CN115677668A - Anserine derivatives and their preparation methods and applications - Google Patents

Abstract

The invention provides an anserine derivative, a preparation method and application thereof, wherein the anserine derivative has a structure shown as the following. The compound of the invention has better inhibitory activity to xanthine oxidase XOD, and is obviously superior to allopurinol serving as a clinical xanthine oxidase inhibitor. The compound of the invention has novel structure, simple and green synthetic method and low price of raw materials.

Description

Anserine derivative and its preparation method and application

technical field

The invention belongs to biomedicine and its preparation method and application, in particular to anserine derivatives and its preparation method and application.

Background technique

Hyperuricemia is a metabolic disease that seriously endangers human health. The global incidence is increasing year by year, and the age of onset is getting younger. Hyperuricemia is the most important biochemical pathological basis of gout, and is closely related to the occurrence of diseases such as hypertension, hyperlipidemia, diabetes, atherosclerosis and chronic kidney disease. In the generation and development of hyperuricemia, xanthine oxidase XOD plays a vital role and is the decisive enzyme for uric acid production. Xanthine oxidase XOD is a flavoproteinase present in various organisms that catalyzes the formation of uric acid from purine substrates in vivo. The crystal structure of xanthine oxidase XOD has been resolved, it consists of 1330 amino acids, its amino acid sequence has 90% homology between mouse and human, it is composed of two completely symmetrical structural units, each The structural unit is 145ku, and its catalytic center includes a molybdopterin center, two iron-sulfur centers and a flavin adenine dinucleotide, in which the molybdenum pterin center is the key for xanthine oxidase XOD to catalyze xanthine to generate uric acid site. At present, the main strategy for drug treatment of hyperuricemia is to reduce uric acid production and increase uric acid excretion. Drugs that reduce uric acid production are mainly xanthine oxidase inhibitors (XOIs), such as allopurinol, which have adverse reactions such as allergic rashes, nephrotoxicity, and liver necrosis. Therefore, research and development of XOIs with better efficacy and fewer side effects is very necessary.

Anserine (β-alanyl-1-methyl-L-histidine) is a multifunctional dipeptide, its main components are methylhistidine and β-alanine, naturally occurring in In the brain tissue and skeletal muscle tissue of vertebrates, it has certain water solubility and strong thermal stability, and has obvious antioxidant effect, which can buffer the physiological pH value, and also play a certain role in vasodilation and enzyme coordination. effect. Compared with other biological effects, scholars at home and abroad have done some in-depth research on the uric acid-lowering effect of anserine, especially in inhibiting the activity of xanthine oxidase XOD, applied it in real life, and found that its It has good development prospects in the field of medicine.

Contents of the invention

Purpose of the invention: the purpose of the present invention is to provide anserine derivatives and their preparation methods and applications.

Technical scheme: the described anserine derivative has a structure shown in formula (I):

Wherein, R is pyridyl substituted by a substituent selected from alkyl, alkoxy or halogen.

In an embodiment of the present invention, R is selected from the following groups:

Wherein, R ₁ is monosubstituted or double substituted on the pyridine ring, R ₁ is selected from F, Cl, Br, I; R ₂ is methyl or ethyl.

时，R₁在吡啶环上单取代或双取代，选自F、Cl、Br、I；R为

时，R₁在吡啶环上单取代，为F，R₂选自甲基或乙基。In an embodiment of the invention, R is

When, R ₁ is monosubstituted or double substituted on the pyridine ring, selected from F, Cl, Br, I; R is

, R ₁ is monosubstituted on the pyridine ring and is F, and R ₂ is selected from methyl or ethyl.

