Use of an isoflavone compound or a pharmaceutically acceptable salt thereof

Abstract

The present invention relates to the fields of medicinal chemistry and therapeutics, and particularly relates to an isoflavone compound or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof, a preparation method thereof, and uses thereof in the preparation of drugs for treating analgesia and hypoglycemia. The isoflavone compound in the isoflavone compound or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof is defined as Compound I. The isoflavone compound has obvious inhibitory activity against TRPV1, can significantly inhibit pain response, and also has an obvious hypoglycemic effect.

Description

Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and therapeutics, and particularly to an isoflavone compound or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof, a preparation method, and uses thereof in the preparation of drugs for treating analgesia and hypoglycemia. Background Art

[0002] 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 one of the members of the transient receptor potential non-selective cation channel protein family, mainly expressed on the nociceptors of primary afferent sensory neurons, and plays a very crucial role in the initiation of the neuroinflammatory response and the transduction process of pain. David Julius won the Nobel Prize in Physiology or Medicine in 2021 for discovering TRPV1 and revealing the mechanism of the body's perception of temperature and pain. TRPV1 antagonists can directly block the influx of calcium ions, inhibit the conduction of pain signals from peripheral nerves to the central nervous system, and block various pathological states associated with the receptor, thus achieving an analgesic effect. In addition, TRPV1 plays an important role in glucose metabolism and blood glucose control. The continuous activation of TRPV1 will increase the release of vasoactive neuropeptides and calcitonin gene-related peptides, thereby inhibiting insulin secretion and damaging insulin sensitivity. In recent years, a series of TRPV1 antagonists have successively entered clinical research, mainly used for treating toothache, osteoarthritis, and post-herpetic neuralgia, etc.

[0003] Diabetic neuropathic pain is a peripheral nerve microvascular lesion caused by hyperglycemia and its secondary metabolic abnormalities. Due to the complexity of its pathological mechanism, there is currently no drug on the market targeting its pathogenesis. Strengthening the blood glucose control of patients helps to target the source of its pathogenesis. The commonly used analgesic drugs in clinical practice are mainly opioid drugs and non-steroidal anti-inflammatory drugs (NSAIDs). Opioid drugs produce an analgesic effect by binding to opioid receptors. Such drugs have a rapid onset of action and can significantly relieve or eliminate pain. At the same time, such drugs are prone to drug resistance and addiction, and withdrawal symptoms are likely to occur after discontinuation. NSAIDs inhibit the biosynthesis of prostaglandins by inhibiting cyclooxygenase of arachidonic acid. Such drugs have good clinical efficacy and are not prone to tolerance and addiction. However, the gastrointestinal reactions, gastric ulcers, gastric bleeding, and allergic reactions caused by such drugs limit their clinical application.

[0004] Therefore, in view of the deficiencies of the prior art, it is very necessary to provide an isoflavone compound or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof, a preparation method, and uses thereof in the preparation of drugs for treating analgesia and hypoglycemia to solve the deficiencies of the prior art. Summary of the Invention

[0005] The first object of the present invention is to avoid the deficiencies of the prior art and provide an isoflavone compound or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof can inhibit the hTRPV1 receptor and thus produce a therapeutic effect on pain.

[0006] The above object of the present invention is achieved by the following technical measures:

[0007] Provide an isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof, and define the isoflavone compound as Compound I. The structure of Compound I is:

[0008]

[0009] Wherein ring A is an aryl or heteroaryl group;

[0010] R1 is hydrogen, halogen, alkyl, nitrile, alkoxy or cycloalkoxy, and at least one hydrogen of the alkoxy is substituted by halogen, and at least one hydrogen of the cycloalkoxy is substituted by halogen;

[0011] R2 is hydrogen, halogen, alkyl, nitrile, alkoxy or cycloalkoxy, and at least one hydrogen of the alkoxy is substituted by halogen, and at least one hydrogen of the cycloalkoxy is substituted by halogen;

[0012] R3 is hydrogen, halogen, alkyl, nitrile, alkoxy or cycloalkoxy, and at least one hydrogen of the alkoxy is substituted by halogen, and at least one hydrogen of the cycloalkoxy is substituted by halogen;

[0013] Preferably, the above ring A is a benzene ring or a thiazole ring.

[0014] Preferably, the above ring A is a benzene ring,

[0015] Preferably, the above R1 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile, methoxy.

[0016] Preferably, the above R2 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile, methoxy.

[0017] Preferably, the above R3 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile, methoxy.

[0018] Preferably, the above

[0019] The isoflavone compound is 3-(4-methoxyphenyl)-7-(4-trifluoromethyl)benzyloxy)-4H-chromen-4-one, and define 3-(4-methoxyphenyl)-7-(4-methyl)benzyloxy)-4H-chromen-4-one as Compound I-1. The structural formula of Compound I-1 is:

[0020]

[0021] or

[0022] The isoflavone compound is 7-(4-isopropylbenzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one, and 7-(4-isopropylbenzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one is defined as Compound I-2. The structure of Compound I-2 is:

[0023]

[0024] or

[0025] The isoflavone compound is 3-(4-methoxyphenyl)-7-(2,4,6-trimethylbenzyloxy)-4H-chromen-4-one, and 3-(4-methoxyphenyl)-7-(2,4,6-trimethylbenzyloxy)-4H-chromen-4-one is defined as Compound I-3. The structure of Compound I-3 is:

[0026]

