Monoamine oxidase b inhibitors and pharmaceutical use thereof

Abstract

The application belongs to the technical field of medicine, and relates to a monoamine oxidase B inhibitor and a pharmaceutical application thereof. The monoamine oxidase B is a coumarin compound, and has the characteristics of high activity, high selectivity, high blood-brain barrier permeability and low neurocyte toxicity. The monoamine oxidase B can be clinically used for treating Parkinson's disease, Alzheimer's disease, neurodegenerative disease and depression.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a monoamine oxidase B inhibitor and its pharmaceutical uses. This monoamine oxidase B is a coumarin compound with high activity, high selectivity, high blood-brain barrier permeability, and low neurotoxicity. Background Technology

[0002] Monoamine oxidase (MAO) is a flavoprotein protease located on the outer membrane of mitochondria. In the central nervous system and peripheral tissues, it catalyzes the oxidative deamination of monoamine neurotransmitters (such as dopamine and serotonin). It exists in two subtypes: MAO-A and MAO-B. MAO-B is highly expressed in the striatum of the human brain and is a key enzyme in dopamine metabolism. Abnormally elevated MAO-B activity leads to decreased dopamine levels in the brain, which is one of the core pathological mechanisms of Parkinson's disease (PD). Meanwhile, MAO-B inhibitors can exert neuroprotective effects by reducing β-amyloid protein production and inhibiting neuroinflammation, and also have potential therapeutic value for Alzheimer's disease (AD).

[0003] Currently, MAO-B inhibitors used in clinical practice mainly include irreversible (such as rasagiline and selegiline) and reversible (such as salfedipine), but they still have certain limitations: irreversible inhibitors carry the risk of irreversible inhibition of enzyme activity with long-term use, and some drugs have side effects such as hypertensive crisis and insomnia; the activity and selectivity of reversible inhibitors still have room for improvement, and some compounds have problems such as high synthesis difficulty and insufficient drug-likeness. At the same time, most existing inhibitors have defects such as insufficient blood-brain barrier penetration ability and high neurotoxicity, making it difficult to act on the central nervous system efficiently and safely.

[0004] Coumarin compounds are a class of natural / synthetic derivatives with broad biological activities. Their core structure exhibits good enzyme binding affinity, making them an important framework for the development of MAO-B inhibitors. Various coumarin MAO-B inhibitors have been disclosed in the prior art, but the IC50 values ​​of most compounds are limited. 50 MAO-B inhibitors with values ​​above 100 nM exhibit insufficient inhibitory activity, and some compounds suffer from drawbacks such as poor MAO-A selectivity, cumbersome synthesis procedures, poor blood-brain barrier permeability, and high neurotoxicity, failing to meet clinical drug needs. Therefore, developing a novel MAO-B inhibitor with high activity, high selectivity, simple synthesis, good blood-brain barrier permeability, and low neurotoxicity has significant clinical value and market potential.

[0005] Patent CN116478143A discloses a donepezil derivative with structural formula (I), its preparation method, and its application. Compared with the prior art, the donepezil derivative with formula (I) has the effect of alleviating Alzheimer's disease. It works through multiple pathways, such as inhibiting acetylcholinesterase, butyrylcholinesterase, and inhibiting β-amyloid protein. It can be used as a multi-target drug for the treatment of Alzheimer's disease and has great potential for widespread application. This patent discloses a donepezil derivative with structural formula (I). The compound was described, and its effects on alleviating Alzheimer's disease were disclosed, with the mechanism of action being the inhibition of acetylcholinesterase, butyrylcholinesterase, and β-amyloid protein. However, it was not disclosed that this compound could act as a monoamine oxidase B inhibitor. Donepezil, its parent compound, is a drug used to treat Alzheimer's disease (senile dementia), and its core mechanism of action is the reversible inhibition of acetylcholinesterase, which is not the inhibition of monoamine oxidase B. Summary of the Invention

[0006] To address the common problems of insufficient blood-brain barrier penetration, high neurotoxicity, and poor selectivity among existing MAO-B inhibitors, this invention provides an MAO-B inhibitor with an IC50 value of [missing information]. 50 With a concentration as low as 38 nmol / L, it also possesses excellent blood-brain barrier permeability and is almost non-toxic or has extremely low toxicity to human neuroblastoma SH-SY5Y cells. It combines high activity, high safety, and good central delivery performance to overcome the shortcomings of existing technologies.

[0007] The first objective of this invention is to provide a monoamine oxidase B inhibitor, wherein the monoamine oxidase B inhibitor comprises the structural formula... For the purpose of compounding or its pharmaceutically acceptable salt.

[0008] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0009] A second object of the present invention is to provide pharmaceutical uses of the above-mentioned monoamine oxidase B inhibitor. These pharmaceutical uses include: The above-mentioned monoamine oxidase B inhibitors are used in the preparation of drugs for treating Parkinson's disease.

[0010] The above-mentioned monoamine oxidase B inhibitors are used in the preparation of drugs for treating Alzheimer's disease.

[0011] The above-mentioned monoamine oxidase B inhibitors are used in the preparation of drugs for treating neurodegenerative diseases. The neurodegenerative diseases mentioned are Huntington's disease or amyotrophic lateral sclerosis (ALS).

[0012] The above-mentioned monoamine oxidase B inhibitors are used in the preparation of antidepressant drugs.

[0013] The compounds of this invention can be used to prepare medicaments for treating the following diseases: (1) Parkinson's disease (PD): By inhibiting MAO-B activity, it increases the level of dopamine in the brain, improves motor symptoms, and slows the progression of the disease; (2) Alzheimer's disease (AD): Through neuroprotection, it reduces the deposition of β-amyloid protein and improves cognitive function; (3) Other neurodegenerative diseases: such as Huntington's disease, amyotrophic lateral sclerosis (ALS), etc.; (4) Depression: It exerts its antidepressant effect by regulating the level of monoamine neurotransmitters.

[0014] A third object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the monoamine oxidase B inhibitor of claim 1 and a pharmaceutically acceptable carrier.

[0015] A fifth object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0016] The dosage of the monoamine oxidase B inhibitor described in this invention can vary depending on the route of administration, the patient's age, weight, the type and severity of the disease being treated, etc. The dosage range for treating the disease can be 0.0001-20 mg / kg / day / person, preferably 0.0003-10 mg / kg / day / person, and can be administered once or multiple times.

[0017] The monoamine oxidase B inhibitor described in this invention, as the active pharmaceutical ingredient, can constitute 0.1-99.9% by weight in the formulation, with the remainder being a pharmaceutically acceptable carrier, which also constitutes 0.1-99.9% by weight in the formulation. The pharmaceutical composition of this invention exists in unit dose form, where unit dose form refers to a unit of the formulation, such as each tablet, each capsule, each bottle of oral liquid, or each sachet of granules.

[0018] The pharmaceutical compositions of the present invention can be any pharmaceutically acceptable dosage form, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, lozenges, granules, powders, pills, powders, ointments, elixirs, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, and patches. The formulations of the present invention are preferably oral dosage forms, such as: capsules, tablets, oral liquids, granules, pills, powders, elixirs, ointments, etc.

[0019] The compositions of the present invention, in their oral administration formulations, may contain commonly used excipients, such as binders, fillers, diluents, tableting agents, lubricants, disintegrants, colorants, flavoring agents, and humectants, and the tablets may be coated if necessary.

[0020] Suitable fillers include cellulose, mannitol, lactose, and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone, and starch derivatives