Further, the R is selected from the following groups: 2-fluoropyridyl, 3-fluoropyridyl, (2,3-difluoro)pyridyl, 2-chloropyridyl, 3-chloropyridyl, (2, 3-dichloro)pyridyl, 2-bromopyridyl, 3-bromopyridyl, (2,3-dibromo)pyridyl, 2-iodopyridyl, 3-iodopyridyl, (2,3-diiodo ) pyridyl, 2-methyl-3-fluoropyridyl, 2-methyl-5-fluoropyridyl, 2-methyl-6-fluoropyridyl, 3-methyl-2-fluoropyridyl, 3- Methyl-5-fluoropyridyl, 3-methyl-6-fluoropyridyl, 2-methoxy-3-fluoropyridyl, 2-methoxy-5-fluoropyridyl, 2-methoxy- 6-fluoropyridyl, 3-methoxy-2-fluoropyridyl, 3-methoxy-5-fluoropyridyl, 3-methoxy-6-fluoropyridyl, 2-ethoxy-3- Fluoropyridyl, 2-ethoxy-5-fluoropyridyl, 2-ethoxy-6-fluoropyridyl, 3-ethoxy-2-fluoropyridyl, 3-ethoxy-5-fluoropyridyl Base, 3-ethoxy-6-fluoropyridyl. Further, the compound of formula (I) includes the compounds shown in Table 1:

Table 1 Formula (I) compound structure and its HR-MS structural analysis

The present invention provides a preparation method for the compound of formula (I), the method comprising taking anserine as a starting reactant to prepare the compound of formula (I), and the specific steps include:

S1: Dissolve anserine in a solvent, then add propyne bromide and a catalyst, heat and stir the reaction under the protection of nitrogen, TLC to track the reaction process, after the reaction, pour the reaction solution into water, filter, then extract the filtrate, and combine the organic phase , to obtain compound 2 after evaporation to dryness;

S2: Dissolve compound 2 and R-N3 in a solvent, then add a catalyst, heat and stir the reaction under the protection of nitrogen, track the reaction progress by TLC, separate and purify after the reaction to obtain the compound of formula (I).

Further, the molar ratio of anserine, propyne bromide and catalyst consumption in step S1 is 1: (0.5-10): (0.2-5), preferably 1: (1-5.5): (0.5-2.5), more Preferably 1: (1.25-2.5): (1-2); the amount of the solvent is that each mole of anserine is dissolved in 0.5-10L solvent; the reaction temperature is 20-100°C, and the reaction time is 0.5-10h, Preferably, the reaction temperature is 40-80° C., and the reaction is easier to proceed at this reaction temperature; the developer selected by TLC is dichloromethane/methanol=5/1-1/1.

Further, the solvent described in step S1 is selected from water, methanol, absolute ethanol, isopropanol, n-butanol, acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, tetrahydrofuran, N, One or more of N-dimethylformamide and dimethyl sulfoxide, preferably any one of isopropanol, n-butanol, methylene chloride, chloroform, acetonitrile and tetrahydrofuran, in these solvents , the reaction proceeds more easily.

Further, the catalyst described in step S1 is selected from one or more of strontium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, ammonia water, diethylamine, triethylamine, pyridine and piperidine, preferably It is any one of strontium carbonate, diethylamine, triethylamine, pyridine and piperidine, under the catalysis of these catalysts, the reaction can be carried out more easily.

Further, the reagent selected for the extract described in step S1 is petroleum ether, diethyl ether, isopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, ethyl propionate and ethyl acetoacetate one or more.

Further, the molar ratio of compound 2, R-N3 and the amount of catalyst used in step S2 is 1: (0.5-10): (1-5), preferably 1: (1.0-5.5): (1.5-3.5), more Preferably 1: (1.5-2.5): (1.5-2.0); the amount of the solvent is dissolved in 1-10L of solvent per mole of compound 2; the reaction temperature is 40-150°C, and the reaction time is 0.5-15h, Preferably, the reaction temperature is 60-100° C., and the reaction is easier to proceed at this reaction temperature; the developer selected by TLC is dichloromethane/methanol=3/1-1/1.

