Vinyl pyrone compound

Abstract

Provided in the present invention is a vinyl pyrone compound. The vinyl pyrone compound has excellent anti-inflammatory and antioxidant activity.

Description

A vinyl pyrone compound Technical Field

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

[0002] Research has shown that excessive free radicals can damage tissue cells, subcellular structures, and molecular structures, harming biomacromolecules such as nucleic acids, lipids, proteins, enzymes, and sugars. As the damage spreads, it causes functional impairment, leading to cardiovascular disease, cancer, and aging. These factors form the pathological basis of many diseases. Antioxidant active ingredients can scavenge free radicals and reduce oxidants, thus 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 onset and progression of disease. Some chronic inflammation can even lead to tumors. Therefore, the control and treatment of inflammation is of paramount importance.

[0004] The search and development of 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.

[0005] Summary of the Invention

[0006] The present invention provides the following vinyl pyrone compounds, their stereoisomers, tautomers, isotope-labeled substances, nitrogen oxides, solvates, polymorphs, metabolites, esters, pharmaceutically acceptable salts or prodrugs:

[0007] The present invention also provides a pharmaceutical composition comprising 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, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesive agents, 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-labeled substance, nitrogen oxide, ester, and 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: an oral preparation and a parenteral preparation. According to an embodiment of the present invention, the preparation includes: a powder, a granule, a capsule, an injection, an inhalant, a tincture, an oral liquid, a tablet, a lozenge, or a pill.

[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 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, prodrugs or the above-mentioned pharmaceutical compositions. Beneficial effects

[0015] The present invention provides a vinyl pyrone compound having excellent anti-inflammatory and antioxidant activities.

[0016] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0017] 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.

[0018] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0019] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0020] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0021] 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.

[0022] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0023] 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 the R and S forms of 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. 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 chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0024] The term "tautomer" refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerism is possible (such as in solution), the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (proton tautomers) (also known as prototropictautomers) include interconversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valen cetautomers) include interconversions 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-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0025] "Nitrogen oxide" of the present invention refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine to form an N-oxide (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, an amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

[0026] 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 O, 17 O, 18 F, 35 S and 36 Isotope-labeled compounds of the present invention can be used to determine the tissue distribution of the compounds, 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 offers therapeutic advantages such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present invention can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0027] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness, and the like, when administered to a human.

[0028] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle 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, and the like. Water and aqueous saline solutions and aqueous dextrose and glycerol solutions are preferred for use as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0029] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzyme conversion to the parent structure in the blood or tissue. The prodrug compound of the present invention can be an ester. In the existing 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 containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see 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.

[0030] As used herein, the term "metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0031] Pharmaceutically acceptable salts may be acid addition salts of compounds of the invention having a nitrogen atom in a chain or ring with sufficient basicity, 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, digluconic 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, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

[0032] In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having 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 -COOH formed with 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, and 1-amino-2,3,4-butanetriol.

[0033] In addition, basic nitrogen-containing groups can be quaternized using reagents such as 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.

[0034] Since the compounds of the present invention may have multiple salt-forming sites, the pharmaceutically acceptable salts include not only salts formed at one of the salt-forming sites of the compounds of the present invention, but also salts formed at two, three or all of the salt-forming sites. To this end, the molar ratio of the compound of formula (I) to the radical ion (anion) of the acid or cation of the base required for salt formation in the pharmaceutically acceptable salts may vary over a wide range, for example, from 4:1 to 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.

[0035] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a 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 when the solvent molecule is water.

[0036] "Esters" herein refer to in vivo hydrolyzable esters formed from compounds containing hydroxyl or carboxyl groups. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol or acid. The compounds of formula (I) herein contain a carboxyl group and can form in vivo hydrolyzable esters with suitable groups, including, but not limited to, alkyl groups, arylalkyl groups, and the like.

[0037] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting 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 a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0038] 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 following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific compound selected, the dosage regimen used, 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 used.

[0039] The pharmaceutical excipients described herein can be those widely used in the field of pharmaceutical production. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after administration to a subject, or to promote effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients described herein can be inert fillers, or can provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient in the composition. The pharmaceutical excipients described herein can include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0040] Examples of 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, polyvinylpyrrolidone, 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.

[0041] The pharmaceutical compositions 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.

