CN113336769B - A kind of thienopyrimidinone acylsulfonamide derivatives and preparation method and application thereof - Google Patents

Abstract

The invention relates to a thienopyrimidone acyl sulfonamide derivative and a preparation method and application thereof. The compound has a structure shown in formula I. The invention also relates to a preparation method and a pharmaceutical composition of the compound containing the structure of the general formula I. The invention also provides application of the compound in preparing anti-gout drugs.

Description

A kind of thienopyrimidinone acylsulfonamide derivatives and preparation method and application thereof

technical field

The invention belongs to the technical field of organic compound synthesis and medical application, in particular to a thienopyrimidinone acyl sulfonamide derivative and a preparation method and application thereof.

Background technique

Gout is a metabolic disease caused by the increased production or decreased excretion of uric acid caused by the disorder of purine metabolism, resulting in the deposition of monosodium urate crystals in joint tissues. Its clinical manifestations are mainly hyperuricemia. In recent years, with the improvement of people's living standards and dietary structure, the number of patients with gout and hyperuricemia has been increasing and tending to be younger, bringing a heavy burden to patients and society. In my country, the incidence of gout is 1.1%, and the incidence of hyperuricemia is 13.3%. Gout has become the second largest metabolic disease after diabetes. The "fourth highest" after blood sugar. At present, the clinical drugs used for the treatment of gout and hyperuricemia mainly include non-steroidal anti-inflammatory drugs, drugs that inhibit the production of uric acid, and drugs that promote uricosuric acid excretion. Urate transporter 1 (URAT1) is a transporter protein expressed in the apical membrane of human renal proximal tubule epithelial cells responsible for uric acid reabsorption. Reabsorption, increased metabolism of uric acid. The marketed drugs of this class of inhibitors include Probenecid, Sulfinpyrazone, Benzbromarone and Lesinurad, etc., but these drugs all have poor or serious curative effect. The toxic and side effects greatly limit the clinical use. Therefore, the discovery of novel anti-gout URAT1 inhibitors with high efficiency, low toxicity and independent intellectual property rights has important application value.

SUMMARY OF THE INVENTION

In view of the deficiencies of the prior art, the present invention provides a thienopyrimidinone acylsulfonamide derivative and a preparation method thereof. The present invention also provides the activity screening results of the above compounds as anti-gout drugs and their applications.

The technical scheme of the present invention is as follows:

1. Thienopyrimidinone acylsulfonamide derivatives

The thienopyrimidinone acylsulfonamide derivatives of the present invention have the structure shown in the following general formula I:

Wherein, R is selected from C ₁ -C ₅ alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocycle or substituted aromatic heterocycle; the aromatic heterocycle is selected from naphthyl, quinolinyl, isoquinoline olinyl, quinazolinyl, indolyl, pyridyl, furanyl, thienyl, pyrrolyl or pyrimidinyl, the substituents being selected from halogen, hydroxy, amino, nitro, hydroxy, cyano, trifluoromethyl group, C ₁ -C ₅ alkyl or cycloalkyl.

Preferably according to the present invention, the thienopyrimidinone acylsulfonamide derivatives are one of the following:

Table 1. Structural formulas of compounds I1～I18

Second, the preparation method of thienopyrimidinone acyl sulfonamide derivatives

The preparation method of thienopyrimidinone acylsulfonamide derivatives of the present invention is as follows:

Using 4-bromo-1-naphthylamine as the starting material, Suzuki coupling with cyclopropylboronic acid under the catalysis of tetrakistriphenylphosphine palladium generates 4-cyclopropyl-1-naphthylamine (I-1), I-1 is then reacted with N,N'-thiocarbonyldiimidazole to obtain the intermediate 1-cyclopropyl-4-isothiocyannaphthalene (I-2), and then I-2 is reacted with 2-aminothiophene-3-carboxylic acid The methyl ester is reacted in pyridine solution to give intermediate 1-3. Then, using DMF as solvent, nucleophilic substitution with methyl bromoacetate under the catalysis of K ₂ CO ₃ to obtain intermediate I-4, and I-4 is hydrolyzed under basic conditions to obtain intermediate 2-((3-(4 -Cyclopropylnaphthalen-1-yl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio)acetic acid (1-5), finally 1-5 Condensation with different types of sulfonamides under the catalysis of 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) afforded The target product of formula I structure;

The synthetic route is as follows:

Reagents and conditions: (i) cyclopropylboronic acid, K ₃ PO ₄ , Pd(PPh ₃ ) ₄ , toluene:water=25:2, N ₂ protection, 100°C, 12h; (ii) N,N'- Thiocarbonyldiimidazole, DCM, rt, 12h; (iii) methyl 2-aminothiophene-3-carboxylate, pyridine, 45°C, 12h, NaOH, 90°C, 15h; (iv) methyl bromoacetate, K ₂ CO ₃ , DMF, 45°C, 6h; (v) Lithium hydroxide monohydrate, THF, MeOH, room temperature, 6h; (vi) DMAP, EDCI, DCM, 0°C~RT, 15h.

wherein R is the same as the above general formula I.

The room temperature in the present invention refers to 20-30°C.

3. Application of Thienopyrimidinone Acyl Sulfonamide Derivatives

The invention discloses the screening results of blood uric acid-lowering activity of thienopyrimidinone acyl sulfonamide derivatives and their first application as anti-gout drugs. It is proved by experiments that the thienopyrimidinone acyl sulfonamide derivatives of the present invention can be used as blood uric acid lowering drugs. Specifically, it is used as a compound for lowering blood uric acid in the preparation of anti-gout drugs. The present invention also provides the application of the above-mentioned compounds in the preparation of anti-gout medicines.

Antigout activity of target compounds

The 18 compounds synthesized according to the above method (see Table 1 for the structural formula of the compounds) were screened for their target inhibitory activity in vitro, and their target inhibitory activity data were listed in Table 2, with Lesinurad as the positive control. It can be seen from Table 2 that compounds I6, I10, I14, and I15 all showed good URAT1 inhibitory activity, and they were all stronger than the positive control drug.

