An N-antipyrine oxalamide ethyl hydrazine-based alpha-glucosidase inhibitor and its preparation method and application

Abstract

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to an N-antipyrine oxamide ethyl hydrazine group alpha-glucosidase inhibitor, a preparation method and application thereof, and has a chemical structural formula as shown in formula (I): formula (I); in the formula, Ar is one of an aromatic group and a heterocycle. Compared with the prior art, the application solves the problem that the inhibitory effect of the alpha-glucosidase inhibitor in the prior art is insufficient and it is still difficult to meet the inhibitory requirement. The scheme further improves the inhibitory effect of the alpha-glucosidase inhibitor, and the IC 50 value is 7.84+ / -0.17 muM, which is less than 11.45+ / -0.12 muM of acarbose.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to an N-antipyrine ethylenediamide acetylide α-glucosidase inhibitor, its preparation method, and its application. Background Technology

[0002] Alpha-glucosidase inhibitors competitively bind to the active site of the enzyme, preventing it from binding to its substrate (oligosaccharides), thereby slowing down the breakdown of carbohydrates. This inhibition slows glucose absorption, resulting in a more gradual postprandial blood glucose spike and effectively preventing drastic blood glucose fluctuations. As a core target for controlling postprandial blood glucose, its inhibitory effect is crucial for the management of type 2 diabetes. Of the approximately 460 million people with diabetes worldwide, over 80% rely on alpha-glucosidase inhibitors for treatment. However, existing drugs such as acarbose have significant gastrointestinal side effects and fluctuating efficacy, necessitating the development of novel, highly effective, and low-toxicity inhibitors.

[0003] Patent application 202011115122.7 discloses a pyrazolopyrimidinone α-glucosidase inhibitor, its preparation method, and its application. The structure of the pyrazolopyrimidinone α-glucosidase inhibitor is shown in Formula 1. The pyrazolopyrimidinone α-glucosidase inhibitor described in this invention exhibits good α-glucosidase inhibitory activity, IC50... 50 The value was 45.74 μM, significantly better than the positive control nojirimycin (IC50). 50 The value is 52.02 μM. Patent application 202310472396.9 discloses a chalcone α-glucosidase inhibitor, its preparation method, and its application. The chalcone α-glucosidase inhibitor is prepared by introducing a phenyl group with hydroxyl and methoxy groups onto the chalcone skeleton, as shown in Formula 2. The optimal compound has an IC50 value of 52.02 μM. 50 The value was 239.7 ± 31.5 μM, significantly better than the positive control drug acarbose (IC50). 50 The value is 594.1 ± 3.2 μM. Patent application 202211055602.8 discloses a chromone-phenoxymethyl α-glucosidase inhibitor and its application in hypoglycemic drugs. This invention discloses that chromone-phenoxymethyl compounds inhibit α-glucosidase activity, and its inhibitory activity is much stronger than that of the positive control drug acarbose. The structural formula is shown in Formula 3. The IC50 of the compound is 594.1 ± 3.2 μM. 50 The value is 10.9 ± 0.29 μM.

[0004] Formula 1 Formula 2 Formula 3.

[0005] However, while the existing technologies have a good inhibitory effect on α-glucosidase activity, they can still be improved; moreover, most existing synthetic routes involve expensive raw materials and complex synthetic processes. Summary of the Invention

[0006] The purpose of this invention is to address at least one of the aforementioned problems by providing an N-antipyrine-ethylenediamide-ethylhydrazine-based α-glucosidase inhibitor, its preparation method, and its application. This addresses the issue that existing α-glucosidase inhibitors have insufficient inhibitory effects and still fail to meet the required inhibitory capacity. This solution further enhances the inhibitory effect of α-glucosidase inhibitors, achieving an IC50 value of [missing information]. 50 The value was 7.84±0.17μM, which was less than that of acarbose (11.45±0.12μM).

[0007] The objective of this invention is achieved through the following technical solution: The first aspect of this invention discloses an N-antipyrine-glycidamide-ethylhexylhydrazine-based α-glucosidase inhibitor having the chemical structural formula shown in formula (I): Formula (I); In the formula, Ar is one of the aromatic groups and heterocycles.

[0008] Preferably, Ar is selected from any of the following structural formulas: , , , , , , , , , , , , , and .

[0009] Preferably, Ar is selected from any of the following structural formulas: , , , , , , , , and .

