Coumarin-oxadiazole alpha-glucosidase and PTP1B double-target inhibitor as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a coumarin-oxadiazole alpha-glucosidase and PTP1B double-target inhibitor as well as a preparation method and application thereof. The chemical structure of the alpha-glucosidase and PTP1B double-target inhibitor is # imgabs0. The coumarin-oxadiazole compound provided by the invention has good effects of inhibiting the activity of alpha-glucosidase and PTP1B and reducing postprandial blood sugar, and can be used as a novel lead compound for antidiabetic research; the compound also has relatively low toxicity to human normal HEK-293 cells, and is relatively high in safety; the coumarin-oxadiazole compound provided by the invention is simple in preparation method, relatively short in synthesis route, easy to prepare on a large scale, low in price and suitable for market popularization and application.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and specifically relates to a coumarin-oxadiazole alpha-glucosidase and PTP1B dual-target inhibitor, a preparation method and an application thereof. Background Art

[0002] Diabetes is a lifelong disease caused by absolute or relative insulin deficiency and impaired insulin utilization. The disease is mainly characterized by long-term hyperglycemia, which often leads to multi-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, α-glucosidase inhibitors play a key role. They are mainly located in the brush border of the small intestine and can hydrolyze carbohydrates into glucose to help the body absorb them. Compared with other hypoglycemic drugs, α-glucosidase inhibitors are effective in controlling postprandial blood sugar, have a low risk of hypoglycemia, and can also improve lipid metabolism and reduce the risk of cardiovascular complications of diabetes.

[0004] At the same time, protein tyrosine phosphatase 1B (PTP1B) has attracted much attention as an emerging target for diabetes treatment. Insulin relies on the normal transduction of the insulin signaling pathway to regulate blood sugar, and PTP1B can negatively regulate this pathway. It dephosphorylates tyrosine residues on insulin receptors and substrates, interrupts signal transduction, and induces insulin resistance, which is an important pathogenesis of type 2 diabetes, manifested as reduced sensitivity to insulin and insulin-induced glucose uptake and utilization efficiency. 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 new ideas for diabetes treatment.

[0005] Due to the complex pathogenesis of diabetes, single-target therapeutic drugs are not easy to effectively control blood sugar. In clinical practice, multiple types of anti-diabetic drugs are often used in combination to achieve effective blood sugar lowering effects. α-glucosidase and PTP1B dual-target inhibitors can act on two targets at the same time, giving full play to the synergistic effect. Compared with single-target inhibitors, dual-target inhibitors show more outstanding effects in lowering blood sugar, and are expected to bring new breakthroughs and changes to diabetes treatment.

[0006] Therefore, it is of great significance to research and develop a new, efficient and safe dual-target inhibitor of α-glucosidase and PTP1B. Summary of the invention

[0007] In view of this, the present invention provides a preparation method and application of a novel coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor.

[0008] It should be noted that the present invention designs and synthesizes a group of novel coumarin-oxadiazole derivatives, and further studies their α-glucosidase and PTP1B activities. The experimental results show that this class of compounds can effectively inhibit the activities of α-glucosidase and PTP1B, thereby reducing postprandial blood sugar, providing a more effective strategy for the treatment of diabetes.

[0009] Specifically, coumarin compounds naturally exist in higher plants, and their parent core structure has good rigidity and planarity, which facilitates binding to biomacromolecules through interactions such as π-π stacking and hydrogen bonding; 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. The five-membered heterocyclic structure of oxadiazole gives oxadiazole compounds good electronic and steric effects, enabling them to accurately bind to the active sites of different targets. The present invention is based on the potential inhibitory activity of coumarin and oxadiazole compounds on α-glucosidase and PTP1B, and it is of great significance to combine the two to design and construct dual-target inhibitors.

