A class of TRPV1 antagonists, preparation methods thereof and applications thereof in the preparation of drugs for treating pain

Abstract

The present invention provides a class of TRPV1 antagonists or pharmaceutically acceptable salts thereof, and the general structural formula thereof is as follows: R1 and R2 are each independently selected from a benzene ring, an alkyl group, or a cycloalkyl group; X1 and X2 are each independently selected from O, S, NH, or SO2NH. The present invention also provides a preparation method of the antagonist and the use of a pharmaceutical composition containing the same as a medicament for treating pain. The compound has strong inhibitory activity against TRPV1 and excellent in vivo analgesic activity, and can be used for preparing a medicament for treating pain.

Description

Technical Field

[0001] The present invention belongs to the technical fields of medicinal chemistry and pharmacotherapeutics, and particularly relates to a class of TRPV1 antagonists, a preparation method thereof, a pharmaceutical composition containing such compounds as active ingredients, and their applications in the preparation of drugs for treating pain. Background Art

[0002] Pain is a common clinical symptom, and approximately 500 million people suffer from various pains every year. At present, the most commonly used analgesics clinically are mainly divided into two categories: one is narcotic analgesics that directly activate opioid receptors, and the other is antipyretic analgesics represented by non-steroidal anti-inflammatory drugs (NSAIDs). Although these drugs have good clinical effects, they also have obvious side effects, such as the addiction of opioid drugs and the gastrointestinal side effects of non-steroidal anti-inflammatory drugs. In addition, existing drugs cannot effectively control chronic and neuropathic pain.

[0003] In recent years, with the development of related disciplines and the application of new technologies, certain progress has been made in the research on various receptors related to pain conduction and their selective ligands. TRPV1 is highly expressed in primary sensory neurons and is a non-specific cation channel that can be activated by hydrogen ions (pH < 5.5), high temperature (> 42 °C), and other endogenous and exogenous ligands, and plays an important role in the body's perception of temperature and pain. After TRPV1 is activated, it causes calcium ion influx, leading to the release of substance P and calcitonin gene-related peptide from nerve endings, thereby triggering pain. Downregulating TRPV1 expression or using TRPV1 antagonists can effectively prevent TRPV1 activation, inhibit the conduction of pain signals from peripheral nerves to the central nervous system, and relieve pain caused by various nerve injuries. The research on TRPV1 antagonists has become one of the most promising research directions for analgesics currently. Summary of the Invention

[0004] The object of the present invention is to overcome the defects of the prior art and provide a class of TRPV1 antagonists, a preparation method thereof, a pharmaceutical composition containing such compounds as active ingredients, and their applications in the preparation of analgesic drugs or drugs for treating pain.

[0005] To achieve the above object, the present invention adopts the following technical solutions:

[0006] A class of TRPV1 antagonists or pharmaceutically acceptable salts thereof, the general structural formula of which is shown as the following formula (I):

[0007]

[0008] R1 and R2 are each independently selected from a benzene ring, an alkyl group, or a cycloalkyl group, etc.;

[0009] X1 and X2 are each independently selected from O, S, NH, SO2NH, etc.

[0010] Furthermore, the benzene ring, alkyl group, cycloalkyl group are optionally substituted by one or more groups selected from halogens.

[0011] More preferably, the TRPV1 antagonist or a pharmaceutically acceptable salt thereof is any one of the following compounds:

[0012] 2-(3-((4-(tert-Butyl)benzyl)oxy)benzylidene)-6-ethoxybenzofuran-3(2H)-one (I-1);

[0013] 6-Ethoxy-2-(3-((4-isopropylbenzyl)oxy)benzylidene)benzofuran-3(2H)-one (I-2);

[0014] 6-Ethoxy-2-(3-((4-(trifluoromethyl)benzyl)oxy)benzylidene)benzofuran-3(2H)-one (I-3);

[0015] 6-Ethoxy-2-(3-((2,4,6-trimethylbenzyl)oxy)benzylidene)benzofuran-3(2H)-one (I-4);

[0016] 2-(3-Ethoxybenzylidene)-6-((4-(trifluoromethyl)benzyl)oxy)benzofuran-3(2H)-one (I-5);

[0017] 6-((4-(tert-Butyl)benzyl)oxy)-2-(3-ethoxybenzylidene)benzofuran-3(2H)-one (I-6).