[0010] Preferably, it has any one of the following structural formulas: , and .

[0011] Preferably, it has the following structural formula: .

[0012] A second aspect of this invention discloses a method for preparing an N-antipyrine-glycidyl acetylhydrazine-based α-glucosidase inhibitor as described in any of the preceding embodiments, comprising the following steps: S1: The first intermediate is obtained by reacting 4-aminoantipyrine with monoethyl oxalyl chloride; S2: The second intermediate is obtained by reacting the first intermediate with hydrazine hydrate; S3: The N-antipyrine ethylenediamide ethylhydrazine-based α-glucosidase inhibitor is obtained by reacting the second intermediate with an aromatic compound or a five-membered heterocyclic compound having an Ar structure.

[0013] Preferably, in step S1: Using dichloromethane as an organic solvent, 4-aminoantipyrine and monoethyl oxalyl chloride were mixed at 0-10℃; Triethylamine was used as an acid-binding agent, and the reaction was carried out at 10-40℃ for 8-12 hours.

[0014] Preferably, in step S2: Anhydrous ethanol was used as the organic solvent, and the reaction was carried out at 10-30℃ for 10-30 min.

[0015] Preferably, in step S3: Anhydrous methanol was used as the organic solvent and acetic acid was used as the catalyst. The reaction was carried out at 60-80℃ for 2-6 hours.

[0016] The third aspect of this invention discloses the use of an N-antipyrine ethylenediamide acetylide α-glucosidase inhibitor as described in any of the preceding descriptions in the preparation of a drug that inhibits α-glucosidase activity.

[0017] This invention utilizes a receptor-based molecular docking virtual screening method to screen 500,000 compounds from the ZINC database, obtaining a compound theoretically possessing α-glucosidase inhibitory activity. Subsequently, its structure was modified to design a more rational compound, from which 15 compounds were selected for α-glucosidase testing, using acarbose as a positive control. The IC50 of acarbose was... 50 The value is 11.45±0.12μM.

[0018] Compared with the prior art, the present invention has the following beneficial effects: In the structural formula proposed in this invention, the IC values ​​of the three preferred compounds are...50 The values ​​were all better than 11.45 ± 0.12 μM (acarbose), with the optimal compound having the best IC50 value. 50 The value reached 7.84±0.17μM, exhibiting excellent α-glucosidase inhibitory activity.

[0019] Compared with the prior art, the present invention provides an α-glucosidase inhibitor with a novel scaffold structure and its preparation method. The synthesis method of the α-glucosidase inhibitor with this structure is simple, and the obtained inhibitor has good α-glucosidase inhibitory activity and excellent α-glucosidase inhibitory effect. It can be applied to the preparation of drugs that inhibit α-glucosidase activity.

[0020] This invention utilizes the synergistic design of the antipyrine group and Ar (aromatic group or heterocyclic ring) to enhance hydrogen bonding and hydrophobic interactions with α-glucosidase, significantly improving targeted binding ability. In vitro enzyme inhibition experiments show that the compound exhibits superior inhibitory activity compared to the positive control drug acarbose. The synthetic process of this invention employs a condensation reaction, which is simple and uses inexpensive raw materials such as antipyrine, achieving a final inhibitor yield of >90%. This inhibitor combines high activity with simple preparation, providing an important candidate molecule for the development of highly effective and safe novel antidiabetic drugs. Detailed Implementation

[0021] The present invention will now be described in detail with reference to specific embodiments.

[0022] Unless otherwise specified, all reagents used in the following description are commercially available products, all methods used are known methods, and all other matters not covered herein can be handled using existing technologies.

[0023] This invention proposes an N-antipyrine-glycidyl acetylhydrazine-based α-glucosidase inhibitor, which has the following structural formula (I): Formula (I); In the formula, Ar is one of the aromatic groups and heterocycles.

[0024] Specifically, Ar is selected from any of the following structural formulas: , , , , , , , , , , , , , and .

[0025] Preferably, Ar is selected from any of the following structural formulas: , , , , , , , , and .

[0026] More preferably, Ar is selected from any of the following structural formulas: , and ; The chemical structural formula of this inhibitor is: , and .

