Carboxy chalcone derivatives, processes for their preparation and use

Abstract

The application belongs to the field of pharmaceutical chemistry, and provides a carboxyl chalcone derivative and a preparation method thereof, a structural general formula of the carboxyl chalcone derivative is shown in formula (I) or formula (II); in formula (I), R1 is methyl, ethyl, n-propyl, ethynyl, methylamino, dimethylamino, methylthio or methylsulfonyl; in formula (II), R2 is 3-thiophene, 2-thiazole, dihydrobenzofuran, benzodioxolane, benzodioxane, indole, dihydroindole, quinoline or naphthalene. The carboxyl chalcone derivative has excellent inhibitory effect on xanthine oxidase, and can be applied to the preparation of drugs with xanthine oxidase as a target. The application provides more candidate compounds for the development of xanthine oxidase inhibitors.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry and relates to carboxyl chalcone derivatives and preparation methods and applications thereof. Background Art

[0002] Uric acid (UA) is the final oxidation product of purine catabolism in the human body. It is slightly soluble in water and readily forms crystals. Under normal circumstances, uric acid production and excretion are in balance. However, when UA production is excessive and excretion is impaired, with blood uric acid concentrations exceeding 7 mg / dL, body fluids become acidic, urate crystals form, and accumulate in tissues. Long-term effects can lead to hyperuricemia and even gout, and may also cause various diseases such as urate nephropathy, joint disability, and renal insufficiency. In the treatment of hyperuricemia, it is necessary to normalize serum UA levels and maintain a steady state of urate levels. Xanthine oxidase (XO) catalyzes the final hydroxylation of hypoxanthine to UA in the final step of UA synthesis. Therefore, one effective approach to treating hyperuricemia is to inhibit XO activity and thereby interfere with UA production.

[0003] Currently marketed XO inhibitors include allopurinol, febuxostat, and topiroxetine. Allopurinol is the longest-standing and most widely used XO inhibitor to date, but its metabolite, oxypurinol, can significantly affect metabolism, causing side effects such as fever, allergic rash, abdominal pain, diarrhea, leukopenia and thrombocytopenia, and liver damage. Studies have shown that compared with the non-purine inhibitors febuxostat and topiroxetine, allopurinol has relatively higher efficacy and fewer adverse reactions. However, in many cases, febuxostat and topiroxetine are associated with higher cardiovascular risks. In addition, febuxostat also carries risks for liver function and rash, and topiroxetine may increase the risk of liver damage. Therefore, the discovery of highly effective and low-toxic XO inhibitors for the treatment of hyperuricemia is urgently needed.

[0004] Natural products are an important source of novel bioactive compounds with therapeutic applicability. They are characterized by rich bioactive ingredients, extensive utilization history, and few adverse reactions. Among them, chalcone (1,3-diaryl-2-propen-1-one) is a natural aromatic ketone mainly found in plants. It consists of two aromatic rings (A ring and B ring) connected by an α, β-unsaturated carbonyl group. Its structural formula is

[0005] Chalcone with natural skeleton has the advantages of simple chemical structure, no obvious toxicity and the like, and also has various pharmacological properties such as anti-cancer, anti-diabetes, antibacterial, anti-virus, anti-inflammatory and anti-oxidation. Literature research shows that chalcone has certain XO inhibitory activity, but the XO inhibitory activity is not high, and far cannot meet the requirements of actual clinical application. Therefore, if chalcone is modified to excavate more chalcone derivatives capable of efficiently inhibiting the activity of XO, more candidate compounds for development of XO inhibitors are provided, which will have positive significance for drug research and development for treating hyperuricemia. SUMMARY

[0006] The present application aims at overcoming the deficiencies of the prior art, and provides a carboxyl chalcone derivative, a preparation method and application thereof, so as to effectively improve the activity of chalcone in inhibiting xanthine oxidase, and provide more candidate compounds for development of xanthine oxidase inhibitors.

[0007] To achieve the above-mentioned application purposes, the technical solutions adopted by the present application are as follows:

[0008] The carboxyl chalcone derivative has a structural general formula as shown in formula (I) or formula (II).

[0009]

[0010] In formula (I), R1 is methyl, ethyl, n-propyl, ethynyl, methylamino, dimethylamino, methylthio or methylsulfonyl.

[0011] In formula (II), R2 is 3-thiophene, 2-thiazole, dihydrobenzofuran, benzodioxolane, benzodioxane, indole, dihydroindole, quinoline or naphthalene.

[0012] In the technical solution of the carboxyl chalcone derivative, the carboxyl chalcone derivative with the structural general formula as shown in formula (I) or formula (II) is in trans (E) configuration.

[0013] In the technical solution of the carboxyl chalcone derivative, the carboxyl chalcone derivative with the structural general formula as shown in formula (I) includes compounds I-1 to I-8, and the structural formulae of the compounds I-1 to I-8 are as follows.

[0014]

[0015] In the technical solution of the carboxyl chalcone derivative, the carboxyl chalcone derivative with the structural general formula as shown in formula (II) includes compounds II-1 to II-10, and the structural formulae of the compounds II-1 to II-10 are as follows.

[0016]

[0017] The present application also provides pharmaceutically acceptable salts of the above carboxyl chalcone derivatives. For example, the above compounds I-1 to I-8, or compounds II-1 to II-10 form addition salts with hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

[0018] The term "pharmaceutically acceptable" means suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit / risk ratio as well-known in the art, and effective for direct or indirect delivery of the compounds or prodrugs of the compounds of the present application.

[0019] The present application also provides a method for preparing the above carboxyl chalcone derivatives, the synthetic route and steps of which are as follows:

[0020]

[0021] ① Compound 1 or compound 2 is dissolved in a solvent to obtain a solution of compound 1 or compound 2, the pH value of the solution of compound 1 or compound 2 is adjusted to 9-13, then methyl 3-formyl-4-hydroxybenzoate is added and mixed uniformly to obtain a reaction precursor solution, and the reaction is carried out under the condition of 80-100℃ and 100-300W microwave;

[0022] The compound 1 is p-methylacetophenone, p-ethylacetophenone, p-propylacetophenone, p-ethynylacetophenone, p-methylaminoacetophenone, p-dimethylaminoacetophenone, p-methylthioacetophenone or p-methylsulfonylacetophenone; and the compound 2 is 3-acetylthiophene, 2-acetylthiazole, 5-acetyl-2,3-dihydrobenzofuran, 3',4'-methylenedioxyacetophenone, 6-acetyl-1,4-benzodioxane, 1-(2,3-dihydro-1H-indol-5-yl)-ethanone, 5-acetylindole, 6-acetylquinoline, 2-acetylnaphthalene or 1-acetylnaphthalene.

