Dual-target piperine compounds for use as alpha-glucosidase inhibitors and aldose reductase inhibitors, and methods of preparation and use

Abstract

The application provides a dual-target piperine compound used as an alpha-glucosidase inhibitor and an aldose reductase inhibitor, the compound has a general structure of piperine, a series of structural modifications are carried out based on piperine, and finally a series of dual-target piperine compounds are synthesized. The dual-target piperine compound provided by the application can simultaneously inhibit the activities of alpha-glucosidase and aldose reductase, has the function of dual targets, can be used as a new alpha-glucosidase inhibitor and aldose reductase inhibitor, and is used as an anti-diabetic drug or for preparing an anti-diabetic drug.

Description

Technical Field

[0001] This invention relates to a piperine compound, its preparation method, and its uses. Specifically, it relates to a dual-target piperine compound used as an α-glucosidase inhibitor and aldose reductase inhibitor in antidiabetic drugs, its preparation method, and its uses, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Diabetes mellitus is a chronic, progressive metabolic disease in which the body is unable to utilize glucose. It can be caused by reduced insulin secretion from pancreatic cells or a lack of insulin responsiveness in the body. Insulin helps cells assimilate glucose, keeping blood sugar levels within a healthy range. Therefore, a lack of insulin in the body results in high blood sugar.

[0003] Alpha-glucosidase is a key carbohydrate hydrolase that specifically hydrolyzes 1,4α-glucanopyranoside bonds to produce α-glucose, thereby increasing blood glucose levels. Therefore, inhibiting α-glucosidase activity is an effective treatment for type 2 diabetes. Since the 1990s, only three drugs—acarbose, miglitol, and voglic acid—have been used clinically as α-glucosidase inhibitors. However, these drugs have long synthetic routes and common gastrointestinal side effects, including flatulence, bloating, diarrhea, and abdominal discomfort.

[0004] Aldose reductase (EC 1.1.1.21, AKR1B1, ALR2) is a small cytoplasmic monomeric enzyme belonging to the aldosterone reductase superfamily. It is a target protein associated with diabetic complications and a key enzyme in the polyol pathway. In a hyperglycemic state, the polyol pathway is activated, and aldose reductase in the body promotes the conversion of glucose into sorbitol, which cannot freely cross cell membranes, leading to a series of complications. Currently available aldose reductase inhibitors include epalrestat, but its bioavailability is low.

[0005] Existing drugs for treating diabetes are all single-target drugs, and their effects on treating patients' symptoms are singular; therefore, safe and effective multi-target anti-diabetic small molecules urgently need to be developed. Summary of the Invention

[0006] To address the problems existing in the prior art, the inventors, through research and experimentation, successfully synthesized a class of piperine-like compounds. These compounds possess the general formula structure of piperine-like compounds, differing only in their end groups. The dual-target piperine-like compounds provided by this invention, used as both α-glucosidase and aldose reductase inhibitors, can simultaneously inhibit both α-glucosidase and aldose reductase, and can be used as antidiabetic drugs or for the preparation of antidiabetic drugs.

[0007] According to a first embodiment of the present invention, a dual-target piperine compound is provided for use as an α-glucosidase inhibitor and an aldose reductase inhibitor.

[0008] A dual-target piperine compound for use as an α-glucosidase inhibitor and an aldose reductase inhibitor, the dual-target piperine compound having the chemical structural formula shown in formula (A):

[0009] (A);

[0010] Wherein, R is selected from any of the following structures: (Aa), (Ab), (Ac), (Ad):

[0011] , , , ;

[0012] (Aa) (Ab) (Ac) (Ad);

[0013] Wherein: R1, R2, and R3 are each independently hydrogen, halogen, alkyl, substituted alkyl, or nitro; R4 is a heterocyclic group or a substituted heterocyclic group; and R5 is one or two of hydrogen, alkyl, substituted alkyl, and nitro.

[0014] Preferably, R1 is hydrogen, fluorine, chlorine, bromine, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, or nitro. More preferably, R1 is one of hydrogen, fluorine, chlorine, or bromine.

[0015] Preferably, R2 is hydrogen, fluorine, chlorine, bromine, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, or nitro. More preferably, R2 is one of hydrogen, fluorine, chlorine, or bromine.

[0016] Preferably, R3 is hydrogen, fluorine, chlorine, bromine, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, or nitro. More preferably, R3 is one of methyl, ethyl, or chlorine.

[0017] Preferably, R5 is hydrogen, a C1-C3 alkyl group, a halogen-substituted C1-C3 alkyl group, or a nitro group. More preferably, R5 is one of methyl, trifluoromethyl, or nitro.

[0018] In this invention, R5 can be one group or two groups. For example, R5 can be any one of methyl, trifluoromethyl, and nitro; R5 can also be any two of methyl, trifluoromethyl, and nitro, such as methyl and nitro, methyl and trifluoromethyl, or trifluoromethyl and nitro. When R5 is two groups, each of the three carbon atoms on the pyrazole ring is attached to a substituent, one of which is fixed as methyl, and the other two can be any combination of methyl and nitro, methyl and trifluoromethyl, or trifluoromethyl and nitro.

[0019] Preferably, R4 is a five-membered heterocyclic group.

[0020] Preferably, R4 is a heterocyclic group containing halogen, alkyl, or substituted alkyl groups. More preferably, R4 is any one of thiazole, thiadiazole, pyrazole, halogen-substituted thiazole, alkyl-substituted thiadiazole, or substituted alkyl-substituted pyrazole.

[0021] More preferably, R4 is , , , One of them.

[0022] As a preferred embodiment, in equation (A), R is... , , , , , , , , , , , , , , , One of them.

[0023] Preferably, the dual-target piperine compound is selected from one of the following compounds:

[0024] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(4-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0025] ;

[0026] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(4-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0027] ;

[0028] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(4-chlorophenyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0029] ;

[0030] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(4-bromophenyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0031] ;

[0032] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(2-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0033] ;

[0034] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(2,4-difluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0035] ;

[0036] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one:

[0037] ;

[0038] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(5-ethylpyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one:

[0039] ;

[0040] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one:

[0041] ;

[0042] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-((3,4-dichloroisothiazol-5-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0043] ;

[0044] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-((4-methyl-1,2,3-thiadiazol-5-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0045] ;

[0046] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4((3-(difluoromethyl)-1-methylpyrazol-4-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0047] ;

[0048] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4((1-methyl-3-(trifluoromethyl)pyrazol-4-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one:

[0049] ;

[0050] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(3,5-dimethyl-pyrazol-1-yl)pent-2,4-dien-1-one:

[0051] ;

[0052] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(3,5-dimethyl-4-nitro-pyrazol-1-yl)pent-2,4-dien-1-one:

[0053] ;

[0054] (2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)-1-(3-methyl-5-(trifluoromethyl)-pyrazol-1-yl)pent-2,4-dien-1-one:

[0055] .

[0056] According to a second embodiment of the present invention, a method for preparing a dual-target piperine compound as an α-glucosidase inhibitor and aldose reductase inhibitor as described in the first embodiment is provided, the method comprising the following steps:

[0057] (1) Mix piperine with a methanol solution of potassium hydroxide, heat to react, cool after reaction, separate to obtain filter cake, dissolve filter cake, add hydrochloric acid to adjust pH, separate to obtain a pale yellow solid, dry to obtain intermediate A1;

[0058] (2) Dissolve A1 synthesized in step (1) in a solvent, add polypeptide condensation reagent, base, and 1-tert-butyloxycarbonylpiperazine, and carry out the reaction; after the reaction is complete, wash the organic layer, then dry, remove the solvent, recrystallize, and obtain intermediate A2.

[0059] (3) Dissolve the A2 synthesized in step (2) in a solvent, add trifluoroacetic acid under stirring, and stir to carry out the reaction; after the reaction stops, remove the solvent, adjust the pH of the system, wash, and dry to obtain intermediate A3;

[0060] When R in the target product is of the (Aa) structure, proceed to step (4a).

[0061] (4a) Dissolve A1 synthesized in step (1) in a solvent, add a polypeptide condensation reagent, a base, and 4-(substituted phenyl)piperazine, and carry out the reaction; after the reaction is completed, wash the organic layer and dry it to obtain the target product I;

[0062] When R in the target product is of the (Ab) structure, proceed to step (4b).

[0063] (4b) The A3 synthesized in step (3) is mixed with 2-chloro-5-substituted pyrimidine, base and solvent, and reacted; after the reaction is completed, it is separated and dried; the target product II is obtained.

