TRPV1 / URAT1 dual inhibitor containing naphthalene ring and 2, 2-difluorobenzodioxole structure and application of TRPV1 / URAT1 dual inhibitor

Abstract

The invention relates to a TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2, 2-difluorobenzodioxole structure and an application of the TRPV1 / URAT1 dual inhibitor. The invention relates to a TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2, 2-difluorobenzodioxole structure, and the structural formula of the TRPV1 / URAT1 dual inhibitor is as follows: # imgabs0 #. The compound is unique and novel in structure, a preparation method of the compound is researched and provided, the compound has high inhibitory activity as a TRPV1 / URAT1 dual inhibitor, IC50 to TRPV1 is smaller than or equal to 100 nM, IC50 to URAT1 is smaller than or equal to 1 mu M, and inhibitory activity IC50 to an hERG channel is larger than 30 mu M; the traditional Chinese medicine composition has an excellent treatment effect on hyperuricemia, gout, inflammatory pain and the like, also has a better analgesic effect, and can be used as an analgesic medicine, a medicine for treating gout or hyperuricemia and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and in particular relates to a TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure, and its application in preparing analgesics, drugs for treating gout or hyperuricemia, and the like. Background Art

[0002] Gout is a common metabolic disease caused by chronically elevated uric acid levels (≥ 0.42 mmol / L). It typically presents with joint deformities and painful arthritis. In severe cases, it can lead to damage to vital organs, causing significant suffering for patients. With improvements in living standards, changes in diet, and unhealthy lifestyle habits, the incidence of gout has continued to rise, with the disease becoming increasingly prevalent among younger patients. The pathogenesis of gout is complex, primarily due to excessive uric acid production and / or decreased uric acid excretion, leading to increased blood uric acid levels and the formation of uric acid crystals (urate stones) in the joints, which in turn triggers inflammatory and painful reactions.

[0003] First-line treatment for gout primarily involves lowering serum uric acid levels with xanthine oxidase inhibitors or urate transporter 1 (URAT1) inhibitors, combined with nonsteroidal anti-inflammatory drugs, colchicine, or short-term oral glucocorticoids to achieve anti-inflammatory and analgesic effects. Representative xanthine oxidase inhibitors include febuxostat and allopurinol, while URAT1 inhibitors include benzbromarone and lecithin. However, existing therapeutic agents have limited efficacy and are associated with potential adverse reactions such as drug interactions and hepatotoxicity. Promoting the dissolution of urate stones by continuously lowering serum uric acid levels and reducing acute gout attacks by controlling inflammatory pain responses are two major unmet clinical needs in this field. Therefore, the development of new anti-gout drugs with dual uric acid-lowering and analgesic effects has important clinical significance and broad application prospects.

[0004] URAT1 mediates over 90% of uric acid reabsorption in the proximal renal tubules through an ion exchange mechanism on the apical membrane of the proximal renal tubule. When URAT1 function is abnormal, uric acid excretion in the body is reduced, blood uric acid levels are elevated, and hyperuricemia and related diseases such as gout are triggered. Given the important role of URAT1 in uric acid excretion, URAT1 inhibitors have become a hot topic in the development of uric acid-lowering drugs. Currently available URAT1 inhibitors include probenecid, sulfinpyrazone, benzbromarone, lecithinide, and decitonide. However, these drugs still have various defects. For example, benzbromarone can easily induce serious adverse reactions such as fulminant hepatitis due to its inhibition of CYP2C9 activity; decitonide has been issued a black box warning by the FDA due to its side effect of acute renal failure.

[0005] TRPV1 is a subfamily of transient receptor potential cation channels that play an important role in the body's perception of temperature and pain. Upon activation, TRPV1 triggers an influx of calcium ions, leading to the release of substances like substance P and calcitonin gene-related peptide from nerve endings, thus inducing pain. Downregulating TRPV1 expression or using TRPV1 antagonists can effectively block TRPV1 activation, inhibit the transmission of pain signals, and relieve pain caused by various inflammatory conditions and injuries. The development of TRPV1 antagonists has become one of the most promising analgesic research directions. Currently, no TRPV1 inhibitors are marketed, but several are in Phase II / III clinical trials for the treatment of toothache, post-herpetic pain, and osteoarthritis pain.

