Preparation method and analgesic application of monoterpenoids in jasmine roots and polymers of monoterpenoids

Abstract

The invention discloses an iridoid glycoside compound, an iridoid glycoside polymer and application of pharmaceutically acceptable salt of the iridoid glycoside compound in a medicine for preventing and / or treating pain. The compound disclosed by the invention has a remarkable treatment effect on acute and chronic inflammatory pains, chronic neuropathic pains and the like. Belongs to the technical field of medicine.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to an iridoid glycoside compound 12 and an iridoid glycoside polymer 1-11, including new compounds 1-8 and known compounds 9-12, and use of the compounds in preparing drugs for preventing and / or treating pain. Background Art

[0002] Pain is one of the most common clinical symptoms. Pain is usually caused by harmful stimuli that cause tissue damage. Mechanical stimuli such as knife cutting and stick hitting, and physical and chemical factors such as electric current, high temperature, strong acid and strong alkali can all become harmful stimuli. Bioactive substances such as potassium ions, 5-hydroxytryptamine, acetylcholine, bradykinin, histamine, etc. released into the extracellular fluid when tissue cells are inflamed or damaged can also cause pain or hyperalgesia. Therefore, pain can serve as a warning that the body is injured, causing a series of defensive protective reactions in the body. But on the other hand, some long-term severe pain has become an unbearable torture for the body. Therefore, the development of analgesics has a broad market space.

[0003] Pain can be divided into acute pain, chronic inflammatory pain and neuropathic pain. The mainstream analgesics on the market are mainly non-steroidal anti-inflammatory drugs and opioids. Non-steroidal anti-inflammatory drugs are often ineffective for severe pain, while opioids are prone to cause adverse reactions such as severe constipation and addiction. Therefore, finding potential non-opioid analgesics is of great clinical significance.

[0004] Natural products have always been an important source of analgesics. The analgesics currently used in clinical practice are all natural products found from medicinal plants. Jasmine root (Jasminum sambac (L.) Ait.) is the root of the jasmine plant of the genus Jasminum. It is bitter, warm and poisonous in nature. "Compendium of Materia Medica" says: "Grind one inch of it with wine and take it, and the patient will wake up after one day of coma, two inches for two days, and three inches for three days. Anyone who falls, dislocates or sets bones will not feel pain if he uses this." It has the effects of anesthesia, analgesia, and treatment of broken bones, caries, headaches, and insomnia. Researchers from China (Zhang YJ, et al. Iridoidal glycosides from Jasminum sambac [J]. Phytochemistry, 1995, 38 (4): 899-903) and Japan (Takao, Tanahashi, et al. Sambacosides a, e and f, novel tetrameric iridoid glucosides from jasminum sambac [J]. Tetrahedron Letters, 1988, 29 (15): 1793-1796) have studied the chemical composition of this plant and have isolated and identified the structures of compounds 8-12, but their strong analgesic effect has not been discovered. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a new type of analgesic drugs, specifically, the use of iridoid glycoside compounds, iridoid glycoside polymers and pharmaceutically acceptable salts thereof in the preparation of products for preventing and / or treating pain, wherein the compounds are derived from jasmine roots.

[0006] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0007] The first aspect: provides the use of the compound (1-12) or a pharmaceutically acceptable salt thereof in the preparation of a product for preventing and / or treating pain;

[0008]

[0009] <![CDATA[R 1 ]]> <![CDATA[R 2 ]]> <![CDATA[R 3 ]]> <![CDATA[R 4 ]]> Compound 1 OH OH OH Ac Compound 2 OH Ac OH OH Compound 3 A A OH Ac Compound 4 OH B OH OH Compound 5 A OH Ac OH Compound 6 A Ac A OH Compound 7 OH OH A OH Compound 8 OH A OH A .

[0010]

[0011] The pharmaceutically acceptable salts include pharmaceutically acceptable organic salts or inorganic salts, wherein the organic salts include sulfonates, carboxylates, amino acid salts and fatty acid salts, and the inorganic salts include hydrochlorides, bromates, iodates, sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, dihydrogen phosphates and nitrates.

[0012] The sulfonates include alkyl sulfonates containing 1 to 15 carbon atoms, benzene sulfonates, p-toluene sulfonates, o-toluene sulfonates, and m-toluene sulfonates; carboxylates include tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate, and lactate; amino acid salts include glutamate and aspartate; fatty acid salts include long-chain fatty acid salts containing 2 to 18 carbon atoms.