[0064] When R is (Ac) in the target product, proceed to step (4c).

[0065] (4c) Dissolve the carboxylic acid derivative in a solvent, mix it with a polypeptide condensation reagent, an activating reagent, and a base, add A3 synthesized in step (3), and react; after the reaction is complete, wash and dry; to obtain the target product III;

[0066] When R in the target product is of the (Ad) structure, proceed to step (4d).

[0067] (4d) Dissolve A1 synthesized in step (1) in a solvent, add polypeptide condensation reagent, activating reagent, base, and pyrazole derivative, and carry out the reaction; after the reaction is completed, wash and dry; to obtain the target product IV.

[0068] When the target product to be prepared is When (target product I), steps (1) and (4a) are selected.

[0069] When the target product to be prepared is When (target product II), steps (1), (2), (3) and (4b) are selected.

[0070] When the target product to be prepared is When processing (target product III), steps (1), (2), (3), and (4c) are selected.

[0071] When the target product to be prepared is When (target product IV), use steps (1) and (4d).

[0072] Preferably, in steps (2) and (4a), the polypeptide condensation reagent is HATU, and the base is DIEA.

[0073] Preferably, in step (4b), the base is DIEA and the solvent is DMF.

[0074] Preferably, in steps (4c) and (4d), the polypeptide condensation reagent includes EDCI; the activating reagent is HOBt; and the base is DIEA.

[0075] Preferably, the solvent is dichloromethane.

[0076] Preferably, in step (1), the ratio of piperine, potassium hydroxide, and methanol is 1 mol: 50-100 mol: 10-20 L. For example, the ratio of piperine, potassium hydroxide, and methanol is 8 mmol: 0.6 mol: 100 mL.

[0077] Preferably, in step (2), the ratio of intermediate A1, 1-tert-butyloxycarbonylpiperazine, HATU, DIEA, and solvent is 1 mol : 0.9-2 mol : 0.8-5 mol : 1-10 mol : 1-6 L. For example, the ratio of A1, 1-tert-butyloxycarbonylpiperazine, HATU, DIEA, and organic solvent is 9 mmol : 11 mmol : 9 mmol : 18 mmol : 30 mL.

[0078] Preferably, in step (3), the ratio of intermediate A2, trifluoroacetic acid, and solvent (dichloromethane) is 1 mol : 0.5-3 L : 1-10 L. For example, the ratio of A2, trifluoroacetic acid, and dichloromethane is 2.5 mmol : 2.5 mL : 10 mL. A2 (Boc derivative), trifluoroacetic acid, and dichloromethane are added in a ratio of 1 mmol : 1 mL : 4 mL during the reaction.

[0079] Preferably, in step (4a), the molar ratio of intermediate A1, 4-(substituted phenyl)piperazine, HATU, and DIEA is 1:1-5:0.5-3:1-3. For example, the ratio of A1, 4-(substituted phenyl)piperazine, HATU, and DIEA is 1 mmol : 2 mmol : 1 mmol : 2 mmol. 10 mL of dichloromethane is added for every 1 mmol of piperic acid A1.

[0080] Preferably, in step (4b), the ratio of intermediate A3, 2-chloro-5-substituted pyrimidine, DIEA, and solvent is 1 mol : 1-10 mol : 2-50 L : 1-30 L. For example, the ratio of A3, 2-chloro-5-substituted pyrimidine, and DIEA is 1 mmol : 3 mmol : 24 mL. 10 mL of N,N-dimethylformamide is added for every 1 mmol of A3.

[0081] Preferably, in step (4c), the molar ratio of intermediate A3, carboxylic acid derivative, EDCI, HOBt, and DIEA is 1:1-5:2-6:2-6:5-20. For example, the ratio of A3, carboxylic acid derivative, EDCI, HOBt, and DIEA is 1 mmol : 3 mmol : 3.6 mmol : 3.6 mmol : 9 mmol. 3–5 mmol of dichloromethane is added for every 1 mmol of carboxylic acid derivative.

[0082] Preferably, in step (4d), the molar ratio of intermediate A1, pyrazole derivative, EDCI, HOBt, and DIEA is 1:1-5:1-5:1-5:1-10. For example, the ratio of A1, pyrazole derivative, EDCI, HOBt, and DIEA is 1 mmol : 2 mmol : 1.5 mmol : 1.5 mmol : 2 mmol. 10 mL of dichloromethane is added for every 1 mmol of A1.

[0083] As a preferred embodiment, step (1) specifically involves: mixing piperine with a methanol solution of potassium hydroxide and heating under reflux for 12-48 hours; after the reaction is completed, cooling to room temperature, filtering to obtain a filter cake, dissolving the filter cake with distilled water, adding 2-10 mol / L hydrochloric acid to adjust the pH to 0.5-3, filtering to obtain a pale yellow solid, drying to obtain intermediate A1.

[0084] As a preferred embodiment, step (2) specifically involves dissolving the synthesized A1 in step (1) in dichloromethane, adding HATU, DIEA, and 1-tert-butyloxycarbonylpiperazine, and reacting at room temperature for 4-24 hours. After the reaction is completed, an appropriate amount (e.g., 50-2000 ml) of distilled water is added to the system to quench the reaction. The system is then extracted with dichloromethane 1-5 times, and the organic layer is washed with saturated NaHCO3 solution and saturated brine, respectively. The system is then dried with anhydrous Na2SO4, the solvent is removed under reduced pressure, and the system is recrystallized with anhydrous ethanol to obtain intermediate A2.

[0085] As a preferred embodiment, step (3) is as follows: A2 synthesized in step (2) is dissolved in dichloromethane, and trifluoroacetic acid is added under stirring. The mixture is stirred at room temperature for 0.5-6 h. After the reaction stops, the solvent and excess trifluoroacetic acid are evaporated, and then an appropriate amount (e.g., 50-2000 ml) of distilled water is added. The pH of the system is adjusted to 7-10 with 0.5-5 mol / L NaOH. The mixture is extracted with dichloromethane 1-5 times. The organic phase is washed with saturated NaHCO3 solution and saturated brine respectively, and then dried with anhydrous Na2SO4. The mixture is evaporated and dried to obtain intermediate A3.

[0086] As a preferred embodiment, step (4a) specifically involves: dissolving A1 synthesized in step (1) in dichloromethane, adding HATU, DIEA, and 4-(substituted phenyl)piperazine, and stirring at room temperature for 6-48 h; after the reaction is completed, adding an appropriate amount of distilled water to quench the reaction, extracting with dichloromethane 1-5 times, washing the organic layer with saturated NaHCO3 solution and saturated brine respectively, drying with anhydrous Na2SO4, concentrating with a rotary evaporator, and separating and purifying by column chromatography with DCM:EA = 2-10:1 to obtain the target product I.

[0087] As a preferred embodiment, step (4b) specifically involves: mixing the A3 synthesized in step (3) with 2-chloro-5-substituted pyrimidine, DIEA, and DMF, and reacting at 40-80°C for 6-48 h; after the reaction is completed, cooling to room temperature, adding an appropriate amount (e.g., 50-2000 ml) of cold distilled water to the reaction system, precipitating a white solid, then filtering, washing with water, filtering again, and drying; the obtained solid is purified by column chromatography with PE:EA = 1-5:1 to obtain the target product II.

[0088] As a preferred embodiment, step (4c) specifically involves: dissolving the carboxylic acid derivative in dichloromethane, mixing it with EDCI, HOBt, and DIEA, reacting it at room temperature for 0.2-6 h, adding the A3 synthesized in step (3), and then reacting it at room temperature for 12-48 h; after the reaction is complete, adding an appropriate amount (e.g., 50-2000 ml) of distilled water to the reaction system, extracting it with dichloromethane 1-5 times, washing the organic phase with saturated NaHCO3 solution and saturated brine respectively, drying it with anhydrous Na2SO4, filtering, concentrating under reduced pressure, and separating and purifying it by column chromatography with DCM:CH3OH = 40-200:1 to obtain the target product III.

[0089] As a preferred embodiment, step (4d) is as follows: A1 synthesized in step (1) is dissolved in dichloromethane, EDCI, HOBt, and DIEA are added, and the reaction is carried out at room temperature for 0.2-6 h. Then, pyrazole derivatives are added, and the reaction is continued for 12-48 h. After the reaction is completed, an appropriate amount (e.g., 50-2000 ml) of distilled water is added to the reaction system, and the system is extracted with dichloromethane 1-5 times. The organic phase is washed with saturated NaHCO3 solution and saturated brine, respectively, and then dried with anhydrous Na2SO4. The phase is filtered, concentrated under reduced pressure, and purified by column chromatography with PE:DCM = 1-5:1 to obtain the target product IV.