Further, the solvent described in step S2 is a mixed solution selected from methanol-water-N,N-dimethylformamide, ethanol-water-N,N-dimethylformamide, n-propanol-water-N , N-dimethylformamide, isopropanol-water-N,N-dimethylformamide, n-butanol-water-N,N-dimethylformamide, tert-butanol-water-N,N - Dimethylformamide, Methanol-Water-THF, Ethanol-Water-THF, n-Propanol-Water-THF, Isopropanol-Water-THF, n-Butanol-Water-THF and tert-Butanol-Water-THF One of them, the volume ratio of the three solvents is V1: V2: V3 = (1-10): (0.5-5.5): (0.2-2.5); preferably isopropanol-water-N, N-dimethyl One of methyl formamide, tert-butanol-water-N,N-dimethylformamide, isopropanol-water-tetrahydrofuran and tert-butanol-water-tetrahydrofuran, the volume ratio of the three solvents is preferably V1:V2 : V3=(1-5):(1-3.5):(0.2-1), more preferably V1:V2:V3=(1-1.5):(1.5-2):(0.2-0.5), here The reaction proceeds more easily in a solvent.

Further, the catalyst described in step S2 is a combined catalyst selected from sodium carbonate-anhydrous sodium sulfate, sodium carbonate-anhydrous copper sulfate, sodium bicarbonate-anhydrous sodium sulfate, sodium bicarbonate-anhydrous copper sulfate, carbonic acid One of potassium-anhydrous sodium sulfate, potassium carbonate-anhydrous copper sulfate, sodium ascorbate-anhydrous sodium sulfate, sodium ascorbate-anhydrous copper sulfate, sodium acetate-anhydrous sodium sulfate and sodium acetate-anhydrous copper sulfate , preferably one of sodium carbonate-anhydrous sodium sulfate, sodium bicarbonate-anhydrous sodium sulfate, potassium carbonate-anhydrous sodium sulfate and sodium ascorbate-anhydrous sodium sulfate, under the effect of this combined catalyst, the reaction Easier to proceed.

Further, the method of separation and purification in step S2 is selected from a combination of one or more of resin treatment, water washing, distillation, crystallization, extraction, activated carbon treatment, molecular sieve treatment and chromatography.

The separation and purification method described in step S2 of the present invention can be: for example, after TLC detects that anserine has completely reacted, the reaction solution is spun until the volume of the reaction solution is reduced to 1/3 of its original volume, and the spun reaction solution is left overnight at room temperature. Cooling and crystallization, HPLC traces the separation and purification process of the reaction and the product, and the precipitated solid is dried, such as vacuum drying at 50°C for 6 hours, to obtain the target product; for another example, after TLC detects that anserine has completely reacted, cool down to room temperature, and then add to the reaction Add water to the liquid, extract it several times with dichloromethane, chloroform, acetone or ethyl acetate, recover and dry the extract (such as anhydrous sodium sulfate or anhydrous magnesium sulfate), evaporate the extract to dryness to obtain a solid, for example, at 50°C After vacuum drying for 6h, the target product was obtained.

The present invention provides the application of the compound of formula (I) in the preparation of urate-lowering drugs or xanthine oxidase inhibitors; in the embodiment of the present invention, the target is xanthine oxidase XOD.

Beneficial effects: the anserine derivatives of the present invention exhibit better inhibitory activity (IC ₅₀ : 0.54-11.47 μmol/L) to xanthine oxidase, and the activity of some compounds is much higher than that of the clinical drug allopurinol (IC 50 : 0.54-11.47 μmol/L). ₅₀ : 7.49 μmol/L).

Detailed ways

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as are familiar to those skilled in the art. The reagents or raw materials used in the present invention can be purchased through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in accordance with conventional methods in the art or according to product instructions. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention.