[0013] The pain includes acute pain, chronic inflammatory pain, diabetic peripheral neuropathy pain, cancer pain, trigeminal neuralgia, post-herpetic neuralgia, post-traumatic neuralgia, chemotherapy-induced polyneuropathy pain, complex regional pain syndrome, HIV sensory neuropathy pain, post-operative neuralgia, phantom limb pain, radicular neuropathy, post-radiotherapy plexus disease pain, and neuropathic pain caused by spinal cord injury.

[0014] The second aspect: provides an application of a pharmaceutical composition in the preparation of a product for preventing and / or treating pain, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compounds 1-12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0015] The pharmaceutical composition can be prepared according to methods known in the art. For this purpose, the compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to prepare an appropriate administration form or dosage form that can be used as a human or veterinary drug. Usually, the pharmaceutical composition of the present invention contains 0.1-95% by weight of the compound of the present invention. In a unit dosage form, the compound of the present invention generally contains 0.05-100 mg, and a preferred unit dosage form contains 0.5-10 mg.

[0016] The compound of the present invention or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intramuscular, subcutaneous, intravenous, nasal, oral mucosa, skin, peritoneum or rectum.

[0017] The administration route of the compound of the present invention or the pharmaceutical composition containing the compound can be injection, which includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.

[0018] The dosage form for administration can be a liquid dosage form or a solid dosage form. For example, the liquid dosage form can be a true solution, a colloid, a microparticle dosage form, an emulsion dosage form, a suspension dosage form, etc. Other dosage forms include tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, etc.

[0019] The compound of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0020] For example, in order to formulate a unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of carriers include diluents and absorbents, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders, such as water, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown seaweed starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption promoters, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0021] For example, in order to make the dosing unit into a pill, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, Gelucire, kaolin, talc, etc.; binders, such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methyl cellulose, ethyl cellulose, etc.

[0022] For example, in order to prepare the dosing unit into a capsule, the active ingredient compound of the present invention is mixed with the above-mentioned various carriers, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. The active ingredient compound of the present invention can also be prepared into a microcapsule, suspended in an aqueous medium to form a suspension, or loaded into a hard capsule or prepared as an injection for use.

[0023] For example, the compound of the present invention is made into an injection preparation, such as a solution, suspension, emulsion, or freeze-dried powder injection. This preparation may be aqueous or non-aqueous, and may contain one or more pharmacodynamically acceptable carriers, diluents, adhesives, lubricants, preservatives, surfactants, or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose, or glycerol may be added to the injection preparation. In addition, conventional cosolvents, sustained-release agents, pH regulators, and the like may also be added. These adjuvants are commonly used in the art.

[0024] In addition, if necessary, colorants, preservatives, perfumes, flavoring agents, sweeteners or other materials may be added to the pharmaceutical preparations.

[0025] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0026] The dosage of the pharmaceutical composition of the compound of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, and the purpose of treatment. Therefore, the therapeutic dose of the present invention can vary widely. Generally speaking, the dosage of the pharmaceutical ingredients in the present invention is well known to those skilled in the art. It can be appropriately adjusted according to the actual amount of drugs contained in the final preparation of the compound composition of the present invention to achieve the requirements of its therapeutically effective amount and complete the prevention or treatment purpose of the present invention. The daily suitable dosage range of the compound of the present invention: the dosage of the compound of the present invention is 0.0001-100 mg / kg body weight, which can be taken once or in multiple doses. The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.

[0027] Beneficial technical effects:

[0028] Jasmine is widely distributed in southern China, and the raw materials are abundant and convenient to source. The water extract of jasmine root has weak analgesic activity. The compound of the present invention is separated from the water extract of jasmine root, and its analgesic activity is much stronger than that of the water extract. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Flow chart of extraction and separation of jasmine root

[0030] Figure 2 Analgesic activity of compound 1-12 in the acetic acid writhing model in mice (20 mg / kg)

[0031] Figure 3Dose-effect relationship of analgesic activity of compounds 1, 5, and 10

[0032] Figure 4 Comparison of analgesic activity of total iridoid glycosides from jasmine root by intraperitoneal injection and oral administration DETAILED DESCRIPTION