[0027] or

[0028] The isoflavone compound is 7-((4-tert-butyl)benzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one, and 7-((4-tert-butyl)benzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one is defined as Compound I-4. The structure of Compound I-4 is:

[0029]

[0030] or

[0031] The isoflavone compound is 4-(((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)methyl)benzonitrile, and 4-(((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)methyl)benzonitrile is defined as Compound I-5. The structure of Compound I-5 is:

[0032]

[0033] or

[0034] The isoflavone compound is 7-benzyloxy-3-(4-methoxyphenyl)-4H-chromen-4-one, and 7-benzyloxy-3-(4-methoxyphenyl)-4H-chromen-4-one is defined as Compound I-6. The structure of Compound I-6 is:

[0035]

[0036] or

[0037] The isoflavone compound is 3-((4-methoxyphenyl)-7-(2-methylthiazol-4-yl)methoxy)-4H-chromen-4-one, and 3-((4-methoxyphenyl)-7-(2-methylthiazol-4-yl)methoxy)-4H-chromen-4-one is defined as Compound I-7. The structure of Compound I-7 is:

[0038]

[0039] or

[0040] The isoflavone compound is 3-((4-methoxyphenyl)-7-(2-methylthiazol-5-yl)methoxy)-4H-chromen-4-one, and 3-((4-methoxyphenyl)-7-(2-methylthiazol-5-yl)methoxy)-4H-chromen-4-one is defined as Compound I-8. The structure of Compound I-8 is:

[0041]

[0042] A second object of the present invention is to provide a preparation method of an isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof, avoiding the deficiencies of the prior art. This preparation method synthesizes the isoflavone compound from Compound II and Compound III in one step, so the preparation method is simple, and the obtained product has the effect of inhibiting the hTRPV1 receptor and thus treating pain.

[0043] The above object of the present invention is achieved by the following technical measures:

[0044] Provided is a preparation method of an isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof as described above. The isoflavone compound is prepared from Compound II and Compound III as raw materials under a base. The reaction formula is as follows:

[0045]

[0046] wherein W is a leaving group.

[0047] Preferably, the above-mentioned leaving group is Cl, Br, I, halo C1-C6 alkylsulfonyloxy or C6-C 10 arylsulfonyloxy having a substituent.

[0048] Preferably, the above-mentioned base is an inorganic base or an organic base.

[0049] The third object of the present invention is to avoid the deficiencies of the prior art and provide a use of an isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof in the preparation of a drug for treating pain in the body. This isoflavone compound has the effect of treating pain by inhibiting the hTRPV1 receptor.

[0050] The above object of the present invention is achieved by the following technical measures:

[0051] Provide a use of an isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof in the preparation of a drug for treating pain in the body.

[0052] The use of the present invention produces a therapeutic effect on pain by inhibiting the hTRPV1 receptor.

[0053] Preferably, the above pain is diabetic neuropathic pain, toothache, osteoarthritis pain or post-herpetic pain.

[0054] The fourth object of the present invention is to avoid the deficiencies of the prior art and provide a use of an isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof in the preparation of an antidiabetic drug. This isoflavone compound can reduce blood sugar.

[0055] The above object of the present invention is achieved by the following technical measures:

[0056] Provide a use of an isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof in the preparation of an antidiabetic drug.

[0057] The isoflavone compound, preparation method and use thereof in the preparation of drugs for treating analgesia and hypoglycemia of the present invention, wherein the isoflavone compound has obvious inhibitory activity on TRPV1, can significantly inhibit the pain response, and also has an obvious blood sugar lowering effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The present invention is further illustrated by the accompanying drawings, but the content in the drawings does not constitute any limitation to the present invention.

[0059] Figure 1 It is the hydrogen spectrum of Compound I-1.

[0060] Figure 2 It is the carbon spectrum of Compound I-1.

[0061] Figure 3 It is the hydrogen spectrum of Compound I-2.

[0062] Figure 4 It is the carbon spectrum of Compound I-2.

[0063] Figure 5 1H NMR spectrum of Compound I-3

[0064] Figure 6 13C NMR spectrum of Compound I-3

[0065] Figure 7 1H NMR spectrum of Compound I-4

[0066] Figure 8 13C NMR spectrum of Compound I-4

[0067] Figure 9 1H NMR spectrum of Compound I-5

[0068] Figure 10 13C NMR spectrum of Compound I-5

[0069] Figure 11 1H NMR spectrum of Compound I-6

[0070] Figure 12 13C NMR spectrum of Compound I-6

[0071] Figure 13 1H NMR spectrum of Compound I-7

[0072] Figure 14 13C NMR spectrum of Compound I-7

[0073] Figure 15 1H NMR spectrum of Compound I-8

[0074] Figure 16 13C NMR spectrum of Compound I-8 Detailed Embodiments

[0075] The technical solutions of the present invention will be further described in conjunction with the following embodiments.

[0076] Unless otherwise specified, the experimental methods in the following embodiments are all conventional methods. Unless otherwise specified, the raw materials, reagent materials, etc. used in the following embodiments can all be obtained from conventional biochemical reagent stores or drug operating enterprises.

[0077] Unless otherwise indicated, the following terms used in the specification and claims have the following meanings.

[0078] "Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups having 1 to 20 carbon atoms. Alkyl groups having 1 to 10 carbon atoms are preferred, alkyl groups having 1 to 6 carbon atoms are more preferred, alkyl groups having 1 to 3 carbon atoms are even 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 can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available point of attachment, preferably by one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0079] "Cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, which include 3 to 20 carbon atoms, preferably include 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.

