CN120081835A - Thiochromone derivative, preparation method and use thereof - Google Patents

Abstract

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a thiochromone derivative, a preparation method and use thereof. The structural formula of the thiochromone derivative is as follows: The R is H, the Ar is The R ₁ is halogen or C1-3 alkyl, the R ₂ is C1-3 alkoxy; the R is NO ₂ , Ar is The _R3 is chlorine, C1-3 alkyl or C1-3 haloalkyl, the _R4 is halogen, C1-3 alkyl, C1-3 alkoxy or C1-3 haloalkyl, and the _R5 is halogen or C1-3 haloalkyl. The present invention has a good effect of inhibiting MAO-B and selectivity relative to inhibiting MAO-A.

Description

Thiochromone derivative, preparation method and application

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a thiochromone derivative, a preparation method and application thereof.

Background

Monoamine oxidase (MAOs) is a mitochondrial outer membrane enzyme widely present in brain and peripheral tissues (heart, lung, liver, intestine, placenta, etc.), and is capable of catalyzing the oxidation of monoamine compounds typified by neurotransmitters (norepinephrine, dopamine, tyramine, serotonin) to the corresponding aldehydes, as well as ammonia (substituted ammonia) and hydrogen peroxide byproducts. The overexpressed MAOs increase H ₂O₂ concentration, causing oxidative stress. Monoamine oxidase includes monoamine oxidase A and B, i.e., MAO-A and MAO-B.

Inhibition of MAO-B has proven to be an effective strategy for the regulation of dyslipidemia, mainly involving total cholesterol and low density lipoprotein cholesterol (LDL-C), elevated triglycerides and/or reduced High Density Lipoprotein (HDL) cholesterol. In 2023 Wang and colleagues found that inhibition of MAO-B was effective in lowering serum Triglyceride (TG) and cholesterol production, enhancing Low Density Lipoprotein (LDL) and cholesterol scavenging Tian and colleagues also found that High Fat Diet (HFD) fed mice were low in blood lipid level after selegiline inhibition of MAO-B and that plaque area was smaller than mice not taken selegiline, indicating that MAO-B might be an effective potential therapeutic target. However, the inhibition of MAO B function by conventional non-selective MAOs inhibitors inevitably inhibits MAO A function at the same time, which enhances the sympathomimetic effects of dietary amines and tyramines, resulting in a rapid rise in fatal blood pressure, the "cheese effect". In clinical studies, it was found that increasing the selectivity of MAOs inhibitors against MAOs B could avoid this safety problem. Thus, increasing selectivity is central to the further development of MAO B inhibitors.

Currently, MAO B inhibitors are largely classified into irreversible and reversible inhibitors, which are bound by forming stable covalent bonds or hydrogen bonds with specific sites, hydrophobic interactions, etc., respectively. Structurally, MAO B inhibitors can be largely classified into phenethylamine or benzylamine, nitrogen-containing five-membered heterocycles, flavonoids and coumarin MAO-B inhibitors. Selegiline, rasagiline and salfenamide, which are currently in clinical use, are phenethylamine or benzylamine MAO B inhibitors. However, the types of MAO B-selective inhibitors in clinical medicine are very limited, and it is difficult to meet the diversity of therapeutic requirements. Meanwhile, the selectivity of phenethylamine or benzylamine MAO B inhibitor has dose dependency, and long-term administration can increase the incidence rate of heart diseases and hypertension. Therefore, the development of the high-efficiency and high-selectivity MAO B inhibitor is significant for the clinical treatment of various diseases such as cardiovascular and cerebrovascular diseases, alzheimer's disease, parkinson's disease, depression, schizophrenia and cancers.

Disclosure of Invention

The invention aims to solve the technical problem of providing up>A thiochromone derivative, up>A preparation method and application thereof, which have higher MAO-B inhibition effect and selectivity relative to MAO-A inhibition.

The embodiment of the invention provides a thiochromone derivative, which has the following structural formula:

r is H, ar is R ₁ is halogen or C1-3 alkyl, and R ₂ is C1-3 alkoxy;

R is NO ₂, ar is R ₃ is chlorine, C1-3 alkyl or C1-3 haloalkyl, R ₄ is halogen, C1-3 alkyl, C1-3 alkoxy or C1-3 haloalkyl, and R ₅ is halogen or C1-3 haloalkyl.