Example 1

Anserine (24g, 0.1mol) was added in 100mL of tetrahydrofuran, and after being completely dissolved, propyne bromide (14.8g, 0.125mol) and strontium carbonate (29.6g, 0.2mol) were added to the solution, and heated to 60°C, reacted for 3 hours, TLC traced the reaction progress (dichloromethane/methanol=5/1), after the reaction was completed, the reaction solution was poured into 200mL water, filtered, and then extracted with 50mL methyl tert-butyl ether for 4 times, The organic phases were combined and evaporated to dryness to obtain intermediate I (24.2g, 0.87mol), ¹³ CNMR (150MHz, DMSO) δ179.4, 173.3, 137.5, 132.8, 126.6, 82.7, 73.2, 59.2, 48.3, 40.2, 34.7, 33.1, 26.1. HRMS: M/e (278.1352), molecular formula: C ₁₃ H ₁₈ N ₄ O ₃ .

Example 2

Intermediate I (27.8g, 0.1mol) and 2-fluoropyridyl azide (20.7g, 0.15mol) were added to 150mL mixed solution (isopropanol-water-N,N-dimethylformamide), Then add catalyst sodium carbonate-anhydrous sodium sulfate (1.68g-1.0g), heat to 70°C for 5h under nitrogen protection, TLC traces the reaction process (dichloromethane/methanol=3/1), separates and purifies after the reaction 29.4 g of light yellow powder was obtained, ¹³ C NMR (150 MHz, DMSO) δ179.5, 172.8158.6, 145.7137.4, 135.2, 132.8, 127.4, 126.7, 124.5, 122.8, 118.1, 59.8, 50.6, 46.1, 35.6, 33.8, 27.5. HRMS: M/e (416.1735), molecular formula: C ₁₈ H ₂₁ FN ₈ O ₃ , namely compound 1 in Table 1.

According to the method similar to Example 2, selecting suitable substituted pyridyl can prepare compound 4 (substituent R is (2-chloropyridyl)), compound 7 (substituent R is (2-bromopyridyl)) and Compound 10 (substituent R is (2-iodopyridyl)).

Example 3

Intermediate I (27.8g, 0.1mol) and 3-fluoropyridyl azide (20.7g, 0.15mol) were added to 150mL mixed solution (tert-butanol-water-N,N-dimethylformamide), Then add the catalyst sodium bicarbonate-anhydrous sodium sulfate (1.68g-1.0g), heat to 85°C for 7h under nitrogen protection, TLC traces the reaction process (dichloromethane/methanol=3/1), and separates after the reaction Purified to obtain 30.6 g of light yellow powder product, ¹³ C NMR (150 MHz, DMSO) δ179.6, 172.4158.6, 145.7137.4, 135.2, 132.5, 127.8, 126.2, 124.8, 122.5, 118.1, 59.3, 50.9, 46.7, 35.1 , 33.4, 27.2. HRMS: M/e (416.1744), molecular formula: C ₁₈ H ₂₁ FN ₈ O ₃ , namely compound 2 in Table 1.

According to the method similar to Example 3, select suitable substituted pyridyl and can prepare compound 5 (substituent R is (3-chloropyridyl)), compound 8 (substituent R is (3-bromopyridyl)) and Compound 11 (substituent R is (3-iodopyridyl)).

Example 4

Add intermediate I (27.8g, 0.1mol) and (2,3-difluoro)pyridyl azide (23.4g, 0.15mol) to 150mL mixed solution (isopropanol-water-tetrahydrofuran), then add the catalyst Potassium carbonate-anhydrous sodium sulfate (1.68g-1.0g), heated to 95°C for 10h under the protection of nitrogen, and followed the reaction progress by TLC (dichloromethane/methanol=3/1), separated and purified after the reaction to obtain light yellow 33.2 g of powder product, ¹³ C NMR (150 MHz, DMSO) δ179.6, 172.4, 158.6, 145.7137.4, 135.2, 132.5, 127.8, 126.2, 124.8, 118.1, 106.8, 59.3, 50.9, 46.7, 35.1, 33.4, 27.2 .HRMS: M/e (434.1653), molecular formula: C ₁₈ H ₂₀ F ₂ N ₈ O ₃ , namely compound 3 in Table 1.