[0090] According to a third embodiment of the present invention, a dual-target piperine compound is provided for use as an α-glucosidase inhibitor and an aldose reductase inhibitor.

[0091] The use of a dual-target piperine compound as an α-glucosidase inhibitor and aldose reductase inhibitor as described in the first embodiment, or a dual-target piperine compound as an α-glucosidase inhibitor prepared by the method described in the second embodiment, wherein the dual-target piperine compound as an α-glucosidase inhibitor and aldose reductase inhibitor is used as an antidiabetic drug or for the preparation of an antidiabetic drug.

[0092] More specifically, exemplary, the present invention provides a dual-target piperine compound for use as an α-glucosidase inhibitor and an aldose reductase inhibitor, the dual-target piperine compound having the structure shown in formulas (I-IV):

[0093] (I), (II)

[0094] (III) (IV);

[0095] In formula (I), R1 and R2 are one of hydrogen, fluorine, chlorine, and bromine; in formula (II), R3 is one of methyl, ethyl, and chlorine; and in formula (III), R4 is... , , , One of them; R5 in general formula (IV) is one of methyl, trifluoromethyl, or nitro.

[0096] More specifically, exemplary, the present invention provides a method for preparing a dual-target piperine compound as an α-glucosidase inhibitor and an aldose reductase inhibitor, the method specifically comprising the following steps:

[0097] Step 1: Mix piperine with a methanol solution of potassium hydroxide and heat under reflux for 24 h. After the reaction is complete, cool to room temperature, filter to obtain a filter cake, dissolve the filter cake in distilled water, add 6 mol / L hydrochloric acid to adjust the pH to 1, filter again to obtain a pale yellow solid, dry to obtain intermediate A1;

[0098] ;

[0099] Step 2: Dissolve A1 synthesized in Step 1 in dichloromethane, add HATU, DIEA, and 1-tert-butyloxycarbonylpiperazine, and react at room temperature for 16 h. After the reaction is complete, add an appropriate amount of distilled water to quench the reaction, extract with dichloromethane 2-3 times, wash the organic layer with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and recrystallize with anhydrous ethanol to obtain intermediate A2.

[0100] ;

[0101] Step 3: Dissolve the A2 synthesized in Step 2 in dichloromethane, add trifluoroacetic acid while stirring, and stir at room temperature for 2 h. After the reaction stops, evaporate the solvent and excess trifluoroacetic acid to dryness, then add an appropriate amount of distilled water, adjust the pH of the system to 8-9 with 1 mol / L NaOH, extract with dichloromethane 2-3 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, evaporate to dryness, and dry again to obtain intermediate A3.

[0102] ;

[0103] Step 4a: Dissolve A1 synthesized in Step 1 in dichloromethane, add HATU, DIEA, and 4-(substituted phenyl)piperazine, and stir at room temperature for 16 h. After the reaction is complete, add an appropriate amount of distilled water to quench the reaction, extract with dichloromethane 2-3 times, wash the organic layer with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, concentrate with a rotary evaporator, and separate and purify by column chromatography (DCM:EA=6:1) to obtain target product I.

[0104] ;

[0105] Step 4b: The A3 synthesized in Step 3 was mixed with 2-chloro-5-substituted pyrimidine, DIEA, and DMF, and reacted at 60°C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, and an appropriate amount of cold distilled water was added to the reaction system. A white solid precipitated, which was then filtered, washed with water, filtered again, and dried. The obtained solid was purified by column chromatography (PE:EA = 3:1) to obtain the target product II.

[0106] ;

[0107] Step 4c: Dissolve the carboxylic acid derivative in dichloromethane, mix with EDCI, HOBt, and DIEA, and react at room temperature for 1 h. Then add A3 synthesized in step 3 and react at room temperature for another 18 h. After the reaction is complete, add an appropriate amount of distilled water to the reaction system, extract with dichloromethane 2-3 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and separate and purify by column chromatography (DCM:CH3OH=80:1) to obtain the target product III.

[0108] ;

[0109] Step 4d: Dissolve A1 synthesized in Step 1 in dichloromethane, add EDCI, HOBt, and DIEA, react at room temperature for 1 h, then add the pyrazole derivative and continue the reaction for 18 h. After the reaction is complete, add an appropriate amount of distilled water to the reaction system, extract with dichloromethane 2-3 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and separate and purify by column chromatography (PE:DCM = 3:1) to obtain the target product IV.

[0110] .

[0111] Compared with the prior art, the technical solution provided by the present invention has the following beneficial technical effects:

[0112] 1. This invention provides a dual-target piperine compound with piperine as the backbone structure, serving as an inhibitor of α-glucosidase and aldose reductase, along with its preparation method and application. The preparation method is simple and has a short synthetic route. The obtained target compounds (I, II, III, IV) exhibit good inhibitory effects on both α-glucosidase and aldose reductase, and can be applied to the preparation of drugs that simultaneously inhibit the activities of α-glucosidase and aldose reductase.

[0113] 2. The present invention modifies the piperidine ring in the piperine structure by replacing the piperidine ring with piperazine and attaching an aromatic derivative to the terminal N of the piperazine to increase the lipophilicity of the molecule; attaching a carbonyl group to the terminal N of the piperazine to increase the ionizable group; or replacing piperidine with pyrazole and connecting the two pharmacophores together through an amide bond to enhance the inhibitory effect of the molecule on enzymes.

[0114] 3. In this invention, aromatic groups are linked to piperine via amide bonds in the structure of piperine derivatives. 1 H NMR, 13 Verification was performed using C NMR and high-resolution mass spectrometry, and only the obtained compounds showed significant application value. Attached Figure Description

[0115] Figure 1 This is a synthetic route diagram for a piperine-based α-glucosidase inhibitor and an aldose reductase inhibitor according to the present invention.

[0116] Figure 2 The above is the 1H NMR spectrum of compound 5 prepared in Example 5 of this invention.

[0117] Figure 3 The image shows the carbon NMR spectrum of compound 5 prepared in Example 5 of this invention.

[0118] Figure 4 The image shows the nuclear magnetic resonance fluorine spectrum of compound 5 prepared in Example 5 of this invention.

[0119] Figure 5 This is a high-resolution mass spectrum of compound 5 prepared in Example 5 of the present invention. Detailed Implementation

[0120] The technical solution of the present invention will be illustrated below with examples. The scope of protection sought by the present invention includes, but is not limited to, the following embodiments.

[0121] This invention provides a dual-target piperine compound for use as an α-glucosidase inhibitor and an aldose reductase inhibitor, the dual-target piperine compound having the chemical structural formula shown in formula (A):

[0122] (A);

[0123] Wherein, R is selected from any of the following structures: (Aa), (Ab), (Ac), (Ad):

[0124] , , , ;

[0125] (Aa) (Ab) (Ac) (Ad);

[0126] Wherein: R1, R2, and R3 are each independently hydrogen, halogen, alkyl, substituted alkyl, or nitro; R4 is a heterocyclic group or a substituted heterocyclic group; and R5 is one or two of hydrogen, alkyl, substituted alkyl, and nitro.

[0127] Preferably, R1, R2, and R3 are each independently hydrogen, fluorine, chlorine, bromine, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, or nitro; R4 is a five-membered heterocyclic group, or R4 is a heterocyclic group substituted with halogen, alkyl, or substituted alkyl; R5 is one or two of hydrogen, C1-C3 alkyl, substituted C1-C3 alkyl, and nitro.

[0128] This invention provides a method for preparing a dual-target piperine compound having the general structural formula (I) for use as an α-glucosidase inhibitor and an aldose reductase inhibitor, the method comprising the following steps:

[0129] (I);

[0130] (1) Mix piperine with a methanol solution of potassium hydroxide, heat to react, cool after reaction, separate to obtain filter cake, dissolve filter cake, add hydrochloric acid to adjust pH, separate to obtain a pale yellow solid, dry to obtain intermediate A1;

[0131] (4a) Dissolve A1 synthesized in step (1) in a solvent, add a polypeptide condensation reagent, a base, and 4-(substituted phenyl)piperazine, and carry out the reaction; after the reaction is completed, wash the organic layer and dry it to obtain the target product I.

