New use of 2,4-disubstituted-5-fluoropyrimidine derivatives

Abstract

The application provides use of a 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof in preparation of a drug for reducing uric acid, the 2,4-disubstituted-5-fluoropyrimidine derivative having the following structure: the 2,4-disubstituted-5-fluoropyrimidine derivative provides a new selection for a drug for reducing uric acid.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and relates to a new use of a 2,4-disubstituted-5-fluoropyrimidine derivative. BACKGROUND

[0002] Hyperuricemia is a metabolic disease caused by purine metabolism disorder, which can be divided into primary hyperuricemia and secondary hyperuricemia; primary hyperuricemia is generally caused by congenital purine metabolism disorder, and secondary hyperuricemia is mostly caused by systemic diseases or drugs. Clinically, when the fasting blood uric acid level of a male is higher than 420 μmol / L and the fasting blood uric acid level of a female is higher than 360 μmol / L on two different days, it is called hyperuricemia.

[0003] At present, the drugs for treating hyperuricemia on the market can be divided into two categories: uric acid synthesis inhibitors and uric acid excretion promoters. The representative drug of the uric acid synthesis inhibitor is febuxostat, which inhibits the synthesis of uric acid by inhibiting the activity of xanthine oxidase (XO), thereby achieving the purpose of reducing uric acid. However, its side effects are also obvious, including liver failure and renal tubulointerstitial nephritis. The representative drugs of the uric acid excretion promoter are benzbromarone and lesinurad. Benzbromarone is an inhibitor of uric acid transporter 1 (URAT1) and human glucose transporter 9 (GLUT9), and lesinurad is an inhibitor of URAT1. Both of them achieve the effect of treating hyperuricemia by inhibiting the reabsorption of uric acid. The main side effect of benzbromarone is abnormal liver function, and it may also aggravate liver disease (cytolysis hepatitis), some of which are acute and difficult to control. At present, lesinurad has been withdrawn from the market by FDA due to serious nephrotoxicity.

[0004] CN116514779A discloses a 2,4-disubstituted-5-fluoropyrimidine derivative having the following structure:

[0005]

[0006] The compound is an inhibitor of homology domain interacting protein kinase 2 (HIPK2), which is highly expressed in the lesion site of renal interstitial tubules and participates in the fibrosis and inflammation processes through the regulation of oxidative stress. By inhibiting HIPK2, the fibrosis pathways (TGF-β / Smad3 pathway, Wnt-β-catenin pathway and Notch pathway) and inflammation pathways (activating IκB-α to inhibit NF-κB pathway) can be inhibited, thereby achieving the purpose of treating renal interstitial fibrosis.

[0007] It has been found recently that the compounds of formula II and formula III have the use of inhibiting the activities of URAT1 and GLUT9, and it is expected to obtain a uric acid-lowering drug with better activity and higher safety. SUMMARY

[0008] The present application provides a use of a 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for reducing uric acid, and shows good therapeutic effect; the 2,4-disubstituted-5-fluoropyrimidine derivative has the following structure:

[0009]

[0010] R3 is selected from: R4 is selected from:

[0011]

[0012] X and Y are independently selected from nitrogen atom or carbon atom; Z is selected from hydrogen atom, tert-butyloxycarbonyl, C1-C5 alkyl, C1-C5 alkyl acyl, C1-C3 alkyl hydroxyl, C1-C3 alkyl sulfonyl, C1-C3 substituted phenyl, C1-C5 alkyl amide.

[0013] In some embodiments, when the 2,4-disubstituted-5-fluoropyrimidine derivative is a compound of formula II, R4 is Z is not tert-butyloxycarbonyl.

[0014] In some embodiments, when the 2,4-disubstituted-5-fluoropyrimidine derivative is a compound of formula III, R4 is Z is not tert-butyloxycarbonyl, C4-C5 alkyl, C4-C5 alkyl acyl, C4-C5 alkyl amide.

[0015] In some embodiments, the C1-C5 alkyl in the 2,4-disubstituted-5-fluoropyrimidine derivative includes methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopentyl, isopropyl.