[0023] In this step, the molar ratio of compound 1 or compound 2 to methyl 3-formyl-4-hydroxybenzoate is controlled to be (1-1.5):1;

[0024] ② The solvent of the reaction solution obtained after the reaction in step ① is removed to obtain a reaction product, the reaction product is dissolved in water and washed with ethyl acetate, the pH value of the obtained aqueous phase is adjusted to 5-6, then the organic phase obtained by extraction is washed with saturated sodium chloride solution, and then the water is removed and the ethyl acetate is evaporated to obtain a crude product; the crude product is separated and purified by silica gel column chromatography to obtain a carboxyl chalcone derivative.

[0025] In step ② of the technical solution for the preparation of the above-mentioned carboxychalcone derivatives, when the crude product is separated and purified by silica gel column chromatography, a dichloromethane-methanol mixture is used as the eluent for gradient elution. In the dichloromethane-methanol mixture used for gradient elution, the volume ratio of dichloromethane to methanol is gradually changed from 70:1 to 30:1.

[0026] In the technical solution of the above-mentioned method for preparing carboxychalcone derivatives, the solvent in step ① is water, methanol or ethanol.

[0027] In step ① of the technical solution for preparing the carboxychalcone derivatives, the concentration of compound 1 or compound 2 in the reaction precursor solution is preferably 0.05 to 0.1 mmol / mL.

[0028] In step ① of the technical solution of the above-mentioned method for preparing carboxychalcone derivatives, the pH value of the solution of compound 1 or compound 2 is adjusted to 9-13 using NaOH, KOH, sodium methoxide, sodium ethoxide, etc.

[0029] In step ② of the technical solution for the preparation of the above-mentioned carboxychalcone derivatives, the removal of moisture can generally be performed by drying with anhydrous Na2SO4 to remove moisture.

[0030] The present invention adopts a xanthine oxidase (XO) inhibitor screening model to detect the in vitro XO inhibition activity of carboxy chalcone derivatives (i.e., compounds I-1 to I-8, compounds II-1 to II-10), and allopurinol and febuxostat are used as positive control drugs. The results show that compounds I-1 to I-8 and compounds II-1 to II-10 have excellent XO inhibition effects, and their in vitro XO inhibition activity is measured by IC 50 The values ​​are between 0.064±0.023 and 0.226±0.011μmol / L, while the IC value of allopurinol, which is widely used in clinical practice, for inhibiting XO activity in vitro is 50 The value is 2.588±0.206μmol / L. In comparison, the IC values ​​of compounds I-1 to I-8 and compounds II-1 to II-10 of the present application for inhibiting XO in vitro are 50 The value is reduced by an order of magnitude.

[0031] The present invention also tested the effect of a carboxychalcone derivative (Compound I-5) on serum uric acid in rats with acute hyperuricemia through animal experiments. The results showed that when Compound I-5 was orally administered at a dose of 40 mg / kg, it showed a good uric acid-lowering effect, which was comparable to that of the positive control group (the control group that took allopurinol orally). The serum uric acid level in this group was significantly different from that in the model group ( ****p<0.0001). This shows that the carboxyl chalcone derivative (e.g. compound I-5) of the present application can also significantly inhibit the serum uric acid index of hyperuricemia in vivo, and has good anti-hyperuricemia activity.

[0032] Based on the above experimental results, the present application also provides the use of the above carboxyl chalcone derivative or the pharmaceutically acceptable salt of the above carboxyl chalcone derivative in the preparation of a drug targeting xanthine oxidase. Further, the drug targeting xanthine oxidase includes a drug for treating hyperuricemia.

[0033] Compared with the prior art, the present application has the following beneficial technical effects:

[0034] 1. The present application provides a series of carboxyl chalcone derivatives based on chalcone, in which a hydroxyl group and a carboxyl group are introduced at the ortho and meta positions of the B ring of chalcone, and a specific R1 or R2 group is introduced into the A ring of chalcone for modification. The present application proves by experiments that the carboxyl chalcone derivatives (compounds I-1 to I-8 and compounds II-1 to II-10) provided by the present application have excellent XO inhibitory effect. Their in vitro inhibitory activity on XO is expressed by IC 50 values of 0.064±0.023 to 0.226±0.011 μmol / L, which is reduced by one order of magnitude compared with the IC 50 values of allopurinol, which is widely used in clinical practice. At the same time, the carboxyl chalcone derivative (e.g. compound I-5) provided by the present application can effectively reduce the serum uric acid level of an acute hyperuricemia model rat, and the effect is comparable to that of allopurinol. It can be used in the preparation of a drug targeting xanthine oxidase, and provides a new candidate compound for the research and development of a drug for treating hyperuricemia.

[0035] 2. The present application also provides a preparation method of the carboxyl chalcone derivative, which has a simple process, uses microwave catalytic reaction to greatly shorten the synthesis period, and can obtain the product by "one-pot method", has mild reaction conditions, low cost, and is suitable for industrial production, and is conducive to popularization and application. BRIEF DESCRIPTION OF DRAWINGS

[0036] Fig. 1 is the serum uric acid concentration curve of the blank group (Blank), the model group (Model), the allopurinol group (Allopurinol (40 mg / kg)), the low-dose compound I-5 group (I-5 (10 mg / kg)), the medium-dose compound I-5 group (I-5 (20 mg / kg)), and the high-dose compound I-5 group (I-5 (40 mg / kg)) over time after administration.

[0037] Fig. 2 It is the serum uric acid concentration of blank group (Blank), model group (Model), allopurinol group (Allopurinol (40 mg / kg)), compound I-5 low-dose group (I-5 (10 mg / kg)), compound I-5 medium-dose group (I-5 (20 mg / kg)) and compound I-5 high-dose group (I-5 (40 mg / kg)) 2 hours after administration.