Therefore, the thienopyrimidinone acylsulfonamide derivatives of the present invention are a series of novel URAT1 inhibitors, which can be used as leading compounds against gout.

The thienopyrimidinone acylsulfonamide derivatives of the present invention can be used as urate transporter 1 (URAT1) inhibitors. Specifically, it is used as a urate transporter 1 (URAT1) inhibitor for the preparation of anti-gout drugs.

An anti-gout pharmaceutical composition, comprising the thienopyrimidinone acyl sulfonamide derivatives of the present invention and one or more pharmaceutically acceptable carriers or excipients.

Description of drawings

Figure 1 is the inhibition rate of the target compound GLUT9 at a concentration of 100 μM;

Figure 2 is the GLUT9 inhibitory activity of compound I10.

Detailed ways

The following examples are helpful to understand the present invention, but do not limit the content of the present invention. In the following examples, the numbers of all target compounds are the same as those in Table 1.

synthetic route:

Example 1. Intermediate 2-((3-(4-Cyclopropylnaphthalen-1-yl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl ) Preparation of thio) acetic acid (I-5)

Preparation of intermediate 4-cyclopropyl-1-naphthylamine (I-1):

4-Bromo-1-naphthylamine (3.0 g, 13.51 mmol), cyclopropylboronic acid (1.5 g, 17.44 mmol), K ₃ PO ₄ (10.2 g, 48.05 mmol), tetrakis(triphenylphosphine)palladium ( 1.5g, 1.3mmol) were added to a 250mL double-necked flask in turn, 50mL of toluene and 4mL of distilled water were added as solvents, mixed well, and under the protection of _N2 , heated and refluxed at 100 °C for 12h; TLC monitored the completion of the reaction, and the reaction solution was cooled to At room temperature, celite was filtered, the filtrate was evaporated to dryness, the residue was dissolved in ethyl acetate, washed with saturated NaCl solution (50 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. After concentration under reduced pressure, the product was subjected to flash column chromatography (ethyl acetate:petroleum ether=1:5) to obtain intermediate I-1 as a reddish-brown oil with a yield of 84.8%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.26 (d, J=8.4Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.50 (t, J=7.7Hz, 1H), 7.40 (t, J=7.8Hz, 1H), 7.01 (d, J=7.6Hz, 1H), 6.60 (d, J=7.7Hz, 1H), 5.54 (s, 2H), 2.22–2.09 (m, 1H) ,0.93(d,J=8.7Hz,2H),0.56(d,J=5.4Hz,2H).ESI-MS: m/z 184.2[M+H] ⁺ ,C ₁₃ H ₁₃ N[183.10].

Preparation of Intermediate 1-Cyclopropyl-4-isothiocyanatonaphthalene (I-2)

4-Cyclopropyl-1-naphthylamine (I-1) (2.5 g, 13.64 mmol) was added to a 250 mL round-bottomed flask, 50 mL of dichloromethane was added to dissolve it, and then N,N'-thiocarbonyldicarbonyl was added. Imidazole (3.65 g, 20.48 mmol) was stirred at room temperature for 10 h; after monitoring the completion of the reaction by TLC, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (pure petroleum ether) to obtain intermediate I-2, which was a colorless oil, which was collected rate 92.2%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J=7.8 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.78-7.71 (m, 2H), 7.58 (d, J=7.8Hz, 1H), 7.26(d, J=7.7Hz, 1H), 2.44(t, J=5.8Hz, 1H), 1.09(d, J=8.3Hz, 2H), 0.76(d, J= 5.4Hz,2H).C ₁₄ H ₁₁ NS[225.06].

Preparation of Intermediate 3-(4-Cyclopropylnaphthalen-1-yl)-2-mercaptothieno[2,3-d]pyrimidin-4(3H)-one (I-3)

Intermediate I-2 (1.5 g, 6.66 mmol) and reactant 2-aminothiophene-3-carboxylate methyl ester (1.15 g, 7.32 mmol) were dissolved in about 30 mL of pyridine solution, heated to reflux at 45 °C for 12 h; TLC monitoring After the reaction is complete, cool to room temperature, add about 40 mL of ice water and a small amount of hydrochloric acid, stir for 30 min, add dichloromethane, wash with saturated NaCl solution (50 mL × 3 times), combine the organic phases, dry over anhydrous sodium sulfate, filter , take the filtrate and evaporate the solvent under reduced pressure. The residue was dissolved in 20 mL of 1% NaOH solution, heated under reflux at 90 °C for 15 h, cooled to room temperature, filtered, the filtrate was taken, and the pH was adjusted to 3-4 with 1 mol/L dilute hydrochloric acid, a large amount of light yellow solid was precipitated, filtered, and the filter cake Wash with water to obtain intermediate I-3 as a light yellow solid, yield 27.4%, melting point: 295-298°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.89 (s, 1H), 8.47 (d, J=8.4 Hz, 1H), 7.59 (d, J=7.7 Hz, 2H), 7.47 (dd, J= 8.5, 6.6Hz, 1H), 7.35 (q, J=7.1, 6.6Hz, 3H), 7.26 (d, J=5.6Hz, 1H), 2.46 (dd, J=8.5, 5.3Hz, 1H), 1.12 ( d, J=8.0 Hz, 2H), 0.82 (qd, J=11.6, 6.9 Hz, 2H). ESI-MS: m/z 349.20 [MH] ^- , C ₁₉ H ₁₄ N ₂ OS ₂ [350.05]

Intermediate 2-((3-(4-Cyclopropylnaphthalen-1-yl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio)acetic acid Preparation of methyl ester (I-4)