[0132] This invention provides a method for preparing a dual-target piperine compound having the general structural formula (II) for use as an α-glucosidase inhibitor and an aldose reductase inhibitor, the method comprising the following steps:

[0133] (II);

[0134] (1) Mix piperine with a methanol solution of potassium hydroxide, heat to react, cool after reaction, separate to obtain filter cake, dissolve filter cake, add hydrochloric acid to adjust pH, separate to obtain a pale yellow solid, dry to obtain intermediate A1;

[0135] (2) Dissolve A1 synthesized in step (1) in a solvent, add polypeptide condensation reagent, base, and 1-tert-butyloxycarbonylpiperazine, and carry out the reaction; after the reaction is complete, wash the organic layer, then dry, remove the solvent, recrystallize, and obtain intermediate A2.

[0136] (3) Dissolve the A2 synthesized in step (2) in a solvent, add trifluoroacetic acid under stirring, and stir to carry out the reaction; after the reaction stops, remove the solvent, adjust the pH of the system, wash, and dry to obtain intermediate A3;

[0137] (4b) The A3 synthesized in step (3) is mixed with 2-chloro-5-substituted pyrimidine, base and solvent and reacted; after the reaction is completed, it is separated and dried to obtain the target product II.

[0138] This invention provides a method for preparing a dual-target piperine compound having the general structural formula (III) for use as an α-glucosidase inhibitor and an aldose reductase inhibitor, the method comprising the following steps:

[0139] (III);

[0140] (1) Mix piperine with a methanol solution of potassium hydroxide, heat to react, cool after reaction, separate to obtain filter cake, dissolve filter cake, add hydrochloric acid to adjust pH, separate to obtain a pale yellow solid, dry to obtain intermediate A1;

[0141] (2) Dissolve A1 synthesized in step (1) in a solvent, add polypeptide condensation reagent, base, and 1-tert-butyloxycarbonylpiperazine, and carry out the reaction; after the reaction is complete, wash the organic layer, then dry, remove the solvent, recrystallize, and obtain intermediate A2.

[0142] (3) Dissolve the A2 synthesized in step (2) in a solvent, add trifluoroacetic acid under stirring, and stir to carry out the reaction; after the reaction stops, remove the solvent, adjust the pH of the system, wash, and dry to obtain intermediate A3;

[0143] (4c) Dissolve the carboxylic acid derivative in a solvent, mix it with a polypeptide condensation reagent, an activating reagent, and a base, add A3 synthesized in step (3), and react. After the reaction is complete, wash and dry to obtain the target product III.

[0144] This invention provides a method for preparing a dual-target piperine compound having the general structural formula (IV) for use as an α-glucosidase inhibitor and an aldose reductase inhibitor, the method comprising the following steps:

[0145] (IV);

[0146] (1) Mix piperine with a methanol solution of potassium hydroxide, heat to react, cool after reaction, separate to obtain filter cake, dissolve filter cake, add hydrochloric acid to adjust pH, separate to obtain a pale yellow solid, dry to obtain intermediate A1;

[0147] (4d) Dissolve A1 synthesized in step (1) in a solvent, add polypeptide condensation reagent, activating reagent, base, and pyrazole derivative, and carry out the reaction; after the reaction is completed, wash and dry; to obtain the target product IV.

[0148] All substances used in the embodiments of this invention are commercially available products and are structurally stable compounds. The following are descriptions of some of the substances: Piperine: Shanghai Bid Pharmaceutical Technology Co., Ltd.; Purity: 98.70%. HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate: Shanghai Bid Pharmaceutical Technology Co., Ltd.; Purity: 98.80%. DIEA: N,N-diisopropylethylamine, Shanghai Maclean Biochemical Technology Co., Ltd.; Purity: 99%. DMF: N,N-dimethylformamide, Xilong Scientific Co., Ltd.; Purity: AR. EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, Anhui Zesheng Technology Co., Ltd.; Purity: 99.99%. HOBt: 1-hydroxybenzotriazole, Anhui Zesheng Technology Co., Ltd.; Purity: 99.95%. Acarbose: Shanghai Bid Pharmaceutical Technology Co., Ltd.; Purity: 98%. DMSO: Dimethyl sulfoxide, Tianjin Kemei Chemical Reagent Co., Ltd.; Purity: AR. Epalrestat: Shanghai Yuanye Biotechnology Co., Ltd.; Production Batch No.: W09A10H94880. 1-Ter-Butoxycarbonylpiperazine: Anhui Zesheng Technology Co., Ltd.; Purity: 98%. 5-Chloro-2-iodopyrimidine: Shanghai Bide Pharmaceutical Technology Co., Ltd.; Purity: 99.88%. 1-Methyl-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (or named 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid): Shanghai Bide Pharmaceutical Technology Co., Ltd.; Purity: 98%. 3-Methyl-5-trifluoromethyl-1H-pyrazole (or named 3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid): Shanghai Bide Pharmaceutical Technology Co., Ltd.; Purity: 98%.

[0149] Example 1:

[0150] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(4-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one (1), the structural formula of which is shown below:

[0151] .

[0152] The specific preparation steps are as follows:

[0153] Step 1: Dissolve 0.6 mol of potassium hydroxide in 100 mL of methanol and add it to a reaction flask containing 8 mmol of piperine. Heat under reflux for 24 h. After the reaction is complete, cool the reaction mixture to room temperature, filter, and obtain a white solid. Dissolve the white solid in distilled water, and adjust the pH to 1 with 6 mmol / L hydrochloric acid to obtain a pale yellow solid. Filter and dry. Recrystallize from anhydrous ethanol to obtain intermediate A1.

[0154] Step 2: Weigh the intermediates A1 (2.5 mmol), HATU (2.5 mmol), and DIEA (5 mmol) synthesized in Step 1 into a reaction flask, add 25 mL of dichloromethane, and then add N-phenylpiperazine (5 mmol). React at room temperature for 16 h. After the reaction is complete, add an appropriate amount of distilled water to the reaction system, extract with dichloromethane 2-3 times, wash the organic phase with dilute hydrochloric acid, and then wash with saturated NaHCO3 solution and saturated brine respectively. Dry the organic phase with anhydrous Na2SO4, filter, concentrate under reduced pressure using a rotary evaporator, and separate and purify by column chromatography (DCM:EA=6:1) to obtain target compound 1.

[0155] Compound 1 is a pale yellow solid with a yield of 80% and an mp of 164.6 °C at 165.8 °C.

[0156] 1 H NMR (400 MHz, CDCl3) δ 7.51 - 7.42 (m, 1H), 7.29 (td, J = 7.1, 3.4Hz, 2H), 6.99 (d, J = 1.8 Hz, 1H), 6.97 - 6.87 (m, 4H), 6.83 - 6.70 (m, 3H), 6.45 (d, J = 13.9 Hz, 1H), 5.98 (s, 2H), 3.82 (d, J = 43.6 Hz, 4H), 3.21 (t,J = 4.7 Hz, 4H).

[0157] 13C NMR (100 MHz, CDCl3) δ 165.62, 150.96, 148.32, 148.26, 143.38,139.03, 130.88, 129.28, 125.09, 122.74, 120.50, 119.13, 116.62, 108.56,105.73, 101.36, 49.83, 45.69, 41.99.

[0158] HRMS(ESI) m / z calcd for C 22 H 22 N2NaO3 + (M+Na) + 385.1523, found 385.1523.

[0159] Example 2:

[0160] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(4-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one (2), the structural formula of which is shown below, and its preparation method is similar to that of Example 1, except that N-phenylpiperazine in step 2 is replaced with 1(4-fluorophenyl)piperazine.

[0161]

[0162] Compound 2 is a white solid with a yield of 71% and an mp of 190.5-191.5 °C.

[0163] 1 H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 14.6, 9.7 Hz, 1H), 7.03 - 6.94(m, 3H), 6.89 (m, 3H), 6.84 - 6.69 (m, 3H), 6.44 (d, J = 14.6 Hz, 1H), 5.98(s, 2H), 3.80 (d, J = 43.4 Hz, 4H), 3.10 (t, J = 5.1 Hz, 4H).

[0164] 13C NMR (100 MHz, CDCl3) δ 165.61, 155.76 (d, J = 245.9 Hz), 148.30,148.24, 143.37, 139.61 (d, J = 8.5 Hz), 138.98, 130.86, 125.10, 124.60 (d, J = 3.6 Hz), 123.15 (d, J = 7.9 Hz), 122.74, 119.19 (d, J = 11.3 Hz), 116.38,116.18, 108.54, 105.71, 101.36, 51.14, 50.38, 45.89, 42.16.

