CN113336769B

CN113336769B - Thienopyrimidine ketone acyl sulfonamide derivative as well as preparation method and application thereof

Info

Publication number: CN113336769B
Application number: CN202110627081.8A
Authority: CN
Inventors: 刘新泳; 董悦; 展鹏; 赵彤; 庞建新; 吴婷; 孙卓森; 艾炜
Original assignee: Shandong University
Current assignee: Shandong University
Priority date: 2021-04-30
Filing date: 2021-06-04
Publication date: 2022-06-24
Anticipated expiration: 2041-06-04
Also published as: CN113336769A

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

Thienopyrimidone acylsulfonamide derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of organic compound synthesis and medical application, and particularly relates to a thienopyrimidone acylsulfonamide derivative as well as a preparation method and application thereof.

Background

Gout is a metabolic disease caused by increased uric acid production or decreased excretion due to purine metabolic disorder, resulting in deposition of mono-natriuretic urate crystals in joint tissues, and is clinically mainly characterized by hyperuricemia. In recent years, with improvements in living standards and dietary structures, the number of patients with gout and hyperuricemia is increasing and the patients tend to be younger, which places a heavy burden on the patients and the society. In China, the incidence rate of gout is 1.1%, the incidence rate of hyperuricemia is 13.3%, gout is the second largest metabolic disease next to diabetes, and hyperuricemia is the fourth highest after hypertension, hyperlipidemia and hyperglycemia. At present, the drugs clinically used for treating gout and hyperuricemia mainly comprise non-steroidal anti-inflammatory drugs, uric acid production inhibiting drugs and uric acid excretion promoting drugs. The urate transporter 1(URAT1) is a transporter which is expressed in the apical membrane of the epithelial cell of the proximal convoluted tubule of the human kidney and is responsible for the reabsorption of uric acid, is a novel hot target of the existing medicament for promoting the excretion of uric acid, inhibits URAT1, can effectively reduce the reabsorption of uric acid and increases the metabolism of uric acid. The marketed drugs of the inhibitor comprise Probenecid (Probenecid), sulpirenone (Sulfinpyrazone), Benzbromarone (Benzbrolone), Lesinurad (Lesinurad) and the like, but the drugs have poor or serious toxic and side effects after healing, and the clinical use is greatly limited. Therefore, the discovery of a novel gout-resistant URAT1 inhibitor which is efficient, low in toxicity and independent intellectual property has important application value.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a thienopyrimidone acylsulfonamide derivative and a preparation method thereof, and also provides an activity screening result of the compound as an anti-gout drug and application thereof.

The technical scheme of the invention is as follows:

mono, thienopyrimidone acylsulfonamide derivatives

The thienopyrimidone acylsulfonamide derivative has a structure shown in a general formula I:

wherein R is selected from C₁-C₅Alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocycle or substituted aromatic heterocycle of (a); the aromatic heterocyclic ring is selected from naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl and thienylPyrrolyl or pyrimidinyl, said substituents being selected from halogen, hydroxy, amino, nitro, hydroxy, cyano, trifluoromethyl, C₁-C₅Alkyl or cycloalkyl groups of (a).

Preferred derivatives of thienopyrimidinone acylsulfonamides according to the invention are one of the following:

TABLE 1 structural formulas of Compounds I1-I18

Preparation method of di-and thienopyrimidone acyl sulfonamide derivatives

The preparation method of the thienopyrimidone acyl sulfonamide derivative comprises the following steps:

4-bromo-1-naphthylamine is used as an initial raw material, and undergoes Suzuki coupling with cyclopropylboronic acid under the catalysis of tetratriphenylphosphine palladium to generate 4-cyclopropyl-1-naphthylamine (I-1), the I-1 is reacted with N, N' -thiocarbonyldiimidazole to obtain an intermediate 1-cyclopropyl-4-isothiocyanato naphthalene (I-2), and then the I-2 and 2-aminothiophene-3-carboxylic acid methyl ester are reacted in a pyridine solution to obtain an intermediate I-3. Then DMF as solvent, K₂CO₃Carrying out nucleophilic substitution with methyl bromoacetate under catalysis to obtain an intermediate I-4, hydrolyzing the intermediate I-4 under alkaline conditions to obtain an intermediate 2- ((3- (4-cyclopropylnaphthalene-1-yl) -4-oxo-3, 4-dihydrothieno [2, 3-d)]Pyrimidine-2-yl) thio) acetic acid (I-5), and finally condensing the I-5 with different types of sulfamide under the catalysis of 4-Dimethylaminopyridine (DMAP) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) to obtain a target product with a structure of a general formula I;