According to the method similar to Example 4, select suitable substituted pyridyl to prepare compound 6 (substituent R is ((2,3-dichloro)pyridyl)), compound 9 (substituent R is ((2, 3-dibromo)pyridyl)) and compound 12 (substituent R is ((2,3-diiodo)pyridyl)).

Example 5

Add intermediate I (27.8g, 0.1mol) and 2-methyl-3-fluoropyridyl azide (22.8g, 0.15mol) to 150mL mixed solution (tert-butanol-water-tetrahydrofuran), then add the catalyst Sodium ascorbate-anhydrous sodium sulfate (1.68g-1.0g), heated to 65°C for 5.5h under the protection of nitrogen, followed the reaction progress by TLC (dichloromethane/methanol=3/1), separated and purified after the reaction to obtain 24.2 g of yellow powder product, ¹³ C NMR (150 MHz, DMSO) δ179.1, 173.6, 160.4, 146, 8, 144.9, 139.4, 132.2, 126.8, 126.2, 118.8, 118.1, 107.2, 60.2, 51.7, 45.9, 36.1, 32.4, 27.1, 11.4. HRMS: M/e (480.1839), molecular formula: C ₁₉ H ₂₃ FN ₈ O ₃ , namely compound 13 in Table 1.

According to the method similar to Example 5, select suitable substituted pyridyl to obtain compound 14 (substituent R is (2-methyl-5-fluoropyridyl) and compound 15 (substituent R is 2-methyl-5-fluoropyridyl) and compound 15 (substituent R is 2-methyl- 6-fluoropyridyl).

Example 6

Intermediate I (27.8g, 0.1mol) and 3-methyl-2-fluoropyridyl azide (22.8g, 0.15mol) were added to 150mL mixed solution (isopropanol-water-tetrahydrofuran), and then the catalyst was added Sodium ascorbate-anhydrous sodium sulfate (1.68g-1.0g), heated to 85°C for 8h under the protection of nitrogen, followed by TLC (dichloromethane/methanol=3/1), separated and purified to obtain light yellow 28.7 g of powder product, ¹³ C NMR (150MHz, DMSO) δ181.6, 174.4, 161.3, 149.4, 145.7, 137.2, 131.9, 127.6, 126.5, 119.5, 118.6, 108.4, 61.7, 52.7, 46.9, 35.9, 31.8, 28.4 , 12.7. HRMS: M/e (480.1815), molecular formula: C ₁₉ H ₂₃ FN ₈ O ₃ , namely compound 16 in Table 1.

According to the method similar to Example 6, select suitable substituted pyridyl to obtain compound 17 (substituent R is (3-methyl-5-fluoropyridyl) and compound 18 (substituent R is 3-methyl-5-fluoropyridyl) and 6-fluoropyridyl).

Example 7

Intermediate I (27.8g, 0.1mol) and 2-methoxy-3-fluoropyridyl azide (25.2g, 0.15mol) were added to 150mL mixed solution (isopropanol-water-N,N-dimethyl base formamide), then add the catalyst sodium bicarbonate-anhydrous sodium sulfate (1.68g-1.0g), and heat to 95°C for 5h under nitrogen protection, TLC traces the reaction process (dichloromethane/methanol=3/1 ), separated and purified after the reaction to obtain 35.6 g of brown yellow powder product, ¹³ C NMR (150 MHz, DMSO) δ180.1, 173.4, 152.3, 139.4, 138.7, 137.2, 131.9, 127.9, 126.8, 121.5, 117.6, 107.9, 60.7 , 55.7, 49.9, 45.9, 35.8, 33.4, 26.7. HRMS: M/e (446.1797), molecular formula: C ₁₉ H ₂₃ FN ₈ O ₄ , namely compound 19 in Table 1.

