Multi-TRP ion channel regulator as well as preparation method and application thereof

Abstract

The invention relates to the field of medicine, in particular to a multi-TRP ion channel regulator and a preparation method and application thereof. The multi-TRP ion channel regulator researched and developed in the invention can inhibit TRPV1, activate TRPM8 and activate TRPA1, and is used for treating functional gastrointestinal diseases, intestinal mucosa injury, intestinal inflammation, immune disorder, dysbacteriosis, digestive tract tumors, pain or peripheral neuritis.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a multi-TRP ion channel modulator and a preparation method and application thereof. BACKGROUND

[0002] Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disease with unknown etiology and recurrent attacks, including ulcerative colitis (UC) and Crohn's disease (CD). UC mainly involves the colorectum, and the lesion is limited to the mucosal layer and submucosal layer; CD has a jumping onset in the entire digestive tract, and the lesion range can involve the entire layer. The pathogenesis of IBD may be related to genetic factors, environmental factors, and mucosal immune disorders.

[0003] Transient receptor potential ion channels (TRP channels) are divided into six groups and 26 subtypes: TRPA1, TRPV (1-6), TRPM (1-8), TRPML (1-3), TRPC (1, 3-7), and TRPP (2, 3, 5). TRP channels are ligand-gated calcium-permeable non-selective cation channels and important temperature receptors. TRPV1, also known as capsaicin receptor and vanilloid receptor, can be activated by various physical and chemical stimuli, such as heat (temperature > 43℃), protons (pH < 5.9), etc. TRPM8 is a cold sensation receptor that can be activated by low temperature (< 28°C), pressure, and cold sensation compounds. TRPA1, also known as ANKTM1, is also a cold sensation receptor that can be activated by many aromatic substances. Currently, TRP channels are widely studied in the nervous system diseases and are considered as important drug targets for pain and peripheral neuritis.

[0004] Existing treatment methods are mainly anti-inflammatory and symptomatic treatment, and there is no effective method for radical cure of the disease. Therefore, it is urgent to find the potential pathogenesis of IBD through scientific research to find new therapeutic targets. SUMMARY

[0005] To solve the above technical problems, the present application develops a multi-TRP ion channel modulator that can inhibit TRPV1, activate TRPM8, and activate TRPA1, and the molecular structure is as follows (molecular weight: 827.95): .

[0006] Applicant's previous studies found that STW5, a European traditional plant preparation for treating functional gastrointestinal disorders, can modulate the activation and desensitization of intestinal primary sensory neurons TRPA1 and TRPV1 (PMID: 32682914); Menthacarin, a European traditional plant preparation for treating functional gastrointestinal disorders, can induce calcium influx and desensitization of macrophages, intestinal primary sensory neurons and colon organoids (PMID: 33127519). Further studies found that the cold sensation receptor TRPM8 can reduce the release of substance P in primary sensory neurons by regulating the binding of PKAca and GSK-3β, thereby inhibiting substance P-induced apoptosis of epithelial cells, reducing intestinal mucosal damage, and relieving intestinal inflammation. It is also clear that TRPM8 agonists (menthol) and substance P receptor antagonists (aprepitant) can be potential drug choices for intestinal inflammation and mucosal damage (PMID: 38280896); alcohol can exacerbate intestinal inflammation and induce macrophage M2b polarization through TRPV1-MAPK / NF-κB, and TRPV1 inhibitor capsaicin (CPZ) can be a potential drug choice for intestinal inflammation. CPZ has a certain activating effect on another TRP channel TRPA1 and has a potential therapeutic effect on intestinal inflammation (PMID: 38810558). Another study found that TRPV1 agonist alcohol can induce circulatory system microbial imbalance, leading to a significant increase in gram-negative bacteria and pro-inflammatory bacterial endotoxins in the body, damaging the colon epithelial barrier function, and exacerbating the occurrence and development of esophageal cancer (PMID: 40001134).

[0007] In summary, TRP ion channels, especially TRPV1, TRPM8 and TRPA1, have certain therapeutic effects on functional gastrointestinal disorders, intestinal mucosal damage, intestinal inflammation, immune disorders, dysbiosis, digestive tract tumors, pain, peripheral neuritis, etc.

[0008] The present application provides a compound or a pharmaceutically acceptable salt thereof, the chemical structural formula of the compound is shown as formula XII: Formula XII.

[0009] The present application also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0010] The present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a medicament.

[0011] The present application also provides a preparation method of the above-mentioned compound, comprising the following steps: 1) mixing the compound shown as formula I with HBr, reacting to obtain a compound shown as formula II; ; 2) mixing and reacting a compound shown as formula III with a compound shown as formula IV to obtain a compound shown as formula V; ; 3) mixing and reacting a compound shown as formula V with TsCl to obtain a compound shown as formula VI through extraction; ; 4) mixing and reacting a compound shown as formula VI with a compound shown as formula VII to obtain a compound shown as formula VIII; ; 5) dissolving a compound shown as formula VIII in a solvent and reacting to obtain a compound shown as formula IX; ; 6) mixing and reacting a compound shown as formula IX with a compound shown as formula X to obtain a compound shown as formula XI; ; 7) mixing and reacting a compound shown as formula XI with a compound shown as formula II to obtain a compound shown as formula XII; .

[0012] The beneficial effects brought by the multi-TRP ion channel modulator proposed in the present specification include but are not limited to: (1) the binding effect on TRPV1 is better than the specific inhibitor CPZ, the binding effect on TRPM8 is better than the agonist Icilin, and the binding effect on TRPA1 is better than the agonist Allyl isothiocyanate; (2) the calcium ion influx of the cell is regulated, and the effect is similar to that of the mixed stimulant of TRPV1 inhibitor CPZ, TRPM8 agonist Icilin and TRPA1 agonist AITC; (3) there is no obvious effect on normal macrophages, but the activation of macrophages in the inflammatory state can be inhibited; compared with the TRPV1 inhibitor CPZ, the TRPM8 agonist Icilin, the TRPA1 agonist AITC and their combination, the multi-TRP ion channel modulator has less effect on normal cells, but has similar inhibitory effect on the activation of macrophages in the inflammatory state; (4) the release of the main pro-inflammatory factors in the macrophages in the inflammatory state is inhibited, and the release of the anti-inflammatory factors is promoted, and the effect is consistent with the respective effects of the TRPV1 inhibitor CPZ, the TRPM8 agonist Icilin and the TRPA1 agonist AITC, but the effect is better than that of the combination of the three; (5) the therapeutic effect on intestinal inflammation and mucosal damage in mice is better than that of the mixed application of the TRPV1 inhibitor CPZ, the TRPM8 agonist Icilin and the TRPA1 agonist AITC, and the effect of the multi-TRP ion channel modulator enema is better than that of oral administration; (6) the effect on the biochemical, liver function, kidney function, blood lipid and the like of mice is small, and the lactate dehydrogenase level is significantly reduced. BRIEF DESCRIPTION OF DRAWINGS

[0013] The present application will be further illustrated in the form of exemplary embodiments, which will be described in detail with reference to the accompanying drawings. These embodiments are not limiting, wherein: Figure 1 : Human TRPV1 protein binding mode display with Compound1. A. Cartoon diagram of Human TRPV1 protein binding with Compound1; B. Surface diagram of Human TRPV1 protein binding with Compound1; C. 2D diagram of Human TRPV1 protein binding with Compound1; D. 3D diagram of Human TRPV1 protein binding with Compound1.