[0016] In some embodiments, the C1-C5 alkyl acyl in the 2,4-disubstituted-5-fluoropyrimidine derivative includes formyl, acetyl, propionyl, butyryl, valeryl, 3,3-dimethyl-1-butyryl, isovaleryl.

[0017] In some embodiments, the C1-C5 alkyl amide in the 2,4-disubstituted-5-fluoropyrimidine derivative includes formamidyl, acetylamidyl, propionamidyl, butyramidyl, valeramidyl, N-tert-butylamidyl, isovaleramidyl.

[0018] In some embodiments, the 2,4-disubstituted-5-fluoropyrimidine derivative is specifically the following compound: tert-butyl-4-(4-((5-fluoro-2-((4-(methoxycarbonyl)phenyl)amino)pyridin-4-yl)amino)phenyl)piperazine-1-carboxylate (compound 6e);

[0019]

[0020] 1 -(5-Fluoro-4-((4-(4-methylpiperazin- 1 -yl)phenyl)amino)pyrimidin-2-yl)- 1 H- benzo[d]imidazol-2-amine (6f compound);

[0021]

[0022] 1 -(4-((4-(4-Ethylpiperazin- 1 -yl)phenyl)amino)-5-fluoropyrimidin-2-yl)- 1 H- benzo[d]imidazol-2-amine (6g compound);

[0023]

[0024] 1 -(5-Fluoro-4-((4-(piperazin- 1 -yl)phenyl)amino)pyrimidin-2-yl)- 1 H-benzo[d]imidazol- 2-amine (7a compound / Formula I compound);

[0025]

[0026] 1 -(5-Fluoro-4-((4-(4-isopentylpiperazin- 1 -yl)phenyl)amino)pyrimidin-2-yl)- 1 H- benzo[d]imidazol-2-amine (8a compound);

[0027]

[0028] 1 -(5-Fluoro-4-(6-(piperazin- 1 -yl)pyridin-3-yl)pyrimidin-2-yl)- 1 H-benzo[d]imidazol-2- amine (12h compound);

[0029]

[0030] The pharmaceutically acceptable salt is a hydrochloride, a sulfate, a phosphate, a perchlorate, a methanesulfonate, a trifluoromethanesulfonate, a formate, an acetate, a propionate, a butyrate, a maleate, a succinate, a trifluoroacetate, a succinate, a salicylate, a DL-aspartate, a D-aspartate, a L-aspartate, a DL-glutamate, a D-glutamate, a L-glutamate, a glycerate, a stearate, a DL-tartrate, a D-tartrate, a L-tartrate, a (±) mandelate, a (R)-(-) mandelate, a (S)-(+) mandelate, a citrate, a mucate, a malonate, a benzoate, a DL-malate, a (±) lactate, a L-(+)-lactate, a D-(+)-lactate, a pamoate, a D-α-galacturonate, a glycerate, a DL-cysteate, a D-cysteate, a L-cysteate, a (4S)-hydroxy-L-proline, a cyclopropane-1,1-dicarboxylate, a 2,2-methylmalonate, a tyrosinate, a proline, a fumarate, a 1-hydroxy-2-naphthoate, a phosphonoacetic acid, a carbonate, a bicarbonate, a 3-phosphonopropionate, a DL-pyroglutamate, a D-pyroglutamate, a L-pyroglutamate, a p-toluenesulfonate, a benzenesulfonate, an ethanesulfonate, a (±) camphorsulfonate, a naphthalenesulfonate, a 1R-(-)-camphorsulfonate, a 1S-(+)-camphorsulfonate, a 1,5-naphthalenedisulfonate, a 1,2-ethanedisulfonate, a 1,3-propanedisulfonate, a 3-(N-morpholino)propanesulfonate, a biphenylsulfonate, a hydroxyethanesulfonate, a 1-hydroxy-2-naphthalenesulfonate, a monobasic phosphate, a dibasic phosphate, a tribasic phosphate, a potassium phosphate, a sodium phosphate, a sodium phosphate, a sodium phosphate, a sodium phosphate, a sodium phosphate, a sodium phosphate, a calcium phosphate, a calcium phosphate, a hexafluorophosphate, a vinylphosphonate, a 2-hydroxyethylphosphonate, and a phenylphosphonate.