[0027] The preparation method of the above-mentioned N-antipyrine ethylenediamide acetylide α-glucosidase inhibitor specifically includes the following steps: (1) After reacting 4-aminoantipyrine and oxaloyl chloride monoethyl ester, the intermediate of formula III was obtained by post-treatment. (2) Dissolve intermediate III in anhydrous ethanol and react it with hydrazine hydrate to obtain intermediate II; (3) Take intermediate formula II and aromatic compound or five-membered heterocyclic compound with Ar structure and dissolve them in anhydrous methanol, an organic solvent. After reaction, the inhibitor shown in formula I is obtained (with the structural formula shown in formula (I), and the R substituent in the following formula is the Ar substituent in formula (I)).

[0028] The equation for this preparation method is shown below: In step (1), triethylamine (ET3N) is used as an acid-binding agent, and dichloromethane (DCM) is used as an organic solvent. The system temperature when adding oxaloyl chloride monoethyl ester to 4-aminoantipyrine is 0-10℃, preferably 0℃. Low temperature control avoids the problem of incomplete reaction or byproduct formation caused by the easy volatilization of oxaloyl chloride monoethyl ester at room temperature. The reaction temperature when the raw materials react is 10-40℃, preferably 25℃, and the reaction time is 8-12h, preferably 10h. The post-treatment process is as follows: the mixture after the reaction is completed is added to a separatory funnel, and then extracted twice with distilled water to collect the organic phase. The organic phase is then washed multiple times with saturated NaHCO3 solution (3×1.0mL) and 20mL of saturated NaCl solution. Finally, the organic layer is dried with anhydrous Na2SO4, and the solvent is removed by vacuum distillation to obtain the pure intermediate of formula III.

[0029] In the above, the ratio of 4-aminoantipyrine, oxaloyl chloride monoethyl ester, triethylamine and the organic solvent dichloromethane (DMC) is (30-60) mmol:(50-80) mmol:(30-60) mmol:(30-50) mL, and the preferred ratio is 49 mmol:63.7 mmol:49 mmol:40 mL.

[0030] In step (2), the reaction temperature is 10-30℃, preferably 25℃, and the reaction time is 10-30min, preferably 20min. The post-processing is as follows: after the material is completely converted, the reaction system temperature is lowered to room temperature for filtration. The filter cake is washed twice with anhydrous ethanol and dried in a vacuum oven to obtain pure compound formula II intermediate.

[0031] In the above, the ratio of the intermediate of Formula III to hydrazine hydrate is (40-60) mmol:(40-60) mmol, and the preferred ratio is 50 mmol:50 mmol.

[0032] In step (3), acetic acid is used as a catalyst; the reaction system is placed in an oil bath and heated at 60-80℃, preferably 65℃, for a reaction time of 2-6 hours, preferably 3 hours. The post-treatment process is as follows: the reaction system is removed and cooled, the reaction solution is cooled to room temperature and then filtered, the filter cake is washed with a small amount of anhydrous methanol or ethyl acetate, and the filter cake is dried to obtain the inhibitor shown in Formula I.

[0033] In the above, the ratio of the intermediate of Formula II, the substituted aromatic group or the five-membered heterocycle and the catalyst acetic acid is (30-50) mmol:(30-50) mmol:(1-3) mL, preferably 35 mmol:35 mmol:2 mL.

[0034] In the following examples, the inhibitors prepared were also tested for their α-glucosidase inhibitory activity. The specific test methods are as follows: 1. Experimental instruments and materials Multifunctional fluorescent microplate reader, SPMax3500FL, Shanghai Flash Spectrum Biotechnology Co., Ltd.; Clean bench; Bond A3 Pipette manual single-channel adjustable pipette, 0.5-10 μL, 10-100 μL, 100-1000 μL, Titan Technology; 96-well plate (white), sterilized, Corning.

[0035] α-Glucosidase was purchased from Beijing Innocare Technology Co., Ltd.; the fluorescent substrate p-nitrobenzene-α-D-glucopyranoside (PNPG) used in the enzyme inhibition experiment was purchased from Shanghai Myriel Biochemical Technology Co., Ltd.; anhydrous disodium hydrogen phosphate, anhydrous disodium hydrogen phosphate, and sodium carbonate were purchased from Titan Technology.

[0036] Positive control drug: acarbose, Shanghai Myrui Biochemical Technology Co., Ltd.

[0037] 2. Reagent preparation a. 0.1 mol / L, pH=6.8 phosphate buffer (PBS): Mix 0.1 mM sodium dihydrogen phosphate solution with 0.1 mM disodium hydrogen phosphate solution and adjust the pH of the solution to 6.80.