[0080] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring.

[0081] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0082] "Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms include oxygen, sulfur, and nitrogen. Preferably 5 to 10 rings. The heteroaryl group is preferably a 5- or 6-membered ring, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring.

[0083] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio groups.

[0084] "Alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio groups.

[0085] "Optional" or "optionally" means that the subsequently described event or circumstance can 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 alkyl" means that alkyl may or may not be present, and this description includes the cases where the heterocyclic group is substituted by alkyl and the cases where the heterocyclic group is not substituted by alkyl.

[0086] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 - 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what substitutions are possible or impossible without much effort. For example, an amino or hydroxy group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0087] "Pharmaceutical composition" means a mixture containing one or more compounds described in the present invention or their pharmaceutically acceptable esters or 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.

[0088] Example 1

[0089] An isoflavone compound having Compound I or its pharmaceutically acceptable ester or pharmaceutically acceptable salt, defining the isoflavone compound as Compound I, and the structure of Compound I is:

[0090]

[0091] Among them, ring A is a benzene ring or a thiazole ring. R1 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile group, methoxy group; R2 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile group, methoxy group; R3 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile group, methoxy group.

[0092] The preparation method of the isoflavone compound having the compound I or its pharmaceutically acceptable ester or pharmaceutically acceptable salt is to obtain the isoflavone compound from compound II and compound III as raw materials under an alkali reaction, and the reaction formula is as follows:

[0093]

[0094] Among them, W is a leaving group. The leaving group is Cl, Br, I, halo C1-C6 alkylsulfonyloxy or substituted C6-C 10 arylsulfonyloxy.

[0095] The base is an inorganic base or an organic base; when the leaving group is halo C1-C6 alkylsulfonyloxy, the leaving group is specifically methanesulfonyloxy, ethanesulfonyloxy or trichloromethanesulfonyl; or when the leaving group is substituted C6-C 10 arylsulfonyloxy, the leaving group is specifically phenylsulfonyloxy, p-toluenesulfonyloxy or m-nitrobenzenesulfonyloxy. When the base is an inorganic base, the base is specifically an alkali metal carbonate, an alkali metal bicarbonate or an alkali metal hydroxide; when the base is an organic base, the base is specifically triethylamine, pyridine, dimethylpyridine, n-butyllithium or potassium tert-butoxide; when the base is an alkali metal carbonate, the base is specifically sodium carbonate, potassium carbonate or cesium carbonate; when the base is an alkali metal bicarbonate, the base is specifically potassium bicarbonate; when the base is an alkali metal hydroxide, the base is specifically lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0096] It should be noted that the compound III of the present invention is a commercially available substance.

[0097] The isoflavone compound or its pharmaceutically acceptable ester or pharmaceutically acceptable salt can inhibit the hTRPV1 receptor and thus produce a therapeutic effect on pain.

[0098] Example 2

[0099] An isoflavone compound having the compound I or its pharmaceutically acceptable ester or pharmaceutically acceptable salt, defining the isoflavone compound as compound I, and the structure of compound I is:

[0100]

[0101] Ring A is an aryl or heteroaryl group. R1 is hydrogen, halogen, alkyl, nitrile, alkoxy or cycloalkoxy, and at least one hydrogen of the alkoxy is substituted by halogen, and at least one hydrogen of the cycloalkoxy is substituted by halogen. R2 is hydrogen, halogen, alkyl, nitrile, alkoxy or cycloalkoxy, and at least one hydrogen of the alkoxy is substituted by halogen, and at least one hydrogen of the cycloalkoxy is substituted by halogen. R3 is hydrogen, halogen, alkyl, nitrile, alkoxy or cycloalkoxy, and at least one hydrogen of the alkoxy is substituted by halogen, and at least one hydrogen of the cycloalkoxy is substituted by halogen. R4 is hydrogen, halogen, alkyl, nitrile, alkoxy or cycloalkoxy, and at least one hydrogen of the alkoxy is substituted by halogen, and at least one hydrogen of the cycloalkoxy is substituted by halogen.

[0102] The preparation method of the isoflavone compound having Compound I or its pharmaceutically acceptable ester or pharmaceutically acceptable salt is obtained by using Compound II and Compound III as raw materials under an alkali reaction to obtain the isoflavone compound, and the reaction formula is as follows:

[0103]

[0104] Wherein W is a leaving group. The leaving group is Cl, Br, I, halo C1-C6 alkylsulfonyloxy or C6-C 10 arylsulfonyloxy with substituents.

[0105] The base is an inorganic base or an organic base; when the leaving group is halo C1-C6 alkylsulfonyloxy, the leaving group is specifically methanesulfonyloxy, ethanesulfonyloxy or trichloromethanesulfonyl; or when the leaving group is C6-C 10 arylsulfonyloxy with substituents, the leaving group is specifically phenylsulfonyloxy, p-toluenesulfonyloxy or m-nitrobenzenesulfonyloxy. When the base is an inorganic base, the base is specifically an alkali metal carbonate, an alkali metal bicarbonate or an alkali metal hydroxide; when the base is an organic base, the base is specifically triethylamine, pyridine, dimethylpyridine, n-butyllithium or potassium tert-butoxide; when the base is an alkali metal carbonate, the base is specifically sodium carbonate, potassium carbonate or cesium carbonate; when the base is an alkali metal bicarbonate, the base is specifically potassium bicarbonate; when the base is an alkali metal hydroxide, the base is specifically lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0106] The isoflavone compound or its pharmaceutically acceptable ester or pharmaceutically acceptable salt can inhibit the hTRPV1 receptor and thus produce a therapeutic effect on pain.