[0038] Fig. 3 It is the area under the curve of the blank group (Blank), model group (Model), allopurinol group (Allopurinol (40 mg / kg)), compound I-5 low-dose group (I-5 (10 mg / kg)), compound I-5 medium-dose group (I-5 (20 mg / kg)) and compound I-5 high-dose group (I-5 (40 mg / kg)) 6 hours after administration. DETAILED DESCRIPTION

[0039] The following examples further illustrate the carboxychalcone derivatives, their preparation methods, and applications of the present invention. It should be noted that the following examples are intended only to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Based on the above disclosure, non-essential improvements and adjustments made by those skilled in the art to the present invention for specific implementation remain within the scope of protection of the invention.

[0040] Example 1

[0041] In this example, compound I-1 was synthesized. The synthesis route is shown in the following formula, and the specific steps are as follows:

[0042]

[0043] Compound 1-1, 2.4 mmol was dissolved in 20 mL of methanol to obtain a p-methylphenylacetone solution, 10 mL of a 20 wt% potassium hydroxide solution was added dropwise to the p-methylphenylacetone solution, then 3-formyl-4-hydroxybenzoic acid methyl ester (compound 3), 2 mmol was added and mixed uniformly, and the reaction was carried out at 80°C under the condition of 200W microwave for 2 hours. The progress of the reaction was monitored by TLC during the reaction. After the reaction was completed, the solvent methanol was removed, the reaction product was dissolved in pure water and washed with ethyl acetate, the aqueous phase was retained, the pH value of the aqueous phase was adjusted to 5-6 with 1 mol / L HCl solution, and then extracted with ethyl acetate. The organic layer obtained by extraction was washed with saturated NaCl solution and dried with anhydrous Na2SO4, and the solvent was evaporated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography, and gradient elution was carried out with dichloromethane-methanol mixture as eluent (the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixture used in gradient elution was changed from 70:1 to 30:1) to obtain compound I-1. Compound I-1 was a yellow solid with a yield of 70.8% and an HPLC purity of 95.8%.

[0044] Compound I-1 1 H NMR and 13 The detection results of H NMR, C NMR and mass spectrum of compound I-1 are as follows:

[0045] 1 H NMR (400 MHz, DMSO-d6): δ 11.36 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 16.0 Hz, 1H), 7.89 (d, J = 16.0 Hz, 1H), 7.84 (dd, J = 8.8, 2.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.8 Hz, 1H), 2.40 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 188.92, 166.97, 161.09, 143.46, 138.33, 135.23, 132.98, 130.40, 129.39, 128.65, 122.01, 121.93, 121.32, 116.24, 21.22. ESI-HRMS: m / z calcd for C 17 H 15 O4[M+H] + 283.0970, found 283.0967.

[0046] Example 2

[0047] In this example, compound I-2 was synthesized, and the preparation method was basically the same as that in Example 1, except that the raw material p-methyl phenylacetone was replaced by p-ethyl phenylacetone. The compound I-2 prepared in this example was a yellow solid, with a yield of 50.7%, and an HPLC purity of 97.0%. The structure of compound I-2 is as follows:

[0048]

[0049] The compound I-2 was prepared according to the method of Example 1, except that the raw material p-methyl phenylacetone was replaced by p-ethyl phenylacetone. The compound I-2 prepared in this example was a yellow solid, with a yield of 50.7%, and an HPLC purity of 97.0%. The structure of compound I-2 is as follows: 1 H NMR and 13 The results of H NMR, C NMR and mass spectrum detection are as follows:

[0050] 1 H NMR (400 MHz, DMSO-d6): δ 8.20 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 15.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 15.6 Hz, 1H), 7.75 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 2.69 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 189.22, 169.49, 149.11, 141.14, 136.00, 133.28, 130.66, 128.50, 128.23, 120.36, 119.71, 116.47, 28.26, 15.29. ESI-HRMS: m / z calcd for C 14 H 17 O4[M+H] + 297.1127, found 297.1120.

[0051] Example 3

[0052] In this example, compound I-3 was synthesized, and the preparation method was basically the same as that in Example 1, except that the raw material p-methyl phenylacetone was replaced by p-ethyl phenylacetone. The compound I-3 prepared in this example was a yellow solid, with a yield of 50.7%, and an HPLC purity of 97.0%. The structure of compound I-2 is as follows:

[0053]

[0054] The compound I-3 was prepared according to the method of Example 1, except that the raw material p-methyl phenylacetone was replaced by p-ethyl phenylacetone. The compound I-3 prepared in this example was a yellow solid, with a yield of 50.7%, and an HPLC purity of 97.0%. The structure of compound I-2 is as follows: 1 H NMR and 13 The results of H NMR, C NMR and mass spectrum detection are as follows:

[0055] 1 H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.0 Hz, 1H), 8.07 - 7.98 (m, 3H), 7.92 - 7.83 (m, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.8 Hz, 1H), 2.64 (t, J = 7.6 Hz, 2H), 1.62 (h, J = 7.6 Hz, 2H), 0.90 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 188.94, 167.49, 161.09, 147.91, 138.50, 135.57, 133.11, 130.41, 128.80, 128.65, 121.82, 121.27, 116.17, 37.23, 23.84, 13.66. ESI-HRMS: m / z calcd for C 19 H 19 O4[M+H] + 311.1283, found 311.1281.

[0056] Example 4

[0057] In this example, compound I-4 was synthesized by the same method as in Example 1, except that the raw material p-methylphenylacetone was replaced by p-ethynylphenylacetone. The compound I-4 prepared in this example was a yellow solid with a yield of 59.9% and an HPLC purity of 96.0%. The structure of compound I-4 is as follows:

[0058]

[0059] The compound I-4 was detected by H NMR and 1 H NMR and 13 The detection results of C NMR and mass spectrum are as follows:

[0060] 1 H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.0 Hz, 1H), 8.07 - 7.98 (m, 3H), 7.92 - 7.83 (m, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.8 Hz, 1H), 2.64 (t, J = 7.6 Hz, 2H), 1.62 (h, J = 7.6 Hz, 2H), 0.90 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ 188.91, 169.97, 163.57, 142.76, 138.34, 133.60, 132.11, 131.15, 128.42, 125.69, 120.20, 118.70, 116.91, 83.68, 82.99. ESI-HRMS: m / z calcd for C 14 H 13 O4[M+H] + 293.0814, found 293.0806.