[0010] In order to achieve the above object, the present invention adopts the following technical solution:

[0011] The first technical purpose of the present invention is to provide a coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor having a structure as shown in formula (I):

[0012]

[0013] Wherein, the coumarin in the general formula I is 4- or 7-coumarin;

[0014] When it 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 it 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 structural formula of the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor is as follows:

[0017]

[0018] The second technical purpose of the present invention is to provide a method for preparing the above-mentioned coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor, which specifically comprises the following steps:

[0019] Step 1: completely dissolving benzoyl hydrazide and potassium hydroxide with different substituents in an appropriate amount of anhydrous ethanol, slowly adding carbon disulfide while stirring, and then stirring and refluxing at 80° C. for 2 h; when the reaction is completed, filtering, and then drying to obtain the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol with different substituents;

[0020]

[0021] Step 2: dissolving 4-hydroxycoumarin or 7-hydroxycoumarin in anhydrous ethanol and adding potassium hydroxide, slowly adding epichlorohydrin while stirring, and reflux reacting at 80° C. for 5 hours; after the reaction is completed, terminating the reaction process, and cooling the reaction mixture to room temperature, filtering it, and then drying the obtained solid to obtain the intermediate 4-(oxiran-2-ylmethyl)-2H-benzopyran-2-one or 7-(oxiran-2-ylmethyl)-2H-benzopyran-2-one;

[0022]

[0023] Step 3: The above-obtained product 4-(oxiran-2-ylmethyl)-2H-benzopyran-2-one or 7-(oxiran-2-ylmethyl)-2H-benzopyran-2-one and the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol with different substituents are dissolved in an appropriate amount of anhydrous ethanol, refluxed at 80°C for 5 hours. After the reaction is completed, the target compound I is purified by column chromatography using petroleum ether: ethyl acetate = 5:1 to obtain the target compound I, which is the coumarin-oxadiazole dual-target inhibitor of α-glucosidase and PTP1B.

[0024]

[0025] Preferably, the ratio of the different substituted benzoyl hydrazides, carbon disulfide, KOH and anhydrous ethanol is 2mmol:5mmol:2.2mmol:15mL.

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

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

[0028] The third technical purpose of the present invention is to request protection for the use of the above-mentioned coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor in pharmaceutical preparations.

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

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

[0031] 1. The coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitors disclosed in the present invention have good effects of inhibiting the activities of α-glucosidase and PTP1B and reducing postprandial blood sugar, and can be used as a new lead compound for anti-diabetic research;

[0032] 2. The preparation method of the coumarin-oxadiazole compounds disclosed in the present invention is simple, the synthetic route is short, it is easy to prepare in large quantities, and the price is low;

[0033] 3. The coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitors provided by the present invention have low toxicity to normal human cells and high safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0035] Figure 1 The present invention provides a preparation route for the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitors.

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

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

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

[0039] Figure 5 This is the high-resolution mass spectrum of compound 9.

[0040] Figure 6 is the H NMR spectrum of compound 11.

[0041] Figure 7 is the carbon NMR spectrum of compound 11.

[0042] Figure 8 This is the high-resolution mass spectrum of compound 11.

[0043] Fig. 9 is the H NMR spectrum of compound 13.

[0044] Fig.10 is the carbon NMR spectrum of compound 13.

[0045] Fig.11 This is the high-resolution mass spectrum of compound 13. DETAILED DESCRIPTION

[0046] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0047] The word "embodiment" used here as an "exemplary" does not necessarily mean that any embodiment described is superior to or better than other embodiments. Unless otherwise specified, the performance index tests in the embodiments of this application are performed using conventional test methods in the art. It should be understood that the terms described in this application are only used to describe specific implementation methods and are not used to limit the content disclosed in this application.

[0048] Unless otherwise specified, the technical and scientific terms used in this document have the same meanings as commonly understood by ordinary technicians in the technical field to which this application belongs; other experimental methods and technical means not specifically specified in this application refer to experimental methods and technical means commonly used by ordinary technicians in this field.

[0049] In order to better illustrate the content of the present application, numerous specific details are provided in the specific examples below. It should be understood by those skilled in the art that the present application can also be implemented without certain specific details. In the embodiments, some methods, means, instruments, equipment, etc. well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present application.

[0050] Under the premise of no conflict, the technical features disclosed in the embodiments of the present application can be combined arbitrarily, and the resulting technical solutions belong to the contents disclosed in the embodiments of the present application.

