Thiochromone derivative and application thereof

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a thiochromone derivative and its application. The thiochromone derivative has the following structural formula: #imgabs0# wherein V is S, SO, SO2 or a derivative thereof, X and Y are independently selected from heteroatoms or derivatives thereof, Z is C, and Ar is selected from aryl, heteroaryl or derivatives thereof; the thiochromone derivative has good MAO-B inhibition ability, improves its hydrophobic properties, and enhances its ability to be absorbed by the human body.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicines and pharmaceuticals, and in particular relates to a thiochromone derivative and its application. Background Art

[0002] Monoamine oxidase (MAO) is a mitochondrial outer membrane enzyme widely present in the brain and peripheral tissues (such as the heart, lungs, liver, intestine, and placenta). It catalyzes the oxidation of monoamines, including neurotransmitters (norepinephrine, dopamine, tyramine, and serotonin), to produce corresponding aldehydes, as well as ammonia (substituted ammonia) and hydrogen peroxide as byproducts. This oxidase regulates monoamine levels in the body and is thought to be involved in numerous diseases, including Alzheimer's disease, Parkinson's disease, depression, schizophrenia, and cancer. MAO consists of two isoforms, MAO-A and MAO-B, both of which contain a covalently bound cofactor, flavin adenine dinucleotide (FAD). These two isoforms exhibit distinct distributions in the body. For example, MAO-A and MAO-B are equally expressed in duodenal villi, crypts, muscularis externa, and mucosal cells. However, MAO-B is more strongly expressed than MAO-A in hepatocytes and renal tubules, and MAO-A is much more highly expressed than MAO-B in cardiomyocytes. It is worth noting that in addition to the common monoamine substrates such as dopamine, norepinephrine, epinephrine, tryptamine and tyramine, MAO-A can preferentially oxidize norepinephrine and serotonin (5-HT, 5-hydroxytryptamine), while MAO-B is more used for the oxidation of benzylamine and 2-phenylethylamine compounds.

[0003] Alzheimer's disease (AD) is a multifactorial disease caused by a variety of dysfunctional processes. These include amyloid-β (Aβ) peptide aggregation, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress-induced neurotoxicity, metal dysregulation, glutamate excitotoxicity, cell cycle dysregulation, and inflammation. Studies have shown that MAO-B activity in brain tissue and cerebrospinal fluid of patients with AD increases with aging. This elevated expression, coupled with changes in brain concentrations of multiple neurotransmitters such as dopamine, has been directly linked to several neurological disorders, including AD and Parkinson's disease. Furthermore, the neurotoxic aldehydes, ammonia (substituted ammonia), and hydrogen peroxide produced by amine oxides can lead to lipid peroxidation, protein damage, DNA and mitochondrial damage, and neuronal apoptosis, leading to inflammation and damage that further accelerate the progression of neurodegenerative diseases. Furthermore, activated monoamine oxidase promotes the aggregation of amyloid-β (Aβ) through the two sequential enzymes of the amyloid precursor protein (APP), the beta-secretase and the g-secretase. As a key target in the current clinical treatment of neuropsychiatric disorders, such as Alzheimer's and Parkinson's, inhibiting MAO-B can not only reduce dopamine catabolism and prolong the duration of dopamine's action in the basal ganglia, but also reduce the production of hydrogen peroxide and toxic aldehydes. Therefore, the development of MAO-B inhibitors is of great significance for the treatment of neurodegenerative diseases and improving patients' quality of life.

[0004] In the 1950s, Zeller, Crane, and others discovered the inhibitory effects of iproniazid on MAO and its therapeutic effects on depression. This led to the development of a series of hydrazine derivatives for the clinical treatment of related psychiatric disorders. However, these compounds' nonselective inhibition of both MAO-A and MAO-B isoforms, particularly MAO-A in the gastrointestinal tract and liver, led to a surge in exogenous amines entering the bloodstream, triggering the release of norepinephrine and increasing systemic blood pressure, a phenomenon known as the "cheese effect." The severe side effects of the "cheese effect," such as hypertensive crises, limited the further application of these compounds. It wasn't until 1970 that deprenyl (selegiline), a first-generation irreversible MAO-B selective inhibitor, was clinically demonstrated to be free of the "cheese effect." This led to the development of rasagiline, a second-generation irreversible MAO-B selective inhibitor with higher potency and selectivity. However, it is worth noting that the selectivity of selegiline and rasagiline is dose-dependent, which can increase the incidence of heart disease and hypertension. Furthermore, after irreversibly inhibiting MAO-B, at least two weeks must pass before the use of other exogenous drugs. To alleviate this problem, the reversible MAO-B inhibitor safinamide has been developed for the clinical treatment of various neurodegenerative diseases, including Alzheimer's disease.