Intermediate 1-3 (3.0 g, 8.6 mmol) and K ₂ CO ₃ (1.77 g, 12.86 mmol) were mixed in a 250 mL round-bottomed flask, dissolved in about 40 mL of DMF, and after stirring at room temperature for 15 min, methyl bromoacetate was added dropwise Ester (2.6 g, 17.14 mmol, 1.61 mL), reacted at 45°C for 6 h; monitored by TLC, after the reaction was completed, cooled to room temperature, added 50 mL of ethyl acetate, washed with saturated NaCl solution (50 mL×3 times), and combined the organic phases , dried over anhydrous sodium sulfate, filtered, the filtrate was taken, and the solvent was evaporated under reduced pressure. The product concentrated under reduced pressure was subjected to flash column chromatography (ethyl acetate:petroleum ether=1:2) to obtain intermediate I-4 as a white solid, yield 64.0%, melting point: 139-142°C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J=8.5 Hz, 1H), 7.69 (t, J=7.1 Hz, 1H), 7.60 (t, J=8.3 Hz, 2H), 7.56 (d, J=5.8Hz, 1H), 7.43 (dd, J=7.9, 3.3Hz, 2H), 7.39 (d, J=5.8Hz, 1H), 3.99–3.86 (m, 2H), 3.64 (s, 3H), 2.57 (dd, J=8.5, 5.2Hz, 1H), 1.20–1.10 (m, 2H), 0.91–0.82 (m, 2H). ESI-MS: m/z 423.00[M+H] ⁺ , C ₂₂ H ₁₈ N ₂ O ₃ S ₂ [422.08]..

Intermediate 2-((3-(4-Cyclopropylnaphthalen-1-yl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thio)acetic acid Preparation of (I-5)

Intermediate I-4 (3.0 g, 7.1 mmol) was dissolved in a mixed solution of 30 mL of methanol and 15 mL of tetrahydrofuran, and lithium hydroxide monohydrate (4.47 g, 106.51 mmol) was dissolved in a small amount of water and slowly added dropwise to the above solution , and the reaction was stirred at room temperature for 6 h; after the reaction was monitored by TLC, 15 mL of clear water was added, and the methanol and tetrahydrofuran in the system were evaporated under reduced pressure, and then 3 mol/L of dilute hydrochloric acid was added dropwise to adjust the pH of the solution to 5-6. , filtered, and the filter cake was washed with water and dried to obtain intermediate I-5 as a white solid, yield 72.4%, melting point: 192-194°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.83 (s, 1H), 8.55 (d, J=8.5Hz, 1H), 7.68 (t, J=7.0Hz, 1H), 7.58 (dd, J= 18.5, 6.7Hz, 3H), 7.46–7.40 (m, 2H), 7.39 (d, J=5.8Hz, 1H), 3.83 (d, J=20.6Hz, 2H), 2.57 (dd, J=8.6, 5.2 Hz, 1H), 1.19–1.11 (m, 2H), 0.85 (td, J=9.0, 4.6 Hz, 2H). ESI-MS: m/z 407.4 [MH] ^- , C ₂₁ H ₁₆ N ₂ O ₃ S ₂ [408.06].

Example 2. Preparation of Compound I1

Intermediate I-5 (0.2 g, 0.49 mmol) was dissolved in 5 mL of dry dichloromethane, stirred in an ice bath for 10 min, added DMAP (0.09 g, 0.74 mmol), continued to stir in an ice bath for 10 min, and then added EDCI (0.14 g) , 0.74 mmol), and finally, after stirring in an ice bath for 30 min, benzenesulfonamide (0.085 g, 0.54 mmol) was added, slowly raised to room temperature, and stirred for 15 h; monitored by TLC, after the reaction was completed, the solvent was evaporated under reduced pressure, and acetic acid was added to the residue. 20 mL of ethyl ester was washed successively with saturated NaHCO ₃ , 1 mol/L dilute hydrochloric acid, and saturated NaCl solution (20 mL×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (methanol: Dichloromethane:glacial acetic acid=1:30:1.5%). White solid, yield 48.5%, melting point: 216～218°C.

Spectral data of compound I1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.56 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 7.89 (d, J=7.3 Hz, 2H), 7.67 (t, J=7.6Hz, 2H), 7.56 (dt, J=10.3, 7.1Hz, 5H), 7.43–7.32 (m, 3H), 3.88 (d, J=4.0Hz, 2H), 2.57–2.53 ( m, 1H), 1.14 (dt, J=7.7, 3.3Hz, 2H), 0.84 (dd, J=6.4, 4.2Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ166.67, 163.54, 158.73, 157.75,142.71,139.83,134.11,134.05,130.61,129.55,128.29,127.99,127.80,127.22,125.44,123.53,123.22,122.56,122.41,120.91,36.81,13.38,7.76,7.54.ESI-MS:m/z 546.00 [MH] ^- ,C ₂₇ H ₂₁ N ₃ O ₄ S ₃ [547.07].

Example 3. Preparation of compound I2

The operation is the same as in Example 2, except that the sulfonamide used is 4-nitrobenzenesulfonamide, white solid, yield 41.4%, melting point: 176-180°C.

Compound I2 spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.70 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.18 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.5Hz, 2H), 7.66 (t, J=7.7Hz, 1H), 7.53 (dd, J=14.8, 6.8Hz, 3H), 7.41 (dd, J=8.0, 5.3Hz, 2H) ,7.35(d,J=5.8Hz,1H),3.75-3.65(m,2H),2.58-2.54(m,1H),1.15(dd,J=8.7,4.2Hz,2H),0.93-0.81(m ,2H). ¹³ C NMR(100MHz,DMSO-d ₆ )δ171.31,164.05,162.79,160.38,157.99,151.90,148.56,142.31,134.14,131.02,129.71,128.57,128.19,127.88,127.09,125.43,123.54,123.39 ,122.91,122.76,122.44,120.64,36.26,13.43,7.72,7.39.ESI-MS: m/z 591.06[MH] ^- ,C ₂₇ H ₂₀ N ₄ O ₆ S ₃ [592.05].

Example 4. Preparation of compound I3

The operation is the same as in Example 2, except that the sulfonamide used is 2-nitrobenzenesulfonamide, white solid, yield 38%, melting point: 189-193°C.