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

[0052] In order to better understand the present invention, the present invention is further specifically described below through the following examples, but it should not be understood as a limitation of the present invention. Some non-essential improvements and adjustments made by technicians in this field based on the above invention content are also considered to fall within the protection scope of the present invention.

[0053] Embodiment 1:

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

[0055] The structural formula of compound 1 is shown below:

[0056]

[0057] The specific preparation steps are as follows:

[0058] Step 1: 2 mmol of benzoyl hydrazide and 2.2 mmol of potassium hydroxide are completely dissolved in 15 mL of anhydrous ethanol, and 5 mmol of carbon disulfide is slowly added while stirring, and then stirred and refluxed at 80° C. for 2 h; when the reaction is completed, the solid is filtered and then dried to obtain the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol;

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

[0060] Step 3: Dissolve 1 mmol of the product 7-(2-oxirane-1-ylmethyl)-2H-benzopyran-2-one and 1 mmol of the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol obtained above in 15 mL of anhydrous ethanol, reflux at 80°C for 5 h. After the reaction is completed, purify by column chromatography with petroleum ether: ethyl acetate = 5:1 to obtain the target compound 1.

[0061] Compound 1 is a white solid with a yield of 68.00% and a melting point of 146.0-147.0°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 1 are as follows:

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

[0063] 13 CNMR(DMSO-d6,100MHz)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) calculation for [M+H] + C20H16N2O5S+:397.0853found397.0861.

[0065] The preparation methods of the following examples are similar to those of Example 1, and the ratio of the raw materials used is the same as that of Example 1, except that the 7-hydroxycoumarin in Example 1 is unchanged or changed to 4-hydroxycoumarin, and the benzohydrazide is replaced with other corresponding benzohydrazides.

[0066] Embodiment 2:

[0067] The preparation of 7-(2-hydroxy-3-((5-(m-tolyl)-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H-benzopyran-2-one (Compound 2) is different from Example 1 except that only benzoyl hydrazide is replaced with 3-methylbenzoyl hydrazide.

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

[0069]

[0070] Compound 2 is a white solid with a yield of 70% and a melting point of 140-141°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 2 are as follows:

[0071] 1 HNMR (DMSO-d 6,400MHz)δ:2.38(s,1H),3.64(d,2H,J=18.4Hz),4.24-4.12(m,3H),5.78(s,1H),6.29-6.27(d,1H,J=7.6Hz ),6.93-6.99(m,2H),7.40-7.47(m,2H),7.61(d,1H,J=9.6Hz),7.73(t,2H,J=6.4Hz),7.98(d,1H,J=7.6Hz).

[0072] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 21 H 18 N 2 O 5 S + :411.0965found411.0977.

[0074] Embodiment three:

[0075] The preparation of 7-(2-hydroxy-3-((5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H-benzopyran-2-one (Compound 3) is different from Example 1 in that only benzohydrazide is replaced by 2-hydroxybenzohydrazide.

[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 H NMR spectrum, C NMR spectrum and high-resolution mass spectrum of compound 3 are as follows:

[0079] 1 HNMR (DMSO-d 6,400MHz)δ:3.43-3.65(m,2H),4.10-4.25(m,3H),5.78(d,1H,J=5.2Hz),6.2 9(d,1H,J=8.0Hz),6.94-6.99(m,2H),7.55-7.63(m,4H),7.93-7.98(m,3H).

[0080] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 20 H 16 N 2 O 5 S + :397.0853found397.0861.

[0082] Embodiment 4:

[0083] The preparation of 7-(2-hydroxy-3-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H-benzopyran-2-one (Compound 4) is different from Example 1 except that only benzohydrazide is replaced by 4-methylbenzohydrazide.

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

[0085]

[0086] Compound 4 is a silver solid with a yield of 70%; melting point: 125-126°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 4 are as follows:

[0087] 1 HNMR (DMSO-d 6,400MHz)δ:2.39(s,3H),3.43-3.63(m,2H),4.12-4.25(m,3H),5.66(d,1H,J=5.2Hz),6.28(d,1H,J=9.2Hz), 6.92-6.97(m,2H),7.38(d,2H,J=8.0Hz),7.60(d,1H,J=8.4Hz),7.82(d,2H,J=8.0Hz),7.96(d,1H,J=9.6Hz).