[0014] Figure 2: Human TRPV1 protein binding mode display with CPZ. A. Cartoon of Human TRPV1 protein binding with CPZ; B. Surface of Human TRPV1 protein binding with CPZ; C. 2D of Human TRPV1 protein binding with CPZ; D. 3D of Human TRPV1 protein binding with CPZ.

[0015] Figure 3 : Human TRPM8 protein binding mode display with Compound 1. A. Cartoon of Human TRPM8 protein binding with Compound 1; B. Surface of Human TRPM8 protein binding with Compound 1; C. 2D of Human TRPM8 protein binding with Compound 1; D. 3D of Human TRPM8 protein binding with Compound 1.

[0016] Figure 4 : Human TRPM8 protein binding mode display with Icilin. A. Cartoon of Human TRPM8 protein binding with Icilin; B. Surface of Human TRPM8 protein binding with Icilin; C. 2D of Human TRPM8 protein binding with Icilin; D. 3D of Human TRPM8 protein binding with Icilin.

[0017] Figure 5 : A. Picture of calcium influx intensity of macrophages under different stimulations, calcium influx intensity was shown by fluorescence intensity; B. Column chart of calcium influx intensity of macrophages under different stimulations, n=5.

[0018] Figure 6 : A. Phosphorylation and non-phosphorylation levels of NF-κB and P38 proteins of unactivated and activated (LPS 1 μg / mL) macrophages after 6 h stimulation with different concentrations of multi-TRP ion channel modulators; B. Phosphorylation and non-phosphorylation levels of NF-κB, P38, and Erk1 / 2 proteins of unactivated and activated (LPS 1 μg / mL) macrophages after 6 h stimulation with 1 μM multi-TRP ion channel modulators, CPZ, AITC, Icilin, and mixture of the three.

[0019] Figure 7The release of IL-1β, TNF-α, IL-23, IFN-γ, IL-12, and IL-10 from macrophages activated with LPS 1 μg / mL for 6 h after stimulation with compound 1 μM of multi-TRP ion channel modulator (Compound1), CPZ 1 μM, Icilin 1 μM, AITC 1 μM, and a mixture of CPZ, Icilin, and AITC (1 μM each). n=5.

[0020] Figure 8 A. Percentage weight curve changes of mice in different groups, n=5; B. Difference in percentage weight of mice in different groups on day 8, n=5; C. Comparison of colon length of mice in different groups, n=5; D. Rectal H&E staining images of mice in different groups; E. Colon images of mice in different groups.

[0021] Figure 9 A. H&E staining images of the liver and kidneys of the control group and mice after oral administration of different concentrations of multi-TRP ion channel modulators for 8 days; B. Serum biochemistry, liver function, kidney function, blood lipids and other indicators of mice in different groups, n=5; C. Bar chart comparing the differences of the above indicators, n=5.

[0022] Figure 10 The binding patterns of Human TRPA1 protein and Compound1 are shown in the following diagrams: A. Cartoon diagram of Human TRPA1 protein binding with Compound1; B. Surface diagram of Human TRPA1 protein binding with Compound1; C. 2D diagram of Human TRPA1 protein binding with Compound1; D. 3D diagram of Human TRPA1 protein binding with Compound1.

[0023] Figure 11 The binding patterns of Human TRPA1 protein with Allyl isothiocyanate are illustrated in the following diagrams: A. Cartoon image of Human TRPA1 protein binding with Allyl isothiocyanate; B. Surface image of Human TRPA1 protein binding with Allyl isothiocyanate; C. 2D image of Human TRPA1 protein binding with Allyl isothiocyanate; D. 3D image of Human TRPA1 protein binding with Allyl isothiocyanate. Detailed Implementation

[0024] In order to more clearly illustrate the technical solutions of the embodiments of the present specification, the following will briefly introduce the drawings needed to be used in the embodiment description. Obviously, the drawings in the following description are only some examples or embodiments of the present specification, and for those skilled in the art, the present specification can also be applied to other similar scenarios without creative labor on the basis of these drawings. Unless it is clear from the language context or otherwise indicated, the same reference numbers in the drawings represent the same structure or operation.

[0025] As shown in the specification and claims, unless the context clearly indicates otherwise, the words "one", "an", "a", and / or "the" do not mean to specify a single number, but can also include a plurality. Generally speaking, the terms "comprise" and "include" only indicate the inclusion of the steps and elements explicitly identified, and these steps and elements do not constitute an exclusive list, and the method or device can also include other steps or elements.

[0026] Flowcharts are used in the present specification to illustrate the operations performed by the system according to the embodiments of the present specification. It should be understood that the preceding or subsequent operations are not necessarily performed in sequence. On the contrary, each step can be processed in reverse order or simultaneously. At the same time, other operations can also be added to these processes, or one or more steps of operation can be removed from these processes.

[0027] The present application provides a compound or a pharmaceutically acceptable salt thereof, the chemical structural formula of the compound is shown as formula XII: Formula XII.

[0028] The present application also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the pharmaceutical composition can further comprise a pharmaceutically acceptable carrier or excipient.

[0030] As generally used herein, "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that is, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0031] The adjuvants include various excipients and diluents, which are not essential active ingredients, and have no excessive toxicity after administration. The adjuvants include sterile water or physiological saline, stabilizers, excipients, antioxidants (ascorbic acid, etc.), buffers (phosphoric acid, citric acid, other organic acids, etc.), preservatives, surfactants (PEG, Tween, etc.), chelating agents (EDTA, etc.), or binders. The adjuvants also include other low-molecular-weight polypeptides, serum albumin, glycine, glutamine, asparagine, arginine, polysaccharides, monosaccharides, mannitol, or sorbitol. The adjuvants for water-soluble injection solutions are selected from physiological saline, glucose isotonic solution, D-sorbitol isotonic solution, D-mannose isotonic solution, D-mannose or sugar alcohol isotonic solution. The water-soluble injection solution contains a solubilizing agent. The solubilizing agent is selected from alcohols (ethanol), polyols (propylene glycol or PEG), and / or non-ionic surfactants (Tween 80 or HCO-50).

[0032] The pharmaceutical composition provided in the present application can be a single effective component, or can be combined with one or more other active components useful for disease treatment to form a combined preparation.

[0033] The content of the active component in the pharmaceutical composition is a safe and effective amount, which should be adjustable for those skilled in the art, for example, the administration amount of the active component of the above-mentioned compound and pharmaceutical composition depends on the weight of the patient, the type of application, and the severity of the disease.

[0034] The present application also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a medicament.

[0035] In some embodiments, the drug can be a multi-TRP ion channel modulator.

[0036] In some embodiments, the drug can inhibit TRPV1, activate TRPM8, and activate TRPA1.