the synthetic route is as follows:

reaction reagents and conditions: (i) cyclopropylboronic acid, K₃PO₄，Pd(PPh₃)₄Toluene: 25:2, N water₂Protection, 100 ℃, 12 h; (ii) n, N' -thiocarbonyl diimidazole, DCM, room temperature, 12 h; (iii) 2-aminothiophene-3-carboxylic acid methyl ester, pyridine, 45 ℃, 12h, NaOH, 90 ℃, 15 h; (iv) bromoacetic acid methyl ester, K₂CO₃DMF, 45 ℃, 6 h; (v) lithium hydroxide monohydrate, THF, MeOH, room temperature, 6 h; (vi) DMAP, EDCI, DCM, 0 ℃ to RT, 15 h.

Wherein R is the same as the general formula I.

The room temperature of the invention is 20-30 ℃.

Application of tri-thienopyrimidone acylsulfonamide derivatives

The invention discloses screening results of blood uric acid reducing activity of thienopyrimidone acylsulfonamide derivatives and application of the thienopyrimidone acylsulfonamide derivatives as anti-gout drugs for the first time. Experiments prove that the thienopyrimidone acyl sulfonamide derivative can be applied as a medicine for reducing blood uric acid. In particular to a compound for reducing blood uric acid and preparing an anti-gout drug. The invention also provides application of the compound in preparing anti-gout drugs.

Anti-gout Activity of Compounds of interest

18 compounds (the structural formula of the compound is shown in table 1) synthesized according to the method are subjected to in vitro target inhibition activity screening, the target inhibition activity data of the compounds are shown in table 2, and Lesinurad is used as a positive control. From table 2, it can be seen that compounds I6, I10, I14, and I15 all exhibited better URAT1 inhibitory activity and were all stronger than the positive control drugs.

Therefore, the thienopyrimidone acylsulfonamide derivatives are a series of URAT1 inhibitors with novel structures, and can be used as anti-gout lead compounds.

The thienopyrimidone acyl sulfonamide derivative can be used as a urate transporter 1(URAT1) inhibitor. In particular to the application of the inhibitor of the urate transporter 1(URAT1) in preparing anti-gout drugs.

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

Drawings

FIG. 1 is a graph showing the inhibition of GLUT9 as the target compound at a concentration of 100. mu.M;

figure 2 is the GLUT9 inhibitory activity of compound I10.

Detailed Description

The present invention will be understood by reference to the following examples, in which all the numbers of the objective compounds are the same as those in Table 1, but the contents of the present invention are not limited thereto.

The synthetic route is as follows:

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

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

4-bromo-1-naphthylamine (3.0g, 13.51mmol), cyclopropylboronic acid (1.5g, 17.44mmol), K₃PO₄(10.2g, 48.05mmol) and tetrakis (triphenylphosphine) palladium (1.5g, 1.3mmol) are added into a 250mL double-necked bottle in sequence, 50mL of toluene and 4mL of distilled water are added as solvents and mixed evenly, and N is added₂Heating and refluxing for reaction for 12h at 100 ℃ under protection; after the completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, filtered through celite, the filtrate was evaporated to dryness, the residue was dissolved in ethyl acetate, washed with saturated NaCl solution (50mL × 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 give intermediate I-1 as a reddish brown oil with a yield of 84.8%.¹H NMR(400MHz,DMSO-d₆)δ8.26(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]⁺,C₁₃H₁₃N[183.10].

Preparation of intermediate 1-cyclopropyl-4-isothiocyanatonaphthalene (I-2)

4-cyclopropyl-1-naphthylamine (I-1) (2.5g, 13.64mmol) was charged into a 250mL round-bottom flask, dissolved by addition of 50mL of dichloromethane, followed by addition of N, N' -thiocarbonyldiimidazole (3.65g, 20.48mmol) and stirring at room temperature for 10 h; after completion of the reaction monitored by TLC, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (pure petroleum ether) to give intermediate I-2 as a colorless oil in a yield of 92.2%.¹H NMR(400MHz,DMSO-d₆)δ8.49(d,J＝7.8Hz,1H),8.03(d,J＝7.9Hz,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).C₁₄H₁₁NS[225.06].