According to the method similar to Example 7, select suitable substituted pyridyl to obtain compound 20 (substituent R is (2-methyl-5-fluoropyridyl) and compound 21 (substituent R is 2-methyl-5-fluoropyridyl) and compound 21 (substituent R is 2-methyl- 6-fluoropyridyl).

Example 8

Intermediate I (27.8g, 0.1mol) and 3-methoxy-2-fluoropyridyl azide (25.2g, 0.15mol) were added to 150mL mixed solution (tert-butanol-water-N,N-dimethyl In base formamide), add catalyst potassium carbonate-anhydrous sodium sulfate (1.68g-1.0g) again, heat to 95 ℃ reaction 5h under the protection of nitrogen, TLC tracking reaction process (dichloromethane/methanol=3/1) After the reaction, separation and purification resulted in 30.6 g of brown yellow powder product, ¹³ C NMR (150 MHz, DMSO) δ178.8, 172.6, 152.3, 149.6, 142.7, 137.7, 131.1, 126.6, 126.2, 121.8, 116.6, 98.9, 59.2, 54.7, 49.1, 46.9, 35.2, 32.6, 24.3. HRMS: M/e (446.1806), molecular formula: C ₁₉ H ₂₃ FN ₈ O ₄ , namely compound 22 in Table 1.

According to the method similar to Example 8, select suitable substituted pyridyl to obtain compound 23 (substituent R is (3-methoxy-5-fluoropyridyl) and compound 24 (substituent R is 3-methoxy base-6-fluoropyridyl).

Example 9

Intermediate I (27.8g, 0.1mol) and 2-ethoxy-3-fluoropyridyl azide (27.3g, 0.15mol) were added to 150mL mixed solution (isopropanol-water-tetrahydrofuran), and then Catalyst sodium bicarbonate-anhydrous sodium sulfate (1.68g-1.0g), heated to 100°C for 7.5h under nitrogen protection, followed by TLC (dichloromethane/methanol=3/1), separated and purified after the reaction 32.7 g of brown yellow powder product was obtained, ¹³ C NMR (150 MHz, DMSO) δ179.5, 173.3, 146.3, 139.6, 139.2, 137.1, 131.8, 126.6, 125.8, 123.2, 121.8, 106.6, 65.4, 58.3, 52.8, 48.1, 45.9, 38.2, 33.6, 27.3. HRMS: M/e (460.1919), molecular formula: C ₂₀ H ₂₅ FN ₈ O ₄ , namely compound 25 in Table 1.

According to the method similar to Example 9, select suitable substituted pyridyl to obtain compound 26 (substituent R is (3-ethoxy-5-fluoropyridyl) and compound 27 (substituent R is 3-ethoxy base-6-fluoropyridyl).

Example 10

Intermediate I (27.8g, 0.1mol) and 3-ethoxy-2-fluoropyridyl azide (27.3g, 0.15mol) were added to 150mL mixed solution (tert-butanol-water-tetrahydrofuran), and then Catalyst sodium carbonate-anhydrous sodium sulfate (1.68g-1.0g), heated to 100°C for 8.5h under nitrogen protection, followed by TLC reaction progress (dichloromethane/methanol=3/1), separated and purified after the reaction to obtain Brown yellow powder product 31.4g, ¹³ C NMR (150MHz, DMSO) δ180.3, 174.1, 149.2, 138.5, 138.1, 136.7, 134.6, 128.4, 128.1, 125.2, 122.5, 108.3, 67.2, 57.4, 56.3, 47.4, 44.2 , 37.9, 34.6, 22.7. HRMS: M/e (460.1933), molecular formula: C ₂₀ H ₂₅ FN ₈ O ₄ , namely compound 28 in Table 1.