[0037] In some embodiments, the drug can be used to treat at least one of the following diseases: functional gastrointestinal disease, intestinal mucosal injury, intestinal inflammation, immune disorder, dysbiosis, digestive tract tumor, pain, or peripheral neuritis.

[0038] In some embodiments, the drug can have one or more of the following functions: bind to TRPV1; modulate calcium ion influx of cells; inhibit activation of macrophages in an inflammatory state; inhibit the release of pro-inflammatory factors in macrophages in an inflammatory state; promoting release of anti-inflammatory factors in macrophages in an inflammatory state; reducing lactate dehydrogenase levels.

[0039] The present application also provides a preparation method of the above-mentioned compound, comprising the following steps: 1) mixing the compound shown in formula I with HBr, reacting to obtain the compound shown in formula II; ; 2) mixing the compound shown in formula III with the compound shown in formula IV, reacting to obtain the compound shown in formula V; ; 3) mixing the compound shown in formula V with TsCl, reacting, extracting to obtain the compound shown in formula VI; ; 4) mixing the compound shown in formula VI with the compound shown in formula VII, reacting to obtain the compound shown in formula VIII; ; 5) dissolving the compound shown in formula VIII in a solvent, reacting to obtain the compound shown in formula IX; ; 6) mixing the compound shown in formula IX with the compound shown in formula X, reacting to obtain the compound shown in formula XI; ; 7) mixing the compound shown in formula XI with the compound shown in formula II, reacting to obtain the compound shown in formula XII; .

[0040] In some embodiments, the reaction condition of step 1) can be 100-150 o C for 3-7 h. In some embodiments, the reaction condition of step 1) can be 105-145 o C for 3.5-6.5 h. In some embodiments, the reaction condition of step 1) can be 110-140 o C for 4.0-6 h. In some embodiments, the reaction condition of step 1) can be 115-135 o C for 4.5-5.5 h. In some embodiments, the reaction condition of step 1) can be 120-130 o C for 4.5-5 h. In some embodiments, the reaction condition of step 1) can be 125-130 o C for 4.5-5 h.

[0041] In some embodiments, preferably, the reaction condition of step 1) can be 130 o reacted for 5h under C.

[0042] In some embodiments, the mass volume ratio of the compound of formula I to HBr in step 1) can be (50-150) mg: (5-15) mL. In some embodiments, the mass volume ratio of the compound of formula I to HBr in step 1) can be (60-140) mg: (6-14) mL. In some embodiments, the mass volume ratio of the compound of formula I to HBr in step 1) can be (70-130) mg: (7-13) mL. In some embodiments, the mass volume ratio of the compound of formula I to HBr in step 1) can be (80-120) mg: (8-12) mL. In some embodiments, the mass volume ratio of the compound of formula I to HBr in step 1) can be (90-110) mg: (9-11) mL. In some embodiments, the mass volume ratio of the compound of formula I to HBr in step 1) can be (100-110) mg: (10-11) mL.

[0043] In some embodiments, preferably, the mass volume ratio of the compound of formula I to HBr in step 1) can be 100 mg: 10 mL.

[0044] In some embodiments, the reaction condition of step 2) can be heating to reflux for 10-14h in a closed device. For example, the reaction condition of step 2) can be heating to reflux for 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5 or 14h in a closed device. Any range created using the above endpoints is also contemplates, to the extent not already described, as being an embodiment of the present application. In some embodiments, preferably, the reaction condition of step 2) can be heating to reflux for 12h in a closed device.

[0045] In some embodiments, the molar ratio of the compound of formula III to the compound of formula IV in step 2) can be (0.5-1.5):(0.5-1.5).

[0046] In some embodiments, step 2) can further comprise a solvent and a carbonate.

[0047] In some embodiments, the solvent in step 2) can be acetonitrile, and the carbonate can be sodium carbonate.

[0048] In some embodiments, the molar ratio of the compound of Formula V to TsCl in step 3) can be (0.5-1.5):(0.5-1.5). In some embodiments, the molar ratio of the compound of Formula V to TsCl in step 3) can be (0.6-1.4):(0.6-1.4). In some embodiments, the molar ratio of the compound of Formula V to TsCl in step 3) can be (0.7-1.3):(0.7-1.3). In some embodiments, the molar ratio of the compound of Formula V to TsCl in step 3) can be (0.8-1.2):(0.8-1.2). In some embodiments, the molar ratio of the compound of Formula V to TsCl in step 3) can be (0.9-1.1):(0.9-1.1). In some embodiments, the molar ratio of the compound of Formula V to TsCl in step 3) can be (1.0-1.1):(1.0-1.1).

[0049] In some embodiments, preferably, the molar ratio of the compound of Formula V to TsCl in step 3) can be 1:1.

[0050] In some embodiments, step 3) can further comprise a solvent and triethylamine.

[0051] In some embodiments, the solvent in step 3) can be dichloromethane.

[0052] In some embodiments, the reaction condition of step 3) can be room temperature stirring for 12 h.

[0053] In some embodiments, the molar ratio of the compound of Formula VI to the compound of Formula VII in step 4) can be (0.5-1.5):(0.5-1.5).

[0054] In some embodiments, the molar ratio of the compound of Formula VI to the compound of Formula VII in step 4) can be (0.6-1.4):(0.6-1.4). In some embodiments, the molar ratio of the compound of Formula VI to the compound of Formula VII in step 4) can be (0.7-1.3):(0.7-1.3). In some embodiments, the molar ratio of the compound of Formula VI to the compound of Formula VII in step 4) can be (0.8-1.2):(0.8-1.2). In some embodiments, the molar ratio of the compound of Formula VI to the compound of Formula VII in step 4) can be (0.9-1.1):(0.9-1.1). In some embodiments, the molar ratio of the compound of Formula VI to the compound of Formula VII in step 4) can be (1.0-1.1):(1.0-1.1).

[0055] In some embodiments, the molar ratio of the compound of Formula VI to the compound of Formula VII in step 4) can be 1:1.

[0056] In some embodiments, the step 4) can further comprise a solvent and a carbonate.

[0057] In some embodiments, the reaction condition of step 4) can be heating to reflux in a closed apparatus for 10-14 h.

[0058] For example, the reaction condition of step 4) can be heating to reflux in a closed apparatus for 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, or 14 h. Any range characterized by a combination of the above end values is also included, without repeating here.

[0059] In some embodiments, the reaction condition of step 4) can be heating to reflux in a closed apparatus for 12 h.

[0060] In some embodiments, the solvent in step 4) can be acetonitrile, and the carbonate can be sodium carbonate.

[0061] In some embodiments, the mass to volume ratio of the compound of Formula VIII to the solvent in step 5) can be (150-300) mg:(5-15) mL. In some embodiments, the mass to volume ratio of the compound of Formula VIII to the solvent in step 5) can be (170-280) mg:(6-14) mL. In some embodiments, the mass to volume ratio of the compound of Formula VIII to the solvent in step 5) can be (190-260) mg:(7-13) mL. In some embodiments, the mass to volume ratio of the compound of Formula VIII to the solvent in step 5) can be (200-250) mg:(8-12) mL. In some embodiments, the mass to volume ratio of the compound of Formula VIII to the solvent in step 5) can be (220-230) mg:(9-11) mL. In some embodiments, the mass to volume ratio of the compound of Formula VIII to the solvent in step 5) can be (220-230) mg:(10-11) mL.