[0031] In some embodiments, the medicament is for inhibiting uric acid transporter 1 (URAT1).

[0032] In some embodiments, the medicament is for inhibiting glucose transporter 9 (GLUT9).

[0033] In some embodiments, the medicament has inhibitory activity against OAT4 and agonistic activity against OAT1 / OAT3.

[0034] In some embodiments, the medicament is for preventing or treating hyperuricemia, gout, gouty arthritis, renal disorder associated with hyperuricemia.

[0035] In some embodiments, the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is used in an amount of 5 to 100 mg per day.

[0036] In some embodiments, the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is administered in an amount selected from the group consisting of 10-80 mg, preferably 20-70 mg, more preferably 30-60 mg, most preferably about 35 mg, 40 mg, 45 mg, 50 mg, 55 mg or 58 mg.

[0037] In some embodiments, the medicament can be prepared as a tablet, capsule, granule, powder, oral solution, injection or external preparation.

[0038] In some embodiments, the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, once every two days, once every three days.

[0039] In some embodiments, the medicament can be administered by any suitable means, and the above-mentioned compounds and pharmaceutically acceptable compositions can be administered orally, topically, etc. to humans or other animals depending on the severity of the disease.

[0040] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present application. The term "pharmaceutically acceptable" means a substance or composition that is chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith.

[0041] The term "treatment" of any disease or disorder, as used herein, means any process intended to slow, interrupt, stop, control or prevent the progression of the disease or disorder, but does not necessarily indicate a total elimination of all disease or disorder symptoms, and also includes prophylactic treatment of the symptoms, especially in patients susceptible to such diseases or disorders. In some embodiments, it refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom of the disease). In other embodiments, "treatment" refers to alleviating or ameliorating at least one physical parameter, including those not discernible by the patient. In other embodiments, "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In other embodiments, "treatment" refers to preventing or delaying the onset, occurrence or worsening of the disease or disorder.

[0042] The term "therapeutically effective amount" or "therapeutically effective dose", as used herein, refers to the amount of a compound of the present application that will elicit the biological or medical response of an individual, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.

[0043] The compound of formula II and the compound of formula III provided by the application have strong inhibitory activity on URAT1 and GLUT9, can reduce blood uric acid by inhibiting uric acid reabsorption, and provide a new choice of uric acid-lowering drugs; in addition to treating hyperuricemia, the compound of formula II and the compound of formula III can also treat renal interstitial fibrosis, and therefore, compared with febuxostat, the compound of formula II and the compound of formula III also reduce the side effects of renal interstitial nephritis. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 Figure 3 is a statistical diagram of the influence of the compound of formula I on the blood uric acid level of adenine diet-induced mice in Example 3;

[0045] Figure 2 Figure 4 is an HE staining diagram (200X) of the influence of the compound of formula I on the renal pathological changes of adenine diet-induced mice in Example 3;

[0046] Figure 3 Figure 5 is a statistical diagram of the HE staining score of the influence of the compound of formula I on the renal pathological changes of adenine diet-induced mice in Example 3;

[0047] Figure 4 Figure 6 is a Masson staining diagram (200X) of the influence of the compound of formula I on the collagen fiber content of the kidney of adenine diet-induced mice in Example 3;

[0048] Figure 5 Figure 7 is a statistical diagram of the Masson staining score of the influence of the compound of formula I on the collagen fiber content of the kidney of adenine diet-induced mice in Example 3;

[0049] Figure 6 Figure 8 is a Sirius red staining (200X) diagram of the influence of the compound of formula I on the collagen fiber content of the kidney of adenine diet-induced mice in Example 3;

[0050] Figure 7 Figure 9 is a statistical diagram of the Sirius red staining score of the influence of the compound of formula I on the collagen fiber content of the kidney of adenine diet-induced mice in Example 3;

[0051] REFERENCE NUMERALS:

[0052] (1) Group: normal diet group; (2) group: 0.2% adenine diet group; (3) group: 0.2% adenine diet + compound of formula I (25 mg / kg) group; (4) group: 0.2% adenine diet + compound of formula I (50 mg / kg) group; (5) group: 0.2% adenine diet + compound of formula I (100 mg / kg) group; (6) group: 0.2% adenine diet + dapagliflozin (10 mg / kg) group. DETAILED DESCRIPTION

[0053] The following examples are used to further illustrate the present disclosure, but are not intended to limit the scope of the present disclosure.