[0165] 19 F NMR (377 MHz, CDCl3) δ -123.31.

[0166] HRMS(ESI) m / z calcd for C 22 H 21 FN2NaO3 + (M+Na) + 403.1428, found 403.1430.

[0167] Example 3:

[0168] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(4-chlorophenyl)piperazin-1-yl)pent-2,4-dien-1-one (3), the structural formula of which is shown below, and its preparation method is similar to that of Example 1, except that N-phenylpiperazine in step 2 is replaced with 1(4-chlorophenyl)piperazine.

[0169]

[0170] Compound 3 is a white solid with a yield of 86%, mp 220.5, and a temperature of 221.6℃.

[0171] 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 14.6, 9.9 Hz, 1H), 7.36 (d, J= 8.9 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 1.7 Hz, 1H), 6.90 (dd,J = 8.0, 1.7 Hz, 1H), 6.86 - 6.82 (m, 1H), 6.81 - 6.69 (m, 4H), 6.43 (d, J =14.6 Hz, 1H), 5.98 (s, 2H), 3.80 (d, J = 37.8 Hz, 4H), 3.17 (d, J = 5.6 Hz, 4H).

[0172] 13 C NMR (100 MHz, CDCl3) δ 165.65, 149.56, 148.26, 143.54, 139.17,129.13, 125.39, 125.01, 122.76, 118.91, 117.80, 108.56, 105.72, 101.35,41.87.

[0173] Example 4:

[0174] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(4-bromophenyl)piperazin-1-yl)pent-2,4-dien-1-one (4), the structural formula of which is shown below, and its preparation method is similar to that of Example 1, except that N-phenylpiperazine in step 2 is replaced with 1(4-bromophenyl)piperazine.

[0175]

[0176] Compound 4 is a white solid with a yield of 88%, mp 235.8, and temperature of 236.4℃.

[0177] 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 14.6, 9.9 Hz, 1H), 7.35 (d, J= 8.9 Hz, 2H), 6.97 (d, J = 1.7 Hz, 1H), 6.89 (dd, J = 8.1, 1.7 Hz, 1H), 6.83- 6.67 (m, 5H), 6.42 (d, J = 14.6 Hz, 1H), 5.97 (s, 2H), 3.79 (d, J = 33.8Hz, 4H), 3.15 (t, J = 5.2 Hz, 4H).

[0178] 13 C NMR (100 MHz, CDCl3) δ 165.64, 149.97, 148.35, 148.26, 143.56,139.18, 132.05, 130.84, 125.00, 122.76, 118.90, 118.16, 112.68, 108.56,105.72, 101.35, 49.57, 41.82.

[0179] Example 5:

[0180] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(2-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one (5), the structural formula of which is shown below, and its preparation method is similar to that of Example 1, except that N-phenylpiperazine in step 2 is replaced with 1(2-fluorophenyl)piperazine.

[0181]

[0182] Compound 5 is a pale yellow solid with a yield of 80%, mp 139.5, and temperature of 140.9℃.

[0183] 1 H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 14.6, 9.3 Hz, 1H), 7.09 - 7.00(m, 2H), 6.96 (d, J = 15.2 Hz, 2H), 6.93 - 6.84 (m, 2H), 6.82 - 6.69 (m, 3H), 6.44 (d, J = 14.6 Hz, 1H), 5.96 (s, 2H), 3.81 (d, J = 49.5 Hz, 4H), 3.08 (s, 4H).

[0184] 13 C NMR (100 MHz, CDCl3) δ 165.61, 155.76(d, J=245.9 Hz), 148.30,148.24, 143.37, 139.61(d, J=8.5 Hz), 138.98, 130.86, 125.10, 124.60(d, J=3.6Hz), 123.15(d, J=7.9 Hz), 122.74, 119.22(d, J=3.0 Hz), 116.38, 116.18,108.54, 105.71, 101.36, 51.14, 50.38, 45.89, 42.16.

[0185] 19 F NMR (377 MHz, CDCl3) δ -122.92.

[0186] HRMS(ESI) m / z calcd for C 22 H 21 FN2NaO3 + (M+Na) + 403.1428, found 403.1428.

[0187] Example 6:

[0188] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(2,4-difluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one (6), the structural formula of which is shown below. Its preparation method is similar to that of Example 1, except that N-phenylpiperazine in step 2 is replaced with 1(2,4-difluorophenyl)piperazine.

[0189]

[0190] Compound 6 is a white solid with a yield of 77%, mp 172.0, and a temperature of 173.9℃.

[0191] 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 14.6, 9.6 Hz, 1H), 6.97 (d, J= 1.6 Hz, 1H), 6.90 – 6.83 (m, 2H), 6.83 – 6.68 (m, 5H), 6.42 (d, J = 14.6Hz, 1H), 5.96 (s, 2H), 3.80 (d, J = 48.2 Hz, 4H), 3.01 (t, J = 5.0 Hz, 4H).

[0192] 13 C NMR (100 MHz, CDCl3) δ 165.62, 158.46 (d, J = 12 Hz), 157.01 (q, J= 11 Hz), 154.51 (d, J = 11.8 Hz), 148.31,148.21, 141.24, 136.19 (q, J = 9Hz), 130.83, 125.05, 122.74, 119.91 (q, J = 9 Hz), 119.05, 110.87 (q, J = 21Hz), 108.54, 105.70, 104.87 (q, J = 26 Hz), 101.36, 51.49, 50.76, 45.89, 42.16.

[0193] 19 F NMR (377 MHz, CDCl3) δ -117.90 (d, J = 5.1 Hz), -118.75 (d, J =5.2 Hz).

[0194] HRMS(ESI) m / z calcd for C 22 H 20 F2N2NaO3 + (M+Na) + 421.1334, found 421.1328.

[0195] Example 7:

[0196] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one (7), the structural formula of which is shown below:

[0197] .

[0198] The specific steps are as follows:

[0199] Step 1: Same as Step 1 in Example 1.

[0200] Step 2: Dissolve A1 (9 mmol) synthesized in Step 1 in dichloromethane (30 mL), add HATU (9 mmol), DIEA (18 mmol), and 1-tert-butyloxycarbonylpiperazine (11 mmol), and react at room temperature for 16 h. After the reaction is complete, add 50 mL of distilled water to quench the reaction, extract with dichloromethane 2-3 times, wash the organic layer with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and recrystallize with anhydrous ethanol to obtain intermediate A2.

[0201] Step 3: Dissolve the A2 synthesized in Step 2 in dichloromethane, add trifluoroacetic acid while stirring, and stir at room temperature for 2 h. After the reaction stops, evaporate the solvent and excess trifluoroacetic acid to dryness, then add an appropriate amount of distilled water, adjust the pH of the system to 8-9 with 1 mol / L NaOH, extract with dichloromethane 2-3 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, evaporate to dryness, and dry again to obtain intermediate A3.

[0202] Step 4: The A3 (3 mmol) synthesized in Step 3 was mixed with 2-chloro-5-methylpyrimidine (9 mmol), DIEA (24 mmol), and DMF (30 mL), and reacted at 60 °C for 16 h. After the reaction was completed, the mixture was cooled to room temperature, and an appropriate amount of cold distilled water was added to the reaction system. A white solid precipitated, which was then filtered, washed with water, filtered again, and dried. The obtained solid was purified by column chromatography (PE:EA = 3:1) to obtain the target compound 7.

[0203] Compound 7 is a white solid with a yield of 70% and an mp of 186.1 at 186.9 °C.

[0204] 1 H NMR (400 MHz, CDCl3) δ 8.14 (s, 2H), 7.50 - 7.39 (m, 1H), 6.95 (d,J = 1.8 Hz, 1H), 6.86 (dd, J = 8.1, 1.7 Hz, 1H), 6.80- 6.68 (m, 3H), 6.42 (d,J = 14.6 Hz, 1H), 5.94 (s, 2H), 3.82 - 3.60 (m, 8H), 2.10 (s, 3H).

[0205] 13C NMR (100 MHz, CDCl3) δ 165.78, 160.44, 157.81, 148.28, 148.23,143.35, 138.98, 130.87, 125.11, 122.69, 119.21, 118.93, 108.52, 105.72,101.33, 45.54, 41.87, 14.61.

[0206] HRMS(ESI) m / z calcd for C 21 H 22 N4NaO3 + (M+Na) + 401.1584, found 401.1583.

[0207] Example 8:

[0208] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(5-ethylpyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one (8), the structural formula of which is shown below, and its preparation method is similar to that of Example 7, except that 2-chloro-5-methylpyrimidin in step 4 is replaced with 2-chloro-5-ethylpyrimidin.