[0062] In some embodiments, preferably, the mass to volume ratio of the compound of Formula VIII to the solvent in step 5) can be 220 mg:10 mL.

[0063] In some embodiments, the reaction condition of step 5) can be at room temperature for 0.5-2 h. For example, the reaction condition of step 5) can be at room temperature for 0.5, 0.75, 1, 1.25, 1.5, 1.75, or 2 h. Any range characterized by a combination of the above end values is also included, without repeating here.

[0064] In some embodiments, preferably, the reaction conditions of step 5) can be room temperature for 1 h.

[0065] In some embodiments, the solvent in step 5) can be trifluoroacetic acid or dichloromethane.

[0066] In some embodiments, the molar ratio of the compound of formula IX to the compound of formula X in step 6) can be (0.5-1.5):(0.5-1.5). In some embodiments, the molar ratio of the compound of formula IX to the compound of formula X in step 6) can be (0.6-1.4):(0.6-1.4). In some embodiments, the molar ratio of the compound of formula IX to the compound of formula X in step 6) can be (0.7-1.3):(0.7-1.3). In some embodiments, the molar ratio of the compound of formula IX to the compound of formula X in step 6) can be (0.8-1.2):(0.8-1.2). In some embodiments, the molar ratio of the compound of formula IX to the compound of formula X in step 6) can be (0.9-1.1):(0.9-1.1). In some embodiments, the molar ratio of the compound of formula IX to the compound of formula X in step 6) can be (1.0-1.1):(1.0-1.1).

[0067] In some embodiments, preferably, the molar ratio of the compound of formula IX to the compound of formula X in step 6) can be 1:1.

[0068] In some embodiments, step 6) can further comprise a solvent and triethylamine. In some embodiments, the solvent in step 6) can be dichloromethane.

[0069] In some embodiments, the reaction conditions of step 6) can be room temperature for 0.5-2 h. For example, the reaction conditions of step 6) can be room temperature for 0.5, 0.75, 1, 1.25, 1.5, 1.75, or 2 h. Any ranges featuring combinations of the above-mentioned endpoints are also included and are hereby expressly conveyed.

[0070] In some embodiments, preferably, the reaction conditions of step 6) can be room temperature for 1 h.

[0071] In some embodiments, the molar ratio of the compound of Formula XI to the compound of Formula II in step 7) can be (0.5-1.5):(0.5-1.5). In some embodiments, the molar ratio of the compound of Formula XI to the compound of Formula II in step 7) can be (0.6-1.4):(0.6-1.4). In some embodiments, the molar ratio of the compound of Formula XI to the compound of Formula II in step 7) can be (0.7-1.3):(0.7-1.3). In some embodiments, the molar ratio of the compound of Formula XI to the compound of Formula II in step 7) can be (0.8-1.2):(0.8-1.2). In some embodiments, the molar ratio of the compound of Formula XI to the compound of Formula II in step 7) can be (0.9-1.1):(0.9-1.1). In some embodiments, the molar ratio of the compound of Formula XI to the compound of Formula II in step 7) can be (1.0-1.1):(1.0-1.1).

[0072] In some embodiments, preferably, the molar ratio of the compound of Formula XI to the compound of Formula II in step 7) can be 1:1.

[0073] In some embodiments, step 7) can further comprise a solvent and triethylamine. In some embodiments, the solvent in step 7) can be dichloromethane.

[0074] In some embodiments, the reaction condition of step 7) can be room temperature reaction for 0.5-2h. For example, the reaction condition of step 7) can be room temperature reaction for 0.5, 0.75, 1, 1.25, 1.5, 1.75, or 2h. Any range characterized by combinations of the above endpoints is also included and is not to be precluded herefrom.

[0075] In some embodiments, preferably, the reaction condition of step 7) can be room temperature reaction for 1h.

[0076] The experimental methods in the following examples are all routine methods unless otherwise specified. The experimental materials used in the following examples are all purchased from routine biochemical reagent companies unless otherwise specified. The quantitative tests in the following examples are all set up with three or more repeated experiments, and the results are averaged.

[0077] Example 1 - Preparation method as follows:

[0078] 1) Dissolve HM-5036_1 (100 mg, 0.41 mmol, 1.0 eq) in 48% HBr (10 mL), 130 oC The reaction was monitored by LCMS for 5 h. When the starting material was almost consumed, the reaction was stopped and the reaction mixture was concentrated to give a yellow solid, 109 mg of crude product.

[0079]

[0080] 2) HM-5036_3 (660 mg, 2.78 mmol, 1.0 eq), HM-417_15 (969 mg, 2.78 mmol, 1.0 eq), acetonitrile (30 mL), K2CO3 (1537 mg, 11.1 mmol, 4 eq) were added into a 100 mL single-neck flask, and refluxed for 12 h. The reaction was monitored by LCMS. When the starting material was almost consumed, the reaction was stopped and the reaction mixture was filtered to give a filtrate, which was concentrated to give a crude product. The crude product was purified by column chromatography (EA / MeOH (V / V=1 / 4)) to give a colorless oil, 910 mg.

[0081]

[0082] 3) HM-5036_4 (900 mg, 2.18 mmol, 1.0 eq), TsCl (415 mg, 2.18 mmol, 1.0 eq), DCM (20 mL), TEA (440 mg, 4.36 mmol, 2 eq) were added into a 50 mL single-neck flask, and stirred at room temperature for 12 h. The reaction was monitored by LCMS. When the starting material was almost consumed, the reaction was stopped and the reaction mixture was poured into water (50 mL), and extracted with DCM (20 mL x 3). The combined organic phase was washed with saturated NaCl, and dried over anhydrous sodium sulfate. The filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (EA / MeOH (V / V=1 / 6)) to give a white solid, 588 mg.

[0083]

[0084] 4) HM-5036_5 (400 mg, 0.7 mmol, 1.0 eq), HM-5036_6 (220 mg, 0.7 mmol, 1.0 eq), acetonitrile (20 mL), K2CO3 (440 mg, 2.8 mmol, 4.0 eq) were added into a 50 mL single-neck flask, and refluxed for 12 h. The reaction was monitored by LCMS. When the starting material was almost consumed, the reaction was stopped and the reaction mixture was filtered to give a filtrate, which was concentrated to give a crude product. The crude product was purified by column chromatography (EA / MeOH (V / V=1 / 4)) to give a colorless oil, 240 mg, in a yield of 48%.

[0085]

[0086] 5) HM-5036_7 (220 mg, 0.31 mmol, 1.0 eq) was dissolved in TFA / DCM (10 mL / 10 mL), and the reaction was allowed to proceed at room temperature for 1 h, with LCMS monitoring of the reaction progress. When the starting material was substantially consumed, the reaction was concentrated to give a crude product, which was purified by column chromatography (EA / MeOH (V / V=1 / 3)) to give 170 mg of a yellowish oil as a crude product.

