Novel URAT1 inhibitor containing 3-(1-substituted-phenyl) benzoic acid as well as preparation method and application of novel URAT1 inhibitor

Abstract

The invention belongs to the field of medicine, and discloses a novel URAT1 inhibitor containing 3-(1-substituted-phenyl) benzoic acid and a preparation method and application thereof, the structure of the URAT1 inhibitor is shown as a formula (A), n is 1 or 2, X is OCH2, NHCH2, O or NH, R1 is hydrogen, alkyl, alkoxy or halogen, R2 is hydrogen, alkyl, alkoxy or halogen, and R3 is hydrogen, alkyl, alkoxy or halogen. URAT1 is a key target spot for treating hyperuricemia or gout, and the novel URAT1 inhibitor containing 3-(1-substituted-phenyl) benzoic acid has a chemical structure different from that of a known URAT1 inhibitor, has excellent inhibition activity on URAT1, and can be applied to preparation of drugs for treating hyperuricemia or gout. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid, and a preparation method and application thereof. Background Art

[0002] With improved living standards and changes in dietary habits, uric acid levels are rising, and the number of patients with hyperuricemia is also increasing. Due to the lengthy treatment cycles and poor prognostic factors for hyperuricemia and gout, hyperuricemia is gradually becoming the "fourth most common hyperuricemia" after hypertension, hyperlipidemia, and hyperglycemia. It is the second most common metabolic disease in China, after diabetes, and is closely linked to obesity, chronic kidney disease, and cardiovascular disease. Approximately 90% of hyperuricemia cases are caused by insufficient renal uric acid excretion, while the remaining 10% are caused by excessive uric acid production due to abnormal purine metabolism. Under normal circumstances, approximately 90% of uric acid in urine is reabsorbed into the blood. Urate transporter 1 (URAT1) is a key protein in uric acid reabsorption in the proximal tubules of the kidneys. Inhibiting URAT1's uric acid reabsorption function promotes uric acid excretion, thereby lowering blood uric acid levels. This is currently the main treatment strategy for hyperuricemia or gout.

[0003] Currently, the URAT1 inhibitors on the market include probenecid, benzbromarone, lecithinide and dotinorel. In addition, the URAT1 inhibitor SHR4640 developed by Jiangsu Hengrui Medicine Co., Ltd. in China was first applied for listing on January 9, 2025, and is expected to be approved for listing in China within 2025. Probenecid was launched in the United States in 1951. It was originally used to inhibit the renal excretion of drugs. It was later found to have URAT1 inhibitory activity. However, probenecid interacts with multiple drugs, resulting in reduced drug efficacy and limiting its clinical use. Benzbromarone was first approved for listing in Japan in 1978. It can significantly inhibit the reabsorption activity of URAT1. 50 The value is 0.22μM. However, due to the poor selectivity and severe hepatotoxicity of benzbromarone, it has not been marketed in the United States and was withdrawn from the European market in 2003. Resinade, the first selective URAT1 inhibitor, has moderate URAT1 inhibitory activity, IC 50 The uric acid concentration of URAT1 was 7.3 μM. It was launched in the US in December 2015 but has since been withdrawn due to severe nephrotoxicity. With the increasing prevalence of hyperuricemia, existing therapeutics are no longer able to meet clinical needs. Therefore, developing novel URAT1 inhibitors to alleviate clinical drug demand is of great practical significance. Summary of the Invention

[0004] In view of the above defects and shortcomings of the prior art, the primary object of the present invention is to provide a new URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid.

[0005] Another object of the present invention is to provide a method for preparing the novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid.

[0006] Another object of the present invention is to provide the use of the novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid in the preparation of drugs for preventing and treating diseases related to URAT1.

[0007] The present invention is achieved through the following solutions:

[0008] A novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid, characterized by having a structural formula as shown in (A):

[0009]

[0010] Wherein, n=1 or 2; X is OCH2, NHCH2, O or NH; R1 is hydrogen, alkyl, alkoxy or halogen; R2 is hydrogen, alkyl, alkoxy or halogen; R3 is hydrogen, alkyl, alkoxy or halogen.

[0011] Preferably, n=1 or 2; X is OCH2, O or NH; R1 is H, Cl or Br, R2 is H or F; R3 is H, CH3, Cl or Br.