Compound I3 spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.86 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.02 (d, J=7.9Hz, 1H), 7.86 (dt, J=29.0, 7.6Hz, 2H), 7.71–7.65 (m, 1H), 7.61–7.49 (m, 3H), 7.40 (d, J=7.9 Hz, 2H), 7.36(d, J＝5.8Hz, 1H), 3.94(d, J＝6.1Hz, 2H), 2.55(t, J＝4.2Hz, 1H), 1.22–1.09(m, 2H), 0.85(q, J=5.5, 4.2Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ164.05, 162.46, 160.30, 157.99, 148.22, 142.34, 134.15, 132.08, 131.15, 130.99, 130.817, 129.72 ,127.88,127.09,125.44,123.40,123.29,122.99,122.74,122.44,120.68,36.26,13.44,7.66,7.43.ESI-MS:m/z 591.08[MH] ^- ,C ₂₇ H ₂₀ N ₄ O ₆ S ₃ [592.05].

Example 5. Preparation of compound I4

The operation is the same as in Example 2, except that the sulfonamide used is 3-nitrobenzenesulfonamide, white solid, yield 41.4%, melting point: 237-242°C.

Spectral data of compound I4: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 8.59 (s, 1H), 8.52 (dd, J=14.9, 8.4 Hz, 2H), 8.32 (d, J=7.9Hz, 1H), 7.88(t, J=8.1Hz, 1H), 7.68(t, J=7.6Hz, 1H), 7.54(dd, J=23.9, 6.8Hz, 3H), 7.37(dt, J=14.3, 6.8Hz, 3H), 3.93–3.81 (m, 2H), 2.58–2.53 (m, 1H), 1.15 (dd, J=8.9, 4.5Hz, 2H), 0.84 (t, J=5.8Hz) ,2H). ¹³ C NMR(100MHz,DMSO-d ₆ )δ167.42,163.41,158.79,157.70,148.04,142.74,141.43,134.13,133.99,131.68,130.60,129.54,128.62,128.28,127.97,127.24,125.46,123.40 ,123.23,122.80,122.55,122.45,120.86,37.02,13.39,7.77,7.53.ESI-MS: m/z 591.14[MH] ^- ,C ₂₇ H ₂₀ N ₄ O ₆ S ₃ [592.05].

Example 6. Preparation of compound 15

The operation was the same as that in Example 2, except that the sulfonamide used was 4-(trifluoromethyl)benzenesulfonamide, white solid, yield 53.07%, melting point: 199-200°C.

Spectral data of compound I5: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.10 (d, J=8.1 Hz, 2H), 7.94 (d, J=8.2Hz, 2H), 7.67 (t, J=7.6Hz, 1H), 7.54 (dd, J=13.9, 6.7Hz, 3H), 7.44–7.31 (m, 3H), 3.89 (d, J=3.7Hz, 2H), 2.55–2.53 (m, 1H), 1.20–1.08 (m, 2H), 0.84 (p, J=3.7Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ167 .24,163.47,158.80,157.72,142.70,134.12,130.63,129.55,128.91,128.27,128.26(q,J=19.8Hz),127.97,127.22,126.75,125.44,124.10(q,6.2,124.10(q,6.2,124.10(q,6.2,124.10(q,6.2,124.10(q,6.2,124.10(q,6.2) , 122.42, 120.85, 37.08, 13.38, 7.76, 7.52. ESI-MS: m/z 614.12 [MH] ^- , C ₂₈ H ₂₀ F ₃ N ₃ O ₄ S ₃ [615.06].

Example 7. Preparation of compound 16

The operation was the same as that in Example 2, except that the sulfonamide used was 3,5-difluorobenzenesulfonamide, white solid, yield 38.5%, melting point: 193-195°C.

Spectral data of compound I6: ¹ H NMR (400MHz, DMSO-d6) δ 12.74(s, 1H), 8.54(d, J=8.5Hz, 1H), 7.71-7.66(m, 2H), 7.57(q, J =6.7,5.8Hz,5H),7.41(d,J=7.7Hz,1H),7.37(dd,J=7.1,4.4Hz,2H),3.89(d,J=6.3Hz,2H),2.56(dd , J=8.6, 5.3Hz, 1H), 1.19–1.12(m, 2H), 0.85(t, J=5.5Hz, 2H). ¹³ C NMR(100MHz, DMSO-d6)δ167.19,163.45,162.38(dd, J=251.5Hz, J=12.3Hz), 158.73, 157.72, 142.96(t, J=8.9Hz), 142.76, 134.14, 130.60, 129.55, 128.29, 127.97, 127.24, 125.47, 123.47, 123.22, 122.91, 122.45 , 111.69 (d, J=29.3Hz), 110.02 (t, J=26.0Hz), 36.89, 13.39, 7.77, 7.54. ESI-MS: m/z 582.11[MH] ^- , C ₂₇ H ₁₉ F ₂ N ₃ O ₄ S ₃ [583.05].

Example 8. Preparation of compound 17

The operation was the same as that in Example 2, except that the sulfonamide used was 2,4-difluorobenzenesulfonamide, white solid, yield 45%, melting point: 218-221°C.

Spectral data of compound I7: ¹ H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.02-7.93 (m, 1H), 7.67 (t, J =7.5Hz,1H),7.57(dt,J=9.8,6.5Hz,4H),7.39(dd,J=10.1,6.8Hz,3H),7.31(t,J=8.5Hz,1H),3.90(s , 2H), 2.55(dd, J=8.8, 5.1Hz, 1H), 1.15(dt, J=7.8, 3.4Hz, 2H), 0.89–0.81(m, 2H). ¹³ C NMR(100MHz, DMSO-d ₆ ) δ166.65, 163.53, 159.80 (dd, J=258.6Hz, J=13.6Hz), 158.71, 157.74, 142.75, 134.11, 133.85 (t, J=11.3Hz), 130.60, 129.57, 128.31, 128.00, 127.23 ESI-MS:m /z 582.09[MH]-,C ₂₇ H ₁₉ F ₂ N ₃ O ₄ S ₃ [583.05].

Example 9. Preparation of compound 18

The operation is the same as in Example 2, except that the sulfonamide used is 4-fluorobenzenesulfonamide, white solid, yield 57.8%, melting point: 210-212°C.