[0088] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 21 H 18 N 2 O 5 S + :411.1009found411.1021.

[0090] Embodiment five:

[0091] The preparation of 7-(3-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 5) is different from Example 1 in that only benzohydrazide is replaced by 4-fluorobenzohydrazide.

[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: 135-136°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 5 are as follows:

[0095] 1 HNMR (DMSO-d 6 ,400MHz)δ:3.43-3.64(m,2H),4.10-4.25(m,3H),5.76(d,1H,J=5.2Hz),6.29(

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

[0097] 13 CNMR (DMSO-d 6 ,100MHz)δ:36.19,67.17,70.93,101.32,112.51,112.60,112.66(d,2C,J=19.

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

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

[0100] HRMS (ESI) calculation for [M+H] + C 20 H 15 FN 2 O 5 S + :415.0759found415.0779.

[0101] Embodiment six:

[0102] The preparation of 7-(3-((5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 6) is different from Example 1 except that only benzohydrazide is replaced with 4-butylbenzohydrazide.

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

[0104]

[0105] Compound 6 is a white solid with a yield of 71%; melting point: 153-155°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 6 are as follows:

[0106] 1 HNMR (DMSO-d 6 ,400MHz)δ:1.30(s,9H),3.42-3.64(m,2H),4.10-4.25(m,3H),5.78(d,1H,J=5.6Hz),6.29(d,1 H,J=9.6Hz),6.93-6.99(m,2H),7.56-7.62(m,3H),7.86(d,2H,J=8.8Hz),7.98(d,1H,J=9.6Hz),

[0107] 13 CNMR (DMSO-d 6 ,100MHz)δ:30.80,34.83,36.21,67.15,70.97,101.34,112.52,112.62,112.67,1 20.33,126.21,129.53,144.29,154.89,155.32,160.26,161.50,163.64,165.10.

[0108] HRMS (ESI) calculation for [M+H] + C 24 H 24 N 2 O 5 S + :453.1479found453.1486.

[0109] Embodiment seven:

[0110] The preparation of 7-(3-((5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 7) is different from Example 1 in that only benzohydrazide is replaced by 3-bromobenzohydrazide.

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

[0112]

[0113] Compound 7 is a light purple solid with a yield of 76%; melting point: 166-167°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 7 are as follows:

[0114] 1 HNMR (DMSO-d 6,400MHz)δ:3.42-3.65(m,2H),4.10-4.38(m,3H),5.76(d,1H,J=5.2Hz),6.29(d,1H,J=9.2Hz),6.95(t ,2H,J=8.8Hz),7.61(d,1H,J=8.4Hz),7.77(d,2H,J=6.4Hz),7.84-7.87(m,2H),7.97(d,1H,J=7.2Hz).

[0115] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 20 H 15 Bn 2 O 5 S + :474.9958found474.9979.

[0117] Embodiment eight:

[0118] Preparation of 4-(2-hydroxy-3-((5-phenyl-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H-benzopyran-2-one (Compound 8), compared with Example 1, except that only 7-hydroxycoumarin was replaced with 4-hydroxycoumarin

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

[0120]

[0121] Compound 8 is a white solid with a yield of 48%; melting point: 143-145°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 8 are as follows:

[0122] 1 HNMR (DMSO-d 6,400MHz)δ:3.44-3.66(m,2H),4.11-4.27(m,3H),5.76(d,1H,J=5.6Hz),6 .26-6.30(m,1H),6.93-6.99(m,2H),7.54-7.62(m,4H),7.92-7.99(m,3H).

[0123] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 20 H 16 N 2 O 5 S + :397.0853found397.0885.

[0125] Embodiment nine:

[0126] The preparation of (E)-2-((2-oxo-2H-benzopyran-7-yl)oxy)ethyl-3-(4-fluorophenyl)acrylate (Compound 9) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 2-hydroxybenzohydrazide.

