is shown below:

[0208]

[0209] Compound 19 was a white solid with a yield of 40% and a melting point of 175-176 °C. The H NMR, C NMR and high resolution mass spectrum data of Compound 19 are shown below:

[0210] 1 HNMR (DMSO-d6, 400 MHz) δ: 3.49-3.69 (m, 2H), 4.22-4.34 (m, 3H), 5.89 (t, 2H, J = 5.2 Hz), 7.32-7.43 (m, 4H), 7.64 (t, 1H, J = 8.8 Hz), 7.92-8.01 (m, 3H).

[0211] 13 CNMR (DMSO-d6, 100 MHz) δ: 35.83, 66.94, 71.75, 90.75, 115.16, 116.42, 116.59 (d, 2C, J = 22.4 Hz, 2 J CF ), 119.78 (d, 1C, J = 3.3 Hz, 4 J CF ), 123.28, 124.18, 129.09 (d, 2C, J = 9.1 Hz, 3 J CF ), 132.87, 152.76, 161.67 (d, 1C, J = 231.9 Hz, 1 J CF ), 162.86, 163.99, 164.46, 164.91.

[0212] HRMS (ESI) calcd for [M+H] + C 20 H 15 FN2O5S + : 415.0758 found 415.0768.

[0213] To further verify the excellent effect of the present application, the inventors also conducted the following comparative experiments:

[0214] Experiment 1

[0215] Different concentrations of the compound or acarbose (10 μL) and a certain concentration of α-glucosidase solution were added to a 96-well plate, and the mixture was incubated at 37°C for 15 minutes. Then 40 μL of p-nitrophenyl-α-D-glucopyranoside (1.25 mM) was added to the above mixture, and after 30 minutes of incubation, detection was performed on an enzyme marker instrument with a detection wavelength of 405 nm, and the IC 50 was calculated.

[0216] Table 1. Inhibitory activity (IC 50 ) of coumarin-oxadiazole compounds on α-glucosidase:

[0217]

[0218]

[0219] As can be seen from Table 1, most of the compounds synthesized in the present application have good inhibitory activity on α-glucosidase, and the inhibitory activity is greater than that of the positive control drug acarbose (339.50 ± 14.61 μM). Among these compounds, compound 11 has the strongest inhibitory activity, with an IC 50 of 30.57 ± 0.22 μM, which is about 10 times that of the positive control.

[0220] Experiment 2

[0221] The above compound 11 with the strongest α-glucosidase activity was dissolved with 10% DMSO, and ursolic acid was used as a positive control for the in vitro biological activity evaluation of PTP1B. The final concentration of DMSO in all reaction systems was controlled to be 1% during the reaction. PTP1B and compound 11 were reacted at room temperature for 30 min in a reaction system containing 25 mM MOPS (pH = 7.0), 50 mM NaCl, 0.05% Tween20, 3 mM DTT and 10 μM DiFMUP, with a total volume of 50 μL. The fluorescence intensity of the reaction system was measured by a Tecan Infinite M1000 enzyme marker instrument at an excitation wavelength of 358 nm and an emission wavelength of 455 nm. Phosphatase activity determination was repeated at each concentration, and the fluorescence intensity data was analyzed by Graphpad Prism8. It can be seen from the experimental results that compound 11 has a certain PTP1B inhibitory activity, with an IC 50 value of 7.58 ± 1.96 μM, and the IC 50 value of the positive control ursolic acid is 4.15 ± 1.09 μM.

[0222] Experiment three

[0223] Compound 11 was used to explore its effect on postprandial blood glucose in normal Kunming mice.

[0224] In this experiment, the purchased Kunming mice were adaptively fed for one week, then the mice were randomly divided into four groups (blank control group, negative control group, drug group and positive control acarbose group), 8 mice in each group, and the mice were fasted without water for 12 h. Before the experiment, the test compound 11 (4 mg / mL), acarbose (2 mg / mL) and sucrose (0.7 g / mL) were uniformly suspended in 0.5% CMC-Na aqueous solution under ultrasonic. Each mouse in each group was numbered and weighed. The drug group and the positive control acarbose group were gavaged with compound 11 and acarbose according to the gavage volume of 20 mg / kg, and gavaged with sucrose solution according to 2.5 g / kg; the blank control group was gavaged with sucrose solution according to 2.5 g / kg and the negative control group was gavaged with 0.5% CMC-Na aqueous solution according to 3.57 mL / kg, then the blood glucose concentration values of the tail vein of the mice at 0, 15, 30, 60, 90 and 150 min after sugar administration in each group were monitored and recorded using Roche Accu-Chek Instant blood glucose meter, and the experimental results were processed by Origin64 software. All procedures involving animals were strictly performed and complied with the Guidelines for the Welfare and Ethics of Laboratory Animals. In addition, these experiments have been approved by the Experimental Animal Management and Ethics Committee of Guizhou Medical University (Ethical Standard: 2001117).