[0018] A pharmaceutical composition, which contains a therapeutically effective amount of the TRPV1 antagonist or a pharmaceutically acceptable salt thereof, and an appropriate amount of a carrier, diluent or excipient. The carrier, diluent or excipient can be obtained by using conventional techniques in the art.

[0019] The present invention provides the use of the above TRPV1 antagonist or a pharmaceutically acceptable salt thereof in the preparation of an analgesic drug or a drug for treating pain.

[0020] The present invention also provides the use of the above pharmaceutical composition in the preparation of an analgesic drug or a drug for treating pain.

[0021] Unless otherwise specified, the following terms used in the specification and claims have the following meanings.

[0022] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups having 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, an alkyl group having 1 to 6 carbon atoms is more preferred, an alkyl group having 1 to 3 carbon atoms is still more preferred, and methyl is most preferred. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and various branched isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available linking point, and is preferably substituted by one or more of the following groups independently selected from halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, and heteroaryl groups.

[0023] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably the cycloalkyl ring contains 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.

[0024] "Optional" or "optionally" means that the subsequently described event or circumstance may but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but does not have to be present, and this description includes the cases where the heterocyclic group is substituted by an alkyl group and the cases where the heterocyclic group is not substituted by an alkyl group.

[0025] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what is possible or impossible substitution without undue effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0026] "Pharmaceutical composition" means a mixture containing one or more compounds described in the present invention or their pharmaceutically acceptable salts, or their prodrugs and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the absorption of the active ingredient by the organism and to facilitate the active ingredient to exert its biological activity in the organism.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] The present invention discovers a new type of TRPV1 antagonist and studies and provides a preparation method thereof. The synthesis process is simple and easy to operate, the raw materials are inexpensive and easily available, and it is suitable for large-scale production. The present invention also provides a pharmaceutical composition containing such compounds as active ingredients, as well as their applications in the preparation of analgesic drugs or drugs for treating pain. Experimental verification shows that the TRPV1 antagonist of the present invention has good analgesic effects and can be used as an analgesic drug or a drug for treating pain. Detailed implementation manners

[0029] The following further details the technical solutions of the present invention in conjunction with embodiments, but the protection scope of the present invention is not limited thereto.

[0030] In the following embodiments, unless otherwise specified, the raw materials used are all ordinary commercially available products that can be directly purchased or can be prepared by conventional methods in the art. Room temperature refers to 25±5°C.

[0031] Example 1 (E)-6-Ethoxy-2-(3-hydroxybenzylidene)benzofuran-3(2H)-one

[0032]

[0033] First step: 6-Hydroxybenzofuranone (0.2 g, 1.33 mmol) of raw material II-1 is dissolved in 20 ml of acetonitrile, bromoethane (0.173 g, 1.60 mmol), anhydrous potassium carbonate (0.46 g, 3.325 mmol), and 0.1 g of catalytic amount of KI are added, and the mixture is heated to 60°C and reacted for 8 h. After filtration, the solvent is removed under reduced pressure to obtain 0.24 g of a yellow oil II-2, which is directly used in the next step without purification.

[0034] Second step: The compound II-2 obtained in the previous step is dissolved in 20 ml of methanol, 3-Hydroxybenzaldehyde (0.178 g, 1.463 mmol) of II-3 and sodium methoxide (0.18 g, 3.325 mmol) are added, and the reaction is carried out at room temperature for 6 h. The solvent is removed under reduced pressure, the residue is dissolved in 30 ml of water, acetic acid is added to adjust the pH to acidic (pH = 2-3), and extraction is carried out with ethyl acetate (20 ml×3). The organic phases are combined, washed with saturated brine (15 ml×2), dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate is removed under reduced pressure. The residue is purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to obtain 0.26 g of a white solid II-4, with a melting point of 163-165°C and a yield of 65%.

[0035] Example 2 2-(3-((4-(tert-Butyl)benzyl)oxy)benzylidene)-6-ethoxybenzofuran-3(2H)-one (I-1)

[0036]

[0037] Step 1: p-tert-Butylbenzaldehyde (0.2 g, 1.23 mmol), the raw material III-1, was dissolved in 20 ml of a mixed solvent (tetrahydrofuran / methanol, 1:1, v / v). Sodium borohydride (0.085 g, 2.26 mmol) was slowly added under an ice bath, and the reaction was carried out for half an hour under the ice bath. After the reaction, 20 ml of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated NaCl solution (20 ml × 2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure from the filtrate. It was directly used for the next reaction without purification.