[0038] b. Substrate solution: Accurately weigh 1.5 mg PNPG and dissolve it in 1 mL of PBS buffer to prepare a 5 mM PNPG solution. Prepare fresh before use.

[0039] c. Enzyme solution: Add 100U of lyophilized enzyme powder to PBS buffer to prepare a stock solution with a concentration of 10U / mL. Store at -20℃. Dilute to 0.4U / mL before use. Prepare fresh before use.

[0040] d. Termination solution: Weigh anhydrous sodium carbonate and dissolve it in distilled water to prepare a 0.2 mol / L sodium carbonate solution.

[0041] e. Positive control and sample solutions: Acarbose and fifteen target compounds (corresponding to Examples 1-15) were dissolved in DMSO to prepare an initial concentration of 4000 μmol / L. This was then serially diluted to eight concentration gradients: 1000 μmol / L, 500 μmol / L, 250 μmol / L, 125 μmol / L, 62.5 μmol / L, 31.25 μmol / L, 15.625 μmol / L, and 7.813 μmol / L. Three sets of each concentration gradient were prepared sequentially.

[0042] 3. Experimental Methods This experiment was conducted in a 96-well plate with a total reaction volume of 200 μL. 100 μL of PBS buffer was added to each well, followed by 20 μL of different concentrations of the α-glucosidase inhibitor sample or positive control sample solution. Then, 20 μL of α-glucosidase solution was added, and the plate was incubated at 37°C for 30 min. Next, 20 μL of PNPG solution was added, and incubation continued for 15 min. Finally, 40 μL of sodium carbonate solution was added to each well to terminate the reaction. The absorbance of each well was measured at 405 nm. The experiment was performed in triplicate.

[0043] The experiment consisted of four groups: Sample group A (enzyme solution + substrate solution + buffer solution + test sample solution / acarbose solution + stop solution); Sample background group A0 (sample solution + substrate solution + buffer solution + stop solution); Negative control group B (enzyme solution + substrate solution + buffer solution + DMSO + stop solution); Negative background control group B0 (substrate solution + buffer solution + DMSO + stop solution).

[0044] The amount of reagents added to each group is shown in Table 1.

[0045] Table 1. Amount of reagents added to the four experimental groups After measuring the absorbance, the corresponding inhibition rate was calculated using a formula. The data was then processed using GraphPadprism software to fit a curve and the corresponding IC. 50 Value. The formula for the inhibition rate of the sample against α-glucosidase is as follows: ; In the formula: A The absorbance indicates the absorbance of the substrate and α-glucosidase in the presence of the sample solvent after incubation at 37°C for 30 min. A 0 indicates the background absorbance of the system after 30 minutes of reaction without the addition of α-glucosidase, in the presence of the sample and solvent; B The absorbance indicates the absorbance of the system after incubation at 37°C for 30 min in the presence of the substrate and α-glucosidase. B 0 indicates the absorbance of the system after incubation at 37°C for 30 min with only substrate and solvent added.

[0046] Example 1 (E)-2-(2-(4-(benzyloxy)-3-methoxyphenylmethylene)hydrazyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxoacetamide.

[0047] Its structural formula is shown below: The specific synthesis steps are as follows: (1) Accurately weigh 10 g (49 mmol) of 4-aminoantipyrine and add it to a round-bottom flask. Then pour in 200 mL of dichloromethane (DCM) and sonicate to dissolve the compound. Mix 8.7 g (63.7 mmol) of oxaloyl chloride monoethyl ester and 5 g (49 mmol) of triethylamine and add them to a constant-pressure dropping funnel. Add the mixture dropwise to the round-bottom flask at 0 °C. After the addition is complete and no obvious white fumes are observed in the round-bottom flask, remove the reaction vessel and place it at 25 °C with stirring for 10 hours. After the reaction is complete, add the mixture to a separatory funnel and extract it twice with distilled water. Collect the organic phase. Wash the organic phase several times with saturated NaHCO3 solution (3 × 1.0 mL) and 20 mL of saturated NaCl solution. Finally, dry the organic layer with anhydrous Na2SO4 and remove the solvent by vacuum distillation to obtain the pure intermediate of formula III.