The thiochromone derivative of the invention can also be pharmaceutically acceptable salts of the thiochromone derivative, including acid addition salts or alkali salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, acetates, adipates, asparagines, benzoates, benzenesulfonates, bicarbonates, bisulphates/sulfates, borates, camphorsulfonates, citrates, cyclosulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucoheptates, gluconates, glucuronates, hexafluorophosphates, hydroxybenzoates, hydrochlorides/chlorides, hydrobromides/bromides, hydroiodides/iodides, isethionates, lactates, malates, maleates, malonates, methanesulfonates, methylsulfates, naphthanates, 2-naphthanesulfonates, nicotinates, nitrates, orotate, oxalates, palmates, pamonates, phosphates/hydrogen phosphates/dihydrogenates, pyroglutamates, gluconates, stearates, succinates, tanninates, tartrates, tosylates, trifluoroacetates, and hydroxynaphthoates, and the like.

Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

Pharmaceutically acceptable salts of the compounds of the present invention may be prepared by one or more of the following three methods:

1. The method comprises the steps of (1) reacting a compound with a desired acid or base, (2) removing acid or base labile protecting groups from suitable precursors of the compound using the desired acid or base, or ring opening suitable cyclic precursors such as lactones or lactams, (3.) reacting one salt of the compound with a suitable acid or base or converting one salt to another salt using a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may be precipitated and collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from complete ionization to little ionization.

The present invention also provides compositions for treating or ameliorating a variety of MAO related disorders, which may be prepared by admixing 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 may be prepared by methods well known in the art including, but not limited to, conventional granulation, mixing, dissolution, encapsulation, lyophilization, emulsification, or trituration. Such compositions include, but are not limited to, forms of granules, powders, tablets, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The compositions of the present invention may be formulated for a variety of routes of administration, such as oral, transmucosal, rectal, topical or subcutaneous administration, intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection. The compounds of the invention may also be administered topically rather than systemically.

For oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills and capsules are acceptable solid dosage forms. These may be prepared, for example, by mixing one or more compounds of the invention or pharmaceutically acceptable salts or tautomers thereof 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 sugars, mannitol, maltitol, dextran, sorbitol, starch, agar, alginate, chitin, chitosan, pectin, tragacanth, acacia, gelatin, collagen, casein, albumin, synthetic or semi-synthetic high molecular compounds or glycerides, methylcellulose, hydroxypropyl methylcellulose, and the like. Optionally, the oral dosage form may contain other components that facilitate administration, such as inert diluents, or lubricants such as magnesium stearate, or preservatives such as parahydroxybenzoic acid or sorbic acid, or antioxidants such as ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents or fragrances. Alternatively, dyes or pigments may be added for identification. Tablets and pills may be further treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration include, but are not limited to, forms of emulsions, syrups, elixirs, suspensions, slurries and solutions, which may contain inert diluents such as water. The pharmaceutical formulation may be prepared as a liquid suspension or solution using sterile liquids, such as, but not limited to, oils, water, alcohols, and combinations thereof. For oral or parenteral administration, pharmaceutically suitable surfactants, suspending agents or emulsifying agents may be added.

The compounds may also be administered topically, (intradermally) subcutaneously or transdermally to the skin or mucosa. 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 alcohols, water, mineral oil, liquid paraffin, petrolatum, glycerin, polyethylene glycol and propylene glycol.

The compounds may also be administered nasally, and the pharmaceutical formulation may be a spray or aerosol formulation comprising a suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof. Propellants for aerosols may include compressed air, nitrogen, carbon dioxide or hydrocarbon-based low boiling solvents.

Injectable dosage forms typically include aqueous or oily suspensions which may be prepared using suitable dispersing or wetting agents and suspending agents. The injectable form may be in the solution phase or in the form of a suspension, prepared with a solvent or diluent. Acceptable solvents or excipients include sterile water, ringer's solution or isotonic saline solution. Alternatively, sterile oils may be employed as a solvent or suspending agent. Typically, the oil or fatty acid is non-volatile and includes natural or synthetic oils, fatty acids, monoglycerides, diglycerides or triglycerides.