[0012] Preferably, the inhibitor is a compound of any one of the following A1 to A8:

[0013]

[0014] The method for preparing a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid according to the present invention is characterized in that it comprises one of the following steps (1), (2), (3) and (4):

[0015]

[0016] (1) dissolving 6-hydroxy-isoindolin-1-one or 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one and compound a in an organic solvent, adding an inorganic base, and reflux reaction to obtain compound B1-3;

[0017] (2) Dissolving 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one and compound b in an organic solvent, adding a copper catalyst and an organic base, and stirring at room temperature to obtain compound B4-5;

[0018] (3) Dissolve 6-bromoisoindolin-1-one or 7-bromo-3,4-dihydroisoquinolin-1(2H)-one and compound c in an organic solvent, add a palladium catalyst, a phosphine ligand, and an inorganic base, protect with argon, and reflux to obtain compound B6-8;

[0019] (4) The product of step (1) or (2) or (3) is extracted, dried, filtered, column chromatographed, and then dissolved in a mixed solvent for ester hydrolysis to obtain target compounds A1 to A8.

[0020] Preferably, the organic solvent in step (1) is acetonitrile, the inorganic base is cesium carbonate; the compound a is one of methyl 3-(bromomethyl)-4-chlorobenzoate, methyl 3-(bromomethyl)-4-bromobenzoate, and methyl 3-bromomethylbenzoate;

[0021] The molar equivalent ratio of the 6-hydroxy-isoindolin-1-one or 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one, compound a and the inorganic base is 1:(1.0-1.2):2.

[0022] Preferably, in step (2), the organic solvent is dichloromethane, the copper catalyst is copper acetate, and the organic base is pyridine; the compound b is one of m-methoxycarbonylphenylboronic acid and 3-methoxycarbonyl-4-bromophenylboronic acid; and the molar equivalent ratio of the 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one, compound b, copper catalyst and organic base is 1:(1.5-3):(0.5-1):2.

[0023] Preferably, the organic solvent in step (3) is dry 1,4-dioxane, the palladium catalyst is tris(dibenzylideneacetone)dipalladium, the phosphine ligand is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, and the inorganic base is cesium carbonate; the compound c is one of 3-amino-5-fluorobenzoic acid methyl ester, 3-amino-4-methylbenzoic acid methyl ester, and 2-chloro-5-aminobenzoic acid methyl ester; and the molar equivalent ratio of the 6-bromo-isoindolin-1-one or 7-bromo-3,4-dihydroisoquinolin-1(2H)-one, compound c, palladium catalyst, phosphine ligand and inorganic base is 1:(1.2-1.6):(0.05-0.1):(0.2-0.3):2.

[0024] Preferably, the mixed solvent in step (4) is a mixed solution of NaOH solution and CH3OH, the volume ratio of the two is 1:1, and the concentration of the NaOH solution is 1M.

[0025] The present invention provides a use of a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid in the preparation of drugs for preventing and treating diseases associated with URAT1.

[0026] Preferably, the drug is a drug for treating hyperuricemia and gout; the drug for treating hyperuricemia and gout comprises as an active ingredient a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid or a pharmaceutically acceptable salt or a pharmaceutically acceptable carrier thereof.

[0027] Compared with the existing invention technology, the present invention has the following advantages and beneficial effects:

[0028] The novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid of the present invention has a novel chemical structure and differs from known similar inhibitors. It has excellent inhibitory effects on URAT1, a target associated with conditions such as hyperuricemia and gout, and its synthesis method is simple and easy. Based on these properties, the inhibitor can be effectively used to prevent and treat URAT1-related diseases such as hyperuricemia, inflammation, and arthritis, providing a new and effective option for the prevention and treatment of related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The invention provides a synthetic route for a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid. DETAILED DESCRIPTION

[0030] The present invention will be further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0031] The synthetic route of a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid of the present invention is as follows: Figure 1 shown.

[0032] Example 1

[0033] Synthesis of 4-chloro-3-(((3-oxoisoindolin-5-yl)oxy)methyl)benzoic acid (A1)

[0034]

[0035] 6-Hydroxyisoindolin-1-one (0.06 g, 0.38 mmol) and methyl 3-(bromomethyl)-4-chlorobenzoate (0.12 g, 0.45 mmol) were dissolved in acetonitrile, cesium carbonate (0.26 g, 0.79 mmol) was added, and the mixture was stirred under reflux for 6 h. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), the obtained intermediate B1 was placed in a 1M NaOH / CH3OH mixed solution (volume ratio of 1:1), refluxed and stirred for 3 h, and ester hydrolysis was performed to obtain 0.07 g of a white solid with a yield of 54.1%.