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

Dissolving intermediate I-2(1.5g, 6.66mmol) and reactant methyl 2-aminothiophene-3-carboxylate (1.15g, 7.32mmol) in about 30mL of pyridine solution, and heating and refluxing at 45 ℃ for 12 h; TLC monitoring, after the reaction is complete, cooling to room temperature, adding about 40mL of ice water and a small amount of hydrochloric acid, stirring for 30min, adding dichloromethane, washing with saturated NaCl solution (50 mL. times.3 times), combining the organic phases, drying over anhydrous sodium sulfate, filtering, taking the filtrate, and evaporating the solvent under reduced pressure. And (3) adding 20mL of 1% NaOH solution to the residue for dissolving, heating and refluxing at 90 ℃ for 15h, cooling to room temperature, filtering, taking the filtrate, adjusting the pH to 3-4 by using 1mol/L dilute hydrochloric acid, separating out a large amount of light yellow solid, filtering, and washing a filter cake by using clear water to obtain an intermediate I-3 which is a light yellow solid, wherein the yield is 27.4%, and the melting point is 295-298 ℃.¹H NMR(400MHz,DMSO-d₆)δ13.89(s,1H),8.47(d,J＝8.4Hz,1H),7.59(d,J＝7.7Hz,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＝8.0Hz,2H),0.82(qd,J＝11.6,6.9Hz,2H).ESI-MS:m/z 349.20[M-H]^-,C₁₉H₁₄N₂OS₂[350.05]

Preparation of intermediate methyl 2- ((3- (4-cyclopropylnaphthalen-1-yl) -4-oxo-3, 4-dihydrothieno [2,3-d ] pyrimidin-2-yl) thio) acetate (I-4)

Intermediate I-3(3.0g, 8.6mmol) was reacted with K₂CO₃(1.77g, 12.86mmol) was mixed in a 250mL round-bottom flask, dissolved in about 40mL DMF, stirred at room temperature for 15min, methyl bromoacetate (2.6g, 17.14mmol, 1.61mL) was added dropwise and reacted at 45 ℃ for 6 h; TLC monitoring, after the reaction is complete, cooling to room temperature, adding 50mL of ethyl acetate, washing with saturated NaCl solution (50 mL. times.3 times), combining the organic phases, drying over anhydrous sodium sulfate, filtering, taking the filtrate, and removing the solvent by evaporation under reduced pressure. The product after reduced pressure concentration is subjected to flash column chromatography (ethyl acetate: petroleum ether: 1:2) to obtain an intermediate I-4 which is a white solid, wherein the yield is 64.0%, and the melting point is 139-142 ℃.¹H NMR(400MHz,DMSO-d₆)δ8.55(d,J＝8.5Hz,1H),7.69(t,J＝7.1Hz,1H),7.60(t,J＝8.3Hz,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]⁺,C₂₂H₁₈N₂O₃S₂[422.08]..

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

Dissolving intermediate I-4(3.0g, 7.1mmol) in a mixed solution of 30mL of methanol and 15mL of tetrahydrofuran, dissolving lithium hydroxide monohydrate (4.47g, 106.51mmol) in a small amount of water, slowly and dropwise adding the solution, and stirring at room temperature for reaction for 6 hours; after TLC monitoring reaction, adding 15mL of clear water, distilling under reduced pressure to remove methanol and tetrahydrofuran in the system, then dropwise adding 3mol/L dilute hydrochloric acid to adjust the pH of the solution to 5-6, standing, precipitating, filtering, washing a filter cake with clear water, and drying to obtain an intermediate I-5 which is a white solid, wherein the yield is 72.4%, and the melting point is as follows: 192-194 ℃.¹H NMR(400MHz,DMSO-d₆)δ12.83(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＝8.6,5.2Hz,1H),1.19–1.11(m,2H),0.85(td,J＝9.0,4.6Hz,2H).ESI-MS:m/z 407.4[M-H]^-,C₂₁H₁₆N₂O₃S₂[408.06].