[0005] Currently, MAO-B inhibitors are primarily categorized as irreversible and reversible inhibitors, each binding to a specific site through stable covalent bonds, hydrogen bonds, and hydrophobic interactions. Structurally, MAO-B inhibitors can be divided into phenylethylamine or benzylamine inhibitors, nitrogen-containing five-membered heterocyclic rings, flavonoids, and coumarins. Currently in clinical use, selegiline, rasagiline, and safinamide are all phenylethylamine or benzylamine MAO-B inhibitors.

[0006] In-depth research into the functions of MAO-B has revealed its involvement in a variety of diseases, including Alzheimer's disease, Parkinson's disease, depression, schizophrenia, and cancer. However, the current range of selective MAO-B inhibitors in clinical use is very limited, failing to meet the diverse therapeutic needs. Furthermore, the selectivity of phenylethylamine or benzylamine MAO-B inhibitors is dose-dependent, and long-term use can increase the incidence of heart disease and hypertension. Therefore, the development of highly effective and selective MAO-B inhibitors is of great clinical significance for the treatment of a variety of diseases, including Alzheimer's disease, Parkinson's disease, depression, schizophrenia, and cancer. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a thiochromone derivative and its application, so as to improve the inhibitory effect of MAO-B, improve its hydrophobic properties and enhance its ability to be absorbed by the human body.

[0008] The present invention is a thiochromone derivative, the structural formula of which is as follows:

[0009]

[0010] Wherein, V is S, SO, SO2 or a derivative thereof, X and Y are independently selected from heteroatoms or derivatives thereof, Z is C, and Ar is selected from aryl, heteroaryl or derivatives thereof.

[0011] Preferably, X and Y are independently selected from O, N, S or derivatives thereof.

[0012] Preferably, Ar is selected from substituted or unsubstituted C6-C20 aryl groups and substituted or unsubstituted C6-C20 heteroaryl groups.

[0013] Preferably, the V is S or SO2.

[0014] Preferably, X is O or NH, and Y is N.

[0015] Preferably, Ar is a substituted or unsubstituted benzene ring.

[0016] Preferably, the number of substituents on the benzene ring is 1.

[0017] Preferably, the substituent on the benzene ring is methyl, methoxy, trifluoromethyl or halogen (preferably Cl or F).

[0018] More preferably, V of the compound of the present invention is S or SO2, X is O or NH, Y is N, Z is C, Ar is a substituted or unsubstituted benzene ring, the number of substituents on the benzene ring is 1, and the substituents on the benzene ring are methyl, methoxy, trifluoromethyl or halogen.

[0019] The present invention provides an application of the thiochromone derivative, wherein the thiochromone derivative is used for preparing a drug for inhibiting MAO-B.

[0020] Specifically, the drug is a drug for treating Alzheimer's disease, Parkinson's disease, depression, schizophrenia or cancer.

[0021] The following are definitions of various terms or symbols used in this document:

[0022] The symbol "" represents a connection point.

[0023] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0024] The term "five-membered heterocycle" refers to a five-membered heterocycle having O, N, S, SO, SO2 or a combination thereof. The five-membered heterocycle may be an aromatic ring or a cyclic alkyl ring. Examples include oxazole, pyrazole and the like.

[0025] The term "substituted aromatic ring" refers to an aromatic ring substituent containing 3 to about 20 carbon atoms, preferably 5 to 10 carbon atoms. The aromatic ring substituent can be a single ring or multiple condensed rings, which include 0-3 substituents, and the types of substituents include, but are not limited to, methyl, trifluoromethyl, methoxy, halogen, etc.

[0026] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the others. Thus, each substituent may be the same as or different from the other substituents.

[0027] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0028] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in mammals and has the desired biological activity.