[0038] Step 2: The compound obtained in the previous step was dissolved in 20 ml of dichloromethane, 0.5 ml of thionyl chloride was slowly added dropwise, 50 μl of DMF was added, and the reaction was carried out at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure to obtain a pale yellow oil III-2 (0.21 g, 1.23 mmol). The compound III-2 obtained in the previous step was dissolved in 20 ml of acetonitrile, II-4 (0.416 g, 1.48 mmol), anhydrous potassium carbonate (0.425 g, 3.075 mmol), and 0.1 g of catalytic amount of KI were added, and the reaction was heated to 60 °C for 8 h. After the reaction, it was filtered, and the solvent was removed under reduced pressure to obtain 0.44 g of a yellow oil. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to obtain 0.31 g of a white solid I-1 with a yield of 58.8%. The spectral data are as follows.

[0039] 1 H NMR (400 MHz, Chloroform-d) δ 7.71–7.56 (m, 1H), 7.49 (t, J = 2.0 Hz, 1H), 7.42–7.23 (m, 6H), 6.93 (dd, J = 8.2, 2.5 Hz, 1H), 6.75–6.58 (m, 3H), 5.01 (s, 2H), 4.06 (q, J = 7.0 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.26 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 183.02, 168.63, 166.91, 159.10, 151.25, 147.98, 133.70, 129.79, 127.66, 125.82, 124.29, 117.28, 116.15, 114.59, 112.67, 111.67, 97.02, 70.02, 64.56, 34.65, 31.37, 29.69, 14.58. ESI-MS m / z: 429.5 [M + H] + ; Calculated value for elemental analysis: For C 28 H 28O4: C, 78.48; H, 6.59; Measured value: C, 78.47; H, 6.61.

[0040] Example 3 6-Ethoxy-2-(3-((4-isopropylbenzyl)oxy)benzylidene)benzofuran-3(2H)-one (I-2)

[0041]

[0042] The synthesis method refers to Example 2, with the difference that: the starting material III-1 was replaced with p-isopropylbenzaldehyde, to obtain 0.28 g of a white solid, melting point 165-167 °C, yield 70%. The spectral data is as follows.

[0043] 1 H NMR (400 MHz, Chloroform-d) δ 7.64–7.56 (m, 1H), 7.34 (dd, J = 13.3, 8.0 Hz, 3H), 7.27 (t, J = 8.0 Hz, 1H), 7.22–7.15 (m, 3H), 6.97–6.90 (m, 1H), 6.69 (s, 1H), 6.67–6.62 (m, 2H), 5.00 (s, 2H), 4.06 (q, J = 7.0 Hz, 2H), 2.85 (hept, J = 6.9 Hz, 1H), 1.40 (d, J = 7.0 Hz, 3H), 1.19 (d, J = 7.0 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 183.02, 168.63, 166.91, 159.09, 148.99, 148.01, 133.70, 129.79, 127.93, 126.78, 125.89, 124.30, 117.27, 116.23, 114.58, 112.74, 111.66, 97.00, 70.11, 68.57, 64.56, 33.95, 29.69, 24.03, 14.58. ESI-MS m / z: 415.5 [M+H] + ; Elemental analysis calculated values: For C 27 H 26 O4: C, 78.24; H, 6.32; Measured value: C, 78.26; H, 6.31.

[0044] Example 4 6-Ethoxy-2-(3-((4-(trifluoromethyl)benzyl)oxy)benzylidene)benzofuran-3(2H)-one (I-3)

[0045]

[0046] The synthesis method was referred to Example 2, with the difference that: the starting material III-1 was replaced by p-trifluoromethylbenzaldehyde, obtaining 0.16 g of white solid, melting point 179 - 181 °C, and the yield was 63%. The spectral data are as follows.

[0047] 1 H NMR(400MHz,Chloroform-d)δ7.61–7.55(m,2H),7.51(d,J=8.1Hz,2H),7.48–7.32(m,2H),7.28(t,J=7.9Hz,1H),6.91(dd,J=8.2,2.6Hz,1H),6.73–6.53(m,3H),5.11(s,2H),4.06(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ182.95,168.60,166.96,158.58,148.04,140.90,133.87,130.40,128.13,127.49,125.86,125.67,124.65,122.72,117.16,116.12,114.53,112.65,111.33,97.02,69.25,64.57,29.73,14.56.ESI-MS m / z:441.4[M+H] + ; Calculated value of elemental analysis: For C 25 H 19 F3O4:C,68.18;H,4.35; Found:C,68.16;H,4.33.

