New application of 2, 4-disubstituted-5-fluoropyrimidine derivative

Abstract

The invention provides an application of a 2, 4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof in preparation of a medicament for reducing uric acid, and the 2, 4-disubstituted-5-fluoropyrimidine derivative has the following structure: # imgabs0 # provides a new choice for the medicament for reducing uric acid.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a new use of 2,4-disubstituted-5-fluoropyrimidine derivatives. Background Art

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

[0003] Currently, the drugs used to treat hyperuricemia on the market can be divided into two categories: uric acid synthesis inhibitors and uric acid excretors. The representative drug of uric acid synthesis inhibitors 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 tubulointerstitial nephritis. The representative drugs of uric acid excretors are benzbromarone and lesinurad. Benzbromarone is an inhibitor of urate transporter 1 (URAT1) and human glucose transporter 9 (GLUT9), and lesinurad is an inhibitor of URAT1. The two 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 exacerbate liver disease (cytolytic hepatitis), and some are acute attacks, which are difficult to control. Currently, lesinurad has been withdrawn from the market by the FDA due to severe nephrotoxicity.

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

[0005]

[0006] This compound is an inhibitor of homeodomain interacting protein kinase 2 (HIPK2), which is highly expressed in the renal interstitial tubule lesion site and participates in the fibrosis and inflammation processes through the regulation of oxidative stress. By inhibiting HIPK2, the fibrosis pathway (TGF-β / Smad3 pathway, Wnt-β-catenin pathway and Notch pathway) and the inflammation pathway (inhibiting the NF-κB pathway by activating IκB-α) can be inhibited, so as to achieve the purpose of treating renal interstitial fibrosis.

[0007] Recently, it has been found 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 anti-hyperuricemic drugs with better activity and higher safety. Summary of the Invention

[0008] The present invention provides the 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 effects; the 2,4-disubstituted-5-fluoropyrimidine derivative has the following structure:

[0009]

[0010] Wherein, R 3 is selected from: R 4 is selected from:

[0011]

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

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

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

[0015] In some embodiments, the C1-C5 alkyl group 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 group 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 group in the 2,4-disubstituted-5-fluoropyrimidine derivative includes formamide, acetamide, propionamide, butyramide, valeramide, N-tert-butylcarbamoyl, isovaleramide.

[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)-1H-benzo[d]imidazol-2-amine (Compound 6f);

[0021]

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

[0023]

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

[0025]

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

[0027]

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

[0029]

[0030] The pharmaceutically acceptable salts are hydrochloride, sulfate, phosphate, perchlorate, mesylate, trifluoromethanesulfonate, formate, acetate, propionate, butyrate, maleate, succinate, trifluoroacetate, suberate, salicylate, DL-aspartate, D-aspartate, L-aspartate, DL-glutamate, D-glutamate, L-glutamate, glycerate, stearate, DL-tartrate, D-tartrate, L-tartrate, (±)-mandelate, (R)-(-)-mandelate, (S)-(+)-mandelate, citrate, mucate, malonate, benzoate, DL-malate, (±)-lactate, L-(+)-lactate, D-(+)-lactate, pimelate, D-α-galacturonate, glycerate, DL-cysteinate, D-cysteinate, L-cysteinate, (4S)-hydroxy-L-prolinate, cyclopropane-1,1-dicarboxylate, 2,2-dimethylmalonate, tyrosine salt, proline salt, fumarate, 1-hydroxy-2-naphthoate, phosphonoacetate, carbonate, hydrogencarbonate, 3-phosphonopropionate, DL-pyroglutamate, D-pyroglutamate, L-pyroglutamate, p-toluenesulfonate, benzenesulfonate, ethanesulfonate, (±)-camphorsulfonate, naphthalenesulfonate, 1R-(-)-camphorsulfonate, 1S-(+)-camphorsulfonate, 1,5-naphthalenedisulfonate, 1,2-ethanedisulfonate, 1,3-propanedisulfonate, 3-(N-morpholino)propanesulfonate, biphenylsulfonate, hydroxyethylsulfonate, 1-hydroxy-2-naphthalenesulfonate, potassium dihydrogen phosphate, potassium hydrogen phosphate, dipotassium phosphate, potassium phosphate, sodium hydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, calcium phosphate, tricalcium phosphate, hexafluorophosphate, vinyl phosphate, 2-hydroxyethyl phosphate, and phenyl phosphate.

[0031] In some embodiments, the drug is used to inhibit urate transporter 1 (URAT1).

[0032] In some embodiments, the drug is used to inhibit glucose transporter 9 (GLUT9).

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

[0034] In some embodiments, the drug is used to prevent or treat hyperuricemia, gout, gouty arthritis, and kidney disorders associated with hyperuricemia.

[0035] In some embodiments, the dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or its pharmaceutically acceptable salt is 5-100 mg / day.