[0029] The phrase "treating" refers to alleviating the symptoms associated with a disease, disorder, or condition, or halting the further development or worsening of those symptoms. Depending on the disease and condition of the patient, the term "treating" as used herein includes one or more of curative, palliative, and prophylactic treatments. The compounds of the present invention may also be administered with other drugs and therapeutic agents.

[0030] The phrase "therapeutically effective" refers to the ability of an agent to prevent or ameliorate the severity of a disease while avoiding the adverse side effects typically associated with alternative treatments. The phrase "therapeutically effective" should be understood as equivalent to the phrase "effective for treatment, prevention, or amelioration," both of which refer to the amount of each agent used in the combination therapy that is capable of achieving the goal of improving the severity of cancer, cardiovascular disease, or pain and inflammation, as well as the morbidity of each agent's own treatment, while avoiding the adverse side effects typically associated with alternative treatments.

[0031] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoylbenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and hydroxynaphthoate, etc. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0032] Drug combination:

[0033] The pharmaceutically acceptable salts of the compounds of the present invention can be prepared by one or more of the following three methods:

[0034] 1. The compound is reacted with the desired acid or base.

[0035] 2. Using the desired acid or base, remove acid- or base-labile protecting groups from a suitable precursor of the compound, or ring-open a suitable cyclic precursor such as a lactone or lactam.

[0036] 3. Convert one salt of the compound into another salt by reaction with a suitable acid or base or using a suitable ion exchange column. All three reactions are typically performed in solution. The resulting salt can be precipitated and collected by filtration or recovered by evaporating the solvent. The degree of ionization in the resulting salt can vary from fully ionized to nearly non-ionized.

[0037] The pharmaceutically acceptable salts of the compounds of the present invention can be prepared by one or more of the following three methods:

[0038] 1. The compound is reacted with the desired acid or base.

[0039] 2. Using the desired acid or base, remove acid- or base-labile protecting groups from a suitable precursor of the compound, or ring-open a suitable cyclic precursor such as a lactone or lactam.

[0040] 3. Convert one salt of the compound into another salt by reaction with a suitable acid or base or using a suitable ion exchange column. All three reactions are typically performed in solution. The resulting salt can be precipitated and collected by filtration or recovered by evaporating the solvent. The degree of ionization in the resulting salt can vary from fully ionized to nearly non-ionized.

[0041] The present invention also provides compositions for treating or ameliorating a variety of MAO-related diseases, which can be prepared by mixing one or more compounds described herein, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents, and the like. The pharmaceutical compositions of the invention can be prepared by methods well known in the art, including but not limited to conventional granulation, mixing, dissolving, encapsulation, lyophilization, emulsification, or grinding. The compositions include but are not limited to granules, powders, tablets, syrups, suppositories, injections, emulsions, elixirs, suspensions, or solutions. The compositions of the present invention can be formulated for a variety of routes of administration, such as oral administration, transmucosal administration, rectal administration, topical administration, or subcutaneous administration, as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular, or intraventricular injection. The compounds of the present invention can also be administered topically rather than systemically.

[0042] For oral, oral and sublingual administration, powders, suspensions, granules, tablets, pills and capsules are acceptable solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the invention or their pharmaceutically acceptable salts or tautomers with at least one additive or excipient such as starch or other additives. Suitable additives or excipients include but are not limited to sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthesis or semi-synthetic macromolecular compound or glyceride, methylcellulose and hydroxypropyl methylcellulose etc. Optionally, oral dosage form can include other components that contribute to administration, such as inert diluents, or lubricants such as magnesium stearate, or preservatives such as p-hydroxybenzoic acid or sorbic acid, or antioxidants such as ascorbic acid, tocopherol or cysteine, disintegrating agents, adhesives, thickening agents, buffers, sweeteners, flavorings or aromatics. Additionally, dyes or pigments may be added for identification.Tablets and pills may be further treated with suitable coating materials known in the art.

[0043] Liquid dosage forms for oral administration include but are not limited to the form of emulsions, syrups, elixirs, suspensions, slurries and solutions, which may include inert diluents such as water. Sterile liquids such as but not limited to oil, water, alcohol and combinations thereof may be used to prepare the pharmaceutical preparation into liquid suspensions or solutions. For oral or parenteral administration, pharmaceutically suitable surfactants, suspending agents or emulsifying agents may be added.