For rectal administration, the pharmaceutical preparations may be in the form of suppositories, ointments, enemas, tablets or creams, which release the compound in the intestine, sigmoid 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 an acceptable excipient such as cocoa butter or polyethylene glycol, which are solid at normal storage temperatures and liquid at temperatures suitable for drug release in vivo, such as in the rectum. Oils may also be used in the preparation of soft gelatin type formulations and suppositories. Water, physiological saline, aqueous dextrose and related sugar solutions, and glycerol can be employed in preparing suspension formulations which may also contain suspending agents such as pectin, carbomers, methylcellulose, hydroxypropyl cellulose, or carboxymethyl cellulose, as well as buffers and preservatives.

The compositions of the invention may also include, for example, micelle or liposome or other encapsulated forms, or may be administered in an extended release form to provide an extended storage or delivery effect. Thus, the pharmaceutical formulation may be compressed into granules or cylinders, may be implanted intramuscularly or subcutaneously, as a depot injection or as an implant such as a stent. Such implants may employ known materials such as silicones and biodegradable polymers.

The composition may contain, for example, from about 0.1% by weight to about 90% by weight or more of the active substance, depending on the method of administration. When the composition comprises dosage units, each unit may contain, for example, from about 0.1 to over 500mg of the active ingredient. Dosages as employed for adult treatment may be, for example, from about 0.1 to 1000 mg/day, depending on the route and frequency of administration.

The specific dosage may be adjusted according to the condition of MAO-related disease, the age, weight, general health, sex and diet of the subject, the interval of administration, the route of administration, the rate of excretion, and the drug combination. Any of the above dosage forms comprising an effective amount are within the scope of routine experimentation and, therefore, are within the scope of the invention. In general, the total daily dose may typically be from about 1 mg/kg/day to about 500 mg/kg/day, administered in single or divided doses. Typically, the dosage for humans may be from about 5mg to about 100mg per day, single or multiple doses. The therapeutically effective dose or amount may vary depending on the route of administration and the dosage form.

The pharmaceutical formulations of the present invention may be a compound of the present invention or in combination with one or more additional agents, which may include, but are not limited to, cyclosporin a, rapamycin, tacrolimus, sirolimus, everolimus, azathioprine, buconazole, deoxyspergualin, leflunomide, aspirin, paracetamol, ibuprofen, naproxen, piroxicam, methotrexate, anti-inflammatory steroids (e.g., prednisolone or dexamethasone), and the like. These combinations may be administered as the same or separate dosage forms, via the same or different routes of administration, and in accordance with the same or different dosing schedules of standard pharmaceutical practice.

Preferably, R ₁ is F, cl or methyl.

Preferably, R ₂ is methoxy.

Preferably, R ₃ is chloro, methyl or trifluoromethyl.

Preferably, R ₄ is F, cl, methyl, methoxy or trifluoromethyl.

Preferably, R ₅ is F, cl or trifluoromethyl.

Preferably, the thiochromone derivative has the following structural formula:

more preferably, the thiochromone derivative has the following structural formula:

The embodiment of the invention provides a preparation method of a thiochromone derivative, which comprises the following steps,

Mixing the solution of the compound 1 with liquid bromine, and reacting to obtain a compound 2, wherein the solvent of the solution of the compound 1 is acetic acid;

Sequentially adding toluene, absolute ethyl alcohol and water into a mixed solution of a compound 2, and heating to react to obtain a compound 3, wherein the mixed solution of the compound 2 is a mixed solution of the compound 2, tetra (triphenylphosphine) palladium, 2-thiopheneboronic acid and potassium carbonate, or the mixed solution of the compound 2 is a mixed solution of the compound 2, tetra (triphenylphosphine) palladium, 2-substituted thiopheneboronic acid and potassium carbonate;

adding the N-bromosuccinimide solution into the compound 3 solution, and reacting to obtain a compound 4;N-bromosuccinimide solution and tetrahydrofuran as a solvent of the compound 3 solution;