[0054] Example 1 Test of the URAT1 target activity of the compound of formula I

[0055] Test method: First, the prepared HEK293T cells were seeded into 96-well plates, and when the cells reached 70-90% confluence, the transfection reagent Lipofectamine 3000 was mixed with the URAT1 recombinant plasmid (100 ng / well) and transferred to the 96-well plate, which was incubated in a 37°C, 5% CO2 incubator for 24 h. The expression of green fluorescent protein EGFP was observed under an inverted fluorescence microscope to verify whether the transfection was successful. After successful transfection, the culture medium in the plate was removed, and the cells were washed twice with phosphate buffer solution (PBS). The remaining waste liquid in the wells was aspirated and discarded, and 50 μl of a solution containing various specific concentrations of the compound of formula I or lesinurad (40 μM, 20 μM, 10 μM, 5 μM, 2.5 μM) was added to each well, and the blank group and the model group were not added with the compound of formula I or lesinurad. After incubation for 30 min, 50 μM [14C]-uric acid solution (diluted with prepared buffer) was added to each well for 15 min. The experiment was terminated by adding PBS and washing the cells three times. Then 40 μL of 0.1 M NaOH aqueous solution was added to each well for 30 min. After complete lysis of the cells, 0.2 mL of scintillation fluid was added to each well, and the plate was shaken on a shaker at 260 rpm / min for 15 min. The intracellular liquid radioactivity (CPM) was measured using a Micro Beta2 liquid scintillation detector. All tests were repeated three times, and the average value was taken.

[0056] Experimental results: Under the conditions of this experiment, the results show that both lesinurad and the compound of formula I have inhibitory activity on URAT1, wherein the IC 50 = 6.03 ± 1.06 μM, and the IC 50 = 10.91 ± 1.23 μM of the tested sample of the compound of formula I, have strong URAT1 inhibitory activity, indicating that the compound of formula I can reduce blood uric acid by inhibiting uric acid reabsorption.

[0057] In another embodiment, the inhibition rate of GLUT9 at a concentration of 10 μm of the compound of formula I is 21.45%, which is slightly lower than the 30.12% of the positive control drug (benzbromarone), indicating that the compound of formula I also has inhibitory activity on GLUT9.

[0058] Example 2 Test of the effect of the compound of formula I on the potassium oxonate-induced hyperuricemia rat model

[0059] Test method: 56 SPF level male SD rats were selected and randomly divided into 7 groups according to body weight, namely normal control group, model control group, febuxostat group (2 mg / kg, the effective data of febuxostat showed that 1 mg / kg could significantly reduce the blood uric acid level of oxonate potassium induced hyperuricemia mice), formula I compound dose 1, 2, 3, 4 groups (6.3 mg / kg, 12.5 mg / kg, 25 mg / kg, 50 mg / kg), 8 animals in each group. The animals were fasted for more than 12 h before administration, and the hyperuricemia model was replicated by intraperitoneal injection of 300 mg / kg oxonate potassium (OAPS) at 10 mL / kg, and the normal control group was given the same volume of 0.9% sodium chloride injection. The animals in each group were given the corresponding concentration of drug solution at 10 mL / kg by oral gavage, and the normal control group and model control group were given the same volume of pure water by gavage, once a day. Blood samples were collected from the jugular vein before modeling, 2 h, 3 h, 4 h, 5 h, 6 h, and 8 h after modeling, and the serum uric acid level was detected by automatic biochemical analyzer.