[0044] The compounds can also be administered topically, intradermally, subcutaneously, or transdermally to the skin or mucous membranes. Formulations for this purpose include, but are not limited to, gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, petrolatum, glycerol, polyethylene glycol, and propylene glycol.

[0045] The compound can also be administered nasally, and the pharmaceutical preparation can be a spray or an aerosol comprising a suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobials, antioxidants, pH regulators, surfactants, bioavailability regulators and combinations thereof. The propellant for the aerosol can comprise compressed air, nitrogen, carbon dioxide or a hydrocarbon-based low-boiling solvent.

[0046] Injectable dosage forms generally include aqueous suspensions or oily suspensions, which can be prepared using suitable dispersants or wetting agents and suspending agents. The injectable form can be in the solution phase, or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or excipients include sterile water, Ringer's solution, or isotonic saline solutions. Alternatively, sterile oils can be used as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, monoglycerides, diglycerides, or triglycerides.

[0047] For rectal administration, pharmaceutical preparations can be in the form of suppositories, ointments, enemas, tablets or creams, which release compounds in the intestinal tract, sigmoid flexure or rectum. Rectal suppositories are prepared by mixing one or more compounds of the invention or pharmaceutically acceptable salts or tautomers of the compounds, and acceptable excipients such as cocoa butter or polyethylene glycol, which are solid phases at normal storage temperatures and liquid phases at temperatures suitable for releasing the drug in the body, such as in the rectum. Oils can also be used in the preparation of soft gelatin-type preparations and suppositories. Water, normal saline, aqueous dextrose and related sugar solutions and glycerol can be used in the preparation of suspension formulations, and the preparations can also include suspending agents such as pectin, carbomer, methylcellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.

[0048] The compositions of the invention may also include, for example, micelles or liposomes or other encapsulated forms, or may be administered in an extended release form to provide a delayed storage or delivery effect. Thus, the pharmaceutical preparations may be compressed into granules or cylinders that may be implanted intramuscularly or subcutaneously as reservoir injections or as implants such as stents. Such implants may be made of known materials such as silicones and biodegradable polymers.

[0049] The composition can contain, for example, from about 0.1% by weight to about 90% or more by weight of the active ingredient, depending on the method of administration. When the composition comprises dosage units, each unit can contain, for example, from about 0.1 to 500 mg or more of the active ingredient. For example, the dosage used for adult treatment can be, for example, from about 0.1 to 1000 mg / day, depending on the route of administration and the frequency of administration.

[0050] The specific dosage can be adjusted according to the situation of MAO related diseases, the age, weight, general health, sex and diet of the experimenter, dosing interval, administration route, excretion rate and drug combination. Any of the above-mentioned dosage forms comprising an effective amount are all within the scope of routine experiments and, therefore, are all within the scope of the present invention. Usually, the total daily dose can typically be from about 1 mg / kg / day to about 500 mg / kg / day, administered in a single dose or divided doses. Typically, the dosage for the human race can be from about 5 mg to about 100 mg / day, administered in a single dose or divided doses. The therapeutically effective dose or quantity can be varied according to the route of administration and dosage form.

[0051] Pharmaceutical preparations of MAO inhibitors, the compounds of the present invention may be combined with one or more additional agents, which may include, but are not limited to, cyclosporine A, rapamycin, tacrolimus, sirolimus, everolimus, azathioprine, brequinar, deoxyspergualin, leflunomide, aspirin, paracetamol, ibuprofen, naproxen, piroxicam, methotrexate, anti-inflammatory steroids (e.g., prednisolone or dexamethasone), etc. These combinations can be administered as the same or separate dosage forms, via the same or different routes of administration, and on the same or different dosing schedules consistent with standard pharmaceutical practice.