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

[0128]

[0129] Compound 9 is a white solid with a yield of 39%; melting point: 204-206°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 9 are as follows:

[0130] 1 HNMR (DMSO-d 6,400MHz)δ:3.48-3.69(m,2H),4.24-4.36(m,3H),5.86(d,1H,J=5.2Hz),5.90(s,1H),6.96(t,1H,J=7 .6Hz),7.09(d,1H,J=8.4Hz),7.31-7.46(m,3H),7.61-7.71(m,2H),7.92-7.94(m,1H),10.19(s,1H).

[0131] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 20 H 16 N 2 O 6 S + :413.0802found413.0812.

[0133] Embodiment ten:

[0134] The preparation of 4-(2-hydroxy-3-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H-benzopyran-2-one (Compound 10) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 4-methylbenzohydrazide.

[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 H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 10 are as follows:

[0138] 1 HNMR (DMSO-d 6,400MHz)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=7.2Hz),7.80-7.83(m,2H),7.95(d,1H,J=7.6Hz).

[0139] 13 CNMR (DMSO-d 6 ,100MHz)δ:21.00,35,78,66.87,71.65,90.60,115.09,116.23,120.23,123.10,1 23.96,126.20,129.79,132.64,142.01,152.66,161.43,163.40,164.77,165.16.

[0140] HRMS (ESI) calculation for [M+H] + C 21 H 18 N 2 O 5 S + :411.1009found411.1013.

[0141] Embodiment eleven:

[0142] The preparation of 4-(3-((5-([1,1'-biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 11) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 4-biphenylbenzohydrazide.

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

[0144]

[0145] Compound 11 is a white powder with a yield of 50%; melting point: 197-199°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 11 are as follows:

[0146] 1 HNMR (DMSO-d 6,400MHz)δ:3.51-3.71(m,2H),4.24-4.36(m,3H),5.90(t,2H,J=5.6Hz),7.32-7.38(m,2H),7.44(t,1H,J=7.2Hz ),7.52(t,2H,J=7.2Hz),7.63(t,1H,J=7.2Hz),7.76(d,2H,J=6.8Hz),7.87(d,2H,J=8.8Hz),7.93-8.01(m,3H).

[0147] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 26 H 20 N 2 O 5 S + :473.1166 found473.1191.

[0149] Embodiment 12:

[0150] The preparation of 4-(3-((5-(2-bromophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 12) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 2-bromobenzohydrazide.

[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 H NMR spectrum, C NMR spectrum and high-resolution mass spectrum of compound 12 are as follows:

[0154] 1 HNMR (DMSO-d 6,400MHz)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,1H),7.82(d,2H,J=8.4Hz),7.92-7.94(m,1H).

[0155] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 20 H 15 Bn 2 O 5 S + :474.9958found474.9969.

[0157] Embodiment 13:

[0158] The preparation of 4-(3-((5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 13) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 2-aminobenzohydrazide.

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

[0160]

[0161] Compound 13 is a light yellow solid with a yield of 56%; melting point: 198-199°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 13 are as follows:

[0162] 1 HNMR (DMSO-d 6,400MHz)δ:3.48-3.69(m,2H),4.24-4.36(m,3H),5.82(d,1H,J=5.2Hz),5.90(s,1H),6.62(t,3H,J=7. 2Hz), 6.89 (s, 1H), 7.24 (t, 1H, J = 6.8Hz), 7.31-7.38 (m, 2H), 7.57-7.66 (m, 2H), 7.94 (d, 1H, J = 6.4Hz).

[0163] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 20 H 17 N 3 O 5 S + :412.0962found412.0970.

[0165] Embodiment 14:

[0166] The preparation of 4-(2-hydroxy-3-((5-(m-tolyl)-1,3,4-oxadiazol-2-yl)thio)propoxy)-2H-benzopyran-2-one (Compound 14) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 3-methylbenzohydrazide.

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

[0168]

[0169] Compound 14 is a white solid with a yield of 42%; melting point: 168-169°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 14 are as follows:

[0170] 1 HNMR (DMSO-d 6,400MHz)δ:2.38(s,3H),3.49-3.69(m,2H),4.24-4.36(m,3H),5.83(d,1H,J=5. 6Hz), 5.89 (s, 1H), 7.31-7.46 (m, 4H), 7.61-7.74 (m, 3H), 7.93 (d, 1H, J = 7.6Hz).