Example 2 preparation of Compound I1

Dissolving intermediate I-5(0.2g, 0.49mmol) in 5mL of dry dichloromethane, stirring in ice bath for 10min, adding DMAP (0.09g, 0.74mmol), continuing to stir in ice bath for 10min, then adding EDCI (0.14g, 0.74mmol), finally stirring in ice bath for 30min, adding benzenesulfonamide (0.085g, 0.54mmol), slowly raising the temperature to room temperature, and stirring for 15 h; TLC monitoring, after the reaction was complete, the solvent was evaporated under reduced pressure and the residue was taken up in 20mL ethyl acetate followed by saturated NaHCO₃Then, the mixture was washed with 1mol/L diluted hydrochloric acid and a saturated NaCl solution (20mL × 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% and melting point 216-218 deg.C.

Compound I1 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.56(s,1H),8.53(d,J＝8.5Hz,1H),7.89(d,J＝7.3Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₇H₂₁N₃O₄S₃[547.07].

example 3 preparation of Compound I2

The operation is the same as example 2, except that the sulfonamide used is 4-nitrobenzenesulfonamide, white solid, yield 41.4% and melting point 176-180 ℃.

Compound I2 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.70(s,1H),8.53(d,J＝8.5Hz,1H),8.18(d,J＝8.7Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₇H₂₀N₄O₆S₃[592.05].

example 4 preparation of Compound I3

The procedure is as in example 2, except that the sulfonamide used is 2-nitrobenzenesulfonamide in the form of a white solid with a yield of 38% and a melting point of 189-193 ℃.

Compound I3 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.86(s,1H),8.53(d,J＝8.4Hz,1H),8.14(d,J＝7.8Hz,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＝7.9Hz,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).¹³C NMR(100MHz,DMSO-d₆)δ164.05,162.46,160.30,157.99,148.22,142.34,134.15,132.08,131.15,130.99,130.87,129.72,128.21,127.88,127.09,125.44,123.40,123.29,122.99,122.74,122.44,120.68,36.26,13.44,7.66,7.43.ESI-MS:m/z 591.08[M-H]^-,C₂₇H₂₀N₄O₆S₃[592.05].

EXAMPLE 5 preparation of Compound I4

The procedure is as in example 2, except that the sulfonamide used is 3-nitrobenzenesulfonamide, white solid, yield 41.4%, melting point: 237-242 ℃.

Compound I4 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.82(s,1H),8.59(s,1H),8.52(dd,J＝14.9,8.4Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₇H₂₀N₄O₆S₃[592.05].

EXAMPLE 6 preparation of Compound I5

The procedure is as in example 2, except that the sulfonamide used is 4- (trifluoromethyl) benzenesulfonamide as a white solid in 53.07% yield and 199-200 ℃ melting point.

Compound I5 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.88(s,1H),8.53(d,J＝8.5Hz,1H),8.10(d,J＝8.1Hz,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).¹³C NMR(100MHz,DMSO-d₆)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,J＝261.8Hz),123.22,122.56,122.42,120.85,37.08,13.38,7.76,7.52.ESI-MS:m/z614.12[M-H]^-,C₂₈H₂₀F₃N₃O₄S₃[615.06].

example 7 preparation of Compound I6

The procedure is as in example 2, except that 3, 5-difluorobenzenesulfonamide is used as sulfonamide as a white solid in 38.5% yield and 193-195 ℃ melting point.

Compound I6 spectroscopic data:¹H NMR(400MHz,DMSO-d6)δ12.74(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).¹³C 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),142.76,134.14,130.60,129.55,128.29,127.97,127.24,125.47,123.47,123.22,122.51,122.45,120.91,111.69(d,J＝29.3Hz),110.02(t,J＝26.0Hz),36.89,13.39,7.77,7.54.ESI-MS:m/z 582.11[M-H]^-,C₂₇H₁₉F₂N₃O₄S₃[583.05].

example 8 preparation of Compound I7

The procedure is as in example 2, except that the sulfonamide used is 2, 4-difluorobenzenesulfonamide as a white solid in a yield of 45% and a melting point of 218-221 ℃.

Compound I7 spectroscopic data:¹H NMR(400MHz,DMSO-d6)δ12.90(s,1H),8.53(d,J＝8.4Hz,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).¹³C NMR(100MHz,DMSO-d₆)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),130.60,129.57,128.31,128.00,127.23,125.44,123.53,123.22,122.52(d,J＝13.6Hz),120.94,112.77(d,J＝24.0Hz),106.62(t,J＝25.7Hz),36.69,13.38,7.77,7.54.ESI-MS:m/z 582.09[M-H]-,C₂₇H₁₉F₂N₃O₄S₃[583.05].

example 9 preparation of Compound I8

The procedure is as in example 2, except that the sulfonamide used is 4-fluorobenzenesulfonamide as a white solid in a yield of 57.8% and a melting point of 210-212 ℃.