[0048] (2) Accurately weigh 6.5 g (50 mmol) of intermediate III into a 50 mL round-bottom flask, add 20 mL of anhydrous ethanol, heat to dissolve, then use a 5 mL disposable syringe to add 1.1 g (50 mmol) of hydrazine hydrate to the system, and react at 25 °C for 20 minutes. After the material conversion is complete, cool the reaction system to room temperature and filter. Wash the filter cake twice with anhydrous ethanol and dry it in a vacuum oven to obtain pure intermediate II.

[0049] (3) Accurately weigh 1 g (35 mmol) of intermediate II and 0.43 g (35 mmol) of 3-benzyloxy-4-methoxybenzaldehyde into a 50 mL round-bottom flask, add 12 mL of anhydrous methanol, and then use a 1 mL disposable syringe to add 1 mL of acetic acid dropwise to the system. React at 65 °C for 3 hours. After the reaction is complete, remove the reaction system and cool it. After the reaction solution is cooled to room temperature, filter it. Wash the filter cake with a small amount of anhydrous methanol or ethyl acetate, and dry the filter cake to obtain the inhibitor shown in the above formula.

[0050] Experimental results (E)-2-(2-(4-(benzyloxy)-3-methoxyphenylmethylene)hydrazinyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxoacetamide, a pale yellow powder solid, 97% yield, IC5050 The value was 7.84±0.17μM, and the IC50 of the positive control drug acarbose was... 50 The value is 11.45±0.12μM.

[0051] 1HNMR(400MHz,DMSO)δ12.13(s,1H),9.92(s,1H),8.52(s,1H),7.55–7.44(m,4H),7.43–7.33(m,7H),7.19(dd,J=8.4,1.9Hz, 1H),7.13(d,J=8.4Hz,1H),5.15(s,2H),3.83(s,3H),3.10(s,3H),2.19(s,3H).13CNMR(101MHz,DMSO)δ161.60,159.85,156.4 2,152.72,151.67,150.63,149.83,137.15,135.34,129.62,128.93,128.46,128.39,127.30,126.89,124.16,124.03,122.77,113.50,109.22,106.54,70.34,56.03,40.61,40.56,40.41,40.35,40.15,39.94,39.73,39.52,39.31,36.25,11.78,11.42. Example 2 (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxo-2-(2-(2,4,6-trihydroxyphenylmethylene)hydrazone)acetamide.

[0052] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Brown powdery solid, 95% yield, IC 50 The value is 9.97±7.57μM.

[0053] 1HNMR(600MHz,DMSO)δ12.42(s,1H),11.06(s,2H),9.91(s,2H),8.93(s,1H),7.56–7.49(m ,2H),7.39–7.31(m,3H),5.84(s,2H),3.10(s,3H),2.18(s,3H).13CNMR(151MHz,DMSO)δ162 .58,161.59,160.57,159.52,155.93,152.82,150.31,135.37,129.61,126.85,124.11,106.55,99.53,94.85,40.51,40.39,40.25,40.11,39.98,39.84,39.70,39.56,36.29,11.38. Example 3 (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxo-2-(2-((2-phenyl-1H-indene-3-yl)methylene)hydrazone)acetamide.

[0054] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Yellow powdery solid, 94% yield, IC 50 The value is 10.22 ± 0.21 μM.

[0055] 1HNMR(400MHz,DMSO)δ12.07(s,1H),11.95(s,1H),9.83(s,1H),8.94(s,1H),8.45(d,J=7.8Hz,1H),7.72-7.67(m,2H),7.59(t ,J=7.4Hz,2H),7.55-7.46(m,4H),7.40-7.31(m,3H),7.29-7.18(m,2H),3.10(s,3H),2.20(s,3H).13CNMR(101MHz,DMSO)δ161 .66,160.19,155.90,152.69,148.64,142.94,136.98,135.38,131.36,129.72,129.61,129.46,129.38,129.28,126.85,126.04,124.11,123.63,123.08,121.45,112.04,108.39,106.73,40.60,40.39,40.18,39.97,39.76,39.56,39.35,36.31,11.48. Example 4 (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(2-(4-nitrobenzylimino)-2-oxoacetamide).

[0056] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Pale yellow powdery solid, yield 92%, IC 50 The value was 22.85±4.97μM.