[0087]

[0088] 6) HM-5036_8 (170 mg, 0.28 mmol, 1.0 eq), HM-5036_9 (65 mg, 0.28 mmol, 1.0 eq), DCM (20 mL), TEA (57 mg, 0.56 mmol, 2.0 eq) were added to a 100 mL single-neck flask, and the reaction was allowed to proceed at room temperature for 1 h, with LCMS monitoring of the reaction progress. When the starting material was substantially consumed, the reaction was removed from the apparatus, and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (EA / MeOH (V / V=1 / 4)) to give 100 mg of a yellow solid as a crude product.

[0089]

[0090] 7) HM-5036_10 (100 mg, 0.15 mmol, 1 eq), HM-5036_2 (40 mg, 0.15 mmol, 1 eq), DCM (20 mL), TEA (31 mg, 0.3 mmol, 2 eq) were added to a 100 mL single-neck flask, and the reaction was allowed to proceed at room temperature for 1 h, with LCMS monitoring of the reaction progress. When the starting material was substantially consumed, the reaction was removed from the apparatus, and the crude product was concentrated at room temperature. The crude product was purified by Prep-HPLC and lyophilized under reduced pressure to give 2 mg of a white solid.

[0091]

[0092] Table 1

[0093] Table 2

[0094] Example 2 - Detection of TRP channel modulation 1) Molecular docking: Scheme: 1. Protein preparation: The three-dimensional structures of Human TRPV1, Human TRPM8, Human TRPA1 were downloaded from RCSB PDB database (Human TRPV1 PDB ID: 8JQR; Human TRPM8 PDB ID: 8BDC; Human TRPA1 PDB ID: 6PQO). The Protein Preparation Wizard module was used to add hydrogens to the Human TRPV1, Human TRPM8, Human TRPA1 proteins, respectively, and delete other small molecules, protein chains, ligand molecules, leaving only the A chain and A chain ligand. Subsequently, energy optimization (OPLS2005 force field, RMSD of 0.30 Å) was performed.

[0095] 2. Definition of binding pocket grid file: The processed protein was used to make a grid file with the Receptor Grid Generation module to generate a grid file centered on the binding pocket of the antagonist ligand SAF312 of Human TRPV1, the small molecule ligand POV / Y01 of Human TRPM8, and the covalent agonist JT010 of Human TRPA1. The box size was set to 20 Å × 20 Å × 20 Å.

[0096] 3. Ligand molecule preparation: The 2D format of the multi-TRP ion channel modulator, TRPV1 inhibitor (CPZ), TRPM8 agonist (Icilin), and TRPA1 agonist (Allyl isothiocyanate) small molecule compound was processed by the LigPrep module for energy minimization (OPLS2005 force field, RMSD of 0.30 Å), and the corresponding 3D structure was output.

[0097] 4. Molecular docking: a. The high-precision (XP) mode of the Ligand docking module was used to perform molecular docking of the Human TRPV1 protein with the multi-TRP ion channel modulator and CPZ, i.e., the multi-TRP ion channel modulator and CPZ were docked with the Human TRPV1 protein through geometric matching and energy matching.

[0098] b. The high-precision (XP) mode of the Ligand docking module was used to perform molecular docking of the Human TRPM8 protein with the multi-TRP ion channel modulator and Icilin, i.e., the multi-TRP ion channel modulator and Icilin were docked with the Human TRPM8 protein through geometric matching and energy matching.

[0099] c. High precision (XP) mode of the Ligand docking module was used to perform molecular docking of Human TRPA1 protein with multi-TRP ion channel modulator, Allyl isothiocyanate, i.e. multi-TRP ion channel modulator, Allyl isothiocyanate and Human TRPA1 protein were docked to each other through geometric matching and energy matching.

[0100] Results: 1. Molecular docking results Docking scores of Human TRPV1, Human TRPM8, Human TRPA1 and small molecule compounds are shown in Table 3. (Docking_score is an important indicator to evaluate the binding ability of protein and small molecule compound, the higher the absolute value, the stronger the binding force of compound and protein).

[0101] Table 3 Protein Name Compound Docking Score Human TRPV1 (PDB ID: 8JQR) Compound1 -8.183 Human TRPV1 (PDB ID: 8JQR) HY-15640 -6.052 Human TRPM8 (PDB ID: 8BDC) Compound1 -8.760 Human TRPM8 (PDB ID: 8BDC) HY-11062 -6.579 Human TRPA1 (PDB ID: 6PQO) Compound1 -5.599 Human TRPA1 (PDB ID: 6PQO) HY-B1515 -1.474 Compound 1: multi-TRP ion channel modulator; HY-15640: CPZ; HY-11062: Icilin; HY-B1515: Allyl isothiocyanate 2. Plotting of virtual screening results a. Human TRPV1-multi-TRP ion channel modulator The binding mode of Human TRPV1-multi-TRP ion channel modulator (docking score: -8.183) and Human TRPV1 protein was plotted in 2D and 3D. The interaction mode of multi-TRP ion channel modulator and Human TRPV1 is shown in Figure 1 A, B, Human TRPV1 protein is shown as blue cartoon, and multi-TRP ion channel modulator is shown as magenta stick. Figure 1 In D, Human TRPV1 protein C skeleton is shown in blue, N atom is shown in blue, O atom is shown in dark red, H atom is shown in white, multi-TRP ion channel modulator is shown as magenta stick, π-π interaction is shown as green dotted line, and hydrogen bond interaction is shown as purple dotted line, wherein the longer the hydrogen bond length, the weaker the hydrogen bond interaction. As Figure 1As shown in C, D, the multi-TRP ion channel modulator can form 1 hydrogen bond and 2 π-π interactions with the Human TRPV1 protein: the phenolic hydroxyl group as a hydrogen bond donor forms 1 hydrogen bond with ASN551, with a distance of 1.9 Å; in addition, the multi-TRP ion channel modulator can also form 2 π-π interactions with TYR511.

[0102] b. Human TRPV1-CPZ The binding mode of Human TRPV1-CPZ (docking score: -6.052) with the Human TRPV1 protein was plotted in 2D, 3D. The interaction mode of the multi-TRP ion channel modulator with Human TRPV1 is shown in Figure 2 As shown in A, B, the Human TRPV1 protein is shown as a blue cartoon, and the multi-TRP ion channel modulator is shown as a yellow stick. Figure 2 In D, the Human TRPV1 protein C backbone is shown in blue, the N atom is shown in blue, the O atom is shown in dark red, the H atom is shown in white, the CPZ is shown as a yellow stick, and the π-π interaction is shown as a green dotted line. As shown in Figure 2 As shown in C, D, CPZ can form 1 π-π interaction with the Human TRPV1 protein: one benzene ring of the multi-TRP ion channel modulator can form 1 π-π interaction with TYR511.