[0036] The structural characterization data of the product are as follows:

[0037] 1 H NMR (600MHz, DMSO-d6) δ13.27(s,1H),8.59(s,1H),8.15(d,J=2.4Hz,1H),7.93(dd,J=8.4,2.4Hz ,1H),7.67(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),7.33-7.24(m,2H),5.31(s,2H),4.31(s,2H).

[0038] 13 C NMR (151 MHz, DMSO-d6) δ 170.16, 166.81, 158.51, 137.62, 137.26, 135.22, 134.51, 130.96, 130.88, 130.39, 130.36, 125.30, 120.28, 107.58, 67.42, 44.93. Example 2

[0039] Synthesis of 4-bromo-3-(((3-oxoisoindolin-5-yl)oxy)methyl)benzoic acid (A2)

[0040]

[0041] 6-Hydroxyisoindolin-1-one (0.05 g, 0.32 mmol) and methyl 3-(bromomethyl)-4-bromobenzoate (0.11 g, 0.35 mmol) were dissolved in acetonitrile, and cesium carbonate (0.21 g, 0.65 mmol) was added and stirred under reflux for 6 h. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), the obtained intermediate B2 was placed in a 1M NaOH / CH3OH mixed solution (volume ratio of 1:1), refluxed and stirred for 3 h, and ester hydrolysis was performed to obtain 0.06 g of a yellow solid with a yield of 55.4%.

[0042] The structural characterization data of the product are as follows:

[0043] 1 H NMR(600MHz,DMSO-d6)δ8.60(s,1H),8.12(s,1H),7.84(s,2H),7.52(d,J=8.4Hz, 1H),7.28(dd,J=8.4,2.4Hz,1H),7.25(d,J=2.4Hz,1H),5.27(s,2H),4.31(s,2H).

[0044] 13C NMR (151MHz, DMSO-d6) δ170.2,166.9,158.5,137.3,136.8,134.5,133.7,131.0,130.9,130.8,128.2,125.3,120.7,107.6,69.6,45.4.

[0045] Example 3

[0046] Synthesis of 3-(((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)methyl)benzoic acid (A3)

[0047]

[0048] 7-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one (0.12 g, 0.74 mmol) and methyl 3-bromomethylbenzoate (0.19 g, 0.82 mmol) were dissolved in acetonitrile, cesium carbonate (0.49 g, 1.50 mmol) was added, and the mixture was stirred under reflux for 6 h. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), the obtained intermediate B3 was placed in a 1M NaOH / CH3OH mixed solution (volume ratio of 1:1), refluxed and stirred for 3 h, and ester hydrolysis was performed to obtain a white solid 0.10 with a yield of 47.0%.

[0049] The structural characterization data of the product are as follows:

[0050] 1 H NMR (600MHz, DMSO-d6) δ13.02(s,1H),8.03(s,1H),7.94(s,1H),7.90(d,J=7.8Hz,1H),7.70(d,J=7.8Hz,1H),7.51-7.54 (m,1H),7.45(d,J=2.4Hz,1H),7.24(d,J=8.4Hz,1H),7.14(m,1H),5.22(s,2H),3.34-3.33(m,2H),2.82(t,J=6.6Hz,2H).

[0051] 13 C NMR(151MHz,DMSO-d6)δ167.61,164.76,157.44,138.14,132.28,132.17,131.45 ,130.91,129.26,129.24,129.15,128.60,119.52,112.57,69.20,39.80,27.32.

[0052] Example 4

[0053] Synthesis of 3-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)benzoic acid (A4)

[0054] 7-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one (0.12 g, 0.76 mmol) and m-methoxycarbonylphenylboronic acid (0.40 g, 2.19 mmol) were dissolved in dichloromethane, pyridine (0.12 g, 1.51 mmol) and copper acetate (0.07 g, 0.39 mmol) were added, and the mixture was stirred at room temperature for 24 h. The solvent was removed by distillation under reduced pressure, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), the obtained intermediate B4 was placed in a 1M NaOH / CH3OH mixed solution (volume ratio of 1:1), refluxed and stirred for 3 h, and ester hydrolysis was performed to obtain a white solid 0.07 with a yield of 32.6%.