[0209]

[0210] Compound 8 is a white solid with a yield of 73%, mp 170.8, and temperature 171.5℃.

[0211] 1 H NMR (400 MHz, CDCl3) δ 8.19 (s, 2H), 7.55 - 7.39 (m, 1H), 6.98 (d,J = 1.7 Hz, 1H), 6.89 (dd, J = 8.1, 1.7 Hz, 1H), 6.85 - 6.68 (m, 3H), 6.44(d, J = 14.5 Hz, 1H), 5.97 (s, 2H), 4.04 - 3.55 (m, 8H), 2.47 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H).

[0212] 13C NMR (100 MHz, CDCl3) δ 165.80, 160.59, 157.18, 148.29, 148.24,143.40, 139.02, 130.86, 125.28, 125.09, 122.73, 119.18, 108.54, 105.71,101.35, 45.56, 41.91, 22.72, 15.61.

[0213] HRMS(ESI) m / z calcd for C 22 H 24 N4NaO3 + (M+Na) + 415.1741, found 415.1739.

[0214] Example 9:

[0215] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one (9), the structural formula of which is shown below, and its preparation method is similar to that of Example 7, except that 2-chloro-5-methylpyrimidine in step 4 is replaced with 5-chloro-2-iodopyrimidine.

[0216]

[0217] Compound 9 is a white solid with a yield of 86%, mp 207.1, and temperature 207.9℃.

[0218] 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 2H), 7.47 (dd, J = 14.6, 9.6 Hz,1H), 6.98 (s, 1H), 6.89 (d, J = 1.7 Hz, 1H), 6.85 - 6.68 (m, 3H), 6.43 (d, J= 14.6 Hz, 1H), 5.98 (s, 2H), 3.98 - 3.53 (m, 8H).

[0219] 13C NMR (100 MHz, CDCl3) δ 165.84, 159.69, 155.97, 148.34, 148.26, 143.60, 139.20, 130.84, 125.02, 122.76, 118.98, 118.87, 108.55, 105.74,101.36, 45.41, 44.04, 41.77.

[0220] HRMS(ESI) m / z calcd for C 20 H 20 ClN4O3 + (M+H) + 399.1218, found 399.1223.

[0221] Example 10:

[0222] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-((3,4-dichloroisothiazo-5-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one (10), the structural formula of which is shown below:

[0223] .

[0224] The specific steps are as follows:

[0225] Step 1: Same as Step 1 in Example 7.

[0226] Step 2: Same as step 2 in Example 7.

[0227] Step 3: Same as step 3 in Example 7.

[0228] Step 4: Dissolve 3,4-dichloroisothiazolium-5-carboxylic acid (6 mmol) in dichloromethane (30 mL), mix with EDCI (7.2 mmol), HOBt (7.2 mmol), and DIEA (18 mmol), and react at room temperature for 1 h. Then add A3 (3 mmol) synthesized in Step 3, and react at room temperature for another 18 h. After the reaction is complete, add an appropriate amount of distilled water to the reaction system, extract with dichloromethane 2-3 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and separate and purify by column chromatography (DCM:CH3OH=80:1) to obtain the target compound 10.

[0229] Compound 10 is a pale yellow solid with a yield of 61% and an mp of 194.6 °C at 195.8 °C.

[0230] 1 H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 14.6, 10.6 Hz, 1H), 6.98 (d, J= 1.7 Hz, 1H), 6.90 (dd, J = 8.1, 1.7 Hz, 1H), 6.85 - 6.68 (m, 3H), 6.37 (d,J = 14.6 Hz, 1H), 5.98 (s, 2H), 3.75 (s, 6H), 3.46 (s, 2H).

[0231] 13 C NMR (100 MHz, CDCl3) δ 165.84, 158.66, 154.74, 148.56, 148.52,148.29, 144.48, 139.91, 130.63, 124.69, 122.94, 120.45, 118.02, 108.58,105.73, 101.41.

[0232] HRMS(ESI) m / z calcd for C 20 H 18 Cl2N3O4S + (M+H) + 466.0390, found 466.0391.

[0233] Example 11:

[0234] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4-((4-methyl-1,2,3-thiadiazole-5-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one (11), the structural formula of which is shown below, and its preparation method is similar to that of Example 10, except that the 3,4-dichloroisothiazolium-5-carboxylic acid in step 4 is replaced with 4-methyl-1,2,3-thiadiazole-5-carboxylic acid.

[0235]

[0236] Compound 11 is a white solid with a yield of 69% and an mp of 239.4–240.5 °C.

[0237] 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 14.5, 10.5 Hz, 1H), 6.98 (d, J= 1.7 Hz, 1H), 6.90 (dd, J = 8.1, 1.7 Hz, 1H), 6.84 - 6.67 (m, 3H), 6.36 (s, 1H), 5.98 (s, 2H), 3.74 (d, J = 47.4 Hz, 6H), 3.37 (d, J = 5.1 Hz, 2H), 2.76 (s, 3H).

[0238] 13 C NMR (100 MHz, CDCl3) δ 168.21, 165.82, 159.49, 148.47, 148.28,144.25, 139.72, 130.66, 124.75, 122.86, 118.21, 108.55, 105.72, 101.38,47.19, 42.52, 19.14.

[0239] Example 12:

[0240] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4((3-(difluoromethyl)-1-methylpyrazol-4-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one (12), the structural formula of which is shown below, and its preparation method is similar to that of Example 10, except that the 3,4-dichloroisothiazol 5-carboxylic acid in step 4 is replaced with 3(difluoromethyl)1-methyl1Hpyrazol 4-carboxylic acid.

[0241]

[0242] Compound 12 is a pale yellow solid with a yield of 83% and an mp of 220.9–221.9 °C.

[0243] 1 H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.44 (dd, J = 14.6, 10.3 Hz, 1H), 6.95 (d, J = 11.0 Hz, 1H), 6.88 (dd, J = 8.1, 1.7 Hz, 1H), 6.85 - 6.63(m, 4H), 6.36 (d, J = 14.6 Hz, 1H), 5.96 (s, 2H), 3.93 (s, 3H), 3.65 (s, 8H).

[0244] 13 C NMR (100 MHz, CDCl3) δ 165.83, 162.94, 148.42, 148.27, 143.98,139.52, 130.91, 130.73, 124.85, 123.32, 122.77 (d, J = 10.7 Hz), 118.50,117.62, 112.86(t, J=234.2 Hz), 108.56, 105.73, 101.37, 39.52.

[0245] 19 F NMR (377 MHz, CDCl3) δ -113.43.

[0246] Example 13:

[0247] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(4((1-methyl-3-(trifluoromethyl)pyrazol-4-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one (13), the structural formula of which is shown below, and its preparation method is similar to that of Example 10, except that the 3,4-dichloroisothiazol 5-carboxylic acid in step 4 is replaced with 3(trifluoromethyl)1-methyl1Hpyrazol 4-carboxylic acid.

[0248]

[0249] Compound 13 is a white solid with a yield of 67% and an mp of 204.2–205.5 °C.

[0250] 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.44 (dd, J = 14.6, 10.4 Hz,1H), 6.96 (d, J = 1.7 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.83 - 6.67 (m, 3H), 6.36(d, J = 14.6 Hz, 1H), 5.96 (s, 2H), 3.96 (s, 3H), 3.54 (d, J = 84.8 Hz, 8H).

[0251] 13C NMR (100 MHz, CDCl3) δ 165.82, 162.11, 148.44, 148.27, 144.09,139.60, 138.78(d, J=38.4 Hz), 130.96, 130.70, 124.76(d, J=7.0 Hz), 122.86,120.71(q, J=268.0 Hz), 115.60, 108.56, 105.72, 101.38, 47.30, 45.34, 41.99,39.82.

[0252] 19 F NMR (377 MHz, CDCl3) δ -109.67, -113.43, -116.02.

[0253] Example 14:

[0254] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(3,5-dimethyl-pyrazol-1-yl)pent-2,4-dien-1-one (13), the structural formula of which is shown below:

[0255] .

[0256] The specific synthesis steps are as follows:

[0257] Step 1: Same as Step 1 in Example 1.