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

[0037] In some embodiments, the drug can be formulated into tablets, capsules, granules, powders, oral liquids, injections or topical preparations.

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

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

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

[0041] As used herein, the term "treat" any disease or disorder means all that can slow down, interrupt, stop, control or halt the progression of the disease or disorder, but does not necessarily mean that all symptoms of the disease or disorder disappear. It also includes prophylactic treatment of the symptoms, especially in patients who are prone to such diseases or disorders. In some of these embodiments, it refers to improving the disease or disorder (i.e., slowing down or preventing or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treat" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceptible to the patient. In other embodiments, "treat" refers to modulating the disease or disorder physically (e.g., stabilizing the perceptible symptoms) or physiologically (e.g., stabilizing the physical parameters) or both. In other embodiments, "treat" refers to preventing or delaying the onset, occurrence or worsening of the disease or disorder.

[0042] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of the compound of the present invention that is capable of eliciting a biological or medical response in an individual (e.g., reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating the disorder, slowing down or delaying disease development, or preventing the disease, etc.).

[0043] The compounds of formula II and formula III provided by the present invention have strong inhibitory activities against URAT1 and GLUT9, and can reduce the blood uric acid level by inhibiting the reabsorption of uric acid, providing a new option for anti-hyperuricemic drugs; since the compounds of formula II and formula III can not only treat hyperuricemia, but also treat renal interstitial fibrosis, therefore, compared with febuxostat, the compounds of formula II and formula III also reduce the side effect of interstitial nephritis. Description of the Drawings

[0044] Figure 1 It is a statistical chart showing the effect of the compound of formula I in Example 3 on the blood uric acid level in mice induced by adenine diet;

[0045] Figure 2 It is a HE staining picture (200X) showing the effect of the compound of formula I in Example 3 on the pathological changes of the kidneys in mice induced by adenine diet;

[0046] Figure 3 It is a statistical chart of HE staining scores showing the effect of the compound of formula I in Example 3 on the pathological changes of the kidneys in mice induced by adenine diet;

[0047] Figure 4 It is a Masson staining picture (200X) showing the effect of the compound of formula I in Example 3 on the content of collagen fibers in the kidneys of mice induced by adenine diet;

[0048] Figure 5 It is a statistical chart of Masson staining scores showing the effect of the compound of formula I in Example 3 on the content of collagen fibers in the kidneys of mice induced by adenine diet;

[0049] Figure 6 It is a Sirius red staining (200X) picture showing the effect of the compound of formula I in Example 3 on the content of collagen fibers in the kidneys of mice induced by adenine diet;

[0050] Figure 7 It is a statistical chart of Sirius red staining scores showing the effect of the compound of formula I in Example 3 on the content of collagen fibers in the kidneys of mice induced by adenine diet;

[0051] Reference Signs:

[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 Embodiments

[0053] The following embodiments are used to further describe the present disclosure, but these embodiments do not limit the scope of the present disclosure.

[0054] Example 1 Activity Test of Compound of Formula I on URAT1 Target

[0055] Test method: First, seed the prepared HEK293T cells into 96-well plates. When the cells reach 70 - 90% confluence, transfer the mixture of transfection reagent Lipofectamine 3000 and URAT1 recombinant plasmid (100 ng / well) to the 96-well plate, and place it in an incubator at 37 °C with 5% CO 2 for 24 h. Use an inverted fluorescence microscope to observe the expression of green fluorescent protein EGFP to verify whether the transfection is successful. After success, remove the culture medium in the plate and wash the cells twice with phosphate buffer (PBS). Aspirate and discard the remaining waste liquid in the wells, and add 50 μl of solutions containing various specific concentrations of the compound of formula I or lesinurad (40 μM, 20 μM, 10 μM, 5 μM, 2.5 μM) to each well, without adding the compound of formula I or lesinurad to the blank group and the model group. After incubating for 30 minutes, add 50 μM [14C]-uric acid solution (diluted with the prepared buffer) to act for 15 minutes. Add PBS to terminate the experiment and wash the cells three times. Subsequently, add 40 μL of 0.1 M NaOH aqueous solution to each well and act for 30 min. After the cells are completely lysed, add 0.2 mL of scintillation fluid to each well, place it on a shaking plate and shake at 260 rpm / min for 15 min. Use a Micro Beta2 liquid scintillation detector to measure the radioactivity value (CPM) of the intracellular fluid. All tests are repeated three times and the average value is taken.

[0056] Experimental results: Under the conditions of this test, the results show that both lesinurad and the compound of formula I have inhibitory activity on URAT1. Among them, the IC 50 of the lesinurad test sample is 6.03 ± 1.06 μM, and the IC 50 of the compound of formula I test sample is 10.91 ± 1.23 μM, showing 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, at a concentration of 10 μm of the compound of formula I, the inhibition rate on GLUT9 is 21.45%, slightly lower than 30.12% of the positive control drug (benzbromarone), indicating that the compound of formula I also has inhibitory activity on GLUT9.