[0055] The structural characterization data of the product are as follows:

[0056] 1 H NMR (600MHz, DMSO-d6) δ13.15(s,1H),7.73(d,J=7.8Hz,1H),7.44(d,J=2.4Hz,1H),7.39-7.38(m, 2H),7.33(d,J=8.4Hz,1H),7.24(dd,J=8.4,2.4Hz,1H),3.41-3.37(m,2H),2.91(t,J=6.6Hz,2H).

[0057] 13 C NMR (151MHz, DMSO-d6) δ167.1,164.3,157.4,155.5,135.4,133.3,131.5,131.0,130.1,124.9,123.7,123.2,118.9,117.1,39.6,27.4.

[0058] Example 5

[0059] Synthesis of 2-bromo-5-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)benzoic acid (A5)

[0060] 7-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one (0.06 g, 0.38 mmol) and 3-methoxycarbonyl-4-bromophenylboronic acid (0.16 g, 0.61 mmol) were dissolved in dichloromethane, pyridine (0.06 g, 0.75 mmol) and copper acetate (0.04 g, 0.22 mmol) were added, and the mixture was stirred at room temperature for 24 h. The solvent was removed by distillation under reduced pressure, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), the obtained intermediate B5 was placed in a 1M NaOH / CH3OH mixed solution (volume ratio of 1:1), refluxed and stirred for 3 h, and ester hydrolysis was performed to obtain 0.02 g of a white solid with a yield of 11.8%.

[0061] The structural characterization data of the product are as follows:

[0062] 1 H NMR (600MHz, DMSO-d6) δ8.07(t,J=3.0Hz,1H),7.71(d,J=8.4Hz,1H),7.40(m,2H),7.30(d,J=3.0, 1H),7.24(dd,J=8.4,3.0Hz,1H),7.10(dd,J=8.4,3.0Hz,1H),3.38(m,2H),2.90(t,J=6.6Hz,2H).

[0063] 13 C NMR (151MHz, DMSO-d6) δ167.17,164.19,156.53,155.13,135.83,135.65,131.58,130.13,123.21,122.89,120.45,117.27,113.88,39.73,27.42.

[0064] Example 6

[0065] Synthesis of 3-fluoro-5-((3-oxoisoindolin-5-yl)amino)benzoic acid (A6)

[0066]

[0067] 6-Bromo-isoindolin-1-one (0.10 g, 0.48 mmol) and methyl 3-amino-5-fluorobenzoate (0.12 g, 0.73 mmol) were dissolved in dry 1,4-dioxane, and 2-dicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl (0.05 g, 0.10 mmol), tris(dibenzylideneacetone)dipalladium (0.02 g, 0.03 mmol) and cesium carbonate (0.32 g, 1.00 mmol) were added. The argon atmosphere was replaced three times, and the mixture was refluxed and stirred overnight. The mixture was extracted with saturated brine and ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), the obtained intermediate B6 was placed in a 1M NaOH / CH3OH mixed solution (volume ratio of 1:1), refluxed and stirred for 3 h, and ester hydrolysis was performed to obtain 0.02 g of a white solid with a yield of 13.1%.

[0068] The structural characterization data of the product are as follows:

[0069] 1 H NMR (600MHz, DMSO-d6) δ9.04(s,1H),8.59(s,1H),7.55-7.47(m,2H),7.47-7.36(m,2H),7.18-7.04(m,2H),4.32(s,2H).

[0070] 13 C NMR(151MHz,DMSO-d6)δ170.30,166.79(J CF =3.0Hz,166.80,166.78),163.30(J CF =243.1Hz,164.10,162.49),146.51(d,J CF =10.6Hz,146.55,146.48),142.24,137.40,134.26,134.11(d,J CF =9.1Hz,134.14,134.08),125.09,122.90,112.82,111.97,106.48(d,J CF =24.2Hz,106.56,106.40),106.29(d,J CF =25.7Hz,106.37,106.20),45.09.

[0071] Example 7

[0072] Synthesis of 4-methyl-3-((3-oxoisoindolin-5-yl)amino)benzoic acid (A7)

[0073]

[0074] 6-Bromo-isoindolin-1-one (0.23 g, 1.07 mmol) and methyl 3-amino-4-methylbenzoate (0.21 g, 1.29 mmol) were dissolved in dry 1,4-dioxane, and 2-dicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl (0.11 g, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (0.05 g, 0.05 mmol) and cesium carbonate (0.70 g, 2.14 mmol) were added. The argon atmosphere was replaced three times, and the mixture was refluxed and stirred overnight. The mixture was extracted with saturated brine and ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), the intermediate B7 was placed in a 1M NaOH / CH3OH mixed solution (volume ratio of 1:1), refluxed and stirred for 3 h, and ester hydrolysis was performed to obtain 0.08 g of a white solid with a yield of 27.6%.