[0171] 13 CNMR (DMSO-d 6 ,100MHz)δ:20.67,35.81,66.87,71.63,90.60,115.07,116.20,122.87,123.08,123.42,1 23.92,126.54,129.13,132.48,132.61,138.77,152.64,161.41,163.67,164.74,165.14.

[0172] HRMS (ESI) calculation for [M+H] + C 21 H 18 N 2 O 5 S + :411.1009found411.1004.

[0173] Embodiment 15:

[0174] The preparation of 4-(3-((5-(4-bromophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-chromen-2-one (Compound 15) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 4-bromobenzohydrazide.

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

[0176]

[0177] Compound 15 is a white solid with a yield of 50%; melting point: 167-168°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 15 are as follows:

[0178] 1 HNMR (DMSO-d 6,400MHz)δ:3.49-3.70(m,2H),4.22-4.34(m,3H),5.89(t,2H,J=5.2Hz),7.32-7.38(m,2H) ,7.64(t,1H,J=6.8Hz),7.78(d,2H,J=8.8Hz),7.87(d,2H,J=8.8Hz),7.94(d,1H,J=6.0Hz).

[0179] 13 CNMR (DMSO-d 6 ,100MHz)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) calculation for [M+H] + C 20 H 15 Bn 2 O 5 S + :474.9958found474.9980.

[0181] Embodiment 16:

[0182] The preparation of 4-(3-((5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 16) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 2-chlorobenzohydrazide.

[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 H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 16 are as follows:

[0186] 1 HNMR (DMSO-d 6,400MHz)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,1H),7.63(t,1H,J=6.8Hz),7.83(d,1H,J=8.0Hz),7.94(d,2H,J=6.4Hz),8.06(d,1H,J=6.0Hz).

[0187] 13 CNMR (DMSO-d 6 ,100MHz)δ:35.83,66.91,71.69,90.71,115.10,116.33,122.38,123.21,124.07,125 .12,125.37,128.64,131.57,132.77,134.65,152.71,161.56,163.89164.47,164.83.

[0188] HRMS (ESI) calculation for [M+H] + C 20 H 15 C1N 2 O 5 S + :431.0463found431.0474.

[0189] Embodiment 17:

[0190] Preparation of 4-(3-((5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 17), compared with Example 1, except that 7-hydroxycoumarin was replaced with 4-hydroxycoumarin, and benzohydrazide was replaced with 3-bromobenzohydrazide

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

[0192]

[0193] Compound 17 is a white powder with a yield of 43%; melting point: 132-133°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 17 are as follows:

[0194] 1 HNMR (DMSO-d 6,400MHz)δ:3.44-3.66(m,2H),4.12-4.24(m,3H),5.71(d,1H,J=5.6Hz),6.2 8(d,1H,J=6.4Hz),6.92-6.97(m,2H),7.52-7.69(m,4H),7.91-7.97(m,2H).

[0195] 13 CNMR (DMSO-d 6 ,100MHz)δ:36.13,67.09,70.95,79.82,101.31,112.46,112.54,122.14,127.71,129 .40,130.98,131.01,131.57133.08,144.12,155.22,160.09,161.42,163.06,164.49.

[0196] HRMS (ESI) calculation for [M+H] + C 20 H 15 Bn 2 O 5 S + :474.9958found474.9974.

[0197] Embodiment 18:

[0198] The preparation of 4-(3-((5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 18) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 4-butylbenzohydrazide.

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

[0200]

[0201] Compound 18 is a white solid with a yield of 38%; melting point: 172-173°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 18 are as follows:

[0202] 1 HNMR (DMSO-d 6,400MHz)δ:1.31(s,9H),3.48-3.69(m,2H),4.22-4.33(m,3H),5.89(t,2H,J=5.6Hz) ,7.31-7.38(m,2H),7.55-7.65(m,3H),7.85(d,2H,J=8.4Hz),7.94(d,1H,J=9.6Hz).