Compound I8 spectroscopic data:¹H NMR(400MHz,DMSO-d6)δ12.54(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).¹³C NMR(100MHz,DMSO-d₆)δ166.61,165.33(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[M-H]-,C₂₇H₂₀FN₃O₄S₃[565.06].

EXAMPLE 10 preparation of Compound I9

The procedure is as in example 2, except that the sulfonamide used is 4-chlorobenzenesulfonamide in the form of a white solid with a yield of 52.6% and a melting point of 184-187 ℃.

Compound I9 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.59(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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₇H₂₀ClN₃O₄S₃[581.03].

EXAMPLE 11 preparation of Compound I10

The operation was the same as in example 2, except that the sulfonamide used was 4-bromobenzenesulfonamide as a white solid in 55.5% yield and a melting point of 220-223 ℃.

Compound I10 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.58(s,1H),8.53(d,J＝8.4Hz,1H),7.81(q,J＝8.7Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₇H₂₀BrN₃O₄S₃[624.98].

example 12 preparation of Compound I11

The procedure is as in example 2, except that the sulfonamide used is 4-hydroxybenzenesulfonamide as a white solid in 47.1% yield and a melting point of 221-224 ℃.

Compound I11 spectroscopic data:¹H NMR(400MHz,DMSO-d6)δ12.27(s,1H),10.61(s,1H),8.53(d,J＝8.5Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₇H₂₁N₃O₅S₃[563.06].

example 13 preparation of Compound I12

The procedure is as in example 2, except that 4-tert-butylbenzenesulfonamide is used as sulfonamide. White solid, yield 44% and melting point 200-203 ℃.

Compound I12 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.42(s,1H),8.53(d,J＝8.5Hz,1H),7.82(d,J＝8.5Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₃₁H₂₉N₃O₄S₃[603.13].

example 14 preparation of Compound I13

The operation is the same as example 2, except that the sulfonamide used is 2-chlorothiophene-5-sulfonamide, white solid, yield 48.6%, melting point 188-193 ℃.

Compound I13 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.69(s,1H),8.54(d,J＝8.5Hz,1H),7.68(t,J＝7.7Hz,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).¹³C NMR(100MHz,DMSO-d₆)δ167.16,163.51,158.75,157.75,142.75,138.27,137.07,134.25,134.15,130.65,129.57,128.30,128.01,127.97,127.25,125.47,123.46,123.23,122.59,122.41,120.86,36.87,13.40,7.78,7.55.ESI-MS:m/z 585.96[M-H]^-,C₂₅H₁₈ClN₃O₄S₄[586.99].

example 15 preparation of Compound I14

The procedure is as in example 2, except that the sulfonamide used is methylsulfonamide, white solid, yield 37.8%, melting point 156-157 ℃.

Compound I14 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.09(s,1H),8.56(d,J＝8.5Hz,1H),7.70(t,J＝7.7Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₂H₁₉N₃O₄S₃[485.05].

EXAMPLE 16 preparation of Compound I15

The procedure is as in example 2, except that the sulphonamide used is ethyl sulphonamide. White solid, yield 48.9%, melting point 141-143 ℃.

Compound I15 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ11.95(s,1H),8.55(d,J＝8.4Hz,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).¹³C NMR(100MHz,DMSO-d₆)δ168.23,164.42,159.81,158.60,143.59,134.96,131.44,130.41,129.19,128.86,128.07,126.29,124.33,124.07,123.43,123.33,121.84,48.01,37.47,14.22,9.31,8.60,8.38.ESI-MS:m/z 498.30[M-H]^-,C₂₃H₂₁N₃O₄S₃[499.07].

example 17 preparation of Compound I16

The operation was the same as in example 2, except that the sulfonamide used was isopropyl sulfonamide, white solid, yield 47.6%, melting point 216-218 ℃.

Compound I16 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ11.89(s,1H),8.56(d,J＝8.5Hz,1H),7.69(t,J＝7.1Hz,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).¹³C NMR(100MHz,DMSO-d₆)δ167.27,163.63,159.05,157.78,142.76,134.15,130.65,129.61,128.38,128.04,127.25,125.48,123.50,123.26,122.61,122.50,121.04,53.10,36.75,16.15,15.99,13.41,7.78,7.57.ESI-MS:m/z 512.36[M-H]^-,C₂₄H₂₃N₃O₄S₃[513.09].