[0075] The structural characterization data of the product are as follows:

[0076] 1 H NMR(600MHz,DMSO-d6)δ12.79(s,1H),8.48(s,1H),7.75(s,1H),7.72(s,1H),7.49(dd,J=7.8,1.8Hz,1H),7.4 3(d,J=8.4Hz,1H),7.33(d,J=7.8Hz,1H),7.19(dd,J=8.4,2.4Hz,1H),7.12(s,1H),4.28(s,2H),2.27(s,3H).

[0077] 13 C NMR (151MHz, DMSO-d6) δ170.5,167.7,144.9,142.2,135.6,135.0,134.1,131.6,129.7,124.7,123.2,121.4,119.9,110.3,45.0,18.6.

[0078] Example 8

[0079] Synthesis of 2-chloro-5-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)benzoic acid (A8)

[0080] 7-Bromo-3,4-dihydroisoquinolin-1(2H)-one (0.22 g, 1.00 mmol) and methyl 2-chloro-5-aminobenzoate (0.24 g, 1.29 mmol) were dissolved in dry 1,4-dioxane, and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.11 g, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (0.05 g, 0.06 mmol) and cesium carbonate (0.69 g, 2.12 mmol) were added. The argon atmosphere was replaced three times, and the mixture was refluxed and stirred overnight. The mixture was extracted with saturated brine and ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography (V 石油醚 :V 乙酸乙酯 =3:1), the obtained intermediate B8 was placed in a 1M NaOH / CH3OH mixed solution (volume ratio of 1:1), refluxed and stirred for 3 h, and ester hydrolysis was performed to obtain 0.11 g of a white solid with a yield of 35.6%.

[0081] The structural characterization data of the product are as follows:

[0082] 1 H NMR (600MHz, DMSO-d6) δ13.27(s,1H),8.57(s,1H),7.93(t,J=3.0Hz,1H),7.58(d,J=2.4Hz,1H),7.40 (d,J=3.0Hz,1H),7.36(d,J=8.4Hz,1H),7.25-7.11(m,3H),3.36-3.35(m,2H),2.83(t,J=6.6Hz,2H).

[0083] 13 C NMR(151MHz,DMSO-d6)δ167.17,164.89,143.20,141.44,132.22,132.17,131 .85,130.71,128.97,121.81,121.37,119.84,118.08,116.51,39.71,27.48.

[0084] Evaluation of URAT1 inhibitory activity in vitro of product A1-8 obtained in the above examples:

[0085] The URAT1 inhibitory activity of product A1-8 was evaluated using a self-developed fluorescence assay for URAT1 activity. 6-Carboxyfluorescein was used as a URAT1 transport substrate, and the inhibitory activity of the test compound against URAT1 in vitro was determined by the change in fluorescence before and after the addition of the test compound to the reaction system. Self-developed HEK293T / hURAT1 stably transfected cells were plated at a density of 2×10 5cells / mL cell suspension, 200 μL cell suspension was added to each well of a 96-well plate, and blank group, control group and experimental group were set up, with 5 replicates in each group. HEK293T / hURAT1 cell suspension was added to the control group and experimental group, and no cells were added to the blank group. After culturing for 48 h, 100 μL HBSS (without Cl) was added to the blank group. - ) solution, 100 μL of 6-carboxyfluorescein solution (final concentration 239.48 μmol / L) was added to each well of the control group, and 100 μL of the test compound solution containing 6-carboxyfluorescein (239.48 μmol / L) in each concentration gradient was added to each well of the experimental group. After 1 hour, the working solution was removed by aspiration and 200 μL of HBSS (without Cl - ) solution three times, and lyse each well with 100 μL of 0.5 mol / L NaOH solution for 30 min. In a microplate reader, set the excitation wavelength to 490 nm and the emission wavelength to 525 nm, and read the plate after shaking. The results are shown in Table 1.