Sequentially adding toluene, absolute ethyl alcohol and water into a mixed solution of a compound 4, and heating to react to obtain a compound 5a, wherein the mixed solution of the compound 4 is a mixed solution of the compound 4, tetra (triphenylphosphine) palladium, phenyl boric acid and potassium carbonate, or the mixed solution of the compound 4 is a mixed solution of the compound 4, tetra (triphenylphosphine) palladium, substituted phenyl boric acid and potassium carbonate, and the reaction route is as follows:

the embodiment of the application provides an application of a thiochromone derivative, which is used for preparing a medicine for inhibiting MAO-B. The thiochromone derivative can inhibit MAO-B and MAO-A, and the effect of inhibiting MAO-B is obviously better than that of inhibiting MAO-A, namely the thiochromone derivative has inhibition selectivity.

Preferably, the medicament is a medicament for the treatment of Alzheimer's disease, parkinson's disease, depression, schizophrenia or cancer.

The invention has the beneficial effects that through analyzing the crystal structure of hMAO-B (PDB: 6FW 0) and hydroxytryptamine complex, tyr326, tyr435 and Cys172 residues are the key points of the interaction of the small molecule inhibitor and hMAO-B Mars region. The invention introduces isoxazole module in the thiochromanone core to strengthen the interaction between small molecules and Tyr 326. However, the isoxazole moiety does not interact with the critical Cys172 residue. Thus, in the present invention, by introducing a nitro group in the thiophene moiety, a novel hMAO-B inhibitor with higher potency and selectivity was designed by a strong interaction between the nitro group and Cys 172.

Drawings

FIG. 1 is a 1H-NMR spectrum of a thiochromone compound prepared in example 1;

FIG. 2 is a 13C-NMR spectrum of a thiochromone compound prepared in example 1;

FIG. 3 is a 1H-NMR spectrum of a thiochromone compound prepared in example 3;

FIG. 4 is a 13C-NMR spectrum of a thiochromone compound prepared in example 3;

FIG. 5 is a 1H-NMR spectrum of a thiochromone compound prepared in example 4;

FIG. 6 is a 13C-NMR spectrum of a thiochromone compound prepared in example 4.

Detailed Description

The following are definitions of the various terms or symbols used herein:

Sign symbol Representing the connection point.

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

The term "substituted aromatic ring" refers to aromatic ring substituents containing from 3 to about 20 carbon atoms, preferably from 5 to 10 carbon atoms. The aromatic ring substituents may be monocyclic or polycyclic and include 0 to 3 substituents thereon, and the types of substituents include, but are not limited to, for example, methyl, trifluoromethyl, methoxy, halogen, and the like.

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

The term "pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in mammals and which possess the desired biological activity.

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

The phrase "therapeutically effective" refers to the ability of an agent to prevent or ameliorate the severity of a disease while avoiding adverse side effects typically associated with alternative treatments. The phrase "therapeutically effective" should be understood to correspond to the phrase "effective for treatment, prevention or amelioration," both of which are intended to be competent for the amount of each agent used in combination therapy, which is capable of achieving the objective of improving the severity of cancer, cardiovascular disease or pain and inflammation, as well as the incidence of each agent upon treatment itself, while avoiding adverse side effects typically associated with alternative therapies.

Unless otherwise indicated in the examples below, the reagents, starting materials, and solvents used in the examples below were purchased from commercial suppliers (e.g., aldrich, adamas-beta, sigma, etc.), and were used without additional purification.

Example 1

The reaction route is as follows:

the method comprises the following specific steps:

Step a Compound 1 (4.8663 g,30.0mmol,1.0 eq.) and solvent acetic acid (50.0 mL) were placed in a dry three-necked flask (150 mL), warmed to 90℃and dissolved with stirring, liquid bromine (14.3829 g,90.0mmol,3.0 eq.) was added rapidly and stirred for 5h at 90 ℃. After the reaction was completed, excess Br ₂ was removed using a saturated aqueous solution of sodium thiosulfate. The organic phases were extracted with dichloromethane and saturated brine, the combined organic layers dried over anhydrous sodium sulfate and purified by column chromatography (petroleum ether/ethyl acetate, 5/1) to give 5.7864g of rose-red solid product 2 in 80% yield. The spectrogram analysis data were as follows:

¹H NMR(500MHz,Chloroform-d):δ8.58(d,J＝6.9Hz,1H),8.27(s,1H),7.66-7.57(m,3H).¹³C NMR(126MHz,Chloroform-d):δ136.79,136.69,131.68,130.98,129.68,128.36,126.45,118.92.