[0060] Experimental results: Compared with the normal control group, the serum uric acid level of the model control group was significantly increased after modeling (P≤0.01); compared with the model control group, the serum uric acid level of the formula I compound dose 1 group (6.3 mg / kg) was significantly increased 3 h after administration (P≤0.05); the serum uric acid levels of the formula I compound dose 2 group (12.5 mg / kg) were significantly reduced 5 h and 6 h after administration (P≤0.05); the serum uric acid levels of the formula I compound dose 3 group (25 mg / kg) were significantly reduced 4 h, 5 h, and 6 h after administration (P≤0.05 or P≤0.01); the serum uric acid levels of the formula I compound dose 4 group (50 mg / kg) were significantly reduced 4 h, 5 h, and 6 h after administration (P≤0.05 or P≤0.01); the serum uric acid levels of the febuxostat group (2 mg / kg) were significantly reduced 2 h, 4 h, 5 h, 6 h, and 8 h after administration (P≤0.05 or P≤0.01). In summary, formula I compound (12.5 mg / kg, 25 mg / kg, 50 mg / kg) can reduce the blood uric acid level of oxonate potassium induced hyperuricemia rats.

[0061] Table 1 Effect of formula I compound on serum uric acid level in oxonate potassium induced hyperuricemia rat model n=8

[0062]

[0063]

[0064] Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0065] Example 3 Effect of the compound of formula I on blood uric acid in mice with chronic hyperuricemia induced by adenine diet

[0066] 8-week-old male C57-BL6 mice were raised in the SPF animal room of the animal experiment department, and the light mode was 12 hours of light / 12 hours of darkness. After one week of adaptive feeding, the mice were randomly divided into: (1) normal diet group (n=6); (2) 0.2% adenine diet group (n=8); (3) 0.2% adenine diet+compound of formula I (25 mg / kg) (n=8); (4) 0.2% adenine diet+compound of formula I (50 mg / kg) (n=8); (5) 0.2% adenine diet+compound of formula I (100 mg / kg) (n=8); (6) 0.2% adenine diet+dapagliflozin (10 mg / kg) (n=5). The normal diet group was fed with normal control feed (Jiangsu Nantong Trelodge, LAD 3001), and the other five groups were fed with feed containing 0.2% adenine (Jiangsu Nantong Trelodge, TP 1S002) to construct a kidney fibrosis model. The four treatment groups were given the corresponding concentrations of compound of formula I and 10 mg / kg / d of dapagliflozin by gavage at the same time as the 0.2% adenine feed, and the normal control group and the 0.2% adenine diet group were given the same volume of pure water by gavage, once a day. The mice in each group were euthanized on the 21st day of the experiment, blood was collected to determine the uric acid level, and kidney tissue was collected for HE staining, Masson staining and Sirius red staining.

[0067] 1. Blood uric acid level

[0068] Figure 1 It is shown that compared with the normal diet group, the blood uric acid level of the 0.2% adenine diet group mice was significantly increased (p<0.05); and compared with the 0.2% adenine diet group mice, the blood uric acid level of the 0.2% adenine diet+compound of formula I (25 mg / kg, 50 mg / kg and 100 mg / kg) group mice was significantly decreased (p<0.05), and the uric acid level of the 0.2% adenine diet+dapagliflozin (10 mg / kg) group mice had no significant change.

[0069] Figure 1 * indicates that the normal diet group is compared with the 0.2% adenine diet group, P<0.05; # indicates that the treatment group is compared with the 0.2% adenine diet group, P<0.05.

[0070] 2. HE staining

[0071] Figure 2As shown, compared with the normal diet group, the kidney of the 0.2% adenine diet group was obviously infiltrated by inflammatory cells, and the kidney tubule was obviously expanded and atrophied, and the HE staining pathological score was obviously increased; compared with the 0.2% adenine diet group, the kidney of the 0.2% adenine diet + compound I (50 mg / kg) group and the 0.2% adenine diet + compound I (100 mg / kg) group was obviously reduced in inflammatory cell infiltration, and the kidney tubule was obviously reduced in expansion and atrophy. Figure 3 As shown in Table 2, the kidney pathological score of the 0.2% adenine diet + compound I (50 mg / kg) group and the 0.2% adenine diet + compound I (100 mg / kg) group was statistically significant compared with the 0.2% adenine diet group, and the improvement effect of the 0.2% adenine diet + compound I (100 mg / kg) on the pathological changes of the model mice was better than that of the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0072] Table 2: Pathological scores of mice in each group

[0073]

[0074] Figure 3 In Table 2, *** indicates that the normal diet group is compared with the 0.2% adenine diet group, P<0.001; ### indicates that the treatment group is compared with the 0.2% adenine diet group, P<0.001; and @ indicates that the treatment group is compared with the 0.2% adenine diet + dapagliflozin (10 mg / kg) group, P<0.05.