[0203] 13 CNMR (DMSO-d 6 ,100MHz)δ:30.68,34.67,35.82,66.88,71.58,90.59,115.07,116.19,120.21,123.0 7,123.92,126.02,126.09,132.60,152.64,154.82,161.39,163.41,164.74,165.08.

[0204] HRMS (ESI) calculation for [M+H] + C 24 H 24 N 2 O 5 S + :453.1479found453.1494.

[0205] Embodiment 19:

[0206] The preparation of 4-(3-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thio)-2-hydroxypropoxy)-2H-benzopyran-2-one (Compound 19) is different from Example 1, except that 7-hydroxycoumarin is replaced by 4-hydroxycoumarin, and benzohydrazide is replaced by 2-bromobenzohydrazide.

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

[0208]

[0209] Compound 19 is a white solid with a yield of 40%; melting point: 175-176°C; and the data of H-NMR spectrum, C-NMR spectrum and high-resolution mass spectrum of compound 19 are as follows:

[0210] 1 HNMR (DMSO-d 6,400MHz)δ:3.49-3.69(m,2H),4.22-4.34(m,3H),5.89(t,2H,J=5.2Hz),7.32-7.43(m,4H),7.64(t,1H,J=8.8Hz),7.92-8.01(m,3H).

[0211] 13 CNMR (DMSO-d 6 ,100MHz)δ:35.83,66.94,71.75,90.75,115.16,116.42,116.59(d,2C,J=22.4Hz, 2 J CF ),119.78(d,1C,J=3.3Hz, 4 J CF ),123.28,124.18,129.09(d,2C,J=9.1Hz, 3 J CF ),132.87,152.76,161.67(d,1C,J=231.9Hz, 1 J CF ),162.86,163.99,164.46,164.91.

[0212] HRMS (ESI) calculation for [M+H] + C 20 H 15 FN 2 O 5 S + :415.0758found415.0768.

[0213] In order to further verify the excellent effect of the present invention, the inventors also conducted the following comparative experiments:

[0214] Experiment 1

[0215] Different concentrations of compounds 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-pyranoglucoside (1.25 mM) was added to the above mixture, and the mixture was incubated for another 30 minutes before detection on a microplate reader at a wavelength of 405 nm. IC 50 , the results are shown in Table 1.

[0216] Table 1. α-glucosidase inhibitory activity (IC 50 ):

[0217]

[0218]

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

[0220] Experiment 2

[0221] The compound 11 with the strongest α-glucosidase activity was dissolved in 10% DMSO. Ursolic acid was used as a positive control for the in vitro biological activity evaluation of PTP1B. During the reaction, the final concentration of DMSO in all reaction systems was controlled to be 1%. PTP1B and compound 11 were reacted at room temperature for 30 minutes in a reaction system containing 25mM MOPS (pH=7.0), 50mM NaCl, 0.05% Tween20, 3mM DTT and 10μM DiFMUP with a total volume of 50μL. The fluorescence intensity of the reaction system was measured by a Tecan Infinite M1000 microplate reader at an excitation wavelength of 358nm and an emission wavelength of 455nm. The phosphatase activity assay was repeated at each concentration, and the fluorescence intensity data was analyzed using Graphpad Prism 8. The experimental results show that compound 11 has a certain PTP1B inhibitory activity, IC 50 The value was 7.58±1.96μM, and the IC of the positive control ursolic acid was 50 The value was 4.15±1.09μM.

[0222] Experiment 3

[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 first adaptively raised for one week and then randomly divided into four groups (blank control group, negative control group, drug group and positive control acarbose group), with 8 mice in each group, and the mice were fasted but not watered for 12 hours. Before the experiment, the test compound 11 (4 mg / mL), acarbose (2 mg / mL) and sucrose (0.7 g / mL) were evenly suspended in 0.5% CMC-Na aqueous solution under ultrasound. 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 at a volume of 20 mg / kg, and sucrose solution was gavaged at 2.5 g / kg; the blank control group was gavaged with sucrose solution at 2.5 g / kg and the negative control group was gavaged with 0.5% CMC-Na aqueous solution at 3.57 mL / kg. Then, the blood glucose concentration of the mouse tail vein at 0, 15, 30, 60, 90 and 150 min after sugar administration in each group was monitored and recorded using a Roche Accu-Chek Instant blood glucose meter, and the experimental results were processed using Origin64 software. All procedures involving animals were strictly implemented and complied with the "Guidelines for the Welfare and Ethics of Laboratory Animals". In addition, these experiments have been approved by the Laboratory Animal Management and Ethics Committee of Guizhou Medical University (Ethics Code: 2001117).