[0107] Example 3

[0108] An isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound is specifically 3-(4-methoxyphenyl)-7-(4-trifluoromethyl)benzyloxy)-4H-chromen-4-one, and 3-(4-methoxyphenyl)-7-(4-methyl)benzyloxy)-4H-chromen-4-one is defined as Compound I-1. The structural formula of Compound I-1 is:

[0109]

[0110] The synthesis method of Compound I-1 is specifically carried out in two steps as follows:

[0111] The first step:

[0112]

[0113] The second step:

[0114]

[0115] The first step: The starting material is a solution of p-tolualdehyde (0.14 g, 1.15 mmol) dissolved in 20 ml of a mixed solvent (tetrahydrofuran / methanol, 1:1, v / v). Sodium borohydride (0.1 g, 2.3 mmol) was slowly added under an ice bath. After the reaction was completed under the ice bath, 20 ml of water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (30 ml × 3), and the combined organic phases were washed with saturated NaCl solution (20 ml × 2). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was directly used in the subsequent reaction without purification. The crude product was dissolved in 20 ml of dichloromethane, 0.5 ml of thionyl chloride was slowly added dropwise, 1 drop of DMF was added, and the reaction was heated at 25 °C. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a pale yellow oily compound II. It should be noted that Compound II-2 and Compound III in this example were obtained directly from commercial sources.

[0116] The second step: Compound II (0.2 g, 1.03 mmol) was dissolved in 20 ml of acetonitrile, the starting material 7-hydroxy-4-methoxyisoflavone (Compound III, 0.37 g, 1.37 mmol) was added, the base was anhydrous potassium carbonate (0.5 g, 3.62 mmol), and a catalytic amount of KI was added. The reaction was heated to 60 °C for 8 h, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The residue was dissolved in 30 ml of water, extracted with ethyl acetate (20 ml × 3), the combined organic phases were washed with saturated brine (15 ml × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to obtain 0.26 g of a white solid Compound I-1, with a melting point of 163-165 °C and a yield of 65%.

[0117] Among them, for compound I-1 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.62–7.46 (m, 2H), 7.19 (dd, J = 8.9, 2.4 Hz, 1H), 7.08–6.92 (m, 2H), 5.41 (s, 2H), 3.79 (s, 3H), 1.59 (s, 3H), as Figure 1 shown.

[0118] For compound I-1 13 C NMR (101 MHz, DMSO-d6) δ 175.08, 174.66, 162.83, 159.47, 157.77, 154.05, 141.46, 130.54, 128.76, 127.59, 124.46, 123.86, 118.37, 115.69, 114.09, 102.16, 69.54, 55.62, 26.01, as Figure 2 shown.

[0119] ESI-MS mass spectrometry analysis of compound I-1 m / z: 373.1 [M+H] + ; Calculated value for elemental analysis: For C 24 H 20 O4: C, 77.40; H, 5.41; Found: C, 77.42; H, 5.40.

[0120] Example 4

[0121] An isoflavone compound having compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound is 7-(4-isopropylbenzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one, and 7-(4-isopropylbenzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one is defined as compound I-2. The structure of compound I-2 is:

[0122]

[0123] The synthesis method of compound I-2 in this example is the same as that of compound I-1 in Example 3 in terms of raw materials, molar amounts of raw materials, treatment methods, etc. The only difference is that the starting material in compound I-2 is p-2,4,6-trimethylbenzaldehyde. The final product of the synthesis method in this example is 0.28 g of white solid compound I-2, with a melting point of 158-161 °C and a yield of 70%.

[0124] Of compound I-2 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.63–7.49 (m, 2H), 7.46–7.38 (m, 2H), 7.33–7.23 (m, 2H), 7.14 (dd, J = 8.9, 2.4 Hz, 1H), 7.11–6.90 (m, 2H), 5.22 (s, 2H), 3.79 (s, 3H), 2.90 (m, J = 6.9 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H), as Figure 3 shown.

[0125] Of compound I-2 13 C NMR (101 MHz, DMSO-d6) δ 175.07, 163.20, 159.46, 157.80, 153.97, 148.93, 133.91, 130.53, 130.28, 128.69, 127.45, 126.92, 126.14, 124.50, 123.82, 118.12, 115.74, 114.07, 113.98, 101.95, 70.47, 55.61, 33.69, 24.36, 24.33, as Figure 4 shown.

[0126] ESI-MS mass spectrometry analysis of compound I-2 m / z: 401.5 [M+H] + ; Calculated value for elemental analysis: For C 26 H 24 O4: C, 77.98; H, 6.04; Found: C, 77.97; H, 6.03.

[0127] Example 5

[0128] An isoflavone compound having compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound is 3-(4-methoxyphenyl)-7-(2,4,6-trimethylbenzyloxy)-4H-chromen-4-one, and 3-(4-methoxyphenyl)-7-(2,4,6-trimethylbenzyloxy)-4H-chromen-4-one is defined as compound I-3. The structure of compound I-3 is:

[0129]

[0130] The synthesis method of compound I-3 in this example is the same as that of compound I-1 in Example 3 in terms of raw materials, molar amounts of raw materials, treatment methods, etc. The only difference is that the starting material in compound I-2 is p-2,4,6-trimethylbenzaldehyde. The final product of the synthesis method in this example is 0.15 g of compound I-3 as a white solid, with a melting point of 162-165 °C and a yield of 65%.