[0057] 1HNMR(400MHz,DMSO)δ12.55(s,1H),10.03(s,1H),8.71(s,1H),8.35–8.23(m,2H),8.02–7.92(m, 2H),7.58–7.48(m,2H),7.43–7.30(m,3H),3.11(s,3H),2.20(s,3H).13CNMR(101MHz,DMSO)δ161.5 4,159.50,157.04,152.77,149.07,148.66,140.53,135.35,129.61,128.87,126.87,124.59,124.23,124.13,106.46,40.66,40.61,40.45,40.40,40.19,39.98,39.77,39.56,39.35,36.27,11.40. Example 5 (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxo-2-(2-(thiophen-2-methylene)hydrazyl)acetamide.

[0058] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Brown powdery solid, yield 92%, IC 50 The value is 25.40±9.14.

[0059] 1HNMR(400MHz,DMSO)δ12.24(s,1H),9.94(s,1H),8.78(s,1H),7.73(d,J=6.1Hz,1H),7.56–7.45(m ,3H),7.41–7.30(m,3H),7.16(dd,J=5.1,3.6Hz,1H),3.10(s,3H),2.18(s,3H).13CNMR(101MHz,DMS O) δ161.57,159.69,156.41,152.75,146.31,139.04,135.36,132.36,130.25,129.61,128.51,126. 86,124.21,124.12,106.54,40.60,40.45,40.39,40.19,39.98,39.77,39.56,39.35,36.28,11.42. Example 6 (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxo-2-(2-(4-phenoxybenzylmethylene)hydrazone)acetamide.

[0060] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Pale yellow powdery solid, yield 90%, IC 50 The value was 29.56 ± 4.98 μM.

[0061] 1HNMR(400MHz,DMSO)δ12.20(s,1H),9.95(s,1H),8.58(s,1H),7.76–7.71(m,2H),7.52(dd,J=8.4,7.3Hz,2H),7.48– 7.42(m,2H),7.39–7.31(m,3H),7.25–7.19(m,1H),7.13–7.03(m,4H),3.10(s,3H),2.19(s,3H).13CNMR(101MHz,DMS O) δ161.58,159.79,159.48,156.54,156.10,152.75,150.88,135.37,130.73,129.86,129.60,129.28,126.84,124. 76,124.16,124.11,119.98,119.85,118.69,106.59,40.61,40.40,40.19,39.98,39.77,39.57,39.36,36.29,11.42. Example 7 (E)-2-(2-(2-amino-5-chlorophenylmethylene)hydrazone)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxoacetamide.

[0062] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Yellow powdery solid, 93% yield, IC 50 The value was 119.20 ± 6.33 μM.

[0063] 1HNMR(400MHz,DMSO)δ12.28(s,1H),9.92(s,1H),8.60(s,1H),7.57–7.47(m,2H),7.41–7.29(m,3H),7.2 0(d,J=2.6Hz,1H),7.15(dd,J=8.8,2.6Hz,3H),6.78(d,J=8.8Hz,1H),3.10(s,3H),2.19(s,3H).13CNMR(1 01MHz, DMSO) δ161.60,159.65,156.35,153.28,152.75,147.42,135.34,131.52,130.96,129.61,126.89, 124.16,118.46,117.53,115.98,106.49,40.59,40.38,40.17,39.96,39.75,39.55,39.34,36.26,11.42. Example 8 (E)-2-(2-((6-chloropyridin-3-yl)methylene)hydrazyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxoacetamide.

[0064] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Pale yellow powdery solid, yield 90%, IC 50 The value was 178.90±19.75μM.

[0065] 1HNMR(400MHz,DMSO)δ12.50(s,1H),10.00(s,1H),8.70–8.62(m,2H),8.20(dd,J=8.4,2.4Hz,1H),7.62(d,J=8 .3Hz,1H),7.57–7.48(m,2H),7.42–7.30(m,3H),3.11(s,3H),2.19(s,3H).13CNMR(101MHz,DMSO)δ161.55,159 .56,156.89,152.75,152.02,149.70,147.50,137.56,135.34,129.90,129.61,126.88,125.27,124.24,124.14,106.46,40.64,40.59,40.43,40.38,40.18,40.02,39.97,39.76,39.55,39.34,36.32,36.26,11.63,11.40. Example 9 ((E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxo-2-(2-(2,4,6-trimethoxybenzyl)hydrazyl)acetamide.

[0066] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Yellow powdery solid, 93% yield, IC 50 The value was 225.70 ± 13.63 μM.