EXAMPLE 18 preparation of Compound I17

The operation was the same as in example 2, except that the sulfonamide used was t-butylsulfonamide, white solid, yield 42.6%, melting point 206-207 ℃.

Compound I17 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ11.55(s,1H),8.55(d,J＝8.5Hz,1H),7.69(t,J＝7.0Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₅H₂₅N₃O₄S₃[527.10].

EXAMPLE 19 preparation of Compound I18

The operation was the same as in example 2, except that the sulfonamide used was cyclopropanesulfonamide, white solid, yield 47.8%, melting point 196-200 ℃.

Compound I18 spectroscopic data:¹H NMR(400MHz,DMSO-d₆)δ12.03(s,1H),8.56(d,J＝8.4Hz,1H),7.70(t,J＝7.7Hz,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).¹³C NMR(100MHz,DMSO-d₆)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[M-H]^-,C₂₄H₂₁N₃O₄S₃[511.07].

example 20 in vitro assay of URAT1 inhibitory Activity of the Compound of interest

Principle of testing

In HEK293T cells stably expressing hURAT1 protein¹⁴C-labeled substrate uric acid, detecting the effect of the compound and a positive control drug Racinonide on hURAT 1-mediated substrate uric acid uptake at different concentrations, and measuring the radioactive intensity of uric acid taken up by cells to calculate the inhibition effect (IC) of each compound on the protein₅₀)。

Experimental Material

pcDNA3.1(+) -hURAT1-T2A-eGFP plasmid (Shenzhen Shenhai Dongze Biotech, Inc.); plasmid extraction kit (OMEGA biotech); fat powder Agar (OXOID, USA); yeast Extract (OxOID, USA); peptone Tryptone (OXOID, usa); ampicillin (Sigma, usa); purifying the water; glycerol (bi yun sky biotechnology limited); fetal bovine serum (Corning, usa); DMEM medium (Corning, usa); DMSO (Sigma, usa); 96-well microplate (Corning, usa); PBS (Corning corporation, usa); HEPES (American)National Sigma company);¹⁴C-Uric acid (American radio laboratory Chemicals, USA)

Test method

The 96-well plate was preincubated with poly-D-lysine solution (0.1mg/mL) for 12 hours to obtain better cell adhesion. Then inoculating the cells into a flat plate, when the cells are fused to 90%, uniformly mixing the opti and the lip 3000 in a hole of 5 mu L/hole and a hole of 0.15 mu L/hole respectively, and standing for 5 min; simultaneously mixing opti, P3000 and plasmid DNA respectively at 5 μ L/well, 0.2 μ L/well and 500 ng/well, standing for 5 min; mixing the above two steps, and standing at room temperature for 15 min; add to 96-well plates with complete medium replaced. Placing at 37 deg.C, with 5% CO₂Culturing for 16-20h in an incubator, observing the expression of green fluorescent protein EGFP by using a fluorescence inverted microscope to verify whether transfection is successful, removing a culture medium after the transfection is successful, and washing cells twice by using PBS. To evaluate the inhibitory effect of drugs on URAT1, we performed a preliminary screening (20uM) on drugs with resinide as positive drug and absorption rate (additivity CPM-blank CPM)/(model CPM-blank CPM). And carry out IC₅₀The measurement of (1). Prior to the absorption experiment, the wells were aspirated, 50. mu.l each containing compounds at specific concentrations (20. mu.M, 10. mu.M, 5. mu.M, 2.5. mu.M, 1.25. mu.M) were added to each well, and the model group and blank group were not dosed. After 15 minutes incubation, the cells were aspirated off and 50. mu.M solution was added¹⁴Uric acid absorption buffer of C-uric acid to start uric acid absorption, and incubation at 37 ℃ for 15 min. The wells were aspirated and washed three times with 100. mu.L of ice-cold DPBS, and 40. mu.L of 0.1M NaOH was added to each well to lyse the cells. After lysis at room temperature for 30 minutes, 0.2mL of scintillation fluid was added to each well and the plate was placed on a plate shaker and shaken at 260rpm/min for 15 minutes. Measurement with liquid scintillation counter¹⁴The C-uric acid emission value (CPM) was measured in triplicate and averaged.