[0048] Example 5 6-Ethoxy-2-(3-((2,4,6-trimethylbenzyl)oxy)benzylidene)benzofuran-3(2H)-one (I-4)

[0049]

[0050] The synthesis method was referred to Example 2, with the difference that: the starting material III-1 was replaced by 2,4,6-trimethylbenzaldehyde, obtaining 0.23 g of white solid, melting point 181 - 183 °C, and the yield was 68%. The spectral data are as follows.

[0051] 11H NMR (400 MHz, Chloroform-d) δ 7.64–7.53 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 8.1, 2.6 Hz, 1H), 6.86 (s, 2H), 6.78 (s, 1H), 6.71 (s, 1H), 6.65 (d, J = 8.3 Hz, 2H), 4.99 (s, 2H), 4.06 (q, J = 7.0 Hz, 2H), 2.31 (d, J = 1.9 Hz, 9H), 1.39 (t, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 183.06, 168.67, 166.93, 159.59, 159.01, 148.02, 138.58, 138.55, 138.13, 137.95, 137.71, 133.75, 129.80, 129.22, 128.86, 127.07, 125.82, 124.29, 118.02, 117.26, 115.75, 114.89, 112.78, 100.36, 96.97, 68.99, 64.57, 59.20, 31.67, 29.74, 29.68, 21.10, 19.55, 19.50, 14.63. ESI-MS m / z: 415.5 [M+H] + ; Calculated for elemental analysis: For C 27 H 26 O4: C, 78.24; H, 6.32; Found: C, 78.25; H, 6.33.

[0052] Example 6 2-(3-Ethoxybenzylidene)-6-((4-(trifluoromethyl)benzyl)oxy)benzofuran-3(2H)-one (I-5)

[0053]

[0054] First step: p-Trifluoromethylbenzaldehyde (0.2 g, 1.14 mmol) was dissolved in 20 ml of a mixed solvent (tetrahydrofuran / methanol, 1:1, v / v). Sodium borohydride (0.086 g, 2.28 mmol) was slowly added under an ice bath. The reaction was carried out for half an hour under an ice bath. After the reaction was completed, 20 ml of water was added to quench the reaction. The mixture was extracted with ethyl acetate (30 ml × 3). The organic phases were combined, washed with saturated NaCl solution (20 ml × 2). The obtained organic phase was dried over anhydrous sodium sulfate, filtered by suction. The filtrate was evaporated under reduced pressure to remove the solvent and used directly in the next step without purification.

[0055] Step 2: The compound obtained in the previous step was dissolved in 20 ml of dichloromethane, 0.5 ml of thionyl chloride was slowly added dropwise, 50 μl of DMF was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain 0.259 g of a pale yellow oily substance IV-2. The compound IV-2 (0.259 g, 1.33 mmol) obtained in the previous step was dissolved in 20 ml of acetonitrile, II-1 (0.2 g, 1.33 mmol), anhydrous potassium carbonate (0.425 g, 3.075 mmol), and 0.1 g of catalytic amount of KI were added, and the reaction was heated to 60 °C for 8 h. After the reaction was completed, the mixture was filtered, the solvent was removed by distillation under reduced pressure to obtain 0.24 g of a yellow oily substance. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to obtain 0.372 g of a light yellow solid IV-3.

[0056] Step 3: The starting material II-3, 3-hydroxybenzaldehyde (0.178 g, 1.463 mmol), was dissolved in 20 ml of acetonitrile, bromoethane (0.190 g, 1.76 mmol), anhydrous potassium carbonate (0.46 g, 3.325 mmol), and 0.1 g of catalytic amount of KI were added, and the reaction was heated to 60 °C for 8 h. After filtration, the solvent was removed by distillation under reduced pressure to obtain 0.22 g of a yellow oily substance IV-4, which was used directly in the next step without purification.

[0057] Step 4: IV-3 (0.372 g, 1.207 mmol) obtained in Step 2 was dissolved in 20 ml of methanol, IV-4 (0.22 g, 1.463 mmol), sodium methoxide (0.130 g, 2.414 mmol) were added, and the reaction was carried out at room temperature for 6 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 30 ml of water, and acetic acid was added to adjust the pH to acidic (pH = 2 - 3). 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, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to obtain 0.36 g of a white solid I-5, with a melting point of 163 - 165 °C and a yield of 68%. The spectral data are as follows.