[0067] 1HNMR(400MHz,DMSO)δ11.88(s,1H),9.82(s,1H),8.67(s,1H),7.56–7.47(m,2H),7.41–7.29(m ,3H),3.82(d,J=15.8Hz,10H),3.10(s,3H),2.19(s,3H).13CNMR(101MHz,DMSO)δ163.12,161.64 ,160.60,160.10,156.12,152.75,147.70,135.38,129.60,126.83,124.09,106.70,104.27,91.67,91.58,56.47,55.93,40.60,40.44,40.39,40.18,39.97,39.76,39.55,39.34,36.31,11.43. Example 10 (E)-2-(2-(4-chlorophenylimino)hydrazino)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxoacetamide.

[0068] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures).

[0069] Pale yellow powdery solid, yield 94%, IC 50 The value was 362.90 ± 19.22 μM.

[0070] 1HNMR(400MHz,DMSO)δ12.32(s,1H),9.98(s,1H),8.60(s,1H),7.74(d,J=8.6Hz,2H),7. 56–7.49(m,4H),7.42–7.29(m,3H),3.10(s,3H),2.19(s,3H).13CNMR(101MHz,DMSO)δ161 .56,159.67,156.73,152.75,150.21,135.55,135.35,133.29,129.60,129.53,129.51,126.86,124.12,106.53,40.60,40.39,40.18,39.97,39.77,39.56,39.35,36.27,11.41. Example 11 (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(2-(4-hydroxyphenylmethylene)hydrazyl)-2-oxoacetamide.

[0071] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Pale yellow powdery solid, yield 90%, IC 50 The value was 435.20 ± 18.30 μM.

[0072] 1HNMR(401MHz,DMSO)δ12.05(s,1H),10.08(s,1H),9.92(s,1H),8.51(s,1H),7.62–7.50(m,4H), 7.38(dd,J=15.1,7.6Hz,3H),6.88(d,J=8.3Hz,2H),3.12(s,3H),2.21(s,3H).13CNMR(101MHz,DM SO)δ161.63,160.38,159.93,156.34,152.71,151.84,135.35,129.80,129.64,126.93,125.35, 124.20,116.29,116.16,106.56,40.58,40.37,40.16,39.95,39.75,39.54,39.33,36.26,11.43. Example 12 (E)-2-(2-(4-(tert-butyl)benzylphenylmethylene)hydrazyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxoacetamide.

[0073] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Pale yellow powdery solid, yield 95%, IC 50 The value was 673.60±9.62μM.

[0074] 1HNMR(400MHz,DMSO)δ12.19(s,1H),9.94(s,1H),8.58(s,1H),7.66(d,J=8.5Hz,2H),7.56–7.42(m,4H),7.4 2–7.29(m,3H),3.10(s,3H),2.19(s,3H),1.30(s,9H).13CNMR(101MHz,DMSO)δ161.59,159.79,156.58,153. 97,152.75,151.47,135.35,131.66,129.60,127.76,126.86,126.19,126.08,124.12,106.57,40.64,40.59,40.43,40.38,40.22,40.17,39.96,39.75,39.54,39.33,36.35,36.27,35.12,35.06,31.50,31.40,11.42. Example 13 (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxo-2-(2-(4-(trifluoromethoxy)benzyl)hydrazyl)acetamide.

[0075] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Pale yellow powdery solid, yield 92%, IC 50 The value was 717.70 ± 20.65 μM.

[0076] 1HNMR(400MHz,DMSO)δ12.34(s,1H),9.99(s,1H),8.63(s,1H),7.86(d,J=8.8Hz,2H),7.52(dd,J=8.4 ,7.3Hz,2H),7.46(d,J=7.7Hz,2H),7.35(dd,J=16.6,8.0Hz,3H),3.10(s,3H),2.19(s,3H).13CNMR(1 01MHz, DMSO) δ161.57,159.66,156.79,152.75,150.09,149.93,135.35,133.59,129.80,129.59,126 .86,124.13,121.80,119.19,106.52,40.58,40.37,40.16,39.95,39.75,39.54,39.33,36.25,11.39. Example 14 (E)-2-(2-((1H-indol-3-yl)methylene)hydrazyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-oxoacetamide.

[0077] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Yellow powdery solid, 91% yield, IC 50 The value is >1000μM.