[0033] Terms and abbreviations

[0034] ESI-MS Electrospray Mass Spectrometry

[0035] COSY Homonuclear Chemical Shift Correlation Spectroscopy

[0036] DEPT Distortionless Enhanced Polarization Transfer Spectroscopy

[0037] HMBC heteronuclear multiple bond correlation (a two-dimensional nuclear magnetic resonance spectrum that determines the long-range hydrogen-carbon bonding relationship in molecules)

[0038] HPLC High Performance Liquid Chromatography

[0039] HRESI-MS High Resolution Electrospray Mass Spectrometry

[0040] HSQC heteronuclear single quantum correlation (a two-dimensional nuclear magnetic resonance spectrum that measures the direct connection between hydrogen and carbon in a molecule)

[0041] IR infrared spectroscopy

[0042] NMR Nuclear Magnetic Resonance

[0043] NOESY Overhauser Gain Spectroscopy (a two-dimensional nuclear magnetic resonance spectrum that measures the spatial proximity of hydrogen atoms in a molecule)

[0044] UV spectrum

[0045] The following examples and pharmaceutical activity experiments are used to further illustrate the present invention, but they do not mean any limitation of the present invention.

[0046] Example 1: Isolation and structural characterization of compounds 1-12

[0047] 60kg of jasmine root was crushed and extracted with water reflux twice, each time for 3 hours. The extract was concentrated under reduced pressure to obtain 6kg of extract. The total extract was subjected to macroporous resin (D-101) adsorption chromatography column, and eluted with water, 30%, 60% and 95% ethanol in turn to obtain four fractions E1, E2, E3 and E4 respectively. Among them, the E2 fraction (1.2kg) was subjected to silica gel (200-300 mesh) adsorption chromatography column, and eluted with dichloromethane to methanol 15:1, 10:1, 5:1, 1:1 and methanol in turn to obtain seven components Fr1-Fr7 respectively, among which the Fr2 component (28g) was subjected to medium pressure reverse phase ODS chromatography column, at a flow rate of 30ml / min, 30% methanol-water to methanol gradient elution for 3 hours to obtain components F1-F6. Fraction F4 (1.2 g) was subjected to preparative liquid chromatography (Shimadzu LC-6AD chromatograph; Silgreen C18 column, 250×10 mm, 5 μm; 20% acetonitrile water as mobile phase; flow rate 3 ml / min) to obtain compounds 1 and 2. The Fr4 component (370 g) was subjected to a normal pressure reversed phase MCI column, eluted with water, 10% methanol water, 30% methanol water, 50% methanol water, 70% methanol water, and methanol in sequence to obtain four fractions: M1, M2, M3, and M4. The M3 component was subjected to a polyamide chromatography column and eluted with water, 30% methanol water, 60% methanol water, and methanol, respectively, to obtain four fractions of J1, J2, J3, and J4. The J2 component (2.3 g) was subjected to preparative liquid chromatography (Shimadzu LC-6AD chromatograph; Silgreen C18 chromatography column, 250×20 mm, 5 μm; 25% acetonitrile water as mobile phase; flow rate 6 ml / min) to obtain compounds 8 and 9. The J1 fraction (28 g) was subjected to an LH-20 dextran gel chromatography column and eluted isocratically with methanol to water 1:1 to obtain eight fractions of F1-F8. The F5 component (18 g) was subjected to an LH-20 dextran gel chromatography column and eluted isocratically with methanol to obtain four fractions of F5G1-F5G4. The F5G4 component (6 g) was subjected to a silica gel (200-300 mesh) adsorption chromatography column, and eluted with ethyl acetate to methanol to water at 30:1:0.6, 20:1:0.6, 15:1:0.6, 10:1:0.6, 5:1:0.6, methanol to obtain nine fractions F5G4G1-F5G4G9. The F5G4G5 component (314 mg) was subjected to preparative liquid chromatography (Shimadzu LC-6AD chromatograph; Silgreen C18 column, 250×10 mm, 5 μm; 17% acetonitrile water as mobile phase; flow rate 3 ml / min) to obtain compounds 4, 7, and 11. The F5G4G4 fraction (245 mg) was purified by preparative liquid chromatography (Shimadzu LC-6AD chromatograph; YMC-Pack Ph liquid chromatography column, 250×10 mm, 5 μm; 21.5% acetonitrile water as the mobile phase; flow rate 3 ml / min) to give compound 5.The F5G4G7 component (3.2 g) was subjected to preparative liquid chromatography (Shimadzu LC-6AD chromatograph; Silgreen C18 column, 250×20 mm, 5 μm; 25% acetonitrile water as mobile phase; flow rate 6 ml / min) to obtain compound 10. The F8 component (3.2 g) was subjected to silica gel (200-300 mesh) adsorption chromatography column, eluted with ethyl acetate to methanol to water 30:1:0.6, 20:1:0.6, 12:1:0.6, 10:1:0.6, 5:1:0.6, methanol, to obtain nine fractions F8G1-F8G9, of which F8G4 was compound 12. The M4 component (150 g) was subjected to a silica gel (200-300 mesh) adsorption chromatography column, and eluted with ethyl acetate to methanol to water at 20:1:0.5, 40:2.5:0.5, 10:1:0.5, 5:1:0.5, and methanol, respectively, to obtain seven fractions F1-F7. The F6 component (8.7 g) was subjected to a LH-20 dextran gel chromatography column, and isocratically eluted with methanol to obtain four fractions G1-G4. The G2 component was subjected to preparative liquid chromatography (Shimadzu LC-6AD chromatograph; Silgreen C18 chromatographic column, 250×10mm, 5μm; 17% acetonitrile water as mobile phase; flow rate 3ml / min) to obtain compounds 3 and 6.