[0061] Example 5

[0062] In this example, compound I-5 was synthesized by the same method as in Example 1, except that the raw material p-methylacetophenone was replaced by p-methylaminoacetophenone. The compound I-5 prepared in this example was a yellow solid with a yield of 62.9%, and an HPLC purity of 95.2%. The structure of compound I-5 is as follows:

[0063]

[0064] The compound I-5 was detected by H NMR and 1 H NMR and 13 The detection results of C NMR and mass spectrum are as follows:

[0065] 1 H NMR (400 MHz, DMSO-d6): δ 8.34 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 15.6 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.71 (q, J = 4.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 186.12, 167.05, 160.58, 153.91, 135.98, 132.50, 130.97, 130.00, 125.31, 122.36, 121.97, 121.85, 116.03, 110.75, 29.19. ESI-HRMS: m / z calcd for C 17 H 16 NO4[M+H] + 298.1079, found 298.1072.

[0066] Example 6

[0067] In this example, compound I-6 was synthesized using a preparation method essentially identical to that of Example 1, except that the raw material p-methylacetophenone was replaced with p-dimethylaminoacetophenone. Compound I-6 prepared in this example was a yellow solid with a yield of 51.8% and an HPLC purity of 96.4%. The structure of compound I-6 is as follows:

[0068]

[0069] Compound I-6 1 H NMR and 13 The results of C NMR and mass spectrometry are as follows:

[0070] 1 H NMR (400MHz, CD3OD): δ8.38(d,J=2.0Hz,1H),8.10(d,J=15.6Hz,1H),8.01(d,J=9.2H z, 2H), 7.92–7.84 (m, 2H), 6.87 (d, J = 8.4Hz, 1H), 6.77 (d, J = 9.2Hz, 2H), 3.07 (s, 6H). 13 C NMR (100MHz, CD3OD): δ190.51,174.31,160.73,155.37,139.77,133.94,132.08,131.40,129.53,126.80,122.75,122.73,116.29,112.02,40.12. ESI-HRMS:m / z calcd.forC 14 H 18 NO4[M+H] + 312.1236, found 312.1236.

[0071] Example 7

[0072] In this example, compound I-7 was synthesized using a preparation method essentially identical to that of Example 1, except that the raw material p-methylacetophenone was replaced with p-methylthioacetophenone. Compound I-7 prepared in this example was a yellow solid with a yield of 51.8% and an HPLC purity of 97.3%. The structure of compound I-7 is as follows:

[0073]

[0074] Compound I-7 1 H NMR and 13 The results of C NMR and mass spectrometry are as follows:

[0075] 1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 2.0 Hz, 1H), 8.03 - 7.97 (m, 3H), 7.85 (d, J = 15.6 Hz, 1H), 7.76 (dd, J = 8.8, 2.1 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 2.55 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 188.39, 169.17, 144.99, 140.50, 134.28, 133.14, 130.57, 128.84, 125.04, 120.40, 120.01, 116.20, 14.00. ESI-HRMS: m / z calcd for C 17 H 14 NaO4S [M+Na] + 337.0510, found 337.0503.

[0076] Example 8

[0077] In this example, compound I-8 was synthesized by the same method as in Example 1, except that the raw material p-methyl phenylacetone was replaced by p-methylsulfonyl phenylacetone. The compound I-8 prepared in this example was a yellow solid with a yield of 85.6%, and an HPLC purity of 99.5%. The structure of compound I-8 is as follows:

[0078]

[0079] The compound I-8 was detected by H NMR and 1 H NMR and 13 The results of C NMR and mass spectrum detection are as follows:

[0080] 1 H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 2.0 Hz, 1H), 8.03 - 7.97 (m, 3H), 7.85 (d, J = 15.6 Hz, 1H), 7.76 (dd, J = 8.8, 2.1 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 1H), 2.55 (s, 3H). 13 C NMR (100 MHz, DMSO-d6): δ 188.39, 169.17, 144.99, 140.50, 134.28, 133.14, 130.57, 128.84, 125.04, 120.40, 120.01, 116.20, 14.00. ESI-HRMS: m / z calcd for C 17 H 14NaO6S [M + Na] + 369.0409, found 369.0402.

[0081] Example 9

[0082] In this example, compound II-1 was synthesized according to the following scheme and the specific steps are as follows:

[0083]

[0084] Compound 2-1 (3-acetylthiophene) 2.4 mmol was dissolved in 20 mL of methanol to obtain a p-methylacetophenone solution, 10 mL of a 20 wt% potassium hydroxide solution was added dropwise to the p-methylacetophenone solution, then 3-formyl-4-hydroxybenzoic acid methyl ester (compound 3) 2 mmol was added and mixed uniformly, and the reaction was carried out at 80°C under the condition of 200W microwave for 2 hours. During the reaction, the progress of the reaction was monitored by TLC. After the reaction was completed, the solvent methanol was removed, the reaction product was dissolved in pure water and washed with ethyl acetate, the water phase was retained, the pH value of the water phase was adjusted to 5-6 with 1 mol / L HCl solution, and then extracted with ethyl acetate. The organic layer obtained by extraction was washed with saturated NaCl solution and dried with anhydrous Na2SO4, and the solvent was evaporated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography, and during the separation and purification, dichloromethane-methanol mixture was used as the eluent for gradient elution (during gradient elution, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixture was gradually changed from 70:1 to 30:1) to obtain compound II-1. Compound II-1 was a yellow solid with a yield of 41.7% and an HPLC purity of 99.7%.

[0085] The synthesis of compound II-1 1 H NMR and 13 The detection results of H NMR, C NMR and mass spectrum are as follows:

[0086] 1 H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 8.85 (t, J = 2.0 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 16.0 Hz, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 7.82 (d, J = 16.0 Hz, 1H), 7.66 (t, J = 2.0 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 183.23, 166.98, 160.82, 142.90, 137.37, 134.37, 133.10, 130.04, 127.60, 127.16, 122.85, 122.04, 121.31, 116.11. ESI-HRMS: m / z calcd for C 14 H 10 O4S[M+H] + 275.0378, found 275.0371.