TABLE 2 URAT1 inhibitory Activity of series I Compounds in vitro

And (4) conclusion: the test result shows that the compounds of the series I can effectively inhibit URAT 1-mediated¹⁴C-UA intake, and the effect target of the compound is URAT 1. Wherein the activity of the compounds I6, I10, I14 and I15 is stronger than that of the positive control medicament Racinonide. Can be further developed as a drug lead with a brand-new structure.

Example 21 in vitro GLUT9 inhibition Activity assay of a Compound of interest

Principle of testing

The GLUT9 has electrogenesis property when transporting uric acid, specifically, when GLUT9 transports a uric acid anion to enter cells, a negative charge moves to generate current, the potential of a cell membrane changes, then the magnitude change of the current generated by the fact that uric acid external liquid containing different concentrations of compounds stimulates HEK293T cells expressing GLUT9 is recorded by using a patch clamp technology, and the IC of each compound for inhibiting GLUT9 is calculated₅₀The value is obtained. When the compound target inhibition activity is tested, the series I compounds can also inhibit GLUT9, in order to verify the inhibition activity of the series I compounds GLUT9, four compounds with outstanding URAT1 inhibition activity are selected to carry out a GLUT9 primary screening experiment, and IC 10 with the best primary screening activity is carried out₅₀And (6) testing.

Experimental Material

Multicamp 700B patch clamp amplifier, digitata 1550B digitizer, Pclamp 10 software (Molecular Devices, usa), borosilicate glass capillary (BF150-110-10, Sutter Instruments, usa). GLUT9(Gene ID:117591) (Shanghai Biotechnology engineering services Co.), uric acid, NaCl, KCl, MgCl₂、CaCl₂HEPES, 10mM D-glucose, EGTA extracellular fluid fraction (Sigma-Aldrich, USA), Lipofectamine 3000 (Invitrogen, USA).

Test method

The GLUT9 gene fragment is cloned to an expression vector to construct pcDNA3.1(-) -GLUT9 recombinant plasmid. When HEK293T cells were grown to 90% confluency, the cells were seeded into 24-well plates and placed at 37 ℃ with 5% CO₂Culturing in an incubator for 18-24 h. The GLUT9 recombinant plasmid and EGFP were co-transfected into HEK293T cells by the following specific transfection steps: to two 1.5mL EP tubes (tube No. 1 and tube No. 2) were added 25 μ L of Opti medium, respectively, and to tube No. 1 were added two plasmids (mgut 9: EGFP ═ 2:1)600 ng: 250ng and 1 μ L P3000^TMMixing the materials evenly by vortex; no. 2 tube with 0.75 μ L P3000^TMMixing the materials evenly by vortex; mixing the two tubes of liquid, vortexing for 10 s, standing for 20min, adding dropwise into the hole containing new culture medium, standing at 37 deg.C and 5% CO₂Culturing in an incubator for 18-24 h. And after transfection is finished, observing the expression of EGFP, digesting the cells, re-inoculating the cells onto a 0.1mg/mL PDL pretreated cover glass, and recording the cells in a whole-cell patch clamp after the cells are attached to the wall.

A borosilicate capillary glass tube is used, the diameter of a tip is about 1-5 mu M after two-step drawing by a drawing instrument, internal liquid (about one third to one half of an electrode) is added to the tail of a micro-electrode by means of flushing and filling by an injector, and bubbles are removed to prepare the electrode. Placing the glass slide in the extracellular fluid connected with a metal electrode, moving a glass microelectrode above a cell with fluorescence under a microscope, applying negative pressure, performing capacitance compensation after high-resistance sealing of more than 1G omega is formed between the electrode and a cell membrane of HEK293T, clamping the cell at-30 mV, and applying a short and powerful negative pressure to break the membrane. After the cells were stabilized, the uric acid external solution containing the test compound at different concentrations (200. mu.M, 100. mu.M, 50. mu.M, 25. mu.M, 12.5. mu.M) was perfused at a rate of 2-3mL/min, and the change in the magnitude of the current generated by the cells when only the uric acid external solution was perfused and the uric acid external solution containing the test compound were perfused was recorded, with 3 replicates for each administration concentration.

And (4) conclusion: from FIGS. 1 and 2, it can be seen that the compounds represented in series I, I6, I10, I14 and I15, do exhibit strong inhibitory activity against GLUT9 at the primary screening concentration of 100. mu.M, with the IC of I10 being the best inhibitory₅₀The value was 55.96. + -. 10.38. mu.M.