[0058] 1 H NMR (400 MHz, Chloroform-d) δ 7.63 (dd, J = 15.3, 8.5 Hz, 3H), 7.50 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 4.8, 2.4 Hz, 2H), 7.27 (t, J = 8.1 Hz, 1H), 6.86 (dd, J = 8.2, 2.5 Hz, 1H), 6.80–6.65 (m, 3H), 5.16 (s, 2H), 4.02 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 182.98, 168.37, 165.94, 159.12, 147.77, 139.56, 133.49, 130.80, 130.48, 129.79, 127.45, 126.06, 125.84, 124.00, 122.61, 117.14, 115.94, 112.58, 97.75, 69.78, 63.58, 14.86. ESI-MS m / z: 441.4 [M+H] + ; Calculated for C 25 H 19 F3O4: C, 68.18; H, 4.35; Found: C, 68.17; H, 4.33.

[0059] Example 7 6-((4-(tert-Butyl)benzyl)oxy)-2-(3-ethoxybenzylidene)benzofuran-3(2H)-one (I-6)

[0060]

[0061] The synthesis method was referred to Example 6, with the difference that: the starting material IV-1 was replaced by p-tert-butylbenzaldehyde, and 0.27 g of white solid was obtained, melting point 183 - 187 °C, yield 56%. The spectral data are as follows.

[0062] 1 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 4H), 7.35–7.22 (m, 3H), 6.85 (dd, J = 8.1, 2.2 Hz, 1H), 6.76 (d, J = 5.2 Hz, 1H), 6.70 (s, 1H), 5.06 (s, 2H), 4.02 (q, J = 6.8 Hz, 2H), 1.38 (t, J = 6.7 Hz, 3H), 1.26 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 183.08, 168.53, 166.66, 159.12, 151.67, 147.91, 133.61, 132.44, 129.78, 127.56, 125.90, 123.99, 117.04, 115.93, 114.94, 112.85, 111.95, 97.62, 70.71, 63.57, 34.69, 31.34, 14.88. ESI-MS m / z: 429.5 [M+H] + ; Calculated for C 28 H28 O4: C, 78.48; H, 6.59; Measured value: C, 78.47; H, 6.58.

[0063] Analgesic activity test

[0064] The TRPV1 inhibitory activity and in vivo analgesic activity of the compounds in the present invention can be determined by using the assay system described below. The following biological test examples describe and explain the present invention.

[0065] In the test examples of the present invention, the experimental methods for specific conditions are generally carried out under conventional conditions or according to the conditions recommended by the commercial manufacturers. Reagents without specific sources indicated are common reagents purchased from the market.

[0066] Test Example 1 Agonist activity of the compounds of the present invention against hTRPV1-HEK293 stable transfected cells

[0067] The present invention uses the following method to determine the hTRPV1 inhibitory activity of the compounds of the present invention:

[0068] hTRPV1-HEK293 stable transfected cells were seeded into a 96-well black plate at a density of 2.5×10 4 / well and cultured overnight in a cell incubator at 37°C and 5% CO2; at room temperature, the Fluo-3AM calcium ion fluorescent probe was loaded. First, a 2 mM DMSO stock solution of the calcium ion fluorescent probe Fluro-3AM was prepared. 16.5 mg of Pluronic F127 was added to the Fluo-3AM / DMSO solution to prevent the aggregation of Fluo-3AM in HBSS (Hank’s balanced salt solution) and to help it enter the cells. The Fluo-3AM solution was diluted with HBSS to prepare a 5 μM Fluo-3AM working solution. The above working solution was added to the cell plate, 10 μL per well, and cultured at 37°C for 30 minutes. 50 μL of HBSS containing 1% fetal bovine serum was added to each well and cultured for another 40 minutes. The cells were washed 4 times with Tyrode's solution. 40 μL of samples with different concentrations were added to each well, and 3 replicates were set for each sample concentration. The positive control group was added with an equal amount of N-(4-(tert-butyl)phenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC), and the negative control group was added with Tyrode's solution. After incubating at 37°C for 30 minutes, capsaicin stimulation (50 nM) was given, and then the absorbance values at λex = 488 nm and λex = 540 nm before and after capsaicin stimulation were detected to characterize the cytoplasmic calcium ion concentration. The results are shown in Table 1.