[0103] c. Human TRPM8-multi-TRP ion channel modulator The binding mode of Human TRPM8-multi-TRP ion channel modulator (docking score: -8.760) with the Human TRPM8 protein was plotted in 2D, 3D. The interaction mode of the multi-TRP ion channel modulator with Human TRPM8 is shown in Figure 3 As shown in A, B, the Human TRPM8 protein is shown as a gray cartoon, and the multi-TRP ion channel modulator is shown as a magenta stick. Figure 3 In D, the Human TRPM8 protein C backbone is shown in gray, the N atom is shown in blue, the O atom is shown in dark red, the H atom is shown in white, the multi-TRP ion channel modulator is shown as a magenta stick, the π-π interaction is shown as a green dotted line, and the hydrogen bond is shown as a purple dotted line, where the longer the hydrogen bond length, the weaker the hydrogen bond interaction. As shown in Figure 3As shown in C, D, the multi-TRP ion channel modulator can form 1 hydrogen bond and 1 π-π interaction with the Human TRPM8 protein: the phenolic hydroxyl group as a hydrogen bond donor forms 1 hydrogen bond with SER739, with a distance of 1.8 Å; in addition, the multi-TRP ion channel modulator can also form 1 π-π interaction with TRP740.

[0104] d. Human TRPM8-Icilin The binding mode of Human TRPM8-Icilin (docking score: -6.579) with the Human TRPM8 protein was plotted in 2D, 3D. The interaction mode of icilin with the Human TRPM8 is shown in Figure 4 As shown in A, B, the Human TRPM8 protein is shown as a grey-white cartoon, and the multi-TRP ion channel modulator is shown as a green stick. Figure 4 In D, the Human TRPM8 protein C skeleton is shown in grey-white, the N atom is shown in blue, the O atom is shown in bright red, the H atom is shown in white, and icilin is shown as a green stick. The π-π interaction is shown as a green dotted line, and the hydrogen bond is shown as a purple dotted line, where the longer the hydrogen bond length, the weaker the hydrogen bond. As shown in Figure 4 As shown in C, D, icilin can form 1 hydrogen bond and 1 π-π interaction with the Human TRPM8 protein: the amino group on the six-membered ring as a hydrogen bond donor forms 1 hydrogen bond with SER739, with a distance of 2.1 Å; in addition, icilin can also form 1 π-π interaction with PHE738.

[0105] e. Human TRPA1- multi-TRP ion channel modulator The binding mode of Human TRPA1-multi-TRP ion channel modulator (docking score: -5.599) with the Human TRPA1 protein was plotted in 2D, 3D. The interaction mode of the multi-TRP ion channel modulator with the Human TRPA1 is shown in Figure 10 As shown in A, B, the Human TRPA1 protein C skeleton is shown in light blue, the N atom is shown in blue, the O atom is shown in bright red, the H atom is shown in white, and the multi-TRP ion channel modulator is shown as a tan stick. The hydrogen bond is shown as a yellow dotted line, and the π-π conjugation is shown as a green dotted line, where the longer the bond length, the weaker the hydrogen bond. As shown in Figure 10As shown in C, D, the multi-TRP ion channel modulator can form 2 hydrogen bond interactions, 2 π-π conjugation and hydrophobic interactions with Human TRPA1 protein: the hydroxyl group as hydrogen bond donor forms 2 hydrogen bond interactions with TYR680, HIS614 with the distance of 2.3 Å and 3.3 Å; the two benzene rings on the multi-TRP ion channel modulator form π-π conjugation with TYR680, PHE612. In addition, the multi-TRP ion channel modulator can also form hydrophobic interactions with surrounding amino acid residues.

[0106] f. Human TRPA1- Allyl isothiocyanate The binding mode of Human TRPA1-Allyl isothiocyanate (docking score: -1.474) with Human TRPA1 protein was plotted in 2D, 3D. The interaction mode of Allyl isothiocyanate with Human TRPA1 is shown in Figure 11 As shown in A, B, the Human TRPA1 protein C skeleton is shown in light blue, the N atom is shown in blue, the O atom is shown in bright red, the H atom is shown in white, and Allyl isothiocyanate is shown in yellow stick. As shown in Figure 11 As shown in C, D, Allyl isothiocyanate can form hydrophobic interactions with ILE627, CYS621, TYR662, GLN664 and other amino acid residues of Human TRPA1 protein.

[0107] The results show that the binding of the multi-TRP ion channel modulator to TRPV1 is better than the specific inhibitor CPZ, the binding to TRPM8 is better than the agonist Icilin, and the binding to TRPA1 is better than the agonist Allyl isothiocyanate.

[0108] 2) Calcium ion influx detection: Procedure: The macrophage cell line RAW264.7 cells were used for detection, and the stable cells were subcultured and cultured for 1 hour without serum. Then, the cells were loaded with Fluo-4 AM calcium ion influx reagent for 0.5 h. After removing the loading liquid, the cells were cultured in serum-free medium for half an hour and then subjected to experiment. The cells were stimulated with serum-free medium containing different stimulants. After each stimulation, the stimulant was replaced. The fluorescence intensity of the cells at 488 nm wavelength under different stimulations was recorded by microscope, which was the calcium ion influx intensity. The stimulants and concentrations were: multi-TRP ion channel modulator (Compound 1) 1 μM, CPZ 1 μM, Icilin 1 μM, Allylisothiocyanate (AITC) 1 μM, and combinations thereof.

[0109] Results: Figure 5 The fluorescence change pictures of the same macrophage cells under different stimulations are shown in A, and Figure 5 The fluorescence intensity change column chart is shown in B. It can be seen that the multi-TRP ion channel modulator can increase the calcium influx of the cells, and the calcium influx intensity after stimulation with CPZ+Icilin+AITC is similar. The calcium influx intensity after stimulation with Icilin+AITC is further increased, while CPZ+Icilin can decrease the calcium influx intensity of the cells. CPZ+AITC can increase the calcium influx intensity of the cells, but not as much as the multi-TRP ion channel modulator. The calcium influx intensity after stimulation with CPZ alone is the lowest. Icilin alone can increase the calcium influx intensity of the cells, but not as much as AITC.

[0110] In summary, the multi-TRP ion channel modulator has a regulatory effect on the calcium ion influx of the cells, and the effect is similar to that of the mixed stimulants of TRPV1 inhibitor CPZ, TRPM8 agonist Icilin, and TRPA1 agonist AITC.

[0111] II. Detection of cell function regulation as follows: 3) Activation of macrophage function pathway: Procedure: The macrophage cell line RAW264.7 cells were used for detection, and the stable cells were subcultured and cultured for 1 hour without serum. Then, the cells were loaded with Fluo-4 AM calcium ion influx reagent for 0.5 h. After removing the loading liquid, the cells were cultured in serum-free medium for half an hour and then subjected to experiment. The cells were stimulated with serum-free medium containing different stimulants. After each stimulation, the stimulant was replaced. The fluorescence intensity of the cells at 488 nm wavelength under different stimulations was recorded by microscope, which was the calcium ion influx intensity. The stimulants and concentrations were: multi-TRP ion channel modulator (Compound 1) 1 μM, CPZ 1 μM, Icilin 1 μM, Allylisothiocyanate (AITC) 1 μM, and combinations thereof.

