Vinyl pyrone compound

Abstract

The invention provides a vinyl pyrone compound. The vinyl pyrone compound provided by the invention has excellent anti-inflammatory activity and antioxidant activity.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular relates to a vinyl pyrone compound. Background Art

[0002] Studies have shown that excessive free radicals can lead to the destruction of tissue cells, sub-cells and molecular structures, and damage biological macromolecules such as nucleic acids, lipids, proteins, enzymes, sugars, etc., and gradually expand to cause functional damage as the damage level expands, causing cardiovascular diseases, cancer and aging, etc., which is the pathological basis of many diseases. Antioxidant active ingredients can remove free radicals, reduce oxidants, and play a role in protecting the body.

[0003] Inflammation is a defensive response of living tissues with vascular systems to damaging factors. Most diseases are accompanied by inflammation, which can aggravate the occurrence and development of the disease. Some chronic inflammation can lead to the occurrence of tumors. Therefore, the control and treatment of inflammation is of great significance.

[0004] Finding and developing antioxidants and anti-inflammatory substances that can scavenge oxygen free radicals has become an important research topic in the fields of biology, medicine, chemistry, and pharmacy. Summary of the invention

[0005] The present invention provides the following vinyl pyrone compounds, their stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs:

[0006]

[0007] The present invention also provides a pharmaceutical composition, which comprises one, two or more of the above-mentioned vinyl pyrone compounds, their stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, and prodrugs.

[0008] According to an embodiment of the present invention, the pharmaceutical composition may optionally further comprise at least one pharmaceutically acceptable excipient.

[0009] Pharmaceutically acceptable excipients include solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, excipients, flocculants and deflocculating agents, filter aids, and release retardants.

[0010] According to an embodiment of the present invention, the pharmaceutical composition may optionally further comprise at least one additional active ingredient; specifically, the pharmaceutical composition may further comprise one or more active ingredients other than the above-mentioned vinylpyrone compounds, their stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, and prodrugs.

[0011] In the pharmaceutical composition, the dosage of the vinyl pyrone compound, its pharmaceutically acceptable salt, solvate, polymorph, metabolite, stereoisomer, tautomer, isotope label, nitrogen oxide, ester, prodrug can be a therapeutically effective amount.

[0012] According to an embodiment of the present invention, the pharmaceutical composition of the present invention can be prepared into a dosage form suitable for administration by methods known in the art. According to an embodiment of the present invention, the preparation (or pharmaceutical composition) includes: oral preparations and non-oral preparations. According to an embodiment of the present invention, the preparation includes: powders, granules, capsules, injections, inhalants, tinctures, oral liquids, tablets, lozenges, or pills.

[0013] The present invention also provides the use of the above-mentioned vinyl pyrone compounds, their stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, prodrugs or the above-mentioned pharmaceutical compositions in the preparation of anti-inflammatory and antioxidant drugs.

[0014] The present invention also provides an anti-inflammatory and antioxidant method, which comprises administering to a subject a therapeutically effective amount of the above-mentioned vinyl pyrone compound, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, prodrugs or one, two or more of the above-mentioned pharmaceutical compositions.

[0015] Beneficial Effects

[0016] The invention provides a vinyl pyrone compound, which has excellent anti-inflammatory and antioxidant activities.

[0017] Definitions and Explanations of Terms Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0018] The stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0019] "Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0020] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0021] "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0022] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0023] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0024] In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in their R and S forms. Chromatographic enantiomer resolution can also be advantageously performed with the aid of optically active resolving agents (e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile.

[0025] The term "tautomer" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in a solution), the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include mutual conversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valen cetautomers) include mutual conversions carried out by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0026] The "nitrogen oxide" of the present invention refers to when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

[0027] The term "isotopically labeled" includes, but is not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur and chlorine (e.g. 2 H, 3 H, 13 C, 14 C, 15 N, 18 Oh, 17 Oh, 18 F, 35 S and 36 Isotope-labeled compounds of the present invention can be used for determination of tissue distribution of compounds and their prodrugs and metabolites; preferred isotopes for such determinations include 3 H and 14 C. In addition, in some cases, substitution with heavier isotopes such as deuterium (2H or D) can provide increased metabolic stability, which provides therapeutic advantages such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to the methods described herein.

[0028] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reactions, such as gastrointestinal upset, dizziness, and the like, when administered to humans.

[0029] The term "carrier" refers to a diluent, adjuvant, excipient or matrix with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water and aqueous saline solutions and aqueous glucose and glycerol solutions are preferably used as carriers, particularly injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin.

[0030] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, see the following: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0031] The term "metabolite" as used herein refers to a product obtained by metabolism of a specific compound or its salt in vivo. The metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.