[0042] The dosage form of the medicine of the present invention can be selected according to specific circumstances. Pharmaceutical dosage forms are often composed of medicine, excipients and container / sealing systems. 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 profile can be provided. Therefore, the type of excipient added to the medicine can depend on various factors, such as the physical and chemical properties, route of administration and preparation steps of the medicine. There are pharmaceutical excipients in this field and include those listed in various pharmacopoeias. The pharmaceutical composition of the present invention may include one or more physiologically acceptable inactive ingredients, which promote the active molecule to be processed into a preparation for medical use.

[0043] The appropriate formulation depends on the desired route of administration. Routes of administration include intravenous injection, transmucosal or nasal administration, oral administration, and the like. For oral administration, the compound can be formulated into liquid or solid dosage forms and as immediate release or controlled / 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.

[0044] Solid oral dosage forms can be obtained using excipients including fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherents, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavorings. These excipients can be synthetic or natural origin. Examples of the excipient 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 salt, sugar (i.e., dextrose, sucrose, lactose, etc.), talc, mucilage of tragacanth, vegetable oil (hydrogenated), and wax. Ethanol and water can be used as granulation aids. In some cases, tablets may 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 can be delivered in compatible hard or soft shell capsules.

[0045] The therapeutically effective dose can first be estimated using various methods well known in the art. The initial dose used in animal studies can be based on the effective concentration established in cell culture assays. 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.

[0046] The correct formulation, administration route, dosage and dosing interval can be selected according to methods known in the art, taking into account the particularities of the individual situation.

[0047] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean 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 can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0048] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention. DETAILED DESCRIPTION

[0049] Preparation Example 1 Preparation of Compound 5a

[0050] Step 1:

[0051] 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 under reflux at 70 ° C overnight. TLC monitored the reaction completion. 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%).

[0052] Step 2:

[0053] 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 in sequence, followed by addition of 70 mL of 15% aqueous potassium hydroxide solution, and stirred at room temperature overnight. TLC monitored the reaction completion. An appropriate amount of water was added to the reaction mixture, and then extracted three times with dichloromethane. The organic phase was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 3 (6.1 g, 59%) as a yellow oily liquid.

[0054] Step 3:

[0055] Weigh compound 3 (2.0 g, 7.1 mmol) and 1,2-dimethoxy-3-phenylene glycol (1.46 g, 8.9 mmol) and add to a solution of triethylamine (0.90 g, 8.9 mmol) in 20 mL of N,N-dimethylformamide (DMF). Under N protection, palladium acetate (0.16 g, 0.71 mmol) is added to the reaction mixture and stirred at 95 ° C overnight. The reaction is completed by TLC detection. An appropriate amount of water is added to the reaction mixture, which is then extracted 3 times with ethyl acetate. The combined organic layer is washed with water and dried with Na2SO4. The organic layer is concentrated under reduced pressure to dryness to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain product 4a (0.95 g, 37%).

[0056] Step 4:

[0057] Weigh 0.20 g of compound 4a and dissolve it in 10 mL of dry dichloromethane. Under N₂ protection, add 30.5 mL of BBr dropwise. Stir at 0°C. TLC confirms the reaction is complete. Quench the reaction with water and concentrate to dryness under reduced pressure to obtain the crude product. The crude product is purified by silica gel chromatography to afford product 5a (0.078 g, 58%).

[0058] 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.

[0059] Table 1 Compound structural formula and spectral data

[0060] Effect Example 1 Evaluation of in vitro antioxidant activity

[0061] 1 Experimental Materials

[0062] Compounds: Example compounds 5a, 5b, 5d, 5g, 5j, 5k, 5m, 5n; Comparative example compound D30 and resveratrol.

[0063] 2 Experimental methods

[0064] All compounds were screened at a concentration of 2 μM, three replicate wells were set up, and three independent experiments were performed.

[0065] Add 120 μL of fluorescein (FL, 70 nM, final concentration) and 20 μL of the test compound (2 μM, final concentration) to a black 96-well plate. Incubate at 37°C for 15 minutes. Then, quickly add 60 μL of 2,2′-azobisisobutylamidine dihydrochloride solution (AAPH, 12 mM, final concentration) using a multichannel pipette. Fluorescence is recorded every minute for 120 minutes, with the plate shaken automatically before each reading. PBS is used instead of the test compound as a blank. (Excitation wavelength: 485 nm; emission wavelength: 535 nm).

[0066] ORAC-FL value calculation formula:

[0067] [(AUC S -AUC0) / (AUC T -AUC0)]×[C T / C S ]

[0068] AUC S : AUC of the test group; AUC0: AUC of the blank group; AUC T : AUC of Trolox;

[0069] C T : Trolox concentration; C S : Concentration of the sample

[0070] 3 Experimental results

[0071] The experimental results are shown in Table 2. Among the tested compounds, compounds 5a, 5b, 5d, and 5g all exhibited superior antioxidant activity compared with resveratrol and compound D30.