[0052] The present invention has the beneficial effect of adjusting the substituents based on the chromone skeleton structure, particularly the thiochromone, and directly connecting a heterocyclic ring with a substituent to the skeleton heterocyclic structure, significantly improving the ability of the thiochromone derivatives to inhibit MAO-B, achieving the inhibitory ability of the thiochromone derivatives at the μM level, and some of the more effective thiochromone derivatives achieving the inhibitory ability at the nM level. Simultaneously, the hydrophobic properties of the chromone skeleton are improved, and the oil-water partition coefficients (LogP) of some of the more effective thiochromone derivatives fall within the ideal druggable range of 1.0-3.0, effectively improving their ability to be absorbed by the human body. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 1H-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 1;

[0054] Figure 2 13C-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 1;

[0055] Figure 3 1H-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 2;

[0056] Figure 4 13C-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 2;

[0057] Figure 5 1H-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 5;

[0058] Figure 6 This is the 13C-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 5. DETAILED DESCRIPTION

[0059] Chemical synthesis:

[0060] Unless otherwise stated in the following examples, reagents, starting materials and solvents used in the following examples were purchased from commercial suppliers (eg, Aldrich, Fluka, Sigma, etc.) and used without further purification.

[0061] Example 1

[0062]

[0063] Step a: Compound 1 (2.0 g, 12.0 mmol, 1.0 equiv), I2 (3.7 g, 14.4 mmol, 1.2 equiv), and CAN (7.2 g, 13.2 mmol, 1.1 equiv) were placed in a dry Schlenk reaction flask (250 mL). Acetonitrile (50.0 mL) was added by injection under nitrogen and stirred at 55°C for 48 hours. After the reaction, excess I2 was removed with saturated aqueous sodium thiosulfate. The organic phase was extracted with dichloromethane and water. The combined organic layers were dried over anhydrous sodium sulfate and purified by column chromatography (petroleum ether / ethyl acetate / dichloromethane, 5 / 1 / 1) to afford 2.8 g of product 2 as a pale yellow solid in 82% yield.

[0064] The spectrum analysis data are as follows: 1 H NMR (500MHz, CDCl3) δ8.60-8.58(m,1H),8.52(s,1H),7.67-7.58(m,3H).

[0065] 13 C NMR (126MHz, CDCl3) δ174.98,142..50,137.22,131.65,129.92,128.97,128.59,126.33,97.33.

[0066] Steps b, c: Compound 2 (1.7 g, 6.0 mmol, 1.0 equiv), Pd(PPh3)2Cl2 (105 mg, 2.5 mol%, 0.025 equiv) and cuprous iodide (114 mg, 10 mol%, 0.1 equiv) were placed in a dry Schlenk reaction flask (250 mL). Toluene (40.0 mL), Et3N (1.60 mL, 12.0 mmol, 2.0 equiv) and trimethylethynylsilane (1.7 mL, 12.0 mmol, 2.0 equiv) were injected sequentially under nitrogen. The mixture was stirred at room temperature for 1 h and then heated to 70°C and stirred for 48 h. After completion of the reaction, the mixture was extracted, dried, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a gray-brown solid mixture (containing compound 3). In a 100 mL flask equipped with a stirrer, a mixture of 3 (approximately 1.6 g, 6.0 mmol, 1.0 equivalent), potassium carbonate (1.2 g, 9.0 mmol, 1.5 equivalent), and methanol (20 mL) was stirred at room temperature for 45 min. Completion of the reaction was confirmed by thin-layer chromatography (PE / EA = 5:1). The reaction solution was filtered using DCM as the solvent, and the filtrate was concentrated. The mixture was extracted once with distilled water and once with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether / ethyl acetate, 5 / 1) afforded 525 mg of the product 4 as a light brown solid (47%). The chromatographic analysis data are as follows:

[0067] 1 H NMR (500MHz, CDCl3) δ8.59 (d, J = 8.1Hz, 1H), 8.17 (s, 1H), 7.66-7.55 (m, 3H), 3.36 (s, 1H). 13 C NMR (126MHz, CDCl3) δ177.64,142.39,135.99,131.78,131.47,,129.29,128.37,126.73,120.06,82.17,78.65.