Spectral data of compound I8: ¹ H NMR (400MHz, DMSO-d6) δ 12.54 (s, 1H), 8.54 (d, J=8.5Hz, 1H), 7.97 (dd, J=8.8, 5.2Hz, 2H), 7.72–7.64 (m, 1H), 7.56 (dd, J=10.5, 6.6Hz, 3H), 7.45–7.39 (m, 3H), 7.39–7.34 (m, 2H), 3.91–3.81 (m, 2H), 2.56 (dd, J=8.5, 5.3Hz, 1H), 1.18-1.12 (m, 2H), 0.85 (t, J=5.4Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ 166.61, 165.33 ( d, J＝253.5Hz), 163.48, 158.70, 157.73, 142.75, 135.98 (d, J＝2.8Hz), 134.14, 131.19 (d, J＝9.9Hz), 130.62, 129.58, 128.29, 127.98, 127.22, 125.44, 123.46,123.20,122.56,122.44,120.93,116.80(d,J=22.9Hz),36.73,13.38,7.77,7.54.ESI-MS:m/z 564.00[MH]-,C ₂₇ H ₂₀ FN ₃ O ₄ S ₃ [565.06].

Example 10. Preparation of Compound 19

The operation was the same as that in Example 2, except that the sulfonamide used was 4-chlorobenzenesulfonamide, white solid, yield 52.6%, melting point: 184-187°C.

Spectral data of compound I9: ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.59 (s, 1H), 8.53 (d, J=8.5Hz, 1H), 7.91 (d, J=8.4Hz, 2H), 7.66 (t, J=7.0Hz, 3H), 7.55 (dd, J=10.0, 6.6Hz, 3H), 7.40 (d, J=7.7Hz, 1H), 7.36 (dd, J=7.0, 4.6Hz, 2H) , 3.95–3.80 (m, 2H), 2.54 (d, J=4.1Hz, 1H), 1.19–1.11 (m, 2H), 0.90–0.78 (m, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ166.72,163.47,158.69,157.72,142.74,139.17,138.45,134.12,130.60,129.91,129.76,129.55,128.29,128.00,127.23,125.45,123.48,123.22,122.56,122.44,120.92,36.72,13.39,7.78,7.54 .ESI-MS: m/z 580.02 [MH] ^- , C ₂₇ H ₂₀ ClN ₃ O ₄ S ₃ [581.03].

Example 11. Preparation of compound I10

The operation is the same as in Example 2, except that the sulfonamide used is 4-bromobenzenesulfonamide, white solid, yield 55.5%, melting point: 220-223°C.

Compound I10 spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.58 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 7.81 (q, J=8.7 Hz, 4H), 7.67 (t, J=7.0Hz, 1H), 7.55 (dd, J=10.0, 6.7Hz, 3H), 7.40 (d, J=7.7Hz, 1H), 7.36 (t, J=6.6Hz, 2H), 3.91 -3.80(m, 2H), 2.58-2.52(m, 1H), 1.19-1.10(m, 2H), 0.84(dd, J=6.4, 4.2Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ166.73,163.47,158.69,157.73,142.75,138.87,134.12,132.70,130.60,129.94,129.55,128.29,128.26,128.00,127.24,125.45,123.48,123.21,122.55,122.44,120.91,36.71,13.39,7.78,7.54 .ESI-MS: m/z 624.15 [MH] ^- , C ₂₇ H ₂₀ BrN ₃ O ₄ S ₃ [624.98].

Example 12. Preparation of compound I11

The operation was the same as that in Example 2, except that the sulfonamide used was 4-hydroxybenzenesulfonamide, white solid, yield 47.1%, melting point: 221-224°C.

Spectral data of compound I11: ¹ H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.61 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 7.68 (dd, J=14.0 ,8.0Hz,3H),7.55(q,J＝6.2,5.6Hz,3H),7.46–7.31(m,3H),6.86(d,J＝8.5Hz,2H),3.84(d,J＝4.1Hz , 2H), 2.57–2.53 (m, 1H), 1.22–1.10 (m, 2H), 0.85 (t, J=5.7Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ166.45, 163.57, 162.55 ,158.79,157.78,142.68,134.11,130.63,130.37,129.55,128.28,127.99,127.22,125.44,123.52,123.24,122.58,122.40,120.89,115.84,36.83,13.40,7.76,7.53.ESI-MS:m/z 562.17[MH] ^- ,C ₂₇ H ₂₁ N ₃ O ₅ S ₃ [563.06].

Example 13. Preparation of compound I12

The operation is the same as that in Example 2, except that the sulfonamide used is 4-tert-butylbenzenesulfonamide. White solid, yield 44%, melting point: 200～203°C.

Spectral data of compound I12: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.42 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.68 (t, J=7.7Hz, 1H), 7.61–7.51 (m, 5H), 7.38 (dd, J=11.3, 6.7Hz, 2H), 7.27 (d, J=8.4Hz, 1H), 3.86 (q, J=16.3Hz, 2H), 2.57–2.53 (m, 1H), 1.25 (s, 9H), 1.18–1.11 (m, 2H), 0.89–0.79 (m, 2H). ¹³ C NMR (100MHz, DMSO- d ₆ )δ166.55,163.52,158.66,157.72,157.16,142.71,136.81,134.13,130.61,129.54,128.25,127.96,127.86,127.22,126.33,125.43,123.46,123.20,122.56,122.44,120.91,36.65,35.37,31.18 , 13.38, 7.76, 7.53. ESI-MS: m/z 602.19 [MH] ^- , C ₃₁ H ₂₉ N ₃ O ₄ S ₃ [603.13].

Example 14. Preparation of compound I13

The operation was the same as that in Example 2, except that the sulfonamide used was 2-chlorothiophene-5-sulfonamide, white solid, yield 48.6%, melting point: 188-193°C.