[0069] Inhibition rate = (difference in the blank group - difference in the experimental group) / difference in the blank group (difference = difference in fluorescence values before and after capsaicin administration)

[0070] Table 1: hTRPV1 Receptor Inhibitory Activity

[0071]

[0072] The chemical structures corresponding to the compound codes in Table 1 are the same as those in the examples.

[0073] The test results in Table 1 show that all compounds of the present invention have significant inhibitory activity against TRPV1 at different concentrations, and the inhibition rates are all greater than 50% at a concentration of 10 μM. Among them, compound I-6 has strong inhibitory activity, comparable to the positive control BCTC.

[0074] Test Example 2 The in vivo analgesic activity of the compounds of the present invention can be determined by using two mouse pain model measurement systems described as follows:

[0075] (1) Acetic acid-induced writhing test

[0076] Clean-grade Kunming mice at 10 weeks of age, weighing 22 - 25 g, male, were randomly grouped according to body weight, with 6 mice in each group. Before the test, the compounds of the present invention were administered by gavage at a dose of 30 mg / kg, and the blank control group was given an equal volume of 0.5% sodium carboxymethylcellulose solution. During the test, the mice were intraperitoneally injected with 0.6% acetic acid solution, and the number of writhing reactions (abdomen indented, hind limbs extended, hips elevated) of the mice within 15 minutes was recorded. The results are shown in Table 2.

[0077] (2) Formalin-induced pain model experiment

[0078] After the 8-week-old clean-grade ICR mice were adaptively fed, they were randomly grouped according to body weight, with 6 mice in each group. Before the experiment, the compounds of the present invention were administered by gavage to the mice. The dosing dose of the experimental group was 30 mg / kg, and the blank control group was given an equal volume of 0.5% sodium carboxymethylcellulose solution. 1 h later, a formalin solution was subcutaneously injected into the right hind paw toe, and the licking foot time of the I phase (0 - 5 min) and the II phase (15 - 45 min) reactions were recorded respectively.

[0079] Table 2: Effects of Some Compounds on Acetic Acid- and Formalin-Induced Writhing in Mice

[0080]

[0081]

[0082] Note: *P≤0.05 is the result of Student's t-test relative to the blank control group.

[0083] Table 2 Test results show that all compounds of the present invention can significantly inhibit the pain response induced by acetic acid. Among them, compound I-6 has the strongest analgesic activity, comparable to the positive control BCTC. In addition, compound I-6 can also significantly inhibit the inflammatory pain induced by formalin.

[0084] Example 8

[0085] Tablets containing the active ingredient I-6:

[0086]

[0087] The tablets can be prepared by conventional techniques in the art. For example, the active ingredient I-6, pregelatinized starch and microcrystalline cellulose are sieved, fully mixed, polyvinylpyrrolidone and an appropriate amount of ethanol are added, mixed to form a soft material, sieved to make wet granules, dried at 50-60 °C, and sodium carboxymethyl starch, magnesium stearate and talc are sieved and added to the above granules for tableting.

[0088] Verified by experiments, the above composition tablets also have good in vivo analgesic activity.

Claims

1. A class of TRPV1 antagonists or pharmaceutically acceptable salts thereof, characterized in that, The TRPV1 antagonist or a pharmaceutically acceptable salt thereof is any one of the following compounds: 2-(3-((4-(tert-Butyl)benzyl)oxy)benzylidene)-6-ethoxychromen-3(2 H )-one (I-1); 6-Ethoxy-2-(3-((4-isopropylbenzyl)oxy)benzylidene)benzofuran-3(2 H )-one (I-2); 6-Ethoxy-2-(3-((4-(trifluoromethyl)benzyl)oxy)benzylidene)benzofuran-3(2 H )-one (I-3); 6-Ethoxy-2-(3-((2,4,6-trimethylbenzyl)oxy)benzylidene)benzofuran-3(2 H )-one (I-4); 2-(3-Ethoxybenzylidene)-6-((4-(trifluoromethyl)benzyl)oxy)benzofuran-3(2 H )-one (I-5); 6-((4-(tert-Butyl)benzyl)oxy)-2-(3-ethoxybenzylidene)benzofuran-3(2 H )-one (I-6).

2. A pharmaceutical composition, characterized in that, Containing a therapeutically effective amount of the TRPV1 antagonist or a pharmaceutically acceptable salt thereof as claimed in claim 1, and an appropriate carrier or excipient.

3. Use of the TRPV1 antagonist or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of an analgesic drug.

4. Use of the pharmaceutical composition as claimed in claim 2 in the preparation of an analgesic drug.

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