[0032] Pharmaceutically acceptable salts may be acid addition salts of compounds of the invention having a nitrogen atom in a chain or ring which are sufficiently basic, such as acid addition salts formed with inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate, or acid addition salts formed with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, diglucoside. Sugar acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

[0033] In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention with sufficient acidity is an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), an ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with the following substances: sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts of the group -COOH formed with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol.

[0034] In addition, basic nitrogen-containing groups can be quaternized with lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc. As examples, pharmaceutically acceptable salts include hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts, etc.

[0035] Since the compound of the present invention may have multiple salt-forming sites, the pharmaceutically acceptable salt includes not only salts formed at one of the salt-forming sites of the compound of the present invention, but also salts formed at 2, 3 or all of the salt-forming sites. For this reason, the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid or the cation of the base required for salt formation in the pharmaceutically acceptable salt can vary within a large range, for example, it can be 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0036] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0037] The "ester" of the present invention refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl or carboxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce a parent alcohol or acid. The compound of formula (I) of the present invention contains a carboxyl group and can form an in vivo hydrolyzable ester with an appropriate group, such as, but not limited to, an alkyl group, an arylalkyl group, etc.

[0038] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0039] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition to be treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific compound selected, the dosage regimen relied on, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried.

[0040] The pharmaceutical excipients can be excipients widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0041] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0042] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0043] The dosage form of the medicine of the present invention can be selected according to specific circumstances. The pharmaceutical dosage form is often composed of medicine, excipient and container / sealing system. One or more excipients (also known as inactive ingredients) can be added to the compound of the present invention to improve or promote the manufacture, stability, administration and safety of the medicine, and a method for obtaining a desired drug release curve can be provided. Therefore, the type of excipient added to the medicine can depend on various factors, such as the physical and chemical properties of the medicine, the route of administration and the preparation steps. There are pharmaceutical excipients in this field and include those listed in various pharmacopoeias. The pharmaceutical composition of the present invention can include one or more physiologically acceptable inactive ingredients, which can promote the active molecule to be processed into a preparation for medical use.

[0044] The appropriate formulation depends on the desired route of administration. Routes of administration include intravenous injection, transmucosal or nasal administration, oral administration, etc. For oral administration, the compound can be formulated into liquid or solid dosage forms and as immediate release or controlled release / slow release formulations. Suitable dosage forms for oral ingestion by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions, and emulsions.

[0045] Solid oral dosage forms can be obtained using excipients, including fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants and flavorings. These excipients can be synthetic or natural sources. Examples of the excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, mucilage of tragacanth, vegetable oils (hydrogenated) and waxes. Ethanol and water can be used as granulation aids. In some cases, tablets need to be coated with, for example, a taste masking film, a gastric acid resistant film or a delayed release film. Natural and synthetic polymers are often used to coat tablets in combination with colorants, sugars, and organic solvents or water to produce dragees. When capsules are preferred over tablets, drug powders, suspensions, or solutions thereof may be delivered in compatible hard or soft shell capsule forms.

[0046] The therapeutically effective dose can first be estimated using various methods well known in the art. The initial dose for animal studies can be based on the effective concentration established in the cell culture assay. The dosage range suitable for humans can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as a medicament for oral administration.

[0047] The correct formulation, administration route, dosage and administration interval can be selected according to methods known in the art taking into account the particularities of the individual situation.

[0048] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0049] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention. DETAILED DESCRIPTION

[0050] Preparation Example 1 Preparation of Compound 5a

[0051]

[0052] Step 1:

[0053] Pyroconic acid 1 (5.0 g, 45 mmol), NBS (N-bromosuccinimide) (9.9 g, 56 mmol) and ammonium acetate (4.3 g, 56 mmol) were added to 50 mL of tetrahydrofuran in sequence and stirred at 70 ° C for overnight. TLC monitored the reaction to be complete. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration. The filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a light yellow solid compound 2 (7.2 g, 85%).

[0054] Step 2:

[0055] Compound 2 (7.0 g, 37 mmol), 18-crown ether-6 (0.96 g, 3.7 mmol) and benzyl bromide (6.8 g, 40 mmol) were added to 100 mL of dichloromethane, followed by 70 mL of 15% potassium hydroxide aqueous solution, and stirred at room temperature overnight. TLC monitored the reaction to be complete. Add an appropriate amount of water to the reaction mixture, and then extract with dichloromethane three times. The organic phase was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow oily liquid compound 3 (6.1 g, 59%).