[0058] Example 2 Effect Test of Compound of Formula I on a Rat Model of Hyperuricemia Induced by Potassium Oxonate in Rats

[0059] Experimental method: Fifty-six SPF-grade male SD rats with qualified quarantine were randomly divided into 7 groups according to body weight, namely normal control group, model control group, febuxostat group (2 mg / kg, and the febuxostat pharmacodynamic application data showed that 1 mg / kg could significantly reduce the serum uric acid level in hyperuricemic mice induced by potassium oxonate), and groups 1, 2, 3, and 4 of Compound I (6.3 mg / kg, 12.5 mg / kg, 25 mg / kg, 50 mg / kg), with 8 animals in each group. The animals were fasted for more than 12 h with free access to water before drug administration. A hyperuricemia model was replicated by a single intraperitoneal injection of 300 mg / kg potassium oxonate (OAPS) at 10 mL / kg. The normal control group was given an equal volume of 0.9% sodium chloride injection, and the drugs were administered immediately after modeling. The animals in each group were orally gavaged with the corresponding concentration of the medicinal solution at 10 mL / kg. The normal control group and the model control group were gavaged with an equal volume of pure water, and the drugs were administered once a day. Jugular vein blood was collected before modeling and at 2 h, 3 h, 4 h, 5 h, 6 h, and 8 h after modeling, and the serum uric acid level was detected using an automatic biochemical analyzer.

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

[0061] Table 1 Effects of Compound I on the serum uric acid level in the rat model of hyperuricemia induced by potassium oxonate ( 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] Effect of the Compound of Formula I on Blood Uric Acid in Mice with Adenine Diet-Induced Chronic Hyperuricemia in Example 3

[0066] Male C57-BL6 mice at 8 weeks of age were housed in the SPF-class animal room of the Animal Experiment Department, with a light mode of 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 (TROPHIC, LAD 3001, Nantong, Jiangsu), and the other five groups were fed with feed containing 0.2% adenine (TROPHIC, TP 1S002, Nantong, Jiangsu) to establish a renal fibrosis model. The four treatment groups were given intragastric administration of the corresponding concentration of the Compound of Formula I and 10 mg / kg / d of dapagliflozin while being fed with 0.2% adenine feed, and the normal control group and the 0.2% adenine diet group were given intragastric administration of an equal volume of pure water, once a day. On the 21st day of the experiment, the mice in each group were euthanized, blood was collected to measure the uric acid level, and kidney tissues were collected for HE staining, Masson staining, and Sirius red staining.

[0067] 1. Blood Uric Acid Level

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

[0069] Figure 1 * indicates P < 0.05 when comparing the normal diet group with the 0.2% adenine diet group; # indicates P < 0.05 when comparing the treatment group with the 0.2% adenine diet group.

[0070] 2. HE Staining

[0071] Figure 2It was shown that compared with the normal diet group, the mice in the 0.2% adenine diet group had obvious inflammatory cell infiltration, renal tubular dilation and atrophy in the kidneys, and the pathological scores of HE staining were all significantly increased; compared with the 0.2% adenine diet group, the inflammatory cell infiltration, renal tubular dilation and atrophy in the kidneys of the mice in the 0.2% adenine diet + Compound I (50 mg / kg) group and the 0.2% adenine diet + Compound I (100 mg / kg) group were alleviated. Figure 3 And Table 2 showed that the pathological scores of the renal tissues of the mice in the 0.2% adenine diet + Compound I (50 mg / kg) group and the 0.2% adenine diet + Compound I (100 mg / kg) group were statistically significant compared with the 0.2% adenine diet group, and the improvement effect of 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 And in Table 2, *** indicates P < 0.001 when comparing the normal diet group with the 0.2% adenine diet group; indicates P < 0.001 when comparing the treatment group with the 0.2% adenine diet group; @ indicates P < 0.05 when comparing the treatment group with the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0075] 3. Masson staining

[0076] Figure 4 It was shown that compared with the normal diet group, obvious collagen deposition occurred in the renal interstitium of the mice in the 0.2% adenine diet group; compared with the 0.2% adenine diet group, the collagen deposition area in the renal interstitium of the mice in the 0.2% adenine diet + Compound I (50, 100 mg / kg) treatment group decreased, and the treatment effect was most obvious in the 0.2% adenine diet + Compound I (100 mg / kg) group of mice. Figure 5 And Table 3 showed that the collagen areas in the renal interstitium of the mice in the 0.2% adenine diet + Compound I (50 and 100 mg / kg) groups were statistically significant compared with the 0.2% adenine diet group, and the improvement effect of the collagen deposition in the renal interstitium of the mice in the 0.2% adenine diet + Compound I (100 mg / kg) group was better than that of the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