[0087] Example 10

[0088] In this example, compound II-2 was synthesized with the same method as in Example 9, except that the starting material 3-acetylthiophene was replaced by 2-acetylthiazole. The compound II-2 prepared in this example was a yellow solid with a yield of 45.5% and a purity of 96.0% by HPLC. The structure of compound II-2 is as follows:

[0089]

[0090] The H NMR and 1 H NMR and 13 The results of C NMR and mass spectrometry are as follows:

[0091] 1 H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J = 3.2 Hz, 2H), 8.21 (d, J = 3.2 Hz, 1H), 8.14 (d, J = 16.0 Hz, 1H), 8.05 (d, J = 16.0 Hz, 1H), 7.88 (dd, J = 8.4, 2.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 181.26, 167.83, 166.77, 161.54, 145.24, 140.09, 133.62, 131.15, 128.34, 122.13, 120.83, 120.81, 116.49. ESI-HRMS: m / z calcd for C 13 H 10 NO4S[M+H] + 276.0331, found 276.0330.

[0092] Example 11

[0093] In this example, compound II-3 was synthesized by the same method as in Example 9, except that the starting material 3-acetylthiophene was replaced by 5-acetyl-2,3- dihydrobenzofuran. Compound II-3 prepared in this example was a yellow solid with a yield of 46.2% and a purity of 99.2% by HPLC. The structure of compound II-3 is as follows:

[0094]

[0095] The compound II-3 was characterized by 1 H NMR and 13 The results of C NMR and mass spectrometry are as follows:

[0096] 1 H NMR (400 MHz, DMSO-d6): δ 11.39 (s, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 1.6 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.87 (d, J = 15.6 Hz, 1H), 7.82 (dd, J = 8.8, 2.0 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.65 (t, J = 8.8 Hz, 2H), 3.26 (d, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6): δ 187.48, 167.02, 164.01, 161.06, 137.63, 132.77, 130.93, 130.41, 130.25, 128.42, 126.03, 122.04, 121.86, 121.46, 116.24, 108.96, 72.23, 28.46. ESI-HRMS: m / z calcd for C 14 H 14 NaO5[M+Na] + 333.0739, found 333.0729.

[0097] Example 12

[0098] In this example, compound II-4 was synthesized by the same method as in Example 9, except that the starting material 3-acetylthiophene was replaced by 3',4'- methylenedioxyacetophenone. Compound II-4 prepared in this example was a yellow solid with a yield of 48.1% and a purity of 96.7% by HPLC. The structure of compound II-4 is as follows:

[0099]

[0100] The compound II-4 was characterized by1 H NMR and 13 The results of C NMR and mass spectrum detection are as follows:

[0101] 1 H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 15.6 Hz, 1H), 7.83 (d, J = 15.6 Hz, 1H), 7.74 (ddd, J = 8.4, 4.4, 2.0 Hz, 2H), 7.54 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.14 (s, 2H). 13 C NMR (100 MHz, DMSO-d6): δ 187.54, 169.30, 151.16, 147.98, 140.89, 133.09, 132.96, 131.01, 124.53, 120.38, 119.28, 116.48, 108.10, 107.67, 101.99. ESI-HRMS: m / z calcd for C 17 H 13 O6[M+H] + 313.0712, found 313.0709.

[0102] Example 13

[0103] In this example, compound II-5 was synthesized, and the preparation method was basically the same as that in Example 9, except that the raw material 3-acetylthiophene was replaced by 6-acetyl-1,4-benzodioxane. The compound II-5 prepared in this example was a yellow solid, with a yield of 48.9%, and an HPLC purity of 97.5%. The structure of the compound II-5 is as follows:

[0104]

[0105] The preparation of compound II-5 1 H NMR and 13 The results of C NMR and mass spectrum detection are as follows:

[0106] 1H NMR (400MHz, DMSO-d6): δ11.21(s,1H),8.39(d,J=2.0Hz,1H),7.97(d,J=15.6Hz,1H),7.88(d,J=15.6Hz,1H),7.85–7.82(m,1 H), 7.71 (dd, J = 8.4, 2.0Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.05 (d, J = 8.8Hz, 1H), 7.01 (d, J = 8.4Hz, 1H), 4.34 (s, 2H), 4.31 (s, 2H). 13 C NMR (100MHz, DMSO-d6): δ187.49,166.97,160.90,147.92,143.40,137.88,132.92,13 1.31,130.39,122.66,121.97,121.83,121.40,117.44,117.19,116.11,64.59,63.96. ESI-HRMS:m / z calcd.for C 14 H 15 O6[M+H] + 327.0869,found 327.0862.

[0107] Example 14

[0108] In this example, compound II-6 was synthesized using a preparation method essentially the same as in Example 9, except that the raw material 3-acetylthiophene was replaced with 1-(2,3-dihydro-1H-indol-5-yl)-ethanone. Compound II-6 prepared in this example was a yellow solid with a yield of 43.2% and an HPLC purity of 99.3%. The structure of compound II-6 is as follows:

[0109]

[0110] Compound II-6 1 H NMR and 13 The results of C NMR and mass spectrometry are as follows:

[0111] 1 H NMR (400MHz, DMSO-d6): δ8.21(s,1H),7.93(d,J=15.6Hz,1H),7.82–7.72(m,4H),6.91 (d, J=8.4Hz, 1H), 6.50 (d, J=8.4Hz, 1H), 3.56 (t, J=8.8Hz, 2H), 3.00 (t, J=8.8Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ 186.37, 169.41, 156.97, 138.34, 132.50, 130.34, 129.98, 128.89, 126.99, 124.80, 120.73, 120.38, 115.93, 106.27, 46.29, 28.12. ESI-HRMS: m / z calcd for C 14 H 16 NO4[M+H] + 310.1079, found 310.1079.

[0112] Example 15

[0113] In this example, compound II-7 was synthesized by the same method as in Example 9, except that the starting material 3-acetylthiophene was replaced by 5-acetylinindole. The compound II-7 prepared in this example was a yellow solid with a yield of 48.9% and a purity of 99.4% by HPLC. The structure of compound II-7 is as follows:

[0114]

[0115] The compound II-7 was analyzed by H NMR, C NMR and mass spectrometry, and the results are as follows: 1 H NMR and 13 C NMR and mass spectrometry, and the results are as follows:

[0116] 1 H NMR (400 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.53 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 8.02 (d, J = 16.0 Hz, 1H), 8.01 (d, J = 16.0 Hz, 1H), 7.89 (dd, J = 8.8, 2.0 Hz, 1H), 7.85 (dd, J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.48 (t, J = 2.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.65 (t, J = 2.4 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 188.87, 167.04, 160.72, 138.52, 136.96, 132.73, 130.12, 129.55, 127.33, 127.16, 122.78, 122.59, 122.06, 121.68, 121.58, 116.08, 111.64, 103.12. ESI-HRMS: m / z calcd for C 14 H14 NO4[M+H] + 308.0923, found 308.0924.