[0056] Step 3:

[0057] Compound 3 (2.0 g, 7.1 mmol) and 1,2-dimethoxy-3-phenylene (1.46 g, 8.9 mmol) were weighed and added to a solution of triethylamine (0.90 g, 8.9 mmol) in 20 mL of N,N-dimethylformamide (DMF). Under N2 protection, palladium acetate (0.16 g, 0.71 mmol) was added to the reaction mixture and stirred at 95 °C overnight. The reaction was completed by TLC. An appropriate amount of water was added to the reaction mixture, and then extracted with ethyl acetate three times. The combined organic layer was washed with water and dried with Na2SO4. The organic layer was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain product 4a (0.95 g, 37%).

[0058] Step 4:

[0059] Weigh 0.20 g of 4a, dissolve in 10 mL of dry dichloromethane, add 0.5 mL of BBr3 dropwise under N2 protection, stir at 0°C, and complete the reaction by TLC. Add water to quench the reaction, and concentrate to dryness under reduced pressure to obtain a crude product. The crude product is purified by silica gel chromatography to obtain product 5a (0.078 g, 58%).

[0060] Compounds 5b, 5d, 5g, 5j, 5k, 5m and 5n were prepared by referring to the preparation method of compound 5a. The structural formulas and spectral data of compounds 5a, 5b, 5d, 5g, 5j, 5k, 5m and 5n are shown in Table 1.

[0061] Table 1 Compound structural formula and spectral data

[0062]

[0063]

[0064] Effect Example 1 Evaluation of in vitro antioxidant activity

[0065] 1 Experimental Materials

[0066] Compounds: Example compounds 5a, 5b, 5d, 5g, 5j, 5k, 5m, 5n; Comparative example compound D30 and resveratrol.

[0067] 2 Experimental methods

[0068] All compounds were screened at a concentration of 2 μM, and the experiment was set up with 3 replicate wells and 3 independent experiments.

[0069] 120 μL of fluorescein (FL, 70 nM, final concentration) and 20 μL of the test compound (2 μM, final concentration) were added to a black 96-well plate. After incubation at 37°C for 15 min, 60 μL of 2,2'-azobisisobutylamidine dihydrochloride solution (AAPH, 12 mM, final concentration) was quickly added using a multichannel pipette. The fluorescence was recorded once every minute for 120 min, and the plate was automatically shaken before each reading. PBS was used instead of the test compound as the blank group. (Excitation wavelength is 485 nm; emission wavelength is 535 nm).

[0070] ORAC-FL value calculation formula:

[0071] [(AUC S -AUC0) / (AUC T -AUC0)]×[C T / C S ]

[0072] AUC S : AUC of the test group; AUC0: AUC of the blank group; AUC T : AUC of Trolox;

[0073] C T : Trolox concentration; C S : Concentration of sample

[0074] 3 Experimental results

[0075] The experimental results are shown in Table 2. Among the tested compounds, compared with resveratrol and D30 compound, compounds 5a, 5b, 5d, and 5g all showed better antioxidant activity.

[0076] Table 2 ORAC test results of compounds

[0077] Compound ORAC(eq.) 5a 5.50±0.82 5b 3.65±0.48 5d 5.08±0.74 5g 6.51±0.63 5j 1.85±0.13 5k 1.46±0.10 5m 1.62±0.19 5n 1.30±0.19 D30 3.20±0.43 Resveratrol 3.30±0.18

[0078] Effect Example 2 Evaluation of in vitro anti-inflammatory activity

[0079] 1 Experimental Materials

[0080] Compounds: Example compounds 5a, 5b, 5d, 5g, 5j, 5k, 5m, 5n, and compound D30, resveratrol.

[0081] 2 Experimental methods

[0082] In this experiment, mouse microglial cells (BV-2) were used as a model. The MTT method was first used to test whether the compound was cytotoxic to BV-2, and the interference of the compound on cell growth activity was eliminated. The drug concentration when the cell survival rate was >90% was taken, and the NO content in the culture medium was determined by the Griess method, and the interleukin-6 and tumor necrosis factor content in the culture medium was determined by the ELISA method.

[0083] (1) MTT assay to detect the effects of each compound on BV-2 cell viability

[0084] 100 μL of BV-2 cell suspension (cell density 5×10 3 / well), placed at 37 ° C, 5% CO2 for 24 hours, and then administered. Set up three replicate wells for the background well, the test group and the blank group, and add different concentrations of sample solution to the test group (DMEM medium is added to the blank group). After continuing to culture for 24 hours, add 20 μL of MTT solution (5 mg / mL) to each well, incubate in the incubator for 4 hours, crystallize, remove the supernatant, add 150 μL of DMSO to each well, and shake at a low speed on a shaker for 15 minutes to fully dissolve the crystals. Measure the absorbance of each well at 490nm on the microplate reader, and calculate the cell survival rate according to the following formula.