Step b) Compound 2 (4.8220 g,20.0mmol,1.0 eq.) Pd (PPh ₃)₄ (2.3111 g,10mol%,0.1 eq.) 2-thiopheneboronic acid (5.1184 g,40.0mmol,2.0 eq.) and potassium carbonate (13.8210 g,100.0mmol,5.0 eq.) were placed in a dry Schlenk flask (250 mL), toluene (40.0 mL), absolute ethanol (40.0 mL) and water (20.0 mL) were injected sequentially under nitrogen, and stirred at room temperature and warmed to 100℃and stirred for 24h after completion of the reaction, the organic phase was removed by rotary evaporation, the reaction solution was filtered with DCM as solvent, the concentrated filtrate was extracted once with distilled water and saturated brine, respectively, the combined organic layer was dried with anhydrous sodium sulfate, filtered and concentrated, purified by column chromatography (petroleum ether/ethyl acetate, 5/1) to yield 4.2513g of a yellowish green solid product 3, 87%. Analytical data were as follows:

¹H NMR(500MHz,Chloroform-d):δ8.67(d,J＝7.6Hz,1H),8.23(s,1H),7.64-7.59(m,2H),7.57(ddd,J＝8.2,6.0,2.4Hz,1H),7.51(dd,J＝3.7,1.0Hz,1H),7.43(dd,J＝5.1,0.9Hz,1H),7.10(dd,J＝5.1,3.8Hz,1H).¹³C NMR(126MHz,Chloroform-d):δ137.24,136.23,132.43,132.08,131.27,129.57,129.19,127.89,127.52,126.45,126.26,124.77.

Step c Compound 3 (3.6650 g,15.0mmol,1.0 eq.) was dissolved in tetrahydrofuran (20 mL) in a three-necked flask (150 mL), N-bromosuccinimide (4.0046 g,22.5mmol,1.5 eq.) was dissolved in tetrahydrofuran (30 mL), a tetrahydrofuran solution of NBS (N-bromosuccinimide) was slowly added dropwise via a constant pressure dropping funnel under a dark ice bath condition, and after stirring for 2 hours under an ice bath condition, it was allowed to warm to room temperature and stirred for 5 hours. After the reaction was completed, THF was removed by rotary evaporation. The organic phase was extracted with dichloromethane and saturated brine, and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (petroleum ether/dichloromethane/ethyl acetate, 5/1/1) afforded 3.3939g of product 4 as a yellow solid (70%). The spectrogram analysis data were as follows:

¹H NMR(500MHz,Chloroform-d):δ8.68(d,J＝8.4Hz,1H),8.24(s,1H),7.69-7.63(m,2H),7.61(ddd,J＝8.3,6.0,2.4Hz,1H),7.23(d,J＝4.0Hz,1H),7.07(d,J＝4.0Hz,1H).¹³CNMR(126MHz,Chloroform-d):δ176.91,138.08,136.18,131.92,131.73,131.49,129.60,128.68,128.59,128.09,126.50,123.74,115.73.

Step d) Compound 4 (0.64 g,2.0mmol,1.0 eq.) Pd (PPh ₃)₄ (0.2311 g,20mol%,0.2 eq.) phenylboronic acid (0.4877 g,4.0mmol,4.0 eq.) and potassium carbonate (1.3821 g,10.0mmol,10.0 eq.) were placed in a dry Schlenk flask (25 mL), toluene (4.0 mL), absolute ethanol (4.0 mL) and water (2.0 mL) were injected sequentially under nitrogen, and stirred at room temperature and warmed to 95℃and stirred for 24h after completion of the reaction, the organic phase was removed by rotary evaporation, the reaction solution was filtered with DCM as solvent, the filtrate was concentrated, and extracted once with distilled water and saturated brine, respectively, the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (Petroleum ether/dichloromethane/ethyl acetate, 10/1/1) to yield 0.5639g yellow solid product 5a, 88%. Analytical data were as follows:

¹H NMR(500MHz,Chloroform-d):δ8.70(d,J＝7.7Hz,1H),8.25(s,1H),7.69(d,J＝7.3Hz,2H),7.67-7.62(m,2H),7.60(ddd,J＝11.9,5.7,2.8Hz,1H),7.50(d,J＝3.9Hz,1H),7.39(t,J＝7.6Hz,2H),7.32-7.27(m,2H).¹³C NMR(126MHz,Chloroform-d):δ177.07,145.86,136.38,136.19,134.44,131.97,131.87,131.27,129.56,129.07,128.87,127.91,127.50,126.44,125.75,125.55,122.42.

Example 2

The reaction route is as follows:

Step e) compound 5a (0.3204 g,1.0mmol,1.0 eq) and Fe (NO ₃)₃·9H₂ O (0.52 g,1.3mmol,1.3 eq) were placed in a dry Schlenk reaction flask (25 mL), acetic acid (3.0 mL) was injected under nitrogen, stirred and dissolved at room temperature and then warmed to 50 ℃ and stirred for 12h. After the reaction was completed, the organic phase was extracted with saturated brine, the organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether/dichloromethane/ethyl acetate, 10/1/1) to yield 0.2923g of yellow solid product 6a, 80% yield, spectrum resolution data were as follows:

¹H NMR(500MHz,Chloroform-d):δ8.61(d,J＝7.8Hz,1H),8.12(s,1H),7.85(s,1H),7.68(dd,J＝6.2,1.1Hz,2H),7.63-7.59(m,3H),7.47-7.42(m,2H),7.41-7.37(m,1H).¹³C NMR(126MHz,Chloroform-d):δ176.29,145.05,142.89,138.70,137.11,136.21,132.13,131.91,131.80,129.66,129.26,129.08,128.43,127.46,126.62,125.77,119.46.

Example 3

The thiochromone compound was prepared according to the method of example 1, except that the phenylboronic acid compound was replaced with a 2-methylphenylboronic acid compound, as in example 1.

The spectrogram analysis data were as follows:

¹H NMR(500MHz,Chloroform-d):δ8.70(d,J＝7.8Hz,1H),8.25(s,1H),7.67-7.62(m,2H),7.62-7.57(m,1H),7.52(d,J＝3.8Hz,1H),7.51-7.47(m,1H),7.28(t,J＝5.4Hz,1H),7.26-7.21(m,2H),7.08(d,J＝3.8Hz,1H),2.50(s,3H).¹³C NMR(126MHz,Chloroform-d):δ177.15,145.12,136.86,136.26,136.02,134.18,132.06,131.96,131.29,130.83,130.34,129.61,129.29,127.92,127.80,126.48,125.97,125.91,124.91,21.38.

Example 4

Thiochromone oxide was prepared according to the method of example 2, with the difference that the 5a compound was replaced with the 5b compound, as in example 2.

The spectrogram analysis data were as follows:

¹H NMR(500MHz,Chloroform-d):δ8.62(d,J＝8.6Hz,1H),8.14(s,1H),7.71-7.66(m,2H),7.64(s,1H),7.62(ddd,J＝8.3,6.2,2.1Hz,1H),7.41(d,J＝7.3Hz,1H),7.33(dd,J＝6.2,1.4Hz,2H),7.28(dd,J＝7.5,2.6Hz,1H),2.51(s,3H).¹³C NMR(126MHz,Chloroform-d):δ176.33,144.44,142.06,137.75,136.26,136.19,131.93,131.87,131.74,131.17,130.18,129.72,129.18,128.46,127.53,126.64,126.40,122.87,21.10.

The structural formula of the product prepared by the embodiment of the invention is as follows:

activity test

The monoamine oxidase B inhibition activity assay is selected from the Abcam monoamine oxidase B inhibitor screening kit.

The kit mainly comprises MAO-B Assay Buffer, oxiRed Probe (in DMSO), MAO-B Enzyme, MAO-BSubstrate and development. MAO-B Enzyme and development were diluted to pre-work storage concentrations with a predetermined amount of MAO-B Assay Buffer before use, respectively, and MAO-B Substrate was diluted to pre-work storage concentrations with ultrapure water.