[0112] Results: AsFigure 6 As shown in A, after stimulating the cells with multi-TRP ion channel modulator 100 nM / 1 μM / 10 μM, it was found that it had no obvious effect on the molecular level and phosphorylation level of NF-κB and p38 of normal cells. Further stimulation with LPS simulated the inflammatory state, and it was found that under the stimulation of LPS, multi-TRP ion channel modulator 100 nM / 1 μM / 10 μM could inhibit the molecular level and phosphorylation level of NF-κB, and inhibit the molecular level and phosphorylation level of p38, indicating that it had an inhibitory effect on the activation of macrophages in the inflammatory state. Next, by comparing the effects of multi-TRP ion channel modulator, CPZ, Icilin, and AITC under different stimulations, Figure 6 B found that: CPZ can significantly inhibit the phosphorylation of NF-κB of normal cells, affecting the function of normal cells, CPZ, Icilin, and AITC can significantly promote the phosphorylation of p38 of normal cells, affecting the function of normal cells, the combination of the three, AITC alone, and Icilin alone can significantly promote the phosphorylation of NF-κB and Erk1 / 2 of normal cells, affecting the function of normal cells; under the stimulation of LPS, the application of multi-TRP ion channel modulator, the combination of the three molecules, and CPZ can significantly inhibit the phosphorylation of NF-κB, inhibit the activation of macrophages in the inflammatory state, multi-TRP ion channel modulator and CPZ can significantly inhibit the phosphorylation of p38, inhibit the activation of macrophages in the inflammatory state, multi-TRP ion channel modulator, CPZ, and AITC can significantly inhibit the phosphorylation of Erk1 / 2, inhibit the activation of macrophages in the inflammatory state.

[0113] In summary, multi-concentration multi-TRP ion channel modulator has no obvious effect on normal macrophages, but can inhibit the activation of macrophages in the inflammatory state. Compared with CPZ, Icilin, and AITC, and their combinations, multi-TRP ion channel modulator has less effect on normal cells, but has similar inhibitory effect on the activation of macrophages in the inflammatory state.

[0114] 4) Macrophage inflammatory factor release: Process: Detecting the use of macrophage cell line RAW264.7Cells, cells stably passaged in culture were stimulated with LPS 1 μg / mL (mimic inflammatory state) and serum-free medium containing different stimulants for 6 h after serum-free culture for 1 h. The supernatant was collected and ELISA was performed to detect the concentrations of pro-inflammatory factors IL-1β, TNF-α, IL-23, IFN-γ, IL-12 and the concentration of anti-inflammatory factor IL-10. Stimulants and concentrations: multi-TRP ion channel modulator (Compound 1) 1 μM, CPZ 1 μM, Icilin 1 μM, Allyl isothiocyanate (AITC) 1 μM and the combination of CPZ, Icilin and AITC.

[0115] Results: As shown in Figure 7 , stimulation of multi-TRP ion channel modulator can significantly inhibit the release of other pro-inflammatory factors in macrophages under inflammatory state except IL-12, and significantly promote the release of anti-inflammatory factor IL-10. In contrast, CPZ mainly inhibits the release of IFN-γ, Icilin mainly inhibits the release of IL-1β and TNF-α, but promotes the release of IL-23, AITC mainly inhibits the release of IL-1β, TNF-α and IFN-γ, and promotes the release of IL-10, while the combination of the three promotes the release of IL-23.

[0116] In summary, multi-TRP ion channel modulator has an inhibitory effect on the release of major pro-inflammatory factors in macrophages under inflammatory state, and has a promoting effect on the release of anti-inflammatory factors, which is consistent with the respective effects of TRPV1 inhibitor CPZ, TRPM8 agonist Icilin and TRPA1 agonist AITC, but the effect is better than the combination of the three.

[0117] III. Animal experiments are as follows: 1) Regulation of intestinal inflammation: Procedure: Eight-week-old C57BL6 mice were used to model the disease. They were given 2.5% DSS in drinking water for 7 days, and their body weight was measured daily during this period. On the 8th day, the mice were sacrificed, and serum, colon length was measured, and the last 0.5 cm of rectum was taken for H&E staining. The indicators were compared. The administration methods were as follows: 100 μL of PBS solution containing 10 μM, 100 μM, and 1 mM of the multi-TRP ion channel modulator (Compound1) was administered orally, equivalent to 41.3975 μg / kg / day, 413.975 μg / kg / day, and 4.13975 mg / kg / day, respectively; 100 μL of PBS solution containing a mixture of 10 μM, 100 μM, and 1 mM of CPZ, Icilin, and AITC was administered orally, equivalent to CPZ 18.845 μg / kg / day, 188.45 μg / kg / day, and 1.8845 mg / kg / day; Icilin 15.5645 μg / kg / day, 155.645 μg / kg / day, and 1.55645 mg / kg / day, respectively; AITC 4.9575 μg / kg / d, 49.575 μg / kg / d, 495.75 μg / kg / d; 100 μL of PBS solution containing 10 μM of multi-TRP ion channel modulator (Compound1) was administered via enema, which is equivalent to 41.3975 μg / kg / d.

[0118] Result: As Figure 8 As shown in the AE, the control group of the enteritis mouse model exhibited the most severe intestinal inflammation and mucosal damage, with the most significant colonic shortening. In the treatment groups, the 1mM multi-TRP ion channel modulator and the 1mM mixture of CPZ, Icilin, and AITC showed the best therapeutic effects, with the 100μM multi-TRP ion channel modulator showing similar efficacy. Furthermore, compared to the 100μM mixture of CPZ, Icilin, and AITC, it resulted in less mucosal damage. Figure 8 (BD). It is worth noting that an enema of 10 μM of multi-TRP ion channel modulators can achieve similar therapeutic effects as an oral administration of 1 mM of multi-TRP ion channel modulators. Figure 8 BD).

[0119] In summary, the therapeutic effect of multi-TRP ion channel modulators on intestinal inflammation and mucosal damage in mice is slightly better than the combined application of TRPV1 inhibitor CPZ, TRPM8 agonist Icilin, and TRPA1 agonist AITC, and the effect of multi-TRP ion channel modulators via enema is better than that via oral administration.

[0120] 2) Mouse toxicity test: Procedure: After the mice in the control group and the groups orally administered with the multi-TRP ion channel modulator (Compound 1) at 10 μM, 100 μM and 1 mM were sacrificed, the serum was subjected to biochemical, liver function, kidney function, blood lipid and other index determination, and the liver and kidney were subjected to H&E staining for comprehensive evaluation of drug toxicity.

[0121] Results: The liver and kidney staining results are shown in Figure 9 A, and no obvious difference was observed between the groups. The biochemical, liver function, kidney function, blood lipid and other results are shown in Figure 9 B, and some inflammation and damage related indexes were relieved in the administration groups. As shown in Figure 9 C, it was found through comparison that the total protein and albumin amount in the 1 mM group was obviously improved, the total bilirubin was slightly reduced in the 1 mM group, which might be caused by anemia due to intestinal inflammation and bleeding, the alkaline phosphatase was slightly increased in the 100 μM and 1 mM groups, the lactate dehydrogenase was obviously higher in the control group than in the administration groups, which also reflected the reduction of inflammation and tissue damage, the total bile acid was slightly increased in the 100 μM and 1 mM groups, which could also be explained by anemia caused by the aggravation of intestinal inflammation in other groups, and there was no obvious difference in other indexes.