Spectral data of compound I13: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.69 (s, 1H), 8.54 (d, J=8.5 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.64 (d, J=4.1Hz, 1H), 7.58 (t, J=8.3Hz, 2H), 7.53 (d, J=5.8Hz, 1H), 7.44–7.38 (m, 2H), 7.36 (d, J= 5.8Hz, 1H), 7.21 (d, J=4.1Hz, 1H), 3.88 (d, J=6.9Hz, 2H), 2.57–2.53 (m, 1H), 1.19–1.11 (m, 2H), 0.85 ( t, J=5.4Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ167.16, 163.51, 158.75, 157.75, 142.75, 138.27, 137.07, 134.25, 134.15, 130.65, 129.57, 128.30, 127.975, 127.97 ,125.47,123.46,123.23,122.59,122.41,120.86,36.87,13.40,7.78,7.55.ESI-MS: m/z 585.96[MH] ^- ,C ₂₅ H ₁₈ ClN ₃ O ₄ S ₄ [586.99].

Example 15. Preparation of compound I14

The operation was the same as that in Example 2, except that the sulfonamide used was methylsulfonamide, white solid, yield 37.8%, melting point: 156-157°C.

Spectral data of compound I14: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.09 (s, 1H), 8.56 (d, J=8.5 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.65 –7.58(m,2H),7.56(d,J=6.1Hz,1H),7.48–7.42(m,2H),7.40(d,J=5.7Hz,1H),3.92(s,2H),3.21( s, 3H), 2.56 (dt, J=8.3, 3.5Hz, 1H), 1.17 (dd, J=8.1, 4.1Hz, 2H), 0.87 (d, J=5.6Hz, 2H). ¹³ C NMR (100MHz) ,DMSO-d ₆ )δ168.44,164.40,159.78,158.62,143.60,134.96,131.44,130.41,129.16,128.87,128.08,126.30,124.32,124.07,123.42,123.37,121.80,42.20,37.56,14.22,8.61,8.37. ESI-MS: m/z 484.25 [MH] ^- , C ₂₂ H ₁₉ N ₃ O ₄ S ₃ [485.05].

Example 16. Preparation of compound I15

The operation is the same as in Example 2, except that the sulfonamide used is ethylsulfonamide. White solid, yield 48.9%, melting point: 141-143°C.

Spectral data for compound I15: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.95 (s, 1H), 8.55 (d, J=8.4 Hz, 1H), 7.71-7.66 (m, 1H), 7.60 (dd, J=10.6, 7.9Hz, 2H), 7.55(d, J=5.9Hz, 1H), 7.43(t, J=7.8Hz, 2H), 7.39(d, J=5.8Hz, 1H), 3.93(d, J=1.8Hz, 2H), 3.35 (d, J=7.4Hz, 2H), 2.58–2.54 (m, 1H), 1.24 (t, J=7.3Hz, 3H), 1.18–1.13 (m, 2H), 0.86 (dt, J=5.6, 3.3Hz, 2H). ¹³ CNMR (100MHz, DMSO-d ₆ )δ168.23, 164.42, 159.81, 158.60, 143.59, 134.96, 131.44, 130.41, 129.19, 128.86, 128.07, 124.33, 126.29 124.07,123.43,123.33,121.84,48.01,37.47,14.22,9.31,8.60,8.38.ESI-MS:m/z 498.30[MH] ^- ,C ₂₃ H ₂₁ N ₃ O ₄ S ₃ [499.07].

Example 17. Preparation of compound I16

The operation is the same as in Example 2, except that the sulfonamide used is isopropylsulfonamide, white solid, yield 47.6%, melting point: 216-218°C.

Spectral data of compound I16: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.89 (s, 1H), 8.56 (d, J=8.5 Hz, 1H), 7.69 (t, J=7.1 Hz, 1H), 7.64 –7.58(m,2H),7.56(d,J=5.8Hz,1H),7.47–7.42(m,2H),7.40(d,J=5.8Hz,1H),3.94(d,J=2.6Hz, 2H), 3.57 (p, J=6.8Hz, 1H), 2.59–2.55 (m, 1H), 1.30 (d, J=6.8Hz, 6H), 1.17 (dd, J=8.0, 4.7Hz, 2H), 0.91–0.81(m, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ167.27,163.63,159.05,157.78,142.76,134.15,130.65,129.61,128.38,128.04,127.25,125.48,1223.5 122.50, 121.04, 53.10, 36.75, 16.15, 15.99, 13.41, 7.78, 7.57. ESI-MS: m/z 512.36 [MH] ^- , C ₂₄ H ₂₃ N ₃ O ₄ S ₃ [513.09].

Example 18. Preparation of compound I17

The operation was the same as that in Example 2, except that the sulfonamide used was tert-butylsulfonamide, white solid, yield 42.6%, melting point: 206-207°C.

Spectral data of compound I17: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.55 (s, 1H), 8.55 (d, J=8.5 Hz, 1H), 7.69 (t, J=7.0 Hz, 1H), 7.65 –7.53(m,3H),7.44(dd,J=8.0,4.0Hz,2H),7.40(d,J=5.8Hz,1H),3.94(d,J=2.4Hz,2H),2.56(dq, J=8.4, 4.3, 3.0Hz, 1H), 1.36 (s, 9H), 1.16 (dt, J=7.7, 3.2Hz, 2H), 0.92–0.83 (m, 2H). ¹³ C NMR (100MHz, DMSO- d ₆ )δ166.34,163.66,159.25,157.78,142.73,134.16,130.69,129.61,128.36,128.03,127.23,125.47,123.42,123.26,122.60,122.52,121.01,61.23,37.48,24.33,13.40,7.78,7.56.ESI - MS: m/z 526.37 [MH] ^- , C ₂₅ H ₂₅ N ₃ O ₄ S ₃ [527.10].

Example 19. Preparation of compound I18

The operation is the same as in Example 2, except that the sulfonamide used is cyclopropanesulfonamide, white solid, yield 47.8%, melting point: 196-200°C.