[0225] By Figure 2 (A) It can be seen that the blood glucose of the blank control group rapidly increased and reached a peak after oral administration of sucrose, while the blood glucose of the acarbose group and the compound 11 group increased at a lower level than the blank control group after oral administration of sucrose, and the blood glucose was steadily reduced.

[0226] Figure 2 (B) describes the change of blood glucose load level of mice after oral administration of sucrose, and it can be seen from the figure that compound 11 can effectively reduce the postprandial blood glucose level.

[0227] Experiment four

[0228] HEK-293 cells were seeded in sterile 96-well plates at a density of 4x10 5 cells / well, and incubated at 37°C, 5% CO2 for 24 h, then different concentrations of compound 11 prepared with complete culture medium were added. After 24 h of co-incubation of compound and cells, 10-20 μL of 5 mg / mL sterile MTT solution was added and incubated for 1-4 h. After incubation, the supernatant was discarded, 150 μL of DMSO was added and shaken on a shaker until the crystals completely dissolved, then the absorbance value was measured at 490 nm by a multifunctional enzyme label instrument.

[0229] The results show that the calculated half maximal inhibitory concentration (IC50) value of compound 11 for HEK-293 cells was 204.15 ± 1.05 μM. The IC50value of compound 11 for α-glucosidase was 30.57 ± 0.22 μM, which is significantly lower than the IC50value for HEK-293 cells. This indicates that at concentrations at which compound 11 significantly inhibits α-glucosidase, it exhibits low toxicity for HEK-293 cells. 50 50 The results show that the calculated half maximal inhibitory concentration (IC50) value of compound 11 for HEK-293 cells was 204.15 ± 1.05 μM. The IC50value of compound 11 for α-glucosidase was 30.57 ± 0.22 μM, which is significantly lower than the IC50value for HEK-293 cells. This indicates that at concentrations at which compound 11 significantly inhibits α-glucosidase, it exhibits low toxicity for HEK-293 cells. 50

[0230] The above description of disclosed embodiments allows those skilled in the art to make or use the application. Numerous modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein can be applied to other embodiments without departing from the spirit or scope of the application. Therefore, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.​​

Claims

1. A coumarin-oxadiazole class of dual targeting inhibitor of a-glucosidase and PTP1B, characterized in that, The compound has a general structure as shown in formula (I): ； The specific structure is as follows: 。 2. A method for preparing the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor as described in claim 1, characterized in that, The method specifically comprises the following steps: Step 1: completely dissolve benzhydrazide with different substituents and potassium hydroxide in a proper amount of anhydrous ethanol, slowly add carbon disulfide while stirring, then stir and reflux at 80℃ for 2h; after the reaction is completed, filter and dry to obtain intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol with different substituents; Step 2: dissolve 4-hydroxycoumarin or 7-hydroxycoumarin in anhydrous ethanol and add potassium hydroxide, slowly add epichlorohydrin while stirring, and reflux at 80℃ for 5h; after the reaction is completed, cool the reaction mixture to room temperature, filter and dry to obtain intermediate 4-(oxirane-2-ylmethyl)-2H-chromen-2-one or 7-(oxirane-2-ylmethyl)-2H-chromen-2-one; Step 3: dissolve the product obtained in step 2, 4-(oxirane-2-ylmethyl)-2H-chromen-2-one or 7-(oxirane-2-ylmethyl)-2H-chromen-2-one, and the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol with different substituents obtained in step 1 in anhydrous ethanol, reflux at 80℃ for 5h; after the reaction is completed, purify the reaction mixture by column chromatography to obtain the target compound I, i.e. the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor.

3. The method of preparation of coumarin-oxadiazole alpha-glucosidase and PTP1 B dual target inhibitors according to claim 2, characterized in that, In step 1, the ratio of benzhydrazide with different substituents, carbon disulfide, KOH and anhydrous ethanol is 1-20mmol:2-50mmol:1-22mmol:10-300mL.

4. The method of preparing coumarin-oxadiazole alpha-glucosidase and PTP1B dual target inhibitors according to claim 2, characterized in that, In step 2, the ratio of 4-hydroxy or 7-hydroxycoumarin, epichlorohydrin, KOH and anhydrous ethanol is 1-100mmol:12-1200mmol:1-120mmol:10-500mL.

5. The method for preparing the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor according to claim 2, characterized in that, In step 3, the ratio of 4-(oxirane-2-ylmethyl)-2H-chromen-2-one or 7-(oxirane-2-ylmethyl)-2H-chromen-2-one, substituted 5-phenyl-1,3,4-oxadiazole-2-thiol and anhydrous ethanol is 1-20mmol:1-20mmol:15-300mL.

6. Use of the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor of claim 1 or the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor prepared by the method of any one of claims 2-5 in the preparation of a pharmaceutical preparation.

7. Use according to claim 6, characterized in that, The coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor is used for preparing an anti-diabetic drug.

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