[0048] The extraction and separation flow chart is as attached. Figure 1 As shown. Structural formula and identification method of compound 1-12

[0049]

[0050]

[0051] Spectral data and physicochemical properties of compounds 1-12

[0052] Compound 1

[0053] White powder, HRESI-MS m / z 421.14975[M+HCOO] - ; 1 H NMR and 13 C NMR, (see Table 1).

[0054] Compound 2

[0055] White powder, HRESI-MS m / z 421.14975[M+HCOO] - ; 1 H NMR and 13 C NMR, (see Table 1).

[0056] Compound 3

[0057] White powder, HRESI-MS m / z 1041.38159[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 3).

[0058] Compound 4

[0059] White powder, HRESI-MS m / z 613.24664[M+Na] + ; 1 HNMR and 13 C NMR, (see Table 2). Compound 5

[0060] White powder, HRESI-MS m / z 655.25610[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 3).

[0061] Compound 6

[0062] White powder, HRESI-MS m / z 1041.38171[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 3).

[0063] Compound 7

[0064] White powder, HRESI-MS m / z 613.24628[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 2).

[0065] Compound 8

[0066] White powder, HRESI-MS m / z 999.36707[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 4).

[0067] Compound 9

[0068] White powder, HRESI-MS m / z 1385.48840[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 4).

[0069] Compound 10

[0070] White powder, HRESI-MS m / z 999.36780[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 4).

[0071] Compound 11

[0072] White powder, HRESI-MS m / z 613.24628[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 2).

[0073] Compound 12

[0074] Light yellow powder, HRESI-MS m / z 441.13641[M+Na] + ; 1 H NMR and 13 C NMR, (see Table 5).

[0075] Table 1 Compounds 1, 2 1 H and 13 C-NMR data

[0076]

[0077]

[0078] Table 2 Compounds 4, 7, and 11 1 H and 13 C-NMR data

[0079]

[0080]

[0081] Table 3 Compounds 3, 5, and 6 1 H and 13 C-NMR data

[0082]

[0083]

[0084] Table 4 Compounds 8, 9, and 10 1 H and 13 C-NMR data

[0085]

[0086]

[0087] Table 5 Compound 12 1 H and 13 C-NMR data

[0088]

[0089] Pharmacological experiments

[0090] Test Example 1 Analgesic Activity Test of Compound (1-12) Isolated from Jasmine Root

[0091] Acetic acid writhing test in mice (acute pain model)

[0092] Experimental principle:

[0093] Injecting a certain volume and concentration of chemical irritants such as acetic acid into the abdominal cavity of mice stimulates the visceral and parietal peritoneum, causing deep, large-area, and long-term inflammatory pain, which causes the mice to have behavioral reactions such as abdominal concavity, trunk and hind limb extension, and buttocks elevation, which is called the writhing reaction. This reaction usually occurs within 15 minutes after injection, so the number of writhings occurring within 15 minutes after injection can be used as a quantitative indicator of pain.

[0094] Materials and methods

[0095] 1. Mice: Kunming mice, 18-22 g, male.

[0096] 2. Sample processing: Prepare the sample into a stock solution with physiological saline before use, and dilute it with culture medium to a certain concentration before use during testing.