[0131] For compound I-3 1 H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.05(d,J=8.9Hz,1H),7.63–7.47(m,3H),7.36(d,J=2.4Hz,1H),7.13(dd,J=8.9,2.4Hz,1H),7.08–6.97(m,3H),5.18(s,2H),3.79(d,J=3.8Hz,3H),2.28(d,J=22.1Hz,9H), as Figure 5 shown.

[0132] For compound I-3 13 C NMR(101MHz,DMSO-d6)δ175.10,175.03,163.80,159.45,159.38,157.95,157.90,153.99,153.57,138.29,138.26,130.54,129.58,129.23,127.71,127.40,124.72,124.53,123.82,123.56,118.12,115.79,115.64,114.08,114.04,102.56,101.72,65.78,55.61,21.14,19.57, as Figure 6 shown.

[0133] ESI-MS mass spectrometry analysis of compound I-3 m / z:=401.5[M+H] + ; Calculated values for elemental analysis: For C 26 H 24 O4:C,77.98;H,6.04;Found:C,77.99;H,6.04.

[0134] Example 6

[0135] An isoflavone compound having compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound is 7-((4-tert-butyl)benzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one, and 7-((4-tert-butyl)benzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one is defined as compound I-4. The structure of compound I-4 is:

[0136]

[0137] The synthesis method of compound I-4 in this example is the same as that of compound I-1 in Example 3 in terms of raw materials, molar amounts of raw materials, treatment methods, etc. The only difference is that the starting material in compound I-2 is p-tert-butylbenzaldehyde. The final product of the synthesis method in this example is 0.18 g of compound I-4 as a white solid, with a melting point of 153 - 156 °C and a yield of 71%.

[0138] Of compound I-4 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.04(d,J=8.9Hz,1H),7.59–7.47(m,2H),7.43(d,J=1.4Hz,3H),7.27(d,J=2.4Hz,1H),7.15(dd,J=8.9,2.4Hz,1H),7.07–6.94(m,2H),5.23(s,2H),3.79(s,3H),1.29(s,9H), as Figure 7 shown.

[0139] Of compound I-4 13 C NMR(101MHz,DMSO-d6)δ175.07,163.21,159.46,157.81,153.99,151.15,133.54,130.54,128.41,127.46,125.77,124.50,123.83,118.13,115.76,114.08,101.96,70.37,55.61,34.81,31.58, as Figure 8 shown.

[0140] ESI-MS mass spectrometry analysis of compound I-4 m / z:=415.5[M+H] + ; Calculated value for elemental analysis: For C 27 H 26 O4:C,78.24;H,6.32; Found: C,78.26;H,6.23.

[0141] Example 7

[0142] An isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound is 4-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzonitrile, and 4-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzonitrile is defined as Compound I-5, and the structure of Compound I-5 is:

[0143]

[0144] The synthesis method of Compound I-5 in this example is the same as that of Compound I-1 in Example 3 in terms of raw materials, molar amounts of raw materials, treatment methods, etc. The only difference is that the starting material in Compound I-2 is p-cyanobenzaldehyde. The final product of the synthesis method in this example is 0.21 g of Compound I-5 as a white solid, with a melting point of 172 - 176 °C and a yield of 73%.

[0145] Of Compound I-5 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.06(d,J=8.9Hz,1H),7.93–7.87(m,2H),7.74–7.66(m,2H),7.57–7.47(m,2H),7.27(d,J=2.4Hz,1H),7.19(dd,J=8.9,2.4Hz,1H),7.05–6.90(m,2H),5.40(s,2H),3.79(s,3H), as Figure 9 shown.

[0146] Of Compound I-5 13 C NMR(101MHz,DMSO-d6)δ175.06,162.74,159.47,157.74,154.05,142.33,133.00,130.54,128.79,127.60,124.45,123.86,119.17,118.40,115.64,114.08,111.25,102.19,69.48,55.61, as Figure 10 shown.

[0147] ESI-MS mass spectrometry analysis of Compound I-5 m / z:=384.4[M+H] + ; Elemental analysis calculated values: For C 24 H 17 NO4: C, 75.19; H, 4.47; Found: C, 75.17; H, 4.44.

[0148] Example 8

[0149] An isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound is 7-benzyloxy-3-(4-methoxyphenyl)-4H-chromen-4-one,

[0150] Define 7-benzyloxy-3-(4-methoxyphenyl)-4H-chromen-4-one as Compound I-6, and the structure of Compound I-6 is:

[0151]

[0152] The synthesis method of Compound I-6 in this example is the same as that of Compound I-1 in Example 3 in terms of raw materials, molar amounts of raw materials, treatment methods, etc. The only difference is that the starting material in Compound I-2 is benzaldehyde. The final product of the synthesis method in this example is 0.20 g of white solid Compound I-6, with a melting point of 180 - 183 °C and a yield of 75%.

[0153] Of Compound I-6 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.55–7.33 (m, 7H), 7.26 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.9, 2.4 Hz, 1H), 7.02–6.97 (m, 2H), 5.27 (s, 2H), 3.78 (s, 3H), as Figure 11 shown.

[0154] Of Compound I-6 13 C NMR (101 MHz, DMSO-d6) δ 174.66, 162.71, 159.03, 157.36, 153.55, 136.11, 130.10, 128.59, 128.22, 128.02, 127.04, 124.06, 123.40, 117.74, 115.31, 113.65, 101.59, 70.11, 55.18, as Figure 12 shown.