[0068] Steps d and e: 4 (1.0 mmol, 1.0 equiv). Pd(PPh3)2Cl2 (0.01 mmol, 0.01 equiv) and cuprous iodide (0.03 mmol, 0.03 equiv) were placed in a dry Schlenk reaction flask (100 mL). THF (5.0 mL), Et3N (0.28 mL, 2.0 equiv), and benzoyl chloride (2.0 equiv) were sequentially injected under nitrogen. The reaction system was kept at 0°C during the dropwise addition of the benzoyl chloride. After the addition was complete, the reaction temperature was raised to room temperature and stirred for a period of time. Complete reaction of the starting materials was confirmed by thin-layer chromatography. Subsequently, 3.0 mL of acetonitrile or DMF was added as a cosolvent, followed by the starting materials hydroxylamine or hydrazine hydrate (0.5 mL, 8.5 mmol). The reaction mixture was stirred at room temperature for a period of time, and complete reaction was confirmed by thin-layer chromatography. The reaction solution was extracted once with dichloromethane containing distilled water and saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether / ethyl acetate / dichloromethane, 1 / 1 / 1) afforded the solid product 5a. The spectral analysis data are as follows:

[0069] 1 H NMR (500MHz, CDCl3) δ9.52(s,1H),8.66-8.64(m,1H),,7.93-7.91(m,2H),7.79-7.74(m,1H),7.72(s,1H),7.67-7.61(m,2H),7.57(d,J=4.3Hz,3H). 13 C NMR (126MHz, CDCl3) δ176.82,151.99,140.32,135.76,134.30,133.43,131.1 7,130.66,130.09,129.52,128.63,128.48,127.54,126.47,125.63,123.56.

[0070] Example 2

[0071]

[0072] Step f: Dissolve compound 5a (0.3 mmol, 1.0 eq) in dichloromethane and place in a 50 mL round-bottom flask equipped with a stirrer. Add m-CPBA (0.63 mmol, 2.1 eq) and stir at room temperature for a specified period of time. Complete reaction of the starting material is confirmed by thin-layer chromatography. After the reaction is completed, excess m-CPBA is removed using a saturated aqueous sodium thiosulfate solution, and the pH is adjusted to a weakly alkaline state using a saturated aqueous sodium bicarbonate solution. The reaction solution is extracted once with dichloromethane containing distilled water and saturated brine. The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether / ethyl acetate / dichloromethane, 1 / 1 / 1) affords the solid product 6a. The spectral analysis data are as follows:

[0073] 1 H NMR (500MHz, CDCl3) δ9.02(s,1H),8.37(d,J=7.8Hz,1H),8.19(d,J=7.8Hz,1H),8.15(s, 1H),7.97(t,J=7.6Hz,1H),7.93-7.90(m,2H),7.87(t,J=7.7Hz,1H),7.58-7.54(m,3H). 13 C NMR (126MHz, CDCl3) δ175.65,154.55,140.73,140.22,135.67,134.67,133.8 4,131.56,130.12,129.95,129.55,129.31,128.78,126.78,123.86,121.63.

[0074] Example 3

[0075]

[0076] A thiochromone compound was prepared according to the method of Example 1, except that the benzoyl chloride compound was replaced by a p-toluoyl chloride compound.

[0077] The spectrum analysis data are as follows:

[0078] 1 H NMR (500MHz, CDCl3) δ9.38 (s, 1H), 8.61 (d, J = 8.0Hz, 1H), 7.81 (d, J = 7.5Hz, 2H), 7.71 (t, J = 7 .5Hz,1H),7.61(d,J=7.5Hz,2H),7.57(t,J=7.5Hz,1H),7.33(d,J=7.0Hz,2H),2.44(s,3H). 13C NMR (126MHz, CDCl3) δ176.84,152.11,141.17,140.38,135.79,,134.42,133.39, 130.08,129.52,129.21,128.65,128.20,127.51,126.48,125.37,123.35,21.55.

[0079] Example 4

[0080]

[0081] Thiochromone ketone oxide was prepared according to the method of Example 2, except that compound 5a was replaced by compound 5b.

[0082] The spectrum analysis data are as follows:

[0083] 1 H NMR (500MHz, CDCl3) δ9.01 (s, 1H), 8.37 (d, J = 7.8Hz, 1H), 8.19 (d, J = 7.8Hz, 1H), 8.14 (s,1H),7.96(t,J=7.6Hz,1H),7.88-7.84(m,3H),7.36(d,J=7.9Hz,2H),2.45(s,3H). 13 C NMR (126MHz, CDCl3) δ175.66,154.62,142.25,140.84,140.19,135.54,134.60,1 33.74,130.04,129.48,129.43,129.23,127.26,126.44,123.81,121.23,21.64.