[0097] 3. Positive control drugs: pethidine hydrochloride (Pethidine, Petd), ibuprofen (Ib).

[0098] 4. Test method: The mice were randomly divided into groups, with 8 mice in each group. Experimental group (20 mg / kg); ibuprofen positive drug control group (20 mg / kg), pethidine hydrochloride control group high concentration (20 mg / kg), low concentration (1 mg / kg); blank control group (same volume of normal saline), the administration method is intraperitoneal injection, the administration volume is 0.1 mL / 10 g, and wait for 10 minutes after the administration is completed. Prepare 0.9% acetic acid solution with normal saline, the dosage is 0.1 mL / 10 g. The administration method is intraperitoneal injection, and wait for 5 minutes. Record the number of mouse twists within 15 minutes, calculate the drug inhibition rate on the twisting reaction according to the following formula, and judge the drug analgesic effect:

[0099] Inhibition rate (%) = (number of twists in the saline group - number of twists in the experimental group) / number of twists in the saline group × 100%

[0100] Test results:

[0101] Table 6. Table of writhing inhibition rates of compounds 1-12 at a dose of 20 mg / kg

[0102]

[0103]

[0104] Note: Significant difference * P<0.05, ** P<0.01, *** P<0.001.

[0105] The experimental results showed that at a concentration of 20 mg / kg, compounds 1, 5, and 10 could significantly inhibit the number of acetic acid writhings in mice, with an inhibition rate of 81.6%-93.2%.

[0106] Experimental Example 2 Dose-effect relationship of analgesic activity of the better active compounds 1, 5, and 10 isolated from jasmine roots

[0107] Experimental principle:

[0108] Injecting a certain volume and concentration of chemical irritants such as acetic acid into the abdominal cavity of mice stimulates the visceral and parietal peritoneum, causing deep, large-area, and long-term inflammatory pain, which causes the mice to have behavioral reactions such as abdominal concavity, trunk and hind limb extension, and buttocks elevation, which is called the writhing reaction. This reaction usually occurs within 15 minutes after injection, so the number of writhings occurring within 15 minutes after injection can be used as a quantitative indicator of pain.

[0109] Materials and methods

[0110] 1. Mice: Kunming mice, 18-22 g, male.

[0111] 2. Sample processing: Prepare the sample into a stock solution with physiological saline before use, and dilute it with culture medium to a certain concentration before use during testing.

[0112] 3. Positive control drugs: pethidine hydrochloride (Pethidine), ibuprofen (Ib).

[0113] 4. Test method: The mice were randomly divided into groups, with 8 mice in each group. The experimental groups were high-dose group (20 mg / kg), medium-dose group (10 mg / kg), and low-dose group (1 mg / kg); the ibuprofen positive drug control group (20 mg / kg), the pethidine hydrochloride control group high concentration (20 mg / kg), and low concentration (1 mg / kg); the blank control group (same volume of normal saline), the administration method was intraperitoneal injection, the administration volume was 0.1 mL / 10 g, and waited for 10 minutes after the administration was completed. Prepare 0.9% acetic acid solution with normal saline, the dosage was 0.1 mL / 10 g. The administration method was intraperitoneal injection, and waited for 5 minutes. Record the number of mouse twists within 15 minutes, and calculate the drug inhibition rate on the twisting reaction according to the following formula to judge the drug analgesic effect:

[0114] Inhibition rate (%) = (number of twists in the saline group - number of twists in the experimental group) / number of twists in the saline group × 100%

[0115] Test results:

[0116] Table 7. Dose-effect relationship of analgesic activity of compounds 1, 5, and 10

[0117]

[0118]

[0119] Note: Significant difference * P<0.05, ** P<0.01, *** P<0.001.

[0120] See attached for the results Figure 3 .

[0121] Experimental Example 3 Comparison of analgesic activity of iridoid glycosides and their polymer crude fractions from jasmine root by intraperitoneal injection and intragastric administration

[0122] Experimental principle:

[0123] Injecting a certain volume and concentration of chemical irritants such as acetic acid into the abdominal cavity of mice stimulates the visceral and parietal peritoneum, causing deep, large-area, and long-term inflammatory pain, which causes the mice to have behavioral reactions such as abdominal concavity, trunk and hind limb extension, and buttocks elevation, which is called the writhing reaction. This reaction usually occurs within 15 minutes after injection, so the number of writhings occurring within 15 minutes after injection can be used as a quantitative indicator of pain.