[0006] Therefore, it is of great significance to research and develop a new type of TRPV1 / URAT1 dual inhibitor drug. Summary of the Invention

[0007] The purpose of the present invention is to overcome the defects of the prior art and provide a TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure. As a TRPV1 / URAT1 dual inhibitor, the inhibitory activity is strong and the inhibitory activity is strong. The inhibitory activity has excellent therapeutic effects on the treatment of gout or hyperuricemia, as well as analgesia.

[0008] The present invention also provides the use of the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure in the preparation of analgesics, drugs for treating gout or hyperuricemia, and the like.

[0009] To achieve the above object, the present invention adopts the following technical solutions: A TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure, the specific structural formula of which is shown below: .

[0010] The present invention provides a method for preparing the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure, and the synthesis route is as follows: ; The specific steps include: 1) Dissolve 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde compound II-1 in anhydrous dichloromethane, add compound II-2 and sodium triacetoxyborohydride, react at room temperature for 2-4 hours, quench the reaction with water, remove the solvent under reduced pressure, adjust the pH to 8-9, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry, filter, remove the solvent from the filtrate under reduced pressure, and separate and purify the residue by column chromatography to obtain compound II-3; 2) Compound II-3 was dissolved in anhydrous dichloromethane, ice-bathed for 15-30 minutes, and then a dichloromethane solution of trifluoroacetic acid was added dropwise. The mixture was reacted at room temperature for 2-4 hours, and the solvent was evaporated under reduced pressure. The mixture was diluted with water and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain compound II-4. 3) Compound II-4 was dissolved in anhydrous dichloromethane, and a solution of compound II-5 in anhydrous dichloromethane was added dropwise under ice bath. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to obtain the target compound C2.

[0011] Specifically, in step 1), the molar ratio of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde compound II-1, compound II-2, and sodium triacetoxyborohydride can be 1:1:2-4.

[0012] Furthermore, in step 3), the molar ratio of compound II-4 to compound II-5 can be 1:1-2.

[0013] The present invention provides the use of the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure in the preparation of analgesics, especially drugs for treating inflammatory pain.

[0014] The present invention also provides the use of the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure in the preparation of drugs for treating gout or hyperuricemia.

[0015] The present invention also provides a pharmaceutical composition comprising the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure. Furthermore, the pharmaceutical composition also includes a pharmaceutically acceptable carrier and adjuvant. The adjuvant includes, but is not limited to, a diluent or excipient.

[0016] The present invention also provides the use of the above-mentioned pharmaceutical composition in preparing analgesics, drugs for treating gout or hyperuricemia, etc.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The TRPV1 / URAT1 dual inhibitor compound containing a naphthalene ring and a 2,2-difluorobenzodioxole structure of the present invention has a unique and novel structure, and a preparation method thereof is provided. The synthesis process is simple and easy to operate, the raw materials are cheap and readily available, and it is suitable for large-scale production; as a TRPV1 / URAT1 dual inhibitor, it has strong inhibitory activity and an IC of 0. 50 ≤100 nM, IC for URAT1 50≤1 μM, IC inhibitory activity on hERG channels 50 >30 μM; It has excellent therapeutic effects on hyperuricemia, gout and inflammatory pain, and also has good analgesic effects. It can be used as an analgesic drug, a drug for treating gout or hyperuricemia, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Figure 2 shows the analgesic and uric acid-lowering effects of compound C2 in mice. (A) Compound C2 inhibits formalin-induced phase I inflammatory pain; (B) Compound C2 inhibits formalin-induced phase II inflammatory pain; (C) Blood uric acid concentration in mice after compound C2 treatment. All values ​​are expressed as mean ± SEM (n = 6 per group). *p ≤ 0.05 and **p ≤ 0.01 were compared with model mice using one-way ANOVA, followed by Tukey's multiple post hoc comparison test. DETAILED DESCRIPTION

[0019] The technical solution of the present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.