According to the method similar to Example 10, select suitable substituted pyridyl to obtain compound 29 (substituent R is (3-ethoxy-5-fluoropyridyl) and compound 30 (substituent R is 3-ethoxy base-6-fluoropyridyl).

Example 11

Xanthine oxidase inhibitory activity screening experiment.

PBS (10 mM, pH=7.4), xanthine oxidase XOD (92 U/L) and xanthine (0.5 mM) were prepared and stored at 4°C for use. Compounds 1-30 in Table 1 were prepared with different gradient concentrations (20, 10, 5, 2.5, 1.25, 0.625 and 0.3125 μM) in PBS. At the same time, a blank group and a control group were set, the blank group replaced the test compound with PBS, the control group 1 replaced the test compound with anserine, and the control group 2 replaced the test compound with allopurinol, the concentration gradient of anserine and allopurinol was the same as in Table 1 The compounds are the same. The reaction was carried out in a 96-microwell plate containing 200 μL of reaction mixture per well, and 5 parallel wells were set up in each group. First, 100 μL of different concentrations of the compounds in Table 1, anserine or allopurinol and 50 μL of xanthine oxidase XOD were added to a 96 microwell plate, mixed evenly, and equilibrated at 37° C. for 5 minutes. Then 50 μL of xanthine was added to initiate the reaction and incubated at 37° C. for 30 min. After the reaction, the OD value of each well was tested at 295 nm using a microplate reader (BioTek Instruments Inc., USA), and each group was repeated 3 times. The inhibition rate (%) is according to the following formula: inhibition rate (%)=(OD blank-OD test)/OD blank×100%, and the IC ₅₀ value of each group is calculated according to the inhibition rate.

See Table 2 for the IC _s0 values of the synthetic formula I compound 1-30 (prepared according to the embodiment of the present invention), allopurinol and anserine on the inhibitory activity of xanthine oxidase XOD.

Table 2 inhibits the _IC50 value of xanthine oxidase XOD activity

Compounds within the scope of other structural formulas all have better activity.

Claims (10)

1. Anserine derivatives having the structure represented by formula (I):

wherein R is pyridyl substituted by a substituent,

the substituent is selected from alkyl, alkoxy or halogen.

2. Anserine derivative according to claim 1, wherein R is selected from the following groups:

wherein R is ₁ Mono-or di-substituted on the pyridine ring, selected from F, cl, br or I;

R ₂ is methyl or ethyl.

3. Anserine derivative according to claim 1 or 2,

r is

When R is ₁ Mono-or di-substituted on the pyridine ring, selected from F, cl, br, I;

r is

When R is ₁ Monosubstituted on the pyridine ring, F, R ₂ Selected from methyl or ethyl.

4. Anserine derivative according to claim 1, wherein R is selected from the following groups: 2-fluoropyridyl, 3-fluoropyridyl, (2,3-difluoro) pyridyl, 2-chloropyridyl, 3-chloropyridyl, (2,3-dichloro) pyridyl, 2-bromopyridyl, 3-bromopyridyl, (2,3-dibromo) pyridyl, 2-iodopyridyl, 3-iodopyridyl, (2,3-diiodo) pyridyl, 2-methyl-3-fluoropyridyl, 2-methyl-5-fluoropyridyl, 2-methyl-6-fluoropyridyl, 3-methyl-2-fluoropyridyl, 3-methyl-5-fluoropyridyl, 3-methyl-6-fluoropyridyl, 2-methoxy-3-fluoropyridyl, 2-methoxy-5-fluoropyridyl, 2-methoxy-6-fluoropyridyl, 3-methoxy-2-fluoropyridyl, 3-methoxy-5-fluoropyridyl, 3-methoxy-6-fluoropyridyl, 2-ethoxy-3-fluoropyridyl, 2-ethoxy-5-fluoropyridyl, 2-ethoxy-6-fluoropyridyl, 3-ethoxy-2-fluoropyridyl, 3-ethoxy-5-fluoropyridyl, 3-ethoxy-6-fluoropyridyl.