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

[0226] Figure 2 (B) describes the changes in blood glucose load levels in mice after oral administration of sucrose. The figure shows that compound 11 can effectively reduce postprandial blood glucose levels.

[0227] Experiment 4

[0228] HEK-293 cells were cultured at 4 × 10 5 Cells were seeded at a density of 10 cells / well in a sterile 96-well plate and placed at 37°C with 5% CO 2 After culturing in an incubator for 24 hours, different concentrations of compound 11 prepared in complete medium were added. After the compound and cells were incubated for 24 hours, 10-20 μL of 5 mg / mL sterile MTT solution was added and incubated for 1-4 hours. After the incubation, the supernatant was discarded, 150 μL DMSO was added and shaken on a shaker until the crystals were completely dissolved, and the absorbance value was measured at 490 nm using a multifunctional microplate reader.

[0229] The experimental results showed that the calculated half inhibitory concentration (IC 50) value was 204.15±1.05μM. IC of compound 11 against α-glucosidase 50 The value was 30.57 ± 0.22 μM, which was significantly lower than its IC for HEK-293 cells. 50 This indicates that at the concentration at which compound 11 significantly inhibits α-glucosidase, it exhibits low toxicity to HEK-293 cells.

[0230] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A coumarin-oxadiazole dual-target inhibitor of α-glucosidase and PTP1B, characterized in that: It has the general structural formula shown in formula (I): Wherein, the coumarin in the general formula I is 4-coumarin or 7-coumarin; When the coumarin is 4-coumarin, R is at least one of H, 3-methyl, 2-hydroxy, 4-methyl, 4-fluoro, 4-butyl, and 3-bromo; When the coumarin is 7-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.

2. A method for preparing the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor according to claim 1, characterized in that: The method specifically comprises the following steps: Step 1: completely dissolve benzoyl hydrazide and potassium hydroxide with different substituents in an appropriate amount of anhydrous ethanol, slowly add carbon disulfide while stirring, and then stir and reflux at 80° C. for 2 h; after the reaction is completed, filter and dry to obtain the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol with different substituents; Step 2: dissolving 4-hydroxycoumarin or 7-hydroxycoumarin in anhydrous ethanol and adding potassium hydroxide, slowly adding epichlorohydrin while stirring, and reflux reacting at 80° C. for 5 hours; after the reaction is completed, the reaction mixture is cooled to room temperature, filtered, and dried to obtain the intermediate 4-(oxiran-2-ylmethyl)-2H-benzopyran-2-one or 7-(oxiran-2-ylmethyl)-2H-benzopyran-2-one; Step 3: Dissolve the product 4-(oxiran-2-ylmethyl)-2H-benzopyran-2-one or 7-(oxiran-2-ylmethyl)-2H-benzopyran-2-one obtained in step 2 and the intermediate 5-phenyl-1,3,4-oxadiazole-2-thiol with different substituents obtained in step 1 in anhydrous ethanol, and reflux for reaction at 80°C for 5 hours; 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 for preparing the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor according to claim 1, characterized in that: In step 1, the ratio of the benzoyl hydrazide with different substituents, carbon disulfide, KOH and anhydrous ethanol is 1-20 mmol: 2-50 mmol: 1-22 mmol: 10-300 mL.

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

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-(oxiran-2-ylmethyl)-2H-benzopyran-2-one or 7-(oxiran-2-ylmethyl)-2H-benzopyran-2-one, substituted 5-phenyl-1,3,4-oxadiazole-2-thiol and anhydrous ethanol is 1-20 mmol: 1-20 mmol: 15-300 mL.

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

7. The use according to claim 6, characterized in that: The application of the coumarin-oxadiazole α-glucosidase and PTP1B dual-target inhibitor in the preparation of anti-diabetic drugs.

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