[0020] In the following examples, unless otherwise specified, the raw materials used are common commercial products that can be purchased directly or can be prepared by conventional methods in the art.

[0021] Room temperature refers to 25 ± 5 °C.

[0022] Example 1 The synthetic route and process of 4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-N-(naphthalen-1-yl)piperazine-1-carboxamide (Compound C2) are shown below.

[0023] .

[0024] 1) 2,2-Difluoro-1,3-benzodioxole-5-carboxaldehyde (Compound II-1, 0.2 g, 1.07 mmol) was dissolved in 20 ml of anhydrous dichloromethane, and 1-boc-piperazine (Compound II-2, 0.21 g, 1.07 mmol) and sodium triacetoxyborohydride (0.68 g, 3.21 mmol) were added. After reacting at room temperature for 3 hours, the reaction was quenched by adding 10 ml of water. The solvent was evaporated under reduced pressure, and the pH was adjusted to 8-9 with saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (20 ml × 3). The organic phases were combined, washed with saturated brine (15 ml × 2), dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure from the filtrate. The residue was separated and purified by column chromatography (eluent, petroleum ether / ethyl acetate = 4:1, v / v) to obtain 0.29 g of Compound II-3 with a yield of 74%.

[0025] 2) Compound II-3 (0.29 g, 0.79 mmol) was dissolved in 20 ml of anhydrous dichloromethane. After an ice bath for 20 minutes, 10 ml of a prepared solution of trifluoroacetic acid in dichloromethane (dichloromethane / trifluoroacetic acid = 1:1, v / v) was slowly added dropwise to the reaction system in a constant pressure dropping funnel. After complete addition, the reaction was allowed to react at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the mixture was diluted with water, adjusted to pH 8-9 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (20 ml x 3). The organic phases were combined, washed with saturated brine (15 ml x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to remove the solvent, yielding 0.17 g of compound II-4 in 85% yield.

[0026] 3) Compound II-4 (0.17 g, 0.63 mmol) was dissolved in 15 ml of anhydrous dichloromethane. A solution of naphthalene isocyanate (Compound II-5, 0.1 g, 0.65 mmol) in anhydrous dichloromethane was slowly added dropwise under ice-cooling. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 4:1, v / v) to obtain 0.18 g of a white solid, the target compound C2, with a melting point of 216-218°C and a yield of 67%. The chromatographic data are shown below.

[0027] 1 H NMR (400 MHz, DMSO- d 6) δ 8.60 (s, 1H), 7.90 (dd, J = 6.4, 3.3 Hz,2H), 7.73 (dd, J = 8.1, 1.3 Hz, 1H), 7.50 (dd, J= 6.4, 3.3 Hz, 2H), 7.48 – 7.43(m, 1H), 7.40 (dd, J = 7.3, 1.4 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.18 (dd, J =8.2, 1.6 Hz, 1H), 3.56 (s, 2H), 3.53 (t, J = 4.9 Hz, 4H), 2.44 (t, J = 5.0 Hz,4H). 13 C NMR (101 MHz, DMSO- d 6) δ 156.60, 143.30, 142.20, 135.98, 135.59,134.21, 131.66, 129.93, 128.35, 126.20,125.97, 125.87, 125.33, 125.15,123.97, 123.32, 110.84, 110.09, 61.69, 52.86, 44.40. ESI-HRMS m / z calcd forC 23 H 21 F2N3O3, 425.1551; [M+H] + found 426.1566.