Spectral data of compound I18: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.03 (s, 1H), 8.56 (d, J=8.4 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.61 (dd,J＝10.7,7.9Hz,2H),7.56(d,J＝5.8Hz,1H),7.45(t,J＝7.9Hz,2H),7.40(d,J＝5.8Hz,1H),3.93 (d, J=1.5Hz, 2H), 2.97–2.87 (m, 1H), 2.56 (td, J=8.5, 4.3Hz, 1H), 1.17 (dd, J=8.0, 4.3Hz, 2H), 1.09 ( dt, J=5.5, 2.8Hz, 2H), 1.05 (dd, J=7.5, 5.2Hz, 2H), 0.92–0.83 (m, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ167.11,163.64, 158.94,157.81,142.77,134.16,130.66,129.62,128.36,128.04,127.26,125.48,123.51,123.26,122.63,122.51,120.99,36.80,31.19,13.41,7.79,7.57,5.99.ESI-MS:m/z 510.29 [MH] ^- ,C ₂₄ H ₂₁ N ₃ O ₄ S ₃ [511.07].

Example 20. In vitro URAT1 inhibitory activity test of target compounds

Test principle

In HEK293T cells stably expressing hURAT1 protein, the ¹⁴ C-labeled substrate uric acid was used to detect the effect of compounds at different concentrations and the positive control drug Recinade on the uptake of the substrate uric acid mediated by hURAT1. The inhibitory effect (IC ₅₀ ) of each compound on this protein was calculated by measuring the radioactivity of uric acid taken up by cells.

Experimental Materials

pcDNA3.1(+)-hURAT1-T2A-eGFP plasmid (Shenzhen Qianhai Dongze Biotechnology Co., Ltd.); Plasmid Extraction Kit (OMEGA Biotechnology Co., Ltd.); Agar (OXOID, USA); Yeast Extract ( U.S. OXOID Company); Peptone Tryptone (U.S. OXOID Company); Ampicillin (U.S. Sigma Company); Purified Water; ); DMSO (Sigma, USA); 96-well microplate (Corning, USA); PBS (Corning, USA); HEPES (Sigma, USA); ¹⁴ C-Uric acid (American Radiolabeled Chemicals, USA)

testing method

The 96-well plate was pre-incubated with poly-D-lysine solution (0.1 mg/mL) for 12 hours for better cell adhesion. Then inoculate the cells into the plate, when the cells reach 90% confluence, mix opti and lip 3000 at 5 μL/well and 0.15 μL/well, respectively, and let stand for 5 min; at the same time, add opti, P3000 and plasmid DNA at 5 μL Mix well with 0.2 μL/well and 500 ng/well, let stand for 5 min; mix the liquid phase mixed in the previous two steps, let stand for 15 min at room temperature; add to 96-well plate with complete medium replaced. Incubate at 37°C in a 5% _CO2 incubator for 16-20h, observe the expression of green fluorescent protein EGFP with a fluorescent inverted microscope to verify the success of the transfection, remove the medium after success, and wash the cells twice with PBS. In order to evaluate the inhibitory effect of the drug on URAT1, we took lesinadide as the positive drug, and conducted a preliminary screening of the drug (20uM). CPM). And the _IC50 was determined. Before the absorption experiment, the liquid in the wells was aspirated, and 50 μl of compounds containing various specific concentrations (20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM) were added to each well. The model group and blank group did not add drugs. After 15 minutes of incubation, the cells were aspirated and discarded, and then uric acid absorption buffer containing 50 μM ¹⁴ C-uric acid was added to start uric acid absorption, and incubated at 37° C. for 15 minutes. The liquid in the well was aspirated and washed three times with 100 μL of ice-cold DPBS, and 40 μL of 0.1M NaOH was added to each well to lyse the cells. After lysis at room temperature for 30 minutes, 0.2 mL of scintillation fluid was added to each well, and the plate was placed on a plate shaker and shaken at 260 rpm/min for 15 minutes. The emission value (CPM) of ¹⁴ C-uric acid was measured using a liquid scintillation counter, and the measurement was repeated three times, and the average value was taken.

Table 2. In vitro URAT1 inhibitory activity of series I compounds

Conclusion: The test results show that the series I compounds can effectively inhibit the ¹⁴ C-UA uptake mediated by URAT1, which verifies that the target of these compounds is URAT1. Among them, the activities of compounds I6, I10, I14, and I15 were stronger than that of the positive control drug lesinard. It can be further developed as a drug lead with a new structure.

Example 21. In vitro GLUT9 inhibitory activity test of target compounds

Test principle

GLUT9 has electricity-generating properties when transporting uric acid. Specifically, when GLUT9 transports a uric acid anion into the cell, a negative charge will move to generate an electric current, and the cell membrane potential will change. The changes of the currents produced by the uric acid exogenous fluid of the compounds stimulated HEK293T cells expressing GLUT9 were used to calculate the IC ₅₀ values of each compound for inhibiting GLUT9. When testing the target inhibitory activity of the compounds, it was unexpectedly found that the series I compounds can also inhibit GLUT9. In order to verify the inhibitory activity of the series I compounds on GLUT9, four compounds with outstanding URAT1 inhibitory activity were selected for the GLUT9 preliminary screening experiment, and the preliminary screening experiments were carried out. The most active I10 was tested for _IC50 .

Experimental Materials

MultiClamp 700B patch clamp amplifier, Digidata 1550B digitizer, Pclamp 10 software (Molecular Devices, USA), borosilicate glass capillary (BF150-110-10, Sutter Instruments, USA). GLUT9 (Gene ID: 117591) (Shanghai Sangon Bioengineering Technology Service Company), uric acid, NaCl, KCl, MgCl ₂ , CaCl ₂ , HEPES, 10mM D-glucose, EGTA extracellular fluid fraction (Sigma-Aldrich, USA) , Lipofectamine 3000 (Invitrogen, USA).

testing method

The GLUT9 gene fragment was cloned into an expression vector to construct pcDNA3.1(-)-GLUT9 recombinant plasmid. When the HEK293T cells grew and confluent to 90%, the cells were seeded into a 24-well plate and placed in a 37°C, 5% _CO2 incubator for 18-24h. The GLUT9 recombinant plasmid and EGFP were co-transfected into HEK293T cells. The specific transfection steps were as follows: add 25 μL Opti medium to two 1.5 mL EP tubes (No. 1 and No. 2 tubes) respectively, and add two kinds of medium to No. 1 tube. Plasmid (mGLUT9:EGFP=2:1) 600ng: 250ng and 1 μL of P3000 ^TM , vortex to mix evenly; add 0.75 μL of P3000 ^TM to No. 2 tube, vortex to mix evenly; then mix the two tubes of liquid, vortex for 10 seconds, and let stand for 20 min , dropwise evenly into the wells containing the new medium, and placed in a 37°C, 5% _CO2 incubator for 18-24h. After transfection, the expression of EGFP was observed, and the cells were digested and re-seeded onto coverslips pretreated with 0.1 mg/mL PDL. After the cells adhered, they could be used for whole-cell patch-clamp recording.