[0078] 1HNMR(400MHz,DMSO)δ11.92(s,1H),11.66(d,J=2.9Hz,1H),9.84(s,1H),8.74(s,1H),8.26(d,J=7.3Hz,1H),7.83(d,J=2 .8Hz,1H),7.53(dd,J=8.5,7.3Hz,2H),7.46(d,J=7.1Hz,1H),7.40–7.32(m,3H),7.25–7.15(m,2H),3.11(s,3H),2.20(s, 3H).13CNMR(101MHz,DMSO)δ161.66,160.20,155.88,152.73,148.44,137.52,135.38,131.66,129.61,126.86,124.79,1 24.12,123.23,122.40,121.10,112.39,111.91,106.72,40.59,40.38,40.17,39.96,39.75,39.54,39.34,36.31,11.47. Example 15 (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(2-(naphthyl-1-methylene)hydrazyl)-2-oxoacetamide.

[0079] Its structural formula is as follows, and it was prepared in a similar manner to Example 1, except that the reactants used in step (3) are different (corresponding to different Ar structures). Pale yellow powdery solid, yield 97%, IC 50 The value is >1000μM.

[0080] 1HNMR(400MHz,DMSO)δ12.36(s,1H),9.99(s,1H),8.77(s,1H),8.15(d,J=1.3Hz,1H),8.08–8.02(m,1H),8.01–7.9 4(m,3H),7.61–7.50(m,4H),7.40–7.32(m,3H),3.11(s,3H),2.20(s,3H).13CNMR(101MHz,DMSO)δ161.59,159.77, 156.72,152.76,151.48,135.37,134.44,133.27,132.10,129.92,129.61,129.08,128.97,128.27,127.89,127.32,126.87,124.13,124.02,123.16,106.56,40.60,40.44,40.39,40.18,39.98,39.77,39.56,39.35,36.29,11.43. The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. An N-antipyrine-glycidyl acetylide α-glucosidase inhibitor, characterized in that, It has the chemical structural formula shown in formula (I): Equation (I); In the formula, Ar is one of the aromatic groups and heterocycles.

2. The N-antipyrine-glycidamide-ethylhexylhydrazine-based α-glucosidase inhibitor according to claim 1, characterized in that, Ar is selected from any of the following structural formulas: , , , , , , , , , , , , , and .

3. The N-antipyrine-glycidamide-ethionylhydrazine-based α-glucosidase inhibitor according to claim 1, characterized in that, Ar is selected from any of the following structural formulas: , , , , , , , , and .

4. The N-antipyrine-glycidamide-acetylide α-glucosidase inhibitor according to claim 1, characterized in that, It has any of the following structural formulas: , and .

5. The N-antipyrine-glycidamide-ethylhexylhydrazine-based α-glucosidase inhibitor according to claim 1, characterized in that, It has the following structural formula: 。 6. A method for preparing an N-antipyrine-glycidamide-ethylhexylhydrazine-based α-glucosidase inhibitor as described in any one of claims 1-5, characterized in that, Includes the following steps: S1: The first intermediate is obtained by reacting 4-aminoantipyrine with monoethyl oxalyl chloride; S2: The second intermediate is obtained by reacting the first intermediate with hydrazine hydrate; S3: The N-antipyrine ethylenediamide ethylhydrazine-based α-glucosidase inhibitor is obtained by reacting the second intermediate with an aromatic compound or a five-membered heterocyclic compound having an Ar structure.

7. The method for preparing an N-antipyrine-glycidamide-ethylhexylhydrazine-based α-glucosidase inhibitor according to claim 6, characterized in that, In step S1: Using dichloromethane as an organic solvent, 4-aminoantipyrine and monoethyl oxalyl chloride were mixed at 0-10℃; Triethylamine was used as an acid-binding agent, and the reaction was carried out at 10-40℃ for 8-12 hours.

8. The method for preparing an N-antipyrine-glycidyl acetylhydrazine-based α-glucosidase inhibitor according to claim 6, characterized in that, In step S2: Anhydrous ethanol was used as the organic solvent, and the reaction was carried out at 10-30℃ for 10-30 min.

9. The method for preparing an N-antipyrine-glycidyl acetylhydrazine-based α-glucosidase inhibitor according to claim 6, characterized in that, In step S3: Anhydrous methanol was used as the organic solvent and acetic acid was used as the catalyst. The reaction was carried out at 60-80℃ for 2-6 hours.

10. The use of an N-antipyrine ethylenediamide acetylide α-glucosidase inhibitor as described in any one of claims 1-5 in the preparation of a medicament for inhibiting α-glucosidase activity.

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