[0028] The TRPV1 and URAT1 inhibitory activities, as well as the analgesic and uric acid-lowering activities of the target compound C2 of the present invention, can be determined using the assay system described below. The specific experimental conditions in the test examples of the present invention generally follow conventional conditions or those recommended by the product manufacturer. Reagents without specific sources are commonly commercially available reagents.

[0029] Test Example 1 The target compound C2 of the present invention has inhibitory activity against hTRPV1-HEK293 (Htrpv1-HEK-293) stably transfected cells.

[0030] The present invention uses the following method to determine the hTRPV1 inhibitory activity of compound C2.

[0031] HEK293 cells stably expressing hTRPV1 were cultured at 2.5 × 10 4Cells were seeded at a density of 100 μg / well onto a 96-well plate and cultured overnight in a 37°C, 5% CO2 incubator in DMEM supplemented with 10% fetal bovine serum (FBS). Fluo-3AM, a fluorescent calcium probe, was loaded at room temperature. First, a 2 mM stock solution of Fluo-3AM in DMSO was prepared. 16.5 mg of Pluronic F127 was added to the Fluo-3AM / DMSO stock solution to prevent Fluo-3AM aggregation in HBSS (Hank's Balanced Salt Solution) and facilitate its entry into the cells. The Fluo-3AM solution was then diluted with HBSS to prepare a 5 μM working solution. 10 μL of this working solution was added to each well of the plate and incubated at 37°C for 30 minutes. Then, 50 μL of HBSS supplemented with 1% fetal bovine serum was added to each well and incubated for a further 40 minutes. The cells were washed four times with Tyrode's solution. 40 µL of samples of varying concentrations were added to each well, with triplicate wells set for each sample concentration. An equal amount of N-(4-(tert-butyl)phenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC) was added to the positive control, and Tyrode's solution was added to the negative control. After incubation at 37°C for 30 minutes, capsaicin (50 nM) was administered. The absorbance at λex = 488 nm and λex = 540 nm was measured before and after capsaicin stimulation to characterize cytoplasmic calcium concentration. The inhibition rate was calculated as (blank group difference - experimental group difference) / blank group difference (difference = the difference in fluorescence before and after capsaicin administration). The results are shown in Table 1. The IC values ​​of each compound were determined. 50 According to the description classification, in Table 1; “+” indicates IC 50 The measured value is less than 100 μM and greater than or equal to 1 μM; “++” means IC 50 The measured value is less than 1 μM and greater than or equal to 100 nM; "+++" means IC 50 The measured value is less than 100 nM and greater than or equal to 1 nM.

[0032] Table 1 hTRPV1 receptor inhibitory activity It can be seen from Table 1 that the compound C2 of the present invention has a strong inhibitory activity against TRPV1, which is comparable to that of the positive control BCTC.

[0033] Test Example 2 The target compound C2 of the present invention has inhibitory activity on hURAT1 stably transfected cells.

[0034] The present invention uses the following method to determine the hURAT1 inhibitory activity of compound C2.

[0035] HEK-293T cells stably expressing hURAT1 were seeded into 96-well cell culture plates at a density of 7,000 cells / well in DMEM supplemented with 10% fetal bovine serum (FBS). After the cells adhered, they were washed once with 200 μL / well of 37°C PBS buffer. Each well was aspirated dry, and then 50 μL / well of the corresponding compound and 2.5 μCi / ml of 14 C-uric acid solution, using benzbromarone as a positive control. The culture plate was incubated in a 37°C incubator for 8 minutes, and 150 µL of 0°C PBS buffer was immediately added to each well to terminate the absorption. The cells were gently rinsed 3 times with PBS buffer, trying to avoid cell detachment. 50 µL of RIPA lysis buffer was added to each well and placed on a shaker at 900 rpm for 5 minutes. Finally, the microplate was sent to a MicroBeta2 (PerkinElmer) instrument to measure radioactivity. The data were analyzed and the IC of each compound was calculated using GraphPad Prism 5 software. 50 The results are shown in Table 2. The IC 50 According to the description classification, in Table 2: “+” indicates IC 50 The measured value is less than 100 μM and greater than or equal to 1 μM; “++” means IC 50 The measured value is less than 1 μM and greater than or equal to 100 nM; "+++" means IC 50 The measured value is less than 100 nM and greater than or equal to 1 nM.