[0258] Step 2: Dissolve A1 (5 mmol) synthesized in Step 1 in dichloromethane (50 mL), add EDCI (7.5 mmol), HOBt (7.5 mmol), and DIEA (10 mmol), react at room temperature for 1 h, then add 3,5-dimethylpyrazole (10 mmol) and continue the reaction for 18 h. After the reaction is complete, add an appropriate amount of distilled water to the reaction system, extract with dichloromethane 2-3 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and separate and purify by column chromatography (PE:DCM = 3:1) to obtain target compound 14.

[0259] Compound 14 is a yellow solid with a yield of 63% and an mp of 187.7–188.6 °C.

[0260] 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 15.2, 6.6, 3.7 Hz, 1H), 7.41 (d, J = 15.2 Hz, 1H), 7.01 (d, J = 1.7 Hz, 1H), 6.94 (dd, J = 8.1, 1.7 Hz,1H), 6.89 (d, J = 6.7 Hz, 2H), 6.80 (d, J = 8.0 Hz, 1H), 5.99 (d, J = 2.7 Hz,3H), 2.59 (s, 3H), 2.27 (s, 3H).

[0261] 13 C NMR (100 MHz, CDCl3) δ 165.60, 151.72, 148.74, 148.32, 146.35,144.30, 141.33, 130.63, 125.21, 123.26, 120.20, 111.25, 108.59, 105.93,101.44, 14.67, 13.86.

[0262] HRMS(ESI) m / z calcd for C 17 H 16 N2NaO3 + (M+Na) + 319.1053, found 319.1061.

[0263] Example 15:

[0264] (2E,4E)-5-(benzo[d][1,3]dioxapentane-5-yl)-1-(3,5-dimethyl-4-nitro-pyrazol-1-yl)pent-2,4-dien-1-one (15), the structural formula of which is shown below, except that 3,5-dimethylpyrazol in step 2 is replaced with 3,5-dimethyl-4-nitropyrazol.

[0265]

[0266] Compound 15 is a yellow solid with a yield of 51% and an mp of 232.0–232.9 °C.

[0267] 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 15.1, 10.7 Hz, 1H), 7.34 (d, J= 15.1 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.97 (t, J = 4.3 Hz, 2H), 6.89 (dd,J = 15.4, 10.7 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.01 (s, 2H), 3.03 (s, 3H), 2.56 (s, 3H).

[0268] 13 C NMR (100 MHz, CDCl3) δ 165.80, 149.29, 149.19, 148.45, 147.41,144.75, 143.63, 134.43, 130.20, 124.68, 123.95, 118.19, 108.70, 106.00,101.61, 14.46, 13.53.

[0269] Example 16:

[0270] (2E,4E)-5-(benzo[d][1,3]dioxane-5-yl)-1-(3-methyl-5-(trifluoromethyl)-pyrazol-1-yl)pent-2,4-dien-1-one (16), the structural formula of which is shown below, except that the 3,5-dimethylpyrazol in step 2 is replaced with 3-methyl-5-trifluoromethyl-1Hpyrazol.

[0271]

[0272] Compound 16 is a yellow solid with a yield of 74% and an mp of 194.6–195.7 °C.

[0273] 1 H NMR (400 MHz, CDCl3) δ 7.75 - 7.65 (m, 1H), 7.39 (d, J = 15.1 Hz,1H), 7.02 (d, J = 1.7 Hz, 1H), 6.99 - 6.88 (m, 3H), 6.80 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 6.00 (s, 2H), 2.66 (s, 3H).

[0274] 13C NMR (100 MHz, CDCl3) δ 165.59, 149.12, 148.55, 148.42, 145.34,144.13 (q, J = 38.5 Hz), 142.95, 130.32, 124.84, 123.70, 120.71 (d, J = 268.0Hz), 118.42, 108.65, 107.53, 101.54, 14.64. 19 F NMR (377 MHz, CDCl3) δ -63.32.

[0275] Experiment 1

[0276] Add the corresponding solutions and perform the corresponding operations in the order shown in Table 1 (final concentrations of the sample and acarbose were 12.5 μmol / L, 25 μmol / L, 50 μmol / L, 100 μmol / L, and 200 μmol / L, respectively). After the time was up, add 250 μL of the mixture to 1 mL of Na₂CO₃ solution and mix well. Use a 100 μL pipette to transfer 100 μL of the mixture to a 96-well plate and measure the absorbance at 405 nm using a microplate reader. Calculate the IC50 of each compound based on the absorbance values ​​measured at the five concentrations. 50 The values ​​are shown in Table 2.

[0277] Table 1. Determination of α-glucosidase inhibitory activity

[0278]

[0279] Table 2. Inhibitory activity of piperine compounds against α-glucosidase

[0280]

[0281] Among them, serial numbers 1-16 correspond to the compounds prepared in Examples 1-16, respectively.

[0282] As shown in Table 2, most of the compounds synthesized in this invention exhibit good α-glucosidase inhibitory activity. Compounds 1, 2, 5, 6, 7, 8, 9, 10, 11, 14, and 15 (IC50, 10 ... 50 =20.04~27.58 μM) has stronger inhibitory activity against α-glucosidase than acarbose (IC50). 50 =49.26 μM), of which compound 6 (IC) 50 The best is (=0.1 μM).

[0283] Experiment 2

[0284] The samples were prepared into 3 mg / mL stock solutions using DMSO, and then diluted with water to achieve final concentrations of 3, 1, 0.3, 0.1, 0.03, 0.01, and 0.003 μg / mL in the reaction system, respectively. The positive control was similarly diluted to achieve final concentrations of 300, 100, 30, 10, 3, 1, and 0.03 μM in the reaction system, respectively. A final DMSO concentration <5% did not affect enzyme activity in the reaction system.

[0285] Extraction of aldose reductase: Take two bovine lens fragments, cut them into small pieces with scissors, and dissolve them in 5 mmol / L (pH=7.4) phosphate buffer solution. Add the phosphate buffer solution to a homogenizer in small amounts (5 ml / time) multiple times, and homogenize in an ice bath. Centrifuge at 15000 rpm / min for 15 minutes. Collect the supernatant, and add 40% ammonium sulfate solution to the supernatant in three batches, stirring intermittently for 30 minutes. Centrifuge again at 15000 rpm / min for 15 minutes. Collect the supernatant, add 75% ammonium sulfate solution to the supernatant, stir intermittently for 30 minutes, and centrifuge again at 10000 rpm / min for 15 minutes. Collect the precipitate obtained by centrifugation, and dissolve it in phosphate buffer solution. Dialyze at a volume ratio of 1:10 (mixture: phosphate buffer = 1:10), changing the dialysate every 4 hours, for a total of 3 dialyzes. All the above operations were performed at a low temperature of 4°C. The aldose reductase extract obtained after dialysis was frozen at -70°C.

[0286] The reaction system for aldose reductase was 0.2 mL. The final concentrations of the components were as follows: β-mercaptoethanol 5 mmol / L, coenzyme II NADPH 0.2 mmol / L, PBS buffer 120 mmol / L (pH = 6.2), Li₂SO₄ 400 mmol / L, DL-glyceraldehyde substrate 2 mmol / L, and 40 µL of aldose reductase extract. The reaction was carried out at 37 °C for 10 minutes, and the absorbance (OD) was measured at 340 nm. The IC₂ of each compound was calculated using the absorbance values ​​measured at seven concentrations. 50 The values ​​are shown in Table 4.

[0287] The order in which the components are added follows the order from top to bottom in Table 3.

[0288] Table 3 Aldose reductase activity test

[0289]

[0290] Table 4. Inhibitory activity of piperine compounds on aldose reductase

[0291]

[0292] Among them, serial numbers 1-16 correspond to the compounds prepared in Examples 1-16.

[0293] As shown in Table 4, most of the compounds disclosed in this invention exhibit good aldose reductase inhibitory activity (IC50). 50 Values ​​ranged from 0.003 μM to 4.939 μM, and were mostly stronger than the positive control epalrestat (IC50). 50 =2.606 μM), compounds 4, 5, 8, 11, 12, and 13 showed stronger inhibitory activity against aldose reductase than the parent nucleus piperine (IC50). 50 =0.258 μM), of which compounds 5 and 12 (IC50) 50 The inhibitory effects were best at concentrations of 0.006 μM and 0.003 μM.