[0117] Example 16

[0118] In this example, compound II-8 was synthesized by the same method as in Example 9, except that the starting material 3-acetylthiophene was replaced by 6-acetylquinoline. The compound II-8 prepared in this example was a yellow solid with a yield of 33.3% and a purity of 97.6% by HPLC. The structure of compound II-8 is as follows:

[0119]

[0120] The compound II-8 was analyzed by H NMR, C NMR and mass spectrometry, and the results are as follows: 1 H NMR and 13 C NMR and mass spectrometry, and the results are as follows:

[0121] 1 H NMR (400 MHz, DMSO-d6): δ 9.26 (dd, J = 4.8, 1.6 Hz, 1H), 9.15 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 8.0 Hz, 1H), 8.55 (dd, J = 8.8, 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 16.0 Hz, 1H), 8.06 (d, J = 16.0 Hz, 1H), 7.98 (dd, J = 8.4, 4.8 Hz, 1H), 7.88 (dd, J = 8.8, 2.0 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 188.61, 166.99, 161.25, 149.66, 143.55, 139.51, 136.59, 133.53, 130.80, 130.69, 130.32, 128.01, 125.24, 122.82, 122.08, 121.55, 121.19, 116.35. ESI-HRMS: m / z calcd for C 19 H 14 NO4[M+H] + 320.0923, found320.0914.

[0122] Example 17

[0123] In this example, compound II-9 was synthesized using a preparation method essentially identical to that of Example 9, except that 2-acetylnaphthalene was substituted for 3-acetylthiophene. Compound II-9 prepared in this example was a yellow solid with a yield of 51.6% and an HPLC purity of 97.9%. The structure of compound II-9 is as follows:

[0124]

[0125] Compound II-9 1 H NMR and 13 The results of C NMR and mass spectrometry are as follows:

[0126] 1 H NMR (400MHz, DMSO-d6): δ8.83(d,J=1.6Hz,1H),8.36(d,J=2.0Hz,1H),8.23–7.9 8(m,6H),7.83(dd,J=8.8,2.0Hz,1H),7.70–7.59(m,2H),7.00(d,J=8.8Hz,1H). 13 CNMR (100MHz, DMSO-d6): δ189.37,168.70,163.26,140.80,135.49,134.92,133.31,132.39 ,130.51,129.87,129.71,128.49,128.42,127.68,126.88,124.27,120.73,119.95,116.65. ESI-HRMS:m / z calcd.for C 20 H 15 O4[M+H] + 319.0970,found 319.0963.

[0127] Example 18

[0128] In this example, compound II-10 was synthesized using a preparation method essentially identical to that of Example 9, except that 1-acetylnaphthalene was substituted for 3-acetylthiophene. Compound II-10 was prepared as a yellow solid in a 57.1% yield and 97.6% HPLC purity. The structure of compound II-10 is as follows:

[0129]

[0130] Compound II-10 1 H NMR and 13 The results of C NMR and mass spectrometry are as follows:

[0131] 1 H NMR (400 MHz, DMSO-d6): δ 8.20 (dd, J = 6.4, 3.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 8.02 (dd, J = 6.4, 3.2 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.69 (dd, J = 8.8, 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.58 (dt, J = 6.4, 3.2 Hz, 2H), 7.48 (d, J = 16.0 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H). 13 C NMR (100 MHz, DMSO-d6): δ 195.35, 169.08, 143.55, 137.46, 133.36, 131.01, 130.82, 129.91, 128.47, 127.17, 126.68, 126.36, 125.34, 124.98, 124.24, 119.92, 117.07. ESI-HRMS: m / z calcd for C 20 H 15 O4[M+H] + 319.0970, found 319.0962.

[0132] Comparative Example 1

[0133] In the present comparative example, compound D1 was synthesized according to the following procedure:

[0134] A solution of p-methylacetophenone (compound 1-1, 2.4 mmol) was prepared by dissolving p-methylacetophenone in 20 mL of methanol, and 10 mL of a 20 wt% potassium hydroxide solution was added dropwise to the solution of p-methylacetophenone, followed by the addition of methyl p-formylbenzoate (2 mmol) and mixing. The mixture was reacted at 80°C under microwave conditions at 200 W for 2 hours, and the progress of the reaction was monitored by TLC during the reaction. After the completion of the reaction, the solvent methanol was removed, and the reaction product was dissolved in pure water and washed with ethyl acetate, and the aqueous phase was retained. The pH of the aqueous phase was adjusted to 5-6 using a 1 mol / L HCl solution, and then extracted with ethyl acetate. The organic layer obtained by extraction was washed with a saturated NaCl solution and dried with anhydrous Na2SO4, and the solvent was evaporated to obtain a crude product. The crude product was separated and purified by column chromatography on silica gel, and the elution was performed using a dichloromethane-methanol mixture as an eluent (the volume ratio of dichloromethane to methanol was changed from 70:1 to 30:1) to obtain compound D1. Compound D1 was a yellow solid, and the yield was 78.7%, and the HPLC purity was 95%. The structural formula of compound D1 is as follows:

[0135]

[0136] Compound D1 1 The H NMR test results are as follows:

[0137] 1 H NMR (400MHz, DMSO-d6): δ8.15(m,2H),8.03(d,J=8.0Hz,2H),7.94(d,J=16.0Hz,1H),7.75(d,J =16.0Hz, 1H), 7.94 (t, J = 8.8Hz, 1H), 7.34 (d, J = 8.0Hz, 2H), 7.13 (t, J = 7.6Hz, 1H), 2.41 (s, 3H).

[0138] Comparative Example 2

[0139] In this comparative example, Compound D2 was synthesized using a method essentially identical to that used in Comparative Example 1, except that the raw material, p-methylacetophenone, was replaced with 3',4'-methylenedioxyacetophenone. Compound D2 was prepared in this example as a yellow solid with a yield of 67.5% and an HPLC purity of 97.2%. The structure of Compound D2 is as follows:

[0140]

[0141] Compound D1 1 The H NMR test results are as follows:

[0142] 1 H NMR (400MHz, DMSO-d6) δ8.45(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),7.96–7.85(m,2H),7.71(d,J=15.6Hz, 1H), 7.65 (d, J = 1.6Hz, 1H), 7.39 (t, J = 7.6Hz, 1H), 7.31 (t, J = 7.6Hz, 1H), 7.08 (d, J = 8.0Hz, 1H), 6.16 (s, 2H).