[0036] Table 2 hURAT1 receptor inhibitory activity It can be seen from Table 2 that the compound C2 of the present invention has a strong inhibitory activity against URAT1, which is comparable to that of the positive control benzbromarone.

[0037] Test Example 3 Inhibitory activity of the target compound C2 of the present invention on hERG stably transfected cells The present invention uses the following method to determine the hERG inhibitory activity of compound C2.

[0038] HEK-293 cells stably expressing hERG were seeded at a density of 600 cells / well on a 24-well plate. Patch clamp analysis was performed after the cells had adhered well. The intracellular solution used was composed of 137 mM NaCl, 1 mM MgCl₂•6H₂O, 4 mM KCl, 2 mM CaCl₂•2H₂O, 10 mM D-glucose, and 10 mM HEPES, adjusted to pH 7.4 with NaOH. The extracellular solution used was composed of 20 mM KCl, 120 mM K-Aspartic Acid, 10 mM HEPES, 10 mM EGTA, and 5 mM Mg-ATP, adjusted to pH 7.2 with KOH. Electrophysiological data were acquired and stored on a computer using Patchmaster software and an EPC-10 amplifier. Remove the cell slide from the culture dish, add 20-30 ml of extracellular fluid, and place it in a bath on the stage of an inverted microscope. Use a P-1000 microelectrode to pull a glass micropipette. Fill the micropipette 1 / 3 full with intracellular fluid. Use a motorized micromanipulator (Scientifica-Double 1U) to bring the recording electrode into contact with the cell surface. Due to a sudden increase in electrode resistance, the current value represented by the seal test pulse displayed in the membrane test window decreases. Remove the positive pressure and apply a negative pressure of 0.5 cm H2O. Observe the seal resistance rise rapidly until it reaches a gigaohm seal. Once the seal resistance between the recording electrode and the cell membrane exceeds 1 GΩ, apply negative pressure to rupture the membrane, establishing whole-cell recording mode. Once the ruptured membrane stabilizes, compensate for the membrane capacitance (Cs) and series resistance (Rs). The clamping voltage was -80 mV. Depolarization to +40 mV was performed for 4000 ms, followed by repolarization to -50 mV for 4000 ms to elicit tail currents. Currents were recorded every 15 s. Raw data were extracted from PatchMaster software and analyzed and statistically analyzed using Graphpad Prism 9.0 software. The results are shown in Table 3.

[0039] Table 3. hERG IC of Compound C2 50 result As can be seen from Table 3, the inhibitory activity of compound C2 on hERG is IC 50 >30μM, indicating a low risk of cardiotoxicity and supporting further preclinical development.

[0040] Test Example 4 The in vivo analgesic activity of the target compound C2 of the present invention can be determined by using the following assay system: After adaptive feeding, 8-week-old clean-grade ICR mice were randomly divided into groups according to body weight, with 6 mice in each group. Before the experiment began, the mice were gavage-administered with the compound of the present invention. The test group was given compound C2 of the present invention at a dose of 3 mg / kg, 10 mg / kg, or 20 mg / kg. The positive control group was given 20 mg / kg of BCTC, and the blank control group was given an equal volume of 0.5% sodium carboxymethylcellulose solution. One hour later, formalin solution was subcutaneously injected into the right hind toe, and the phase I (0-5 min) and phase II (15-45 min) reaction licking times were recorded. Results are shown in Figure 1 A and B.

[0041] Depend on Figure 1 It can be seen that when the compound C2 was administered at a dose of 20 mg / kg, the mice licked their paws for 1.2±0.2 min in phase I reaction and 3.8±0.4 min in phase II reaction, which had a significant analgesic effect and was superior to the positive control BCTC at the same dose.