5. The anserine derivative according to claim 1, which is any one of the following:

6. the method for preparing anserine derivatives according to any one of claims 1 to 5, comprising the steps of:

s1: dissolving anserine in a solvent, adding bromopropyne and a catalyst, heating and stirring under the protection of nitrogen for reaction, tracking the reaction process by TLC, pouring the reaction solution into water after the reaction is finished, filtering, extracting the filtrate, combining organic phases, and evaporating to dryness to obtain an intermediate I;

s2: reacting intermediate I with R-N ₃ Dissolving in a solvent, adding a catalyst, heating and stirring under the protection of nitrogen for reaction, tracking the reaction process by TLC, and separating and purifying after the reaction is finished to obtain the compound shown in the formula (I).

7. The process for producing anserine derivatives according to claim 6, wherein the molar ratio of the amounts of anserine, bromopropyne and the catalyst used in step S1 is 1: (0.5-10): (0.2-5), the amount of the solvent used is such that anserine is dissolved in 0.5-10L of the solvent per mole, the reaction temperature is 20-100 ℃ and the time is 0.5-10h, and the developing solvent selected by TLC is dichloromethane/methanol =5/1-1/1.

8. The method for preparing anserine derivatives according to claim 6, wherein the solvent in step S1 is selected from a mixture of one or more of water, methanol, absolute ethanol, isopropanol, N-butanol, acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, tetrahydrofuran, N-dimethylformamide and dimethylsulfoxide; the catalyst is selected from one or more of strontium carbonate, potassium carbonate, sodium bicarbonate, potassium phosphate, ammonia water, diethylamine, triethylamine, pyridine and piperidine; the reagent selected from the extraction filtrate is one or more of petroleum ether, diethyl ether, isopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, ethyl propionate and ethyl acetoacetate.

9. The method for preparing anserine derivatives according to claim 6, wherein the intermediate I, R-N in step S2 ₃ And the molar ratio of the amount of the catalyst is 1: 0.5-10: 1-5, the amount of the solvent is that each mole of the compound 2 is dissolved in 1-10L of the solvent, the reaction temperature is 40-150 ℃, the time is 0.5-15h, the developing agent selected by TLC is dichloromethane/methanol =3/1-1/1, the solvent is a mixed solution selected from one of methanol-water-N, N-dimethylformamide, ethanol-water-N, N-dimethylformamide, isopropanol-water-N, N-dimethylformamide, N-butanol-water-N, N-dimethylformamide, tert-butanol-water-N, N-dimethylformamide, methanol-water-tetrahydrofuran, ethanol-water-tetrahydrofuran, isopropanol-water-tetrahydrofuran, N-butanol-water-tetrahydrofuran and tert-butanol-water-tetrahydrofuran, the volume ratio of the three solvents is V1: V2: V3= (1-10) = (0.5-5.5: 0.2-2); the catalyst is a combined catalyst and is selected from one of sodium carbonate-anhydrous sodium sulfate, sodium carbonate-anhydrous copper sulfate, sodium bicarbonate-anhydrous sodium sulfate, sodium bicarbonate-anhydrous copper sulfate, potassium carbonate-anhydrous sodium sulfate, potassium carbonate-anhydrous copper sulfate, sodium ascorbate-anhydrous sodium sulfate, sodium ascorbate-anhydrous copper sulfate, sodium acetate-anhydrous sodium sulfate and sodium acetate-anhydrous copper sulfate; the separation and purification method is selected from one or more of resin treatment, water washing, distillation, crystallization, extraction, activated carbon treatment, molecular sieve treatment and chromatography.

10. Use of the anserine derivative according to any one of claims 1 to 5 for the preparation of a xanthine oxidase inhibitor or for the preparation of a medicament for reducing uric acid, both of which target of action are xanthine oxidase XOD.