[0085] Cell survival rate = (OD s -OD r ) / (OD0-OD r )×100%

[0086] OD s : Absorbance of sample group; OD r : absorbance of the background group; OD0: absorbance of the blank group.

[0087] (2) Griess method was used to detect the effects of each compound on LPS-induced NO release in BV-2 cells

[0088] 100 μL of BV-2 cell suspension (cell density 5×10 4 After culturing for 24 hours, LPS (1 μg / mL) was added for 1 hour, and then the drug was administered. After culturing for another 24 hours, 50 μL of the cell supernatant was transferred to another 96-well plate, and 50 μL of Griess A and B reagents were added. The reaction was carried out in the dark and away from light for 10 minutes, and the OD value was measured at 540 nm. The concentration of NO was calculated based on the standard curve made with NaNO2.

[0089] The experiment set up a blank group (added with DMEM culture medium, without LPS stimulation), an LPS model group (added with DMEM culture medium, with LPS stimulation), a positive drug group (resveratrol, with LPS stimulation), and a test group (drug, with LPS stimulation), each with 3 replicate wells, and 3 independent experiments.

[0090] (3) ELISA method was used to detect the effects of each compound on the release of interleukin-6 and tumor necrosis factor α induced by LPS in BV-2 cells

[0091] The effect of different concentrations of LPS on the release of interleukin-6 and tumor necrosis factor from BV-2 cells was determined according to the experimental steps of the Thermo Fisher interleukin-6 and tumor necrosis factor detection kit, and the IC 50 .

[0092] The experiment set up a blank group (added with DMEM culture medium, without LPS stimulation), an LPS model group (added with DMEM culture medium, with LPS stimulation), a positive drug group (resveratrol, with LPS stimulation), and a test group (drug, with LPS stimulation), each with 3 replicate wells, and 3 independent experiments.

[0093] 3 Experimental results

[0094] (1) MTT assay to detect the effects of each compound on BV-2 cell viability

[0095] The MTT method was used to determine that when the concentration of the compound was 20 μM, the cell survival rate of the compound was greater than 90%, so the next step of NO determination was carried out under this condition.

[0096] (2) Griess method was used to detect the effects of each compound on LPS-induced NO release in BV-2 cells

[0097] The experimental results are shown in Table 3. Compared with resveratrol and D30 compound, the tested compounds have better activity in inhibiting the release of NO from BV-2 cells.

[0098] Table 3 Effects of compounds on NO release from BV-2 cells induced by LPS

[0099] Compound <![CDATA[IC that inhibits NO production 50 (μM)]]> 5a 17.96±2.59 5b >20 5d >20 5g 6.57±1.37 5j >20 5k >20 5m >20 5n >20 D30 25.14±1.24 Resveratrol 23.67±1.96

[0100] (3) ELISA was used to detect the effects of each compound on the release of IL-6 and TNF-α from BV-2 cells induced by LPS

[0101] The experimental results are shown in Table 4. Compared with resveratrol and D30 compound, the tested compounds have better performance in inhibiting the release of interleukin-6 and tumor necrosis factor from BV-2 cells.

[0102] Table 4 Effects of various compounds on the release of interleukin-6 and tumor necrosis factor from BV-2 cells induced by LPS

[0103] Compound <![CDATA[IC that inhibits IL-6 production 50 (μM)]]> <![CDATA[IC that inhibits TNF-α production 50 (μM)]]> 5a 7.495±1.93 30.14±2.35 5b 5.495±2.14 >20 5d >20 >20 5g 3.065±0.646 20.71±1.49 5j >20 >20 5k >20 >20 5m >20 >20 5n >20 >20 D30 >20 >20 Resveratrol 35.14±1.56 21.97±0.99

[0104] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. The following vinylpyrone compounds, their stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs:

2. A pharmaceutical composition comprising one, two or more of the vinylpyrone compound according to claim 1, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, and prodrugs.

3. The pharmaceutical composition according to claim 2, characterized in that The pharmaceutical composition may also optionally comprise at least one pharmaceutically acceptable excipient; Preferably, the pharmaceutical composition may optionally further comprise at least one additional active ingredient.

4. Use of the vinylpyrone compound according to claim 1, its stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, prodrugs or the pharmaceutical composition according to any one of claims 2 to 3 in the preparation of anti-inflammatory and antioxidant drugs.

5. An anti-inflammatory and antioxidant method, comprising administering to a subject a therapeutically effective amount of one, two or more of the vinyl pyrone compound of claim 1, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts, prodrugs, or the pharmaceutical composition of any one of claims 2 to 3.

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