Example 22 in vivo anti-gout Activity of Compounds of interest

Test materials and methods

(1) Experimental animals: male Kunming mice, provided by the Experimental animals center of Shandong university.

(2) Sample treatment: selecting a compound to be tested with target inhibition activity superior to Lesinurad, and preparing the compound to be tested with CMC-Na to proper concentration before use.

(3) Molding medicine: xanthine and potassium oxonate.

(4) Positive control drug: lesinurad

(5) The test method comprises the following steps: approximately 20g of male Kunming mice are fed adaptively for 1 week and are randomly divided into a blank group and a model group, the blank group is given with a gavage 5% CMC-Na solution of 0.2mL, the model group is gavage 600mg/Kg hypoxanthine suspension of 0.2mL, and is injected with a suspension of 400mg/Kg Potassium Oxonate of 0.2mL subcutaneously, eyeballs are picked after 4 hours, blood is taken, supernatants are separated, and the concentration of blood uric acid is detected.

TABLE 3 results of serum uric acid lowering Activity in animals

And (4) conclusion: as can be seen from Table 3, the in vivo uric acid reducing activity of the four compounds I6, I10, I14 and I15 is obviously improved compared with that of the positive drug Racinonide, and the feasibility of the modification strategy is verified. Particularly, the compound I10 has the blood uric acid concentration reduction rate of 73.29 percent and far-surpassed Raschindylester (26.89 percent) and is worth further research.

Claims

1. A thienopyrimidone acylsulfonamide derivative is characterized by having a structure shown in the following general formula I:

wherein R is selected from C₁-C₅Alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocycle or substituted aromatic heterocycle of (a); the aromatic heterocyclic ring is selected from thienyl, and the substituent is selected from halogen, hydroxyl, nitro, trifluoromethyl and C₁-C₅Alkyl or cycloalkyl groups of (a).

2. The thienopyrimidinone acylsulfonamide derivative according to claim 1 is one of the compounds of the following structure:

3. the process for producing the thienopyrimidinone acyl sulfonamide derivative according to claim 2, characterized in that the process is as follows:

taking 4-bromo-1-naphthylamine as an initial raw material, carrying out Suzuki coupling with cyclopropylboronic acid under the catalysis of tetratriphenylphosphine palladium to generate 4-cyclopropyl-1-naphthylamine (I-1), reacting the I-1 with N, N' -thiocarbonyldiimidazole to obtain an intermediate 1-cyclopropyl-4-isothiocyanato naphthalene (I-2), and reacting the I-2 with 2-aminothiophene-3-methyl carboxylate in a pyridine solution to obtain an intermediate I-3; then DMF as solvent, K₂CO₃Carrying out nucleophilic substitution with methyl bromoacetate under the catalysis of the (A) to obtain an intermediate I-4, and hydrolyzing the intermediate I-4 under an alkaline condition to obtain an intermediate 2- ((3- (4-cyclopropylnaphthalene-1-yl) -4-oxo-3, 4-dihydrothieno [2, 3-d)]Pyrimidine-2-yl) thio) acetic acid (I-5), and finally condensing the I-5 with different types of sulfamide under the catalysis of 4-Dimethylaminopyridine (DMAP) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) to obtain a target product with a structure of a general formula I;

the synthetic route is as follows:

reaction reagents and conditions: (i) cyclopropylboronic acid, K₃PO₄，Pd(PPh₃)₄Toluene: 25:2, N water₂Protection, 100 ℃, 12 h; (ii) n, N' -thiocarbonyl diimidazole, DCM, room temperature, 12 h; (iii) 2-aminothiophene-3-carboxylic acid methyl ester, pyridine, 45 ℃, 12h, NaOH, 90 ℃, 15 h; (iv) bromoacetic acid methyl ester, K₂CO₃DMF, 45 ℃, 6 h; (v) lithium hydroxide monohydrate, THF, MeOH, room temperature, 6 h; (vi) DMAP, EDCI, DCM, 0-RT, 15 h;

wherein R is represented by the corresponding structure in claim 2.

4. Use of the thienopyrimidinone acyl sulfonamide derivative according to claim 1 or 2 for the preparation of a medicament against gout.

5. An anti-gout pharmaceutical composition comprising the thienopyrimidinone acyl sulfonamide derivative of claim 1 or 2 and one or more pharmaceutically acceptable carriers or excipients.