[0042] Test Example 5 The in vivo uric acid-lowering activity of the target compound C2 of the present invention can be determined by the following test system: Eight-week-old clean-grade Kunming mice were used for adaptive feeding and randomly divided into groups according to body weight, with 6 mice in each group. The positive control group was given 20 mg / kg of benzbromarone, the experimental group was given compound C2 of the present invention at a dose of 3 mg / kg, 10 mg / kg or 20 mg / kg, and the blank control group was given an equal volume of 0.5% sodium carboxymethylcellulose solution. The acute hyperuricemia model was induced by oral administration of 450 mg / kg hypoxanthine and intraperitoneal injection of 300 mg / kg potassium oxonate. Four hours after induction of hyperuricemia, the blood uric acid (SUA) level was detected using uric acid test strips. The results are shown in Figure 2. Figure 1 Middle C.

[0043] Figure 1 It can be seen that the compound C2 of the present invention can significantly reduce the blood uric acid level (598.6±65.1μM, 355.7±43.5μM) at a dose of 10 mg / kg and 20 mg / kg, and the uric acid-lowering effect at a dose of 20 mg / kg is comparable to that of the positive control benzbromarone (378.6±52.4μM) at the same dose.

[0044] In summary, the compounds of the present invention have strong inhibitory activity as TRPV1 / URAT1 dual inhibitors, and their IC 50 ≤100 nM, IC for URAT1 50 ≤1 μM, IC inhibitory activity on hERG channels50 >30 μM; has good analgesic effect on formalin-induced inflammatory pain and can be used to prepare analgesic drugs; also has good uric acid-lowering activity in vivo and can be used to treat hyperuricemia.

[0045] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure, characterized in that: The structural formula is shown below: 。 2. The method for preparing the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure according to claim 1, characterized in that: The synthetic route is as follows: ； The specific steps include: 1) Dissolve 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde compound II-1 in anhydrous dichloromethane, add 1-boc-piperazine compound II-2 and sodium triacetoxyborohydride, react at room temperature for 2-4 hours, quench the reaction with water, remove the solvent under reduced pressure, adjust the pH to 8-9, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry, filter, remove the solvent from the filtrate under reduced pressure, and separate and purify the residue by column chromatography to obtain compound II-3; 2) Compound II-3 was dissolved in anhydrous dichloromethane, ice-bathed for 15-30 minutes, and then a dichloromethane solution of trifluoroacetic acid was added dropwise. The mixture was reacted at room temperature for 2-4 hours, and the solvent was evaporated under reduced pressure. The mixture was diluted with water and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain compound II-4. 3) Compound II-4 was dissolved in anhydrous dichloromethane, and a solution of naphthalene isocyanate (compound II-5 in anhydrous dichloromethane) was added dropwise under ice bath. The solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to obtain the target compound C2.

3. The method for preparing the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure according to claim 1, wherein: In step 1), the molar ratio of 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde compound II-1, compound II-2, and sodium triacetoxyborohydride is 1:1:2-4.

4. The method for preparing a TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure according to claim 1, wherein: In step 3), the molar ratio of compound II-4 to compound II-5 is 1:1-2.

5. Use of the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure according to claim 1 in the preparation of analgesic drugs.

6. Use of the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure according to claim 1 in the preparation of a drug for treating gout or hyperuricemia.

7. A pharmaceutical composition, characterized in that The invention comprises the TRPV1 / URAT1 dual inhibitor containing a naphthalene ring and a 2,2-difluorobenzodioxole structure as claimed in claim 1.

8. The pharmaceutical composition according to claim 7, wherein The pharmaceutical composition further comprises pharmaceutically acceptable carriers and adjuvants.

9. Use of the pharmaceutical composition according to claim 7 or 8 in the preparation of analgesics, or drugs for treating gout or hyperuricemia.

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