[0155] ESI-MS mass spectrometry analysis of Compound I-6 m / z: = 359.4 [M + H] + ; Calculated values for elemental analysis: For C 23 H 18 O4: C, 77.08; H, 5.06; Found: C, 77.07; H, 5.03.

[0156] Example 9

[0157] An isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound is 3-((4-methoxyphenyl)-7-(2-methylthiazol-4-yl)methoxy)-4H-chromen-4-one, and 3-((4-methoxyphenyl)-7-(2-methylthiazol-4-yl)methoxy)-4H-chromen-4-one is defined as Compound I-7. The structure of Compound I-7 is:

[0158]

[0159] The synthesis method of Compound I-7 in this example is the same as that of Compound I-1 in Example 3 in terms of raw materials, molar amounts of raw materials, treatment methods, etc. The only difference is that the starting material in Compound I-2 is 2-methylthiazole-4-carbaldehyde. The final product of the synthesis method in this example is 0.18 g of Compound I-7 as a white solid, with a melting point of 183 - 186 °C and a yield of 64%.

[0160] Of Compound I-7 1 H NMR(400MHz,Chloroform-d)δ8.21(d,J=8.9Hz,1H),7.91(s,1H),7.60–7.43(m,2H),7.20(s,1H),7.07(dd,J=8.9,2.4Hz,1H),7.02–6.91(m,3H),5.23(s,2H),3.83(s,3H),2.75(s,3H), as Figure 13 shown.

[0161] Of Compound I-7 13 C NMR(101MHz,Chloroform-d)δ175.80,167.00,162.65,159.56,157.78,152.10,150.52,130.12,127.88,124.88,124.19,118.74,116.80,114.91,113.96,101.21,66.45,55.34,19.23, as Figure 14 shown.

[0162] ESI-MS mass spectrometry analysis of Compound I-7 m / z:=380.4[M+H] + ; Calculated values for elemental analysis: ForC 21 H 17 NO4S: C, 66.48; H, 4.52; Found: C, 66.47; H, 4.53.

[0163] Example 10

[0164] An isoflavone compound having Compound I or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof. The isoflavone compound is 3-((4-methoxyphenyl)-7-(2-methylthiazol-5-yl)methoxy)-4H-chromen-4-one, and 3-((4-methoxyphenyl)-7-(2-methylthiazol-5-yl)methoxy)-4H-chromen-4-one is defined as Compound I-8. The structure of Compound I-8 is:

[0165]

[0166] The synthesis method of Compound I-8 in this example is the same as that of Compound I-1 in Example 3 in terms of raw materials, molar amounts of raw materials, treatment methods, etc. The only difference is that the starting material in Compound I-2 is 2-methylthiazole-5-carbaldehyde. The final product of the synthesis method in this example is 0.18 g of Compound I-8 as a white solid, with a melting point of 186 - 188 °C and a yield of 68%.

[0167] of Compound I-8 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.9 Hz, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.50–7.36 (m, 2H), 6.95 (dd, J = 8.9, 2.4 Hz, 1H), 6.92–6.80 (m, 3H), 5.21 (s, 2H), 3.76 (s, 3H), 2.65 (s, 3H), as Figure 15 shown.

[0168] of Compound I-8 13 C NMR (101 MHz, Chloroform-d) δ 175.76, 168.09, 162.06, 159.61, 157.71, 152.12, 142.08, 132.07, 130.12, 128.07, 124.97, 124.08, 118.96, 114.83, 113.98, 101.33, 63.04, 55.35, 19.48, as Figure 16 shown.

[0169] ESI-MS mass spectrometry analysis of Compound I-8 m / z: = 380.4 [M+H] + ; Calculated value for elemental analysis: For C 21 H 17 NO4S: C, 66.48; H, 4.52; Found: C, 66.49; H, 4.51.

[0170] Experiments and Results

[0171] I. Evaluation of the inhibitory activity of the isoflavone compounds of the present invention against hTRPV1-HEK293 stable cells

[0172] The hTRPV1 inhibitory activity of the isoflavone compounds of the present invention was determined using the following method:

[0173] The hTRPV1-HEK293 stable cells were inoculated onto a 96-well black plate at a density of 2.5×10 4 / well, and then placed in a cell culture incubator at 37°C and 5% CO2 overnight. Load the Fluo-3AM calcium ion fluorescent probe at room temperature. First, prepare a DMSO stock solution of 2 mM Fluro-3AM, add 16.5 mg of Pluronic F127 to the Fluo-3AM / DMSO solution to prevent the aggregation of Fluo-3AM in Hank's balanced salt solution and help it enter the cells. Dilute the Fluo-3AM solution with HBSS to prepare a 5 μM Fluo-3AM working solution, add 10 μL of the above working solution to each well of the cell plate, and culture at 37°C for 30 minutes.

[0174] Add 50 μL of HBSS containing 1% fetal bovine serum to each well and continue to culture for 40 minutes. Wash the cells 4 times with the tableting solution, add 40 μL of samples of the isoflavone compounds of the present invention at different concentrations to each well, set 3 replicates for each sample concentration, add an equal amount of BCTC to the positive control group, where BCTC is a recognized TRPV1 antagonist, and add the tableting solution to the negative control group. 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 measured to characterize the cytoplasmic calcium ion concentration. The results are shown in Table 1. Among them, the inhibition rate of the present invention = (difference in the blank group - difference in the experimental group) / difference in the blank group (the difference is the difference in fluorescence values before and after capsaicin administration).