The selection index is calculated by MAO-A IC ₅₀/MAO-B IC₅₀, with up>A larger number representing up>A higher inhibition efficiency against MAO B.

As can be seen from the above table, the compounds of the present application have a higher MAO-B inhibitory effect and have a higher selectivity against the MAO B subtype.

It will be appreciated by persons skilled in the art that the above discussion of any embodiment is merely exemplary and is not intended to imply that the scope of the application is limited to these examples, that combinations of technical features in the above embodiments or in different embodiments may also be implemented in any order, and that many other variations of the different aspects of one or more embodiments of the application as described above exist within the spirit of the application, which are not provided in detail for the sake of brevity.

One or more embodiments of the present application are intended to embrace all such alternatives, modifications and variations as fall within the broad scope of the present application. Accordingly, any omissions, modifications, equivalents, improvements and others which are within the spirit and principles of the one or more embodiments of the application are intended to be included within the scope of the application.

Claims (11)

1. A thiochromone derivative is characterized in that, the structural formula of the thiochromone derivative is as follows:

;

r is H, ar is 、Or (b)R ₁ is halogen or C1-3 alkyl, and R ₂ is C1-3 alkoxy;

R is NO ₂, ar is 、Or (b)R ₃ is chlorine, C1-3 alkyl or C1-3 haloalkyl, R ₄ is halogen, C1-3 alkyl, C1-3 alkoxy or C1-3 haloalkyl, and R ₅ is halogen or C1-3 haloalkyl.

2. The thiochromone derivative of claim 1, wherein R ₁ is F, cl or methyl.

3. The thiochromone derivative of claim 1, wherein R ₂ is methoxy.

4. The thiochromone derivative of claim 1, wherein R ₃ is chloro, methyl or trifluoromethyl.

5. The thiochromone derivative of claim 1, wherein R ₄ is F, cl, methyl, methoxy, or trifluoromethyl.

6. The thiochromone derivative of claim 1, wherein R ₅ is F, cl or trifluoromethyl.

7. The thiochromone derivative of claim 1, wherein the thiochromone derivative has the structural formula:

、、、、、、、、、 Or (b) 。

8. The thiochromone derivative of claim 1, wherein the thiochromone derivative has the structural formula:

、、 Or (b) 。

9. A process for the preparation of a thiochromone derivative as defined in any one of claims 1 to 8, comprising the steps of,

Mixing the solution of the compound 1 with liquid bromine, and reacting to obtain a compound 2, wherein the solvent of the solution of the compound 1 is acetic acid;

Sequentially adding toluene, absolute ethyl alcohol and water into a mixed solution of a compound 2, and heating to react to obtain a compound 3, wherein the mixed solution of the compound 2 is a mixed solution of the compound 2, tetra (triphenylphosphine) palladium, 2-thiopheneboronic acid and potassium carbonate, or the mixed solution of the compound 2 is a mixed solution of the compound 2, tetra (triphenylphosphine) palladium, 2-substituted thiopheneboronic acid and potassium carbonate;

adding the N-bromosuccinimide solution into the compound 3 solution, and reacting to obtain a compound 4;N-bromosuccinimide solution and tetrahydrofuran as a solvent of the compound 3 solution;

Sequentially adding toluene, absolute ethyl alcohol and water into a mixed solution of a compound 4, and heating to react to obtain a compound 5a, wherein the mixed solution of the compound 4 is a mixed solution of the compound 4, tetra (triphenylphosphine) palladium, phenyl boric acid and potassium carbonate, or the mixed solution of the compound 4 is a mixed solution of the compound 4, tetra (triphenylphosphine) palladium, substituted phenyl boric acid and potassium carbonate, and the reaction route is as follows:

。

10. Use of a thiochromone derivative according to any one of claims 1 to 8 for the preparation of a medicament for inhibiting MAO-B.

11. The use according to claim 10, wherein the medicament is a medicament for the treatment of alzheimer's disease, parkinson's disease, depression, schizophrenia or cancer.