[0122] In summary, the multi-TRP ion channel modulator has little effect on the biochemical, liver function, kidney function, blood lipid and other indexes of mice, slightly affects the metabolism of bile acid and bilirubin, and can obviously reduce the level of lactate dehydrogenase.

[0123] The above has described the basic concepts, and it is obvious that the above detailed disclosure is only used as an example for the person skilled in the art, and does not constitute a limitation on the present specification. Although it is not explicitly stated here, the person skilled in the art can make various modifications, improvements and corrections to the present specification. Such modifications, improvements and corrections are suggested in the present specification, so such modifications, improvements and corrections still belong to the spirit and scope of the exemplary embodiments of the present specification.

[0124] Meanwhile, specific words are used in the present specification to describe the embodiments of the present specification. As "one embodiment", "an embodiment" and / or "some embodiments" mean a certain feature, structure or characteristic related to at least one embodiment of the present specification. Therefore, it should be emphasized and noted that the "an embodiment" or "one embodiment" or "one alternative embodiment" mentioned in different places in the present specification does not necessarily mean the same embodiment. In addition, some features, structures or characteristics in one or more embodiments of the present specification can be properly combined.

[0125] In some embodiments, numbers that describe amounts, dimensions, and so forth, are used in the description of the embodiments. It should be understood that such numbers are used only to illustrate certain embodiments and that the scope of the embodiments is not limited to the numbers. In some examples, such numbers are modified by the modifier "about" or "approximately." Unless otherwise indicated, "about" or "approximately" means ±20% of the value stated. Accordingly, in some embodiments, numerical parameters in the specification and claims are approximations that can vary depending on the desired properties sought to be obtained by the individual embodiments. In some embodiments, numerical parameters are approximations that can vary from the numerical parameters set forth in the specification and claims. In some embodiments, numerical parameters should be considered in the context of the number of significant digits in which they are set forth. Although the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values set forth in the specific examples are provided to be as precise as practicable.

[0126] Finally, it should be understood that the embodiments described herein are merely exemplary of the principles of the embodiments. Other variations having essentially the same structure and function are within the scope of the embodiments. Accordingly, many modifications can be made by those skilled in the art without departing from the scope of the embodiments. For example, those skilled in the art will recognize that the embodiments described herein can be used in other applications and / or with other structures and / or components.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, the chemical structure of the compound is shown as formula XXI: Formula XII. 2.A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to claim 1.

3. The pharmaceutical composition of claim 2, wherein Further comprising a pharmaceutically acceptable carrier or excipient. 4.Use of the compound or the pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 2 or 3 in the preparation of a medicament.

5. Use according to claim 4, characterized in that, The medicament is a modulator of multiple TRP ion channels; And / or, the medicament inhibits TRPV1, activates TRPM8, and activates TRPA1; And / or, the medicament is used for treating at least one of the following diseases: functional gastrointestinal disease, intestinal mucosal injury, intestinal inflammation, immune disorder, dysbacteriosis, digestive tract tumor, pain, or peripheral neuritis.

6. The use according to claim 4, characterized in that, The medicament has one or more of the following functions: Binding to TRPV1; Regulating calcium ion influx of cells; Inhibiting activation of macrophages in an inflammatory state; Inhibiting release of pro-inflammatory factors in macrophages in an inflammatory state; Promoting release of anti-inflammatory factors in macrophages in an inflammatory state; Reducing lactate dehydrogenase level.

7. The method for preparing the compound according to claim 1, characterized in that, Comprising the following steps: 1) mixing the compound shown as formula I with HBr, reacting to obtain the compound shown as formula II; ； 2) mixing the compound shown as formula III with the compound shown as formula IV, reacting to obtain the compound shown as formula V; ； 3) mixing the compound shown as formula V with TsCl, reacting, extracting to obtain the compound shown as formula VI; ； 4) mixing the compound shown as formula VI with the compound shown as formula VII, reacting to obtain the compound shown as formula VIII; ； 5) dissolving the compound shown as formula VIII in a solvent, reacting to obtain the compound shown as formula IX; ； 6) mixing the compound shown as formula IX with the compound shown as formula X, reacting to obtain the compound shown as formula XI; ； 7) mixing the compound shown as formula XI with the compound shown as formula II, reacting to obtain the compound shown as formula XXI; 。 8. The production method according to claim 7, wherein The reaction conditions of the step 1) are 100-150 o C for 3-7 h; And / or, the mass-volume ratio of the compound shown as formula I to HBr in step 1) is (50-150) mg:(5-15) mL; And / or, the reaction condition of step 2) is heating and refluxing in a closed device for 10-14 h; And / or, the molar ratio of the compound shown as formula III to the compound shown as formula IV in step 2) is (0.5-1.5):(0.5-1.5); And / or, step 2) further comprises a solvent and a carbonate; And / or, the molar ratio of the compound shown as formula V to TsCl in step 3) is (0.5-1.5):(0.5-1.5); And / or, step 3) further comprises a solvent and triethylamine; And / or, the reaction condition of step 3) is stirring at room temperature for 12 h; And / or, the molar ratio of the compound shown as formula VI to the compound shown as formula VII in step 4) is (0.5-1.5):(0.5-1.5); And / or, step 4) further comprises a solvent and a carbonate; And / or, the reaction condition of step 4) is heating and refluxing in a closed device for 10-14 h; And / or, in the step 5), the mass-volume ratio of the compound of formula VIII to the solvent is (150-300) mg:(5-15) mL; And / or, the reaction condition of the step 5) is room temperature for 0.5-2 h; And / or, in the step 6), the molar ratio of the compound of formula IX to the compound of formula X is (0.5-1.5):(0.5-1.5); And / or, the step 6) further comprises a solvent and triethylamine; And / or, the reaction condition of the step 6) is room temperature for 0.5-2 h; And / or, in the step 7), the molar ratio of the compound of formula XI to the compound of formula II is (0.5-1.5):(0.5-1.5); And / or, the step 7) further comprises a solvent and triethylamine; And / or, the reaction condition of the step 7) is room temperature for 0.5-2 h.

9. The production method according to claim 8, wherein The reaction conditions of step 1) are 130 o C for 5 h; And / or, the reaction condition of the step 2) is heating reflux for 12 h in a closed device; And / or, the solvent in the step 2) is acetonitrile, and the carbonate is sodium carbonate; And / or, the solvent in the step 3) is dichloromethane; And / or, the reaction condition of the step 4) is heating reflux for 12 h in a closed device; And / or, the solvent in the step 4) is acetonitrile, and the carbonate is sodium carbonate.

10. The production method according to claim 8, wherein In the step 5), the solvent is trifluoroacetic acid or dichloromethane; And / or, the reaction condition of the step 5) is room temperature for 1 h; And / or, in the step 6), the solvent is dichloromethane; And / or, the reaction condition of the step 6) is room temperature for 1 h; And / or, in the step 7), the solvent is dichloromethane; And / or, the reaction condition of the step 7) is room temperature for 1 h.

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