Use a borosilicate capillary glass tube, the diameter of the tip is about 1-5 μM after being drawn in two steps by the drawing machine, and the inner liquid (about one-third to half of the electrode) is added to the tail of the microelectrode with a syringe. one), and ejected the bubbles to prepare the electrode. Place the glass slide in the extracellular solution connected with the metal electrode, move the glass microelectrode above the fluorescent cells under the microscope, and apply negative pressure until a high resistance seal greater than 1GΩ is formed between the electrode and the HEK293T cell membrane. , perform capacitance compensation, clamp the cell at -30mV, and apply a short and powerful negative pressure to rupture the membrane. After the cells are stabilized, perfuse the uric acid exofluid containing different concentrations (200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM) of the test compound at a rate of 2-3 mL/min, and record the perfusion of the uric acid exofluid only and the uric acid exofluid containing the compound. The magnitude of the current produced by the cells was changed, and three replicates were set for each administration concentration.

Conclusion: It can be seen from Figure 1 and Figure 2 that the representative compounds I6, I10, I14, and I15 in series I do show strong inhibitory activity on GLUT9 at the primary screening concentration of 100 μM, among which the best inhibitory activity is. The _IC50 value of I10 was 55.96±10.38 μM.

Example 22. In vivo anti-gout activity test of the target compound

Test Materials and Methods

(1) Experimental animals: male Kunming mice, provided by the Experimental Animal Center of Shandong University.

(2) Sample treatment: select the test compound whose target inhibitory activity is better than that of Lesinurad, and prepare an appropriate concentration with CMC-Na before use.

(3) Modeling drugs: xanthine, potassium oxonate.

(4) Positive control drug: Lesinurad

(5) Test method: Male Kunming mice of about 20 g were adaptively fed for 1 week, and randomly divided into blank group and model group. 0.2 mL of hypoxanthine suspension and 0.2 mL of 400 mg/kg potassium oxonate suspension were subcutaneously injected. After 4 hours, the eyeballs were removed and blood was collected, the supernatant was separated, and the blood uric acid concentration was detected.

Table 3 Results of blood uric acid lowering activity in animals

Conclusion: It can be seen from Table 3 that the in vivo uric acid-lowering activities of the four compounds I6, I10, I14, and I15 are significantly higher than those of the positive drug lesinad, which verifies the feasibility of the transformation strategy. In particular, compound I10, whose blood uric acid concentration decreased by 73.29%, far exceeded that of Recinade (26.89%), which deserves further study.

Claims (5)

1. a thienopyrimidinone acyl sulfonamide derivative, is characterized in that, has the structure shown in following general formula I:

Wherein, R is selected from C ₁ -C ₅ alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocycle or substituted aromatic heterocycle; the aromatic heterocycle is selected from thienyl, and the substituent is selected from Halogen, hydroxy, nitro, trifluoromethyl, _C1 - _C5 alkyl or cycloalkyl. 2. thienopyrimidinone acyl sulfonamide derivatives as claimed in claim 1, is characterized in that being one of the compounds of following structure:

3. the preparation method of thienopyrimidinone acyl sulfonamide derivatives as claimed in claim 2 is characterized in that the method is as follows: Using 4-bromo-1-naphthylamine as the starting material, Suzuki coupling with cyclopropylboronic acid under the catalysis of tetrakistriphenylphosphine palladium generates 4-cyclopropyl-1-naphthylamine (I-1), I-1 is then reacted with N,N'-thiocarbonyldiimidazole to obtain the intermediate 1-cyclopropyl-4-isothiocyannaphthalene (I-2), and then I-2 is reacted with 2-aminothiophene-3-carboxylic acid The methyl ester was reacted in a pyridine solution to obtain intermediate I-3; then DMF was used as a solvent, and nucleophilic substitution with methyl bromoacetate under the catalysis of K ₂ CO ₃ was carried out to obtain intermediate I-4, and I-4 was then alkaline. Hydrolysis under conditions affords the intermediate 2-((3-(4-cyclopropylnaphthalen-1-yl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl )thio)acetic acid (I-5), and finally 1-5 in 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) ) is condensed with different types of sulfonamide to obtain the target product with the structure of general formula I under the catalysis of ); The synthetic route is as follows:

Reagents and conditions: (i) cyclopropylboronic acid, K ₃ PO ₄ , Pd(PPh ₃ ) ₄ , toluene:water=25:2, N ₂ protection, 100°C, 12h; (ii) N,N'- Thiocarbonyldiimidazole, DCM, rt, 12h; (iii) methyl 2-aminothiophene-3-carboxylate, pyridine, 45°C, 12h, NaOH, 90°C, 15h; (iv) methyl bromoacetate, K ₂ CO ₃ , DMF, 45°C, 6h; (v) Lithium hydroxide monohydrate, THF, MeOH, room temperature, 6h; (vi) DMAP, EDCI, DCM, 0°C～RT, 15h; wherein R is as shown in the corresponding structure in claim 2. 4. The application of the thienopyrimidinone acylsulfonamide derivatives according to claim 1 or 2 in the preparation of anti-gout drugs. 5. An anti-gout pharmaceutical composition, comprising the thienopyrimidinone acylsulfonamide derivatives of claim 1 or 2 and one or more pharmaceutically acceptable carriers or excipients.

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