Claims

1. A dual-target piperine compound used as an α-glucosidase inhibitor and an aldose reductase inhibitor, characterized in that: The dual-target piperine compound is selected from one of the following compounds: (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(4-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(4-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(4-chlorophenyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(4-bromophenyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(2-fluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(2,4-difluorophenyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(5-ethylpyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-(5-chloropyrimidin-2-yl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-((3,4-dichloroisothiazol-5-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4-((4-methyl-1,2,3-thiadiazol-5-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4((3-(difluoromethyl)-1-methylpyrazol-4-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(4((1-methyl-3-(trifluoromethyl)pyrazol-4-yl)carbonyl)piperazin-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(3,5-dimethyl-pyrazol-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxapentane-5-yl)-1-(3,5-dimethyl-4-nitro-pyrazol-1-yl)pent-2,4-dien-1-one: ； (2E,4E)-5-(benzo[ d [1,3]dioxane-5-yl)-1-(3-methyl-5-(trifluoromethyl)-pyrazol-1-yl)pent-2,4-dien-1-one: 。 2. A method for preparing the dual-target piperine compound of claim 1 as an α-glucosidase inhibitor and aldose reductase inhibitor, the method comprising the following steps: (1) Mix piperine with a methanol solution of potassium hydroxide, heat to react, cool after reaction, separate to obtain filter cake, dissolve filter cake, add hydrochloric acid to adjust pH, separate to obtain a pale yellow solid, dry to obtain intermediate A1; A1； (2) Dissolve A1 synthesized in step (1) in a solvent, add polypeptide condensation reagent, base, and 1-tert-butyloxycarbonylpiperazine, and carry out the reaction; after the reaction is complete, wash the organic layer, then dry, remove the solvent, recrystallize, and obtain intermediate A2. A2； (3) Dissolve the A2 synthesized in step (2) in a solvent, add trifluoroacetic acid under stirring, and stir to carry out the reaction; after the reaction stops, remove the solvent, adjust the pH of the system, wash, and dry to obtain intermediate A3; A3； When R in the target product is of the (Aa) structure, proceed to step (4a). (4a) Dissolve A1 synthesized in step (1) in a solvent, add a polypeptide condensation reagent, a base, and 4-(substituted phenyl)piperazine, and carry out the reaction; after the reaction is completed, wash the organic layer and dry it to obtain the target product I; When R in the target product is of the (Ab) structure, proceed to step (4b). (4b) The A3 synthesized in step (3) is mixed with 2-chloro-5-substituted pyrimidine, base and solvent, and reacted; after the reaction is completed, it is separated and dried to obtain the target product II; When R in the target product is of the (Ac) structure, proceed to step (4c). (4c) Dissolve the carboxylic acid derivative in a solvent, mix it with the polypeptide condensation reagent, activating reagent, and base, add A3 synthesized in step (3), and react; after the reaction is complete, wash and dry. Target product III was obtained; When R in the target product is of the (Ad) structure, proceed to step (4d). (4d) Dissolve the A1 synthesized in step (1) in a solvent, add a polypeptide condensation reagent, an activating reagent, a base, and a pyrazole derivative, and carry out the reaction; after the reaction is completed, wash and dry. The target product IV was obtained; （A）； When R is the (Aa) structure, R in the target product (A) is... , , , , or When R is of the (Ab) structure, R in the target product (A) is , or When R is of structure (Ac), R in the target product (A) is , , or When R is the (Ad) structure, R in the target product (A) is , or .

3. The method according to claim 2, characterized in that: In steps (2) and (4a), the polypeptide condensation reagent is HATU; the base is DIEA; and / or In step (4b), the base is DIEA; the solvent is dimethylformamide; and / or In steps (4c) and (4d), the polypeptide condensation reagent is EDCI; the activating reagent is HOBt; the base is DIEA; and the solvent is dichloromethane.

4. The method according to claim 3, characterized in that: In step (1), the ratio of piperine, potassium hydroxide, and methanol added is 1 mol: 50-100 mol: 10-20 L; and / or In step (2), the ratio of intermediate A1, 1-tert-butyloxycarbonylpiperazine, HATU, DIEA, and solvent is 1 mol : 0.9-2 mol : 0.8-5 mol : 1-10 mol : 1-6 L; and / or In step (3), the ratio of intermediate A2, trifluoroacetic acid, and solvent is 1 mol : 0.5-3 L : 1-10 L.

5. The method according to claim 3, characterized in that: In step (4a), the molar ratio of intermediate A1, 4-(substituted phenyl)piperazine, HATU, and DIEA is 1:1-5:0.5-3:1-3; and / or In step (4b), the ratio of intermediate A3, 2-chloro-5-substituted pyrimidine, DIEA, and solvent is 1 mol : 1-10 mol : 2-50 L : 1-30 L; and / or In step (4c), the molar ratio of intermediate A3, carboxylic acid derivative, EDCI, HOBt, and DIEA is 1:1-5:2-6:2-6:5-20; and / or In step (4d), the molar ratio of intermediate A1, pyrazole derivative, EDCI, HOBt, and DIEA is 1:1-5:1-5:1-5:1-10.

6. The method according to claim 2, characterized in that: Step (1) is as follows: Piperine and potassium hydroxide in methanol solution are mixed and heated under reflux for 12-48 h; after the reaction is completed, the mixture is cooled to room temperature, filtered to obtain filter cake, the filter cake is dissolved in distilled water, 2-10 mol / L hydrochloric acid is added to adjust the pH to 0.5-3, filtered to obtain a pale yellow solid, dried to obtain intermediate A1; Step (2) is as follows: Dissolve A1 synthesized in step (1) in dichloromethane, add HATU, DIEA, and 1-tert-butyloxycarbonylpiperazine, and react at room temperature for 4-24 h; after the reaction is completed, add 50-2000 ml of distilled water to the system to quench the reaction, extract with dichloromethane 1-5 times, wash the organic layer with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, recrystallize with anhydrous ethanol to obtain intermediate A2; Step (3) is as follows: Dissolve the A2 synthesized in step (2) in dichloromethane, add trifluoroacetic acid under stirring, and stir at room temperature for 0.5-6 h; after the reaction stops, evaporate the solvent and excess trifluoroacetic acid, then add 50-2000 ml of distilled water, adjust the pH of the system to 7-10 with 0.5-5 mol / L NaOH, extract with dichloromethane 1-5 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, evaporate to dryness, and dry to obtain intermediate A3.

7. The method according to claim 2, characterized in that: Step (4a) is as follows: A1 synthesized in step (1) is dissolved in dichloromethane, HATU, DIEA, and 4-(substituted phenyl)piperazine are added, and the mixture is stirred at room temperature for 6-48 h. After the reaction is completed, an appropriate amount of distilled water is added to the system to quench the reaction. The mixture is extracted with dichloromethane 1-5 times, and the organic layer is washed with saturated NaHCO3 solution and saturated brine, respectively. The mixture is then dried with anhydrous Na2SO4, concentrated by rotary evaporator, and purified by column chromatography with DCM:ethyl acetate = 2-10:1 to obtain the target product I. Step (4b) is as follows: A3 synthesized in step (3) is mixed with 2-chloro-5-substituted pyrimidine, DIEA, and dimethylformamide, and reacted at 40-80℃ for 6-48 h; after the reaction is completed, the mixture is cooled to room temperature, and 50-2000 ml of cold distilled water is added to the reaction system to precipitate a white solid. The solid is then filtered, washed with water, filtered again, and dried. The obtained solid is purified by column chromatography with PE:ethyl acetate = 1-5:1 to obtain the target product II. Step (4c) is as follows: Dissolve the carboxylic acid derivative in dichloromethane, mix it with EDCI, HOBt and DIEA, react at room temperature for 0.2-6 h, add A3 synthesized in step (3), and react at room temperature for 12-48 h; after the reaction is completed, add 50-2000 ml of distilled water to the reaction system, extract with dichloromethane 1-5 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and separate and purify by column chromatography with DCM:CH3OH=40~200:1 to obtain the target product III; Step (4d) is as follows: Dissolve A1 synthesized in step (1) in dichloromethane, add EDCI, HOBt, and DIEA, react at room temperature for 0.2-6 h, then add pyrazole derivatives and continue the reaction for 12-48 h; after the reaction is completed, add 50-2000 ml of distilled water to the reaction system, extract with dichloromethane 1-5 times, wash the organic phase with saturated NaHCO3 solution and saturated brine respectively, then dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and separate and purify by column chromatography with PE:DCM = 1-5:1 to obtain the target product IV.

8. The use of a dual-target piperine compound as an α-glucosidase inhibitor and aldose reductase inhibitor as described in claim 1, or a dual-target piperine compound as an α-glucosidase inhibitor prepared by any one of claims 2-7, characterized in that: The aforementioned dual-target piperine compounds, used as both α-glucosidase inhibitors and aldose reductase inhibitors, are used to prepare antidiabetic drugs.

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