[0175] Table 1. Inhibitory activity of the hTRPV1 receptor

[0176]

[0177]

[0178] From the data in Table 1, it can be seen that hTRPV1 is the TRPV1 gene of the human body, and TRPV1 is the target name. Compounds I-1 to I-8 of the present invention all have obvious inhibitory activity against TRPV1 in the range of 10 μM to 100 nM, and the inhibition rates are all greater than 50%. Among them, the inhibitory activities of compounds I-1 and I-3 are comparable to those of the positive control BCTC. Therefore, compounds I-1 and I-3 have strong TRPV1 inhibitory activities.

[0179] II. Evaluation of the analgesic effect of the isoflavone compounds of the present invention on a mouse pain model

[0180] The in vivo analgesic activity of the isoflavone compounds of the present invention can be evaluated by using two mouse pain models.

[0181] 2.1 Experimental on acetic acid-induced writhing model

[0182] 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. 30 minutes before the test, the compounds I-1 to I-8 of the present invention were orally administered by gavage, with a dose of 30 mg / kg for all. 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 concave, hind limbs extended, hips elevated) of the mice within 15 minutes was recorded. The results are shown in Table 2.

[0183] 2.2 Experimental on formalin-induced pain model

[0184] After adaptively feeding clean-grade ICR mice at 8 weeks of age, they were randomly grouped according to body weight, with 6 mice in each group. Before the experiment, the compounds I-1 to I-8 of the present invention were administered by gavage to the mice, with a dose of 30 mg / kg for all. 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 toe, and the licking foot time of the I phase (0 - 5 min) and the II phase (15 - 45 min) reactions were recorded respectively.

[0185] Table 2. Effects of Compounds I-1 to I-8 on Acetic Acid-Induced Writhing Model and Formalin-Induced Pain Model ( n = 6)

[0186] experimental group number of writhing duration of phase I (min) duration of phase II (min) control 25.16±2.13 1.82±0.20 5.84±0.58 BCTC 16.46±1.35* 1.89±0.20 5.52±0.90 I-1 15.95±2.47* 1.42±0.18* 4.48±0.50* I-2 19.93±3.41* 1.73±0.16 5.12±0.42 I-3 15.12±2.38* 1.44±0.17* 4.67±0.45* I-4 17.90±1.34* 1.81±0.15 4.85±0.33 I-5 18.87±1.47* 1.86±0.19 4.91±0.41 I-6 18.67±1.48* 1.83±0.18 4.87±0.32 I-7 20.16±1.36* 1.84±0.15 5.23±0.56 I-8 19.34±1.19* 1.79±0.14 5.08±0.45

[0187] Note: *P≤0.05 is the result of Student's t-test relative to the blank control group.

[0188] As can be seen from the data in Table 2, Compounds I-1 to I-8 can all significantly inhibit the pain response induced by acetic acid. Among them, the analgesic activities of Compounds I-1 and I-3 are comparable to those of the positive control BCTC. The compounds can basically inhibit the pain induced by formalin. Among them, the analgesic activities of Compounds I-1 and I-3 are significantly better than those of the positive control BCTC.

[0189] III. Evaluation of the in vivo hypoglycemic activity of the isoflavone compounds of the present invention

[0190] Oral Glucose Tolerance Test (OGTT) in Normal Mice: Ten-week-old clean-grade Kunming mice, weighing 22 - 25 g and being male, were randomly grouped according to body weight, with 6 mice in each group. Before the experiment, the mice were fasted but allowed to drink water for 12 hours, and blood was taken from the tail vein to measure the blood glucose value (recorded as -30 min). Then, they were respectively intragastrically administered with blank solvent, BCTC (30 mg / kg), and the isoflavone compound of the present invention (30 mg / kg). After 30 min, the blood glucose value was measured and recorded as 0 min. Immediately afterwards, a glucose solution with a concentration of 2 g / 10 ml was intragastrically administered at 10 ml / kg, and the blood glucose values were measured at 15, 30, 60, and 120 min. The results are shown in Table 3.

[0191] Table 3. Effects of Some Compounds on Oral Glucose Tolerance in Normal Mice ( n = 6

[0192] experimental group -30 min 0 min 15 min 30 min 60 min 120 min control 4.05±0.58 4.25±0.34 15.42±0.93 16.20±0.77 10.33±0.60 4.75±0.38 BCTC 4.16±0.35 4.53±0.27 14.26±1.67 15.57±1.85 9.76±0.39 3.89±0.48 I-1 3.95±0.47 4.15±0.25 <![CDATA[12.25±0.67 * > <![CDATA[11.98±0.9 * > <![CDATA[8.05±0.97 * > 3.98±0.56 I-3 3.93±0.41 4.08±0.16 <![CDATA[11.60±0.73 * > <![CDATA[10.57±0.85 * > <![CDATA[7.62±0.72 * > 3.93±0.67

[0193] Note: *P≤0.05 represents the result of Student's t-test relative to the blank control group.

[0194] The oral glucose tolerance test of normal mice in Table 3 shows that: the well-known TRPV1 antagonist BCTC (positive control) basically has no hypoglycemic activity, and the compounds I-1 and I-3 of the present invention can significantly improve the oral glucose tolerance of normal mice, showing good hypoglycemic effects.

[0195] Example 11

[0196] Use of an isoflavone compound having the compound I as described in Examples 1 to 10, or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof, in the preparation of a hypoglycemic drug.