[0075] 3. Masson staining

[0076] Figure 4 As shown, compared with the normal diet group, the kidney of the 0.2% adenine diet group was obviously infiltrated by inflammatory cells, and the kidney tubule was obviously expanded and atrophied, and the HE staining pathological score was obviously increased; compared with the 0.2% adenine diet group, the kidney of the 0.2% adenine diet + compound I (50 mg / kg) group and the 0.2% adenine diet + compound I (100 mg / kg) group was obviously reduced in inflammatory cell infiltration, and the kidney tubule was obviously reduced in expansion and atrophy. Figure 5 As shown in Table 3, the kidney interstitial collagen area of the 0.2% adenine diet + compound I (50 and 100 mg / kg) group was statistically significant compared with the 0.2% adenine diet group, and the improvement effect of the 0.2% adenine diet + compound I (100 mg / kg) on the kidney interstitial collagen deposition was better than that of the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0077] Table 3: Collagen area represented by Masson staining of mice in each group

[0078]

[0079]

[0080] Figure 5 *** indicates P<0.001 compared with the normal diet group and the 0.2% adenine diet group; # indicates P<0.05 compared with the 0.2% adenine diet group; ## indicates P<0.01 compared with the 0.2% adenine diet group; ### indicates P<0.001 compared with the 0.2% adenine diet group; and @ indicates P<0.05 compared with the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0081] 4. Sirius red staining

[0082] Figure 6 As shown, compared with the normal diet group, the 0.2% adenine diet group had significant collagen deposition in the renal interstitium; compared with the 0.2% adenine diet group, the 0.2% adenine diet + compound of formula I (50, 100 mg / kg) group had reduced collagen deposition in the renal interstitium, i.e. reduced area of red region, and the 0.2% adenine diet + compound of formula I (100 mg / kg) group had the most obvious treatment effect. Figure 7 As shown in Table 4, the 0.2% adenine diet + compound of formula I (50 and 100 mg / kg) group had statistically significant collagen area in the renal interstitium compared with the 0.2% adenine diet group, and the 0.2% adenine diet + compound of formula I (100 mg / kg) group had a better improvement effect on collagen deposition in the renal interstitium than the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0083] Table 4. Collagen area represented by Sirius red staining in mice in each group

[0084]

[0085] Figure 7 *** indicates P<0.001 compared with the normal diet group and the 0.2% adenine diet group; ### indicates P<0.001 compared with the 0.2% adenine diet group; and @@@ indicates P<0.001 compared with the 0.2% adenine diet group + dapagliflozin (10 mg / kg) group.

Claims

1. Use of a 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof having the following structure: ###0001### for the manufacture of a medicament for reducing uric acid, wherein the medicament is for inhibiting urate transporter 1. 。 2. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a medicament for reducing uric acid, characterized in that, The medicament is for inhibiting glucose transporter 9.

3. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a medicament for reducing uric acid, characterized in that, The medicament is for preventing or treating hyperuricemia, gout, gouty arthritis.

4. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a medicament for reducing uric acid, characterized in that, The 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is used in an amount of 5 to 100 mg per day.

5. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a medicament for reducing uric acid, characterized in that, The 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is used in an amount of 10 to 80 mg per day.

6. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 5 for the manufacture of a medicament for reducing uric acid, characterized in that, The 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is used in an amount of 20 to 70 mg per day.

7. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 6 for the manufacture of a medicament for reducing uric acid, characterized in that, The 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is used in an amount of 30 to 60 mg per day.

8. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 7 for the manufacture of a medicament for reducing uric acid, characterized in that, The medicament can be prepared as tablets, capsules, granules, powders, oral solutions, injections, and external preparations.

9. Use of a 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 for the manufacture of a medicament for lowering uric acid, characterized in that, ​

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