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

[0078]

[0079]

[0080] Figure 5 In Table 3, *** indicates P < 0.001 when comparing the normal diet group with the 0.2% adenine diet group; # indicates P < 0.05 when comparing the treatment group with the 0.2% adenine diet group; ## indicates P < 0.01 when comparing the treatment group with the 0.2% adenine diet group; indicates P < 0.001 when comparing the treatment group with the 0.2% adenine diet group; @ indicates P < 0.05 when comparing the treatment group with the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0081] 4. Sirius red staining

[0082] Figure 6 The results showed that compared with the normal diet group, significant collagen deposition occurred in the renal interstitium of mice in the 0.2% adenine diet group; compared with the 0.2% adenine diet group, the area of collagen deposition (the red area) in the renal interstitium of mice in the 0.2% adenine diet + Compound I (50, 100 mg / kg) group decreased, and the treatment effect of 0.2% adenine diet + Compound I (100 mg / kg) was the most obvious. Figure 7 Table 4 and the results showed that the renal interstitial collagen area of mice in the 0.2% adenine diet + Compound I (50 and 100 mg / kg) group was statistically significant compared with that in the 0.2% adenine diet group, and the improvement effect of renal interstitial collagen deposition in the 0.2% adenine diet + Compound I (100 mg / kg) group was better than that in the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

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

[0084]

[0085] Figure 7 In Table 4, *** indicates P < 0.001 when comparing the normal diet group with the 0.2% adenine diet group; indicates P < 0.001 when comparing the treatment group with the 0.2% adenine diet group; @@@ indicates P < 0.001 when comparing the treatment group with the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

Claims

1. Use of a 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof in the preparation of a uric acid-lowering drug, wherein the 2,4-disubstituted-5-fluoropyrimidine derivative has the following structure: in, R3 is selected from: R4 is selected from: X and Y are independently selected from nitrogen atoms or carbon atoms; Z is selected from hydrogen atom, tert-butyloxycarbonyl, C1-C5 alkyl, C1-C5 alkylacyl, C1-C3 alkylhydroxyl, C1-C3 alkylsulfonyl, C1-C3 substituted phenyl, C1-C5 alkylamide.

2. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a uric acid-lowering drug, characterized in that: When the 2,4-disubstituted-5-fluoropyrimidine derivative is a compound of formula II, R4 is When Z is not tert-butyloxycarbonyl.

3. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a uric acid-lowering drug, characterized in that: When the 2,4-disubstituted-5-fluoropyrimidine derivative is a compound of formula III, R4 is When Z is not tert-butyloxycarbonyl, C4-C5 alkyl, C4-C5 alkylacyl, or C4-C5 alkylamide.

4. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a uric acid-lowering drug, characterized in that: The C1-C5 alkyl group in the 2,4-disubstituted-5-fluoropyrimidine derivatives includes methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopentyl and isopropyl.

5. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a uric acid-lowering drug, characterized in that: The C1-C5 alkyl acyl group in the 2,4-disubstituted-5-fluoropyrimidine derivatives includes formyl, acetyl, propionyl, butyryl, valeryl, 3,3-dimethyl-1-butyryl, and isovaleryl.

6. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a uric acid-lowering drug, characterized in that: The C1-C5 alkylamide groups in the 2,4-disubstituted-5-fluoropyrimidine derivatives include formamide, acetamide, propionamide, butyramide, valeramide, N-tert-butylcarbamoyl, and isovaleramide.

7. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a uric acid-lowering drug, characterized in that: 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; 1-(5-Fluoro-4-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine; 1-(4-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine; 1-(5-Fluoro-4-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine; 1-(5-Fluoro-4-((4-(4-isopentylpiperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine; 1-(5-Fluoro-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine.

8. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the preparation of a uric acid-lowering drug, characterized in that: The drug is used to inhibit uric acid transporter 1.

9. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the preparation of a uric acid-lowering drug, characterized in that: The drug is used to inhibit glucose transporter 9.

10. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the preparation of a uric acid-lowering drug, characterized in that: The medicine is used for preventing or treating hyperuricemia, gout, gouty arthritis, and kidney disorders associated with hyperuricemia.

11. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 in the preparation of a uric acid-lowering drug, characterized in that: The dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is 5-100 mg / day.

12. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 11 in the preparation of a uric acid-lowering drug, characterized in that: The dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is 10-80 mg / day.

13. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 12 in the preparation of a uric acid-lowering drug, characterized in that: The dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is 20-70 mg / day.

14. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 13 in the preparation of a uric acid-lowering drug, characterized in that: The dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is 30-60 mg / day.

15. Use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 in the preparation of a uric acid-lowering drug, characterized in that: The medicine can be prepared into tablets, capsules, granules, powders, oral liquids, injections and external preparations.

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