[0143] Example 19

[0144] In this example, a xanthine oxidase (XO) inhibitor screening model was used to detect the in vitro XO inhibition activity of carboxychalcone derivatives (i.e., compounds I-1 to I-8, compounds II-1 to II-10, and compounds D1 to D2), using allopurinol and febuxostat as positive control drugs, respectively. The procedure was as follows:

[0145] (1) Preparation of phosphate buffer solution (PBS solution) at pH 7.4, weigh Na2HPO4·12H2O 15.6 g, add deionized water to 1000 mL to dissolve, obtain Na2HPO4 solution; weigh NaH2PO4·2H2O 17.8 g, add deionized water to 1000 mL to dissolve, obtain NaH2PO4 solution; take 19 mL of NaH2PO4 solution and 81 mL of Na2HPO4 solution, mix thoroughly, adjust pH to 7.4, obtain 0.1 mol / L PBS solution, store at room temperature. -1

[0146] (2) Preparation of substrate xanthine, place xanthine in a 50 mL volumetric flask, dissolve in 1 mL of 0.1 mol / L NaOH solution, adjust pH to 7.4 with dilute hydrochloric acid, add PBS solution to constant volume to 50 mL, obtain 0.5 mmol / L xanthine solution.

[0147] (3) Preparation of XO solution, prepare XO into 0.08 U / mL XO solution with PBS solution.

[0148] (4) Preparation of XO inhibitor solution, accurately weigh compounds I-1 to I-8, compounds II-1 to II-10, compounds D1 to D2, allopurinol, and febuxostat, respectively, dissolve in DMSO to prepare 10 mmol / L stock solution, store at -20°C, dilute to the required concentration (0.1 to 20 μmol / L) with PBS solution when used, prepare and use immediately.

[0149] (5) Inhibition experiment of each test compound on XO

[0150] In a 200 μL reaction system, add 50 μL XO (final concentration 0.025 U·mL -1 ) and 100 μL of different concentrations of XO inhibitor solution (i.e. solutions of compounds I-1 to I-8, compounds II-1 to II-10, compounds D1 to D2, allopurinol, and febuxostat), incubate at 37°C for 30 min. Then, add 50 μL of 0.5 mmol / L -1 of substrate xanthine for experiment. Measure the absorbance of the mixture system every 15 seconds at a wavelength of 295 nm, and the total measurement time is 5 min. Allopurinol and febuxostat are used as positive controls, and blank PBS solution is used as negative control. Each group is measured in triplicate.

[0151] ​In 96-well microplate, 50 μL XO solution with a concentration of 0.08 U / mL and 100 μL chalcone derivative solution or positive control drug solution with different concentrations were added, and incubated at 37 °C for 30 min. Subsequently, 50 μL xanthine solution with a concentration of 0.5 mmol / L was added to start the reaction. The absorbance value at a wavelength of 295 nm was measured on a microplate reader at intervals, and an inhibition curve was drawn. The half maximal inhibitory concentration IC 50 value was calculated by using GraphPad Prism 9 software, and the results are shown in Table 1.

[0152] Table 1 Inhibition of XO activity in vitro by carboxyl chalcone derivatives

[0153]

[0154] a The data are the mean ± SD of three independent experiments.

[0155] As can be seen from Table 1, the difference between compound D1 and compound I-1 in structure is that compound I-1 simultaneously introduces a hydroxyl group and a carboxyl group at the ortho and meta positions of the chalcone B ring, while compound D1 introduces a hydroxyl group on the chalcone B ring. However, compound I-1 has a significantly lower IC 50 value, i.e., compound I-1 has a significantly better XO inhibitory activity. Similarly, the difference between compound D2 and compound II-4 is that compound II-4 simultaneously introduces a hydroxyl group and a carboxyl group at the ortho and meta positions of the chalcone B ring, while compound D2 introduces a hydroxyl group on the chalcone B ring. Compound II-4 has a significantly lower IC 50 value, i.e., compound II-4 has a significantly better XO inhibitory activity. This indicates that simultaneously modifying a hydroxyl group and a carboxyl group at the ortho and meta positions of the chalcone B ring can effectively enhance the XO inhibitory activity of the carboxyl chalcone derivative, compared with the case of modifying only a carboxyl group on the chalcone B ring.

[0156] As can also be seen from Table 1, compared with allopurinol, which is widely used in clinical practice, the carboxyl chalcone derivatives (compounds I-1 to I-8 and compounds II-1 to II-10) provided in the present application have a significantly better XO inhibitory activity, with an IC 50 value that is significantly smaller. The difference between the IC 50 value of allopurinol is more than one order of magnitude. At the same time, the in vitro XO inhibitory activity of compounds I-2, I-5 and II-6 is close to that of febuxostat.

[0157] Example 20

[0158] In this example, the effect of the carboxyl chalcone derivative on serum uric acid in acute hyperuricemia model rats was investigated.

[0159] The experimental animals used in the animal experiments were 6-week-old male SD rats (200 ± 20 grams) from the Experimental Animal Center of Sichuan University. The acute hyperuricemia model was constructed by intraperitoneal injection of potassium oxonate (PO) to increase the uric acid level. Allopurinol was used as a positive control. The rats were adaptively fed in an animal room with a light / dark cycle of 12h:12h, controlled temperature and humidity for one week, and were fasted but not watered for 12h one day before the experiment. Initially, all rats were randomly divided into six groups (n = 7): a blank group, a model group, an allopurinol group, a compound I-5 low-dose group, a compound I-5 medium-dose group and a compound I-5 high-dose group, as shown in Table 2. Except for the blank group injected with normal saline, all rats were intraperitoneally injected with PO (300 mg / kg). After 1h, the blank group and the model group rats were given 0.5% CMC-Na by gavage, and the other groups of rats were given corresponding doses of compounds by gavage. After 1h, 2h, 3h, 4h, 6h, 8h of administration, about 200-300 μL of blood sample was collected from each rat by the orbital blood collection method, and serum was obtained by centrifugation at 3000 r / min at 4°C. The serum uric acid detection was determined according to the instructions of the kit (Nanjing Jiancheng Biological Engineering Institute, China). The time- efficacy curve was plotted according to the serum uric acid concentration of each group of rats.