[0124] Materials and methods

[0125] 1. Mice: Kunming mice, 18-22 g, male.

[0126] 2. Sample processing: Prepare the sample into a stock solution with physiological saline before use, and dilute it with culture medium to a certain concentration before use during testing.

[0127] 3. Test method: The mice were randomly divided into groups, with 8 mice in each group. Intraperitoneal injection group (20 mg / kg), oral gavage high-dose group (200 mg / kg), oral gavage medium-dose group (100 mg / kg), oral gavage low-dose group (50 mg / kg); blank control group (same volume of normal saline). The intraperitoneal injection experimental group was administered by intraperitoneal injection, with a dosing volume of 0.1 mL / 10 g. After the administration was completed, wait for 10 minutes, prepare 0.9% acetic acid solution with normal saline, the dosing volume was 0.1 mL / 10 g, and the dosing method was intraperitoneal injection, and wait for 5 minutes. Record the number of mouse twists within 15 minutes. The blank group and the oral gavage experimental group were administered by oral gavage, with a dosing volume of 0.1 mL / 10 g. After the administration was completed, wait for 30 minutes. Prepare 0.9% acetic acid solution with normal saline, the dosing volume was 0.1 mL / 10 g, and the dosing method was intraperitoneal injection, and wait for 5 minutes. Record the number of mouse twists within 15 minutes. The drug volume was calculated according to the following formula to calculate the inhibition rate of the drug on the writhing reaction and to judge the analgesic effect of the drug:

[0128] Inhibition rate (%) = (Number of twists in the saline group - Number of twists in the experimental group) / Number of twists in the saline group × 100% Test results:

[0129] Table 7. Dose-effect relationship of analgesic activity of compounds 1, 5, and 10

[0130]

[0131] Note: Significant difference * P<0.05, ** P<0.01, *** P<0.001.

[0132] See attached for the results Figure 4 .

Claims

1. The following compound 1-8 or a pharmaceutically acceptable salt thereof; 。 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The pharmaceutically acceptable salts include pharmaceutically acceptable organic salts or inorganic salts, wherein the organic salts include sulfonates, carboxylates, amino acid salts and fatty acid salts, and the inorganic salts include hydrochlorides, bromates, iodates, sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, dihydrogen phosphates and nitrates.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that The sulfonates include alkyl sulfonates containing 1 to 15 carbon atoms, benzene sulfonates, p-toluene sulfonates, o-toluene sulfonates, and m-toluene sulfonates; carboxylates include tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate, and lactate; amino acid salts include glutamate and aspartate; fatty acid salts include long-chain fatty acid salts containing 2 to 18 carbon atoms.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a therapeutically effective amount of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

5. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 4 in the preparation of a drug for preventing and / or treating pain.

6. Use of the following compound or its pharmaceutically acceptable salt or the pharmaceutical composition of claim 4 in the preparation of a drug for preventing and / or treating pain 7. The use according to any one of claims 5-6, characterized in that: The pain includes acute pain, inflammatory pain, diabetic peripheral neuropathy pain, cancer pain, trigeminal neuralgia, post-herpetic neuralgia, post-traumatic neuralgia, chemotherapy-induced polyneuropathy pain, complex regional pain syndrome, HIV sensory neuropathy pain, post-operative neuralgia, phantom limb pain, radicular neuropathy pain, post-radiotherapy plexus disease pain, and neuropathic pain caused by spinal cord injury.

8. Use of a pharmaceutical composition in the preparation of a product for preventing and / or treating pain, characterized in that: The pharmaceutical composition comprises a therapeutically effective amount of the compound of claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

9. The use according to claim 6, characterized in that The pharmaceutically acceptable salts include pharmaceutically acceptable organic salts or inorganic salts, wherein the organic salts include sulfonates, carboxylates, amino acid salts and fatty acid salts, and the inorganic salts include hydrochlorides, bromates, iodates, sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, dihydrogen phosphates and nitrates.

10. The use according to claim 9, characterized in that The sulfonates include alkyl sulfonates containing 1 to 15 carbon atoms, benzene sulfonates, p-toluene sulfonates, o-toluene sulfonates, and m-toluene sulfonates; carboxylates include tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate, and lactate; amino acid salts include glutamate and aspartate; fatty acid salts include long-chain fatty acid salts containing 2 to 18 carbon atoms.

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