[0084] Example 5

[0085]

[0086] The reaction proceeds according to the following equation:

[0087] Steps d, g: 4 (1.0 mmol, 1.0 equiv). Pd(PPh3)2Cl2 (0.01 mmol, 0.01 equiv) and cuprous iodide (0.03 mmol, 0.03 equiv) were placed in a dry Schlenk reaction flask (100 mL). THF (5.0 mL), Et3N (0.28 mL, 2.0 equiv), and benzoyl chloride (2.0 equiv) were sequentially injected under nitrogen. The reaction system was maintained at 0°C during the dropwise addition of the benzoyl chloride. After the addition was complete, the reaction temperature was raised to room temperature and stirred for a period of time. Complete reaction of the starting materials was confirmed by thin-layer chromatography. Subsequently, 3.0 mL of acetonitrile or DMF was added directly to the reaction system as a cosolvent, followed by hydrazine hydrate (0.5 mL, 8.5 mmol) as a starting material. The mixture was stirred at room temperature for a period of time, and complete reaction was confirmed by thin-layer chromatography. The reaction solution was extracted once with dichloromethane containing distilled water and saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether / ethyl acetate / dichloromethane, 1 / 1 / 1) gave a solid product 7. The spectral analysis data are as follows:

[0088] 1 H NMR(500MHz, CDCl3) δ8.69(d,J=8.0Hz,1H),8.46(s,1H),7.79(d,J=8.7Hz,2H),7.68 (d,J=4.1Hz,2H),7.66-7.61(m,1H),6.96(d,J=8.6Hz,2H),6.89(s,1H),3.84(s,3H). 13 C NMR (126MHz, CDCl3) δ178.30,159.68,148.77,136.18,135.62,132.34,131.73,129.37 ,128.33,127.12,126.64,126.47,125.31,123.87,114.16,99.03,55.33.HRMS(ESI)m / z calculated C 19 H 14 N2O2S[M+H] + :335.1530,found 335.1541.

[0089] The structural formula of the product prepared in the embodiment of the present invention is shown in Table 1 below:

[0090]

[0091]

[0092]

[0093] As can be seen from the above examples, the present invention synthesized a series of thiochromone derivatives as MAO-B inhibitors.

[0094] Activity test

[0095] The determination of monoamine oxidase B inhibitory activity was selected from Sigmade monoamine oxidase B inhibitor screening kit.

[0096] The kit consists of MAO-B Assay Buffer, High Sensitivity Probe (in DMSO), MAO-BEnzyme, MAO-B Substrate, and Developer. Before use, dilute the MAO-B Enzyme and Developer to their pre-working concentrations with the specified amount of MAO-B Assay Buffer. Dilute the MAO-B Substrate to its pre-working concentration with ultrapure water. The oil-water partition coefficient was determined. See Table 2 for details.

[0097] Table 2 Activity test table

[0098] Example <![CDATA[MAO-B IC 50 (μM)]]> <![CDATA[MAO-A IC 50 (μM)]]> LogP 1 1.235 - 3.72 2 0.89585 - 3.26 3 0.06214 3.20 4 0.0226 2.77 5 0.01845 3.43 6 0.10906 3.99 7 0.13689 2.69 8 0.00202 >10 4.37 9 0.00231 >10 2.63 10 0.53010 3.44 11 0.09817 3.23 12 0.03510 3.71 13 0.00191 3.39 14 0.01126 2.55 15 0.03180 2.37 16 0.44000 2.46 17 0.0226 4.17 18 0.00509 2.39 19 0.14947 2.43 20 0.00342 >1 1.82 21 0.00338 >1 2.62

[0099] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of protection of the present application is limited to these examples. In line with the present application, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of simplicity.

[0100] The one or more embodiments of this application are intended to encompass all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments of this application should be included in the scope of protection of this application.

Claims

1. A thiochromone derivative characterized by the structural formula as follows: Wherein, V is S or SO2, X is O or NH, Y is N, Z is C, and Ar is methyl, methoxy, trifluoromethyl or halogen-substituted phenyl.

2. A use of the thiochromone derivative according to claim 1, characterized in that: The thiochromone derivative is used for preparing medicine for inhibiting MAO-B.

3. The use of the thiochromone derivative according to claim 2, characterized in that: The drug is a drug for treating Alzheimer's disease, Parkinson's disease, depression, schizophrenia or cancer.

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