[0160] Table 2 Determination scheme of serum uric acid content of hyperuricemia model rats

[0161]

[0162] The experimental results of this example are shown in Figs. 1-3 Fig. 1 is the serum uric acid concentration curve of the blank group (Blank), the model group (Model), the allopurinol group (Allopurinol (40 mg / kg)), the compound I-5 low-dose group (I-5 (10 mg / kg)), the compound I-5 medium-dose group (I-5 (20 mg / kg)) and the compound I-5 high-dose group (I-5 (40 mg / kg)) over time after administration, Fig. 2 is the serum uric acid concentration of the blank group (Blank), the model group (Model), the allopurinol group (Allopurinol (40 mg / kg)), the compound I-5 low-dose group (I-5 (10 mg / kg)), the compound I-5 medium-dose group (I-5 (20 mg / kg)) and the compound I-5 high-dose group (I-5 (40 mg / kg)) after 2h of administration #### p < 0.0001 vs blank; ****p < 0.0001, ***p < 0.001, **p < 0.005, *p < 0.05 vs model, Fig. 3 ​The area under the curve (AUC) of the blank group, model group, allopurinol group (Allopurinol (40 mg / kg)), compound I-5 low-dose group (I-5 (10 mg / kg)), compound I-5 medium-dose group (I-5 (20 mg / kg)) and compound I-5 high-dose group (I-5 (40 mg / kg)) after 6 hours of administration was #### p<0.0001vs blank; ****p<0.0001,***p<0.001,**p<0.005,*p<0.05vsmodel).

[0163] Depend on Figs. 1-3 It can be seen that compared with the blank group, the serum uric acid level in the model group remained at a higher level after intraperitoneal injection of PO (300 mg / kg) ( #### p<0.0001), which proves that the acute hyperuricemia model was successfully induced. When compound I-5 was orally administered at a dose of 10 mg / kg, it showed a certain uric acid-lowering effect, which was smaller than that of the model group ( * When compound I-5 was orally administered at a dose of 20 mg / kg, it showed a moderate uric acid-lowering effect compared with the model group ( ** p<0.005). When compound I-5 was orally administered at a dose of 40 mg / kg, it showed a better uric acid-lowering effect, which was comparable to that of the positive control group. The serum uric acid level in this group was significantly different from that in the model group ( **** p<0.0001). This indicates that the carboxyl chalcone derivatives provided by the present invention (e.g., compound I-5) can significantly inhibit the serum uric acid index of hyperuricemia in vivo, exert good anti-hyperuricemia activity, and their efficacy is positively proportional to the dose.

[0164] The above experimental results show that the carboxyl chalcone derivatives provided by the present invention have good XO inhibitory activity and uric acid-lowering ability in vivo, can reduce serum uric acid levels, and have broad prospects in the development of anti-hyperuricemia drugs.

Claims

1. A carboxychalcone derivative characterized in that, The structural formula of the carboxyl chalcone derivative is shown in formula (I) or (II). In formula (I), R1 is methyl, ethyl, n-propyl, ethynyl, methylamino, dimethylamino, methylthio or methylsulfonyl; In formula (II), R2 is 3-thiophene, 2-thiazole, dihydrobenzofuran, benzodioxolane, benzodioxane, indole, dihydroindole, quinoline or naphthalene.

2. The carboxy chalcone derivative according to claim 1, characterized by, The carboxyl chalcone derivative with the structural formula shown in formula (I) or (II) is in trans (E) configuration.

3. The carboxy chalcone derivative according to claim 1, wherein The carboxyl chalcone derivative with the structural formula shown in formula (II) includes compounds II-1 to II-10, and the structural formula of the compounds II-1 to II-10 is as follows:

4. The carboxyl chalcone derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

5. A process for preparing the carboxy chalcone derivative according to any one of claims 1 to 3, characterized by, The synthesis route and steps are as follows: ① Compound 1 or compound 2 is dissolved in a solvent to obtain a solution of compound 1 or compound 2, the pH value of the solution of compound 1 or compound 2 is adjusted to 9-13, then methyl 3-formyl-4-hydroxybenzoate is added and mixed uniformly to obtain a reaction precursor solution, and the reaction precursor solution is fully reacted under the condition of 80-100℃ and 100-300W microwave; The compound 1 is p-methylacetophenone, p-ethylacetophenone, p-propylacetophenone, p-ethynylacetophenone, p-methylaminoacetophenone, p-dimethylaminoacetophenone, p-methylthioacetophenone or p-methylsulfonylacetophenone; and the compound 2 is 3-acetylthiophene, 2-acetylthiazole, 5-acetyl-2,3-dihydrobenzofuran, 3',4'-methylenedioxyacetophenone, 6-acetyl-1,4-benzodioxane, 1-(2,3-dihydro-1H-indol-5-yl)-ethanone, 5-acetylindole, 6-acetylquinoline, 2-acetylnaphthalene or 1-acetylnaphthalene. In this step, the molar ratio of compound 1 or compound 2 to methyl 3-formyl-4-hydroxybenzoate is controlled to be (1-1.5):1; ② The solvent of the reaction solution obtained after the reaction in step ① is removed to obtain a reaction product, the reaction product is dissolved in water and washed with ethyl acetate, the pH value of the obtained aqueous phase is adjusted to 5-6, then the obtained organic phase is extracted with ethyl acetate, the obtained organic phase is washed with saturated sodium chloride solution, then water is removed, and ethyl acetate is evaporated to obtain a crude product; the crude product is separated and purified by silica gel column chromatography to obtain the carboxyl chalcone derivative.

6. The method of preparing the carboxy chalcone derivative according to claim 5, characterized by, In step ②, when the crude product is separated and purified by silica gel column chromatography, dichloromethane-methanol mixed solution is used as the eluent for gradient elution, and the volume ratio of dichloromethane to methanol in the dichloromethane-methanol mixed solution used for gradient elution is gradually changed from 70:1 to 30:

1.

7. A process for the preparation of the carboxychalcone derivative according to claim 5 or 6, characterized in that, The solvent in step ① is water, methanol or ethanol.

8. A process for preparing the carboxychalcone derivative according to claim 5 or 6, characterized by, In the reaction precursor solution in step ①, the concentration of compound 1 or compound 2 is 0.05-0.1 mmol / mL.

9. Use of the carboxyl chalcone derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a drug for treating hyperuricemia.

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