[0086] Table 1 Comparison of the inhibitory activity of A1-8 and positive drugs on URAT1

[0087]

[0088]

[0089] From the results in Table 1, it can be seen that the compounds A1-8 obtained in the present invention have excellent inhibitory activity against URAT1, especially A2, IC 50 The value was 144.6±27.4μM, which was similar to that of Resinade (IC 50 =119.1±8.30μM), followed by A6, IC 50 The value was 255.8±14.4 μM, which was only twice as effective as that of lesinade. In summary, the novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid of the present invention has excellent inhibitory activity against URAT1 and has a clear uric acid-lowering therapeutic effect.

[0090] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid, characterized in that The structural formula is shown in (A): Wherein, n=1 or 2; X is OCH2, NHCH2, O or NH; R1 is hydrogen, alkyl, alkoxy or halogen; R2 is hydrogen, alkyl, alkoxy or halogen; R3 is hydrogen, alkyl, alkoxy or halogen.

2. A novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid according to claim 1, characterized in that Said n=1 or 2; X is OCH2, O or NH; R1 is H, Cl or Br, R2 is H or F; R3 is H, CH3, Cl or Br.

3. A novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid according to claim 2, characterized in that The inhibitor is any one of the following compounds A1 to A8:

4. A method for preparing a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid according to any one of claims 1 to 3, characterized in that: The method comprises one of the following steps (1), (2), (3) and (4): (1) dissolving 6-hydroxy-isoindolin-1-one or 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one and compound a in an organic solvent, adding an inorganic base, and reflux reaction to obtain compound B1-3; (2) Dissolving 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one and compound b in an organic solvent, adding a copper catalyst and an organic base, and stirring at room temperature to obtain compound B4-5; (3) Dissolve 6-bromoisoindolin-1-one or 7-bromo-3,4-dihydroisoquinolin-1(2H)-one and compound c in an organic solvent, add a palladium catalyst, a phosphine ligand, and an inorganic base, protect with argon, and reflux to obtain compound B6-8; (4) The product of step (1) or (2) or (3) is extracted, dried, filtered, column chromatographed, and then dissolved in a mixed solvent for ester hydrolysis to obtain target compounds A1 to A8.

5. The preparation method according to claim 4, characterized in that The organic solvent described in step (1) is acetonitrile, and the inorganic base is cesium carbonate; the compound a is one of 3-(bromomethyl)-4-chlorobenzoic acid methyl ester, 3-(bromomethyl)-4-bromobenzoic acid methyl ester, and 3-bromomethylbenzoic acid methyl ester; The molar equivalent ratio of the 6-hydroxy-isoindolin-1-one or 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one, compound a and the inorganic base is 1:(1.0-1.2):

2.

6. The preparation method according to claim 4, characterized in that In step (2), the organic solvent is dichloromethane, the copper catalyst is copper acetate, and the organic base is pyridine; the compound b is one of m-methoxycarbonylphenylboronic acid and 3-methoxycarbonyl-4-bromophenylboronic acid; and the molar equivalent ratio of the 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one, the compound b, the copper catalyst, and the organic base is 1:(1.5-3):(0.5-1):

2.

7. The preparation method according to claim 4, characterized in that The organic solvent described in step (3) is dry 1,4-dioxane, the palladium catalyst is tris(dibenzylideneacetone)dipalladium, the phosphine ligand is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, and the inorganic base is cesium carbonate; the compound c is one of 3-amino-5-fluorobenzoic acid methyl ester, 3-amino-4-methylbenzoic acid methyl ester, and 2-chloro-5-aminobenzoic acid methyl ester; the molar equivalent ratio of the 6-bromo-isoindolin-1-one or 7-bromo-3,4-dihydroisoquinolin-1(2H)-one, compound c, palladium catalyst, phosphine ligand and inorganic base is 1:(1.2-1.6):(0.05-0.1):(0.2-0.3):

2.

8. The preparation method according to claim 4, characterized in that The mixed solvent in step (4) is a mixed solution of NaOH solution and CH3OH, the volume ratio of the two is 1:1, and the concentration of the NaOH solution is 1M.

9. Use of a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid according to any one of claims 1 to 3 in the preparation of a medicament for preventing and treating diseases associated with URAT1.

10. The use according to claim 9, characterized in that The drug is a drug for treating hyperuricemia and gout; the drug for treating hyperuricemia and gout comprises a novel URAT1 inhibitor containing 3-(1-substituted-phenyl)benzoic acid or a pharmaceutically acceptable salt or a pharmaceutically acceptable carrier thereof as an effective ingredient.

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