[0197] Through the above evaluation of the inhibitory activity on hTRPV1-HEK293 stable transfected cells, it can be proved that the compound produces a therapeutic effect on pain by inhibiting the hTRPV1 receptor. Moreover, the analgesic effect of the isoflavone compound was further proved by the acetic acid-induced writhing model experiment and the formalin-induced pain model experiment. Therefore, when using these isoflavone compounds or their pharmaceutically acceptable esters or pharmaceutically acceptable salts as drugs, they have the same efficacy.

[0198] Example 12

[0199] Use of an isoflavone compound having the compound I as described in Examples 1 to 10, or a pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof, in the preparation of a drug for treating pain in the body. The pain is diabetic neuropathic pain, toothache, osteoarthritis pain, or post-herpetic pain.

[0200] The above-mentioned isoflavone compounds have been proved to have hypoglycemic effect through the in vivo hypoglycemic activity evaluation experiment. Therefore, when these isoflavone compounds or their pharmaceutically acceptable esters or pharmaceutically acceptable salts are used as drugs, they also have the same effect.

[0201] Embodiment 13

[0202] A tablet containing an isoflavone compound, wherein the formula of each tablet is as follows: compound I-3: 15 mg; microcrystalline cellulose: 80 mg; pregelatinized starch: 40 mg; polyvinyl pyrrolidone: 8 mg; sodium carboxymethyl starch: 6 mg; magnesium stearate: 1.5 mg; talc: 2.5 mg; and ethanol: appropriate amount.

[0203] According to the above formula, compound I-3, pregelatinized starch and microcrystalline cellulose are sieved and fully mixed, polyvinyl pyrrolidone solution is added, mixed, a soft material is prepared, sieved, wet granules are prepared, and dried at 50-60°C. Sodium carboxymethyl starch, magnesium stearate and talc are sieved and added to the above granules and pressed into tablets with an appropriate amount of ethanol.

[0204] Experimental verification has shown that the above composition also has excellent analgesic and hypoglycemic activities in vivo.

[0205] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. Use of an isoflavone compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pain in vivo, characterized in that: By inhibiting the hTRPV1 receptor, a therapeutic effect on pain is produced; Define the isoflavone compound as Compound I, and the structure of Compound I is: ； Among them, ring A is a benzene ring, or ; R1 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile, methoxy; R2 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile, methoxy; R3 is hydrogen, methyl, trifluoromethyl, isopropyl, tert-butyl, nitrile, methoxy.

2. Use of the isoflavone compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating pain in vivo, characterized in that: The isoflavone compound is 3-(4-methoxyphenyl)-7-(4-methyl)benzyloxy)-4H-chromen-4-one. Define 3-(4-methoxyphenyl)-7-(4-methyl)benzyloxy)-4H-chromen-4-one as Compound I-1, and the structural formula of Compound I-1 is: ； Or The isoflavone compound is 7-(4-isopropylbenzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one. Define 7-(4-isopropylbenzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one as Compound I-2, and the structure of Compound I-2 is: ； Or The isoflavone compound is 3-(4-methoxyphenyl)-7-(2,4,6-trimethylbenzyloxy)-4H-chromen-4-one. Define 3-(4-methoxyphenyl)-7-(2,4,6-trimethylbenzyloxy)-4H-chromen-4-one as Compound I-3, and the structure of Compound I-3 is: ； Or The isoflavone compound is 7-((4-tert-butyl)benzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one. Define 7-((4-tert-butyl)benzyloxy)-3-(4-methoxyphenyl)-4H-chromen-4-one as Compound I-4, and the structure of Compound I-4 is: ； Or The isoflavone compound is 4-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzonitrile. Define 4-((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzonitrile as Compound I-5, and the structure of Compound I-5 is: ； Or The isoflavone compound is 7-benzyloxy-3-(4-methoxyphenyl)-4H-chromen-4-one. Define 7-benzyloxy-3-(4-methoxyphenyl)-4H-chromen-4-one as Compound I-6, and the structure of Compound I-6 is: ； Or The isoflavone compound is 3-((4-methoxyphenyl)-7-(2-methylthiazol-4-yl)methoxy)-4H-chromen-4-one. Define 3-((4-methoxyphenyl)-7-(2-methylthiazol-4-yl)methoxy)-4H-chromen-4-one as Compound I-7, and the structure of Compound I-7 is: ； Or The isoflavone compound is 3-((4-methoxyphenyl)-7-(2-methylthiazol-5-yl)methoxy)-4H-chromen-4-one, and 3-((4-methoxyphenyl)-7-(2-methylthiazol-5-yl)methoxy)-4H-chromen-4-one is defined as compound I-8. The structure of compound I-8 is as follows: 。 3. Use of the isoflavone compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating pain in vivo, characterized in that: The preparation method of the isoflavone compound is to obtain the isoflavone compound by using compound II and compound III as raw materials under a base. The reaction formula is as follows: ； Wherein W is a leaving group.

4. Use of the isoflavone compound or a pharmaceutically acceptable salt thereof according to claim 3 in the preparation of a medicament for treating pain in vivo, wherein the leaving group is Cl, Br, I, halo C1-C6 alkylsulfonyloxy or C6-C 10 arylsulfonyloxy with substituents; The base is an inorganic base or an organic base.

5. Use of the isoflavone compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating pain in vivo, characterized in that: The pain is diabetic neuropathic pain, toothache, osteoarthritis pain or post-herpetic pain.

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