[0072] Table 2 ORAC test results of compounds

[0073] Effect Example 2 Evaluation of in vitro anti-inflammatory activity

[0074] 1 Experimental Materials

[0075] Compounds: Example compounds 5a, 5b, 5d, 5g, 5j, 5k, 5m, 5n, and compound D30, resveratrol.

[0076] 2 Experimental methods

[0077] In this experiment, mouse microglial cells (BV-2) were used as a model. The MTT assay was first used to test whether the compound was cytotoxic to BV-2 cells. The interference of the compound on cell growth activity was eliminated. The drug concentration at which the cell viability was greater than 90% was taken. The NO content in the culture medium was determined by the Griess assay, and the interleukin-6 and tumor necrosis factor levels in the culture medium were determined by the ELISA assay.

[0078] (1) MTT assay to detect the effects of each compound on BV-2 cell viability

[0079] 100 μL of BV-2 cell suspension (cell density of 5×10 3 Each well was incubated at 37°C, 5% CO2 for 24 hours before administration. Three replicate wells were set for the background wells, test groups, and blank groups. Sample solutions of varying concentrations were added to the test groups (DMEM medium was added to the blank group). After a further 24 hours of culture, 20 μL of MTT solution (5 mg / mL) was added to each well. After incubation in an incubator for 4 hours, crystals formed. The supernatant was aspirated, and 150 μL of DMSO was added to each well. The cells were shaken at low speed on a shaker for 15 minutes to fully dissolve the crystals. The absorbance of each well was measured at 490 nm on a microplate reader, and the cell viability was calculated as follows.

[0080] Cell viability = (OD s -OD r ) / (OD0-OD r )×100%

[0081] OD s : absorbance of sample group; OD r : absorbance of the background group; OD0: absorbance of the blank group.

[0082] (2) Griess method was used to detect the effects of each compound on LPS-induced NO release in BV-2 cells

[0083] 100 μL of BV-2 cell suspension (cell density of 5×10 4 Cells were cultured for 24 hours. LPS (1 μg / mL) was added for 1 hour before administration. After another 24 hours of culture, 50 μL of the cell supernatant was transferred to another 96-well plate. 50 μL of Griess A and B reagents were added. The plates were incubated in the dark for 10 minutes. The OD value was measured at 540 nm. The NO concentration was calculated using a standard curve prepared using NaNO2.

[0084] The experiment was set up with three replicates, including a blank group (addition of DMEM culture medium, without LPS stimulation), an LPS model group (addition of DMEM culture medium, with LPS stimulation), a positive drug group (resveratrol, with LPS stimulation), and a test group (drug, with LPS stimulation), with 3 replicates each, and three independent experiments were performed.

[0085] (3) ELISA 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

[0086] The release of interleukin-6 and tumor necrosis factor from BV-2 cells induced by LPS at different concentrations was determined according to the experimental procedures of the Thermo Fisher interleukin-6 and tumor necrosis factor detection kit, and the IC values ​​were calculated using GraphPad Prism8 software. 50 .

[0087] The experiment was set up with three replicates, including a blank group (addition of DMEM culture medium, without LPS stimulation), an LPS model group (addition of DMEM culture medium, with LPS stimulation), a positive drug group (resveratrol, with LPS stimulation), and a test group (drug, with LPS stimulation), with 3 replicates each, and three independent experiments were performed.

[0088] 3 Experimental results

[0089] (1) MTT assay to detect the effects of each compound on BV-2 cell viability

[0090] The MTT assay was used to determine that when the compound concentration was 20 μM, the cell survival rate of the compound was greater than 90%, so the next step of NO determination was performed under this condition.

[0091] (2) Griess method was used to detect the effects of each compound on LPS-induced NO release in BV-2 cells

[0092] The experimental results are shown in Table 3. Compared with resveratrol and D30 compound, the tested compounds all have better activity in inhibiting the release of NO from BV-2 cells.

[0093] Table 3 Effects of compounds on LPS-induced NO release in BV-2 cells

[0094] (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

[0095] 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.

[0096] Table 4 Effects of various compounds on the release of interleukin-6 and tumor necrosis factor from BV-2 cells induced by LPS

[0097] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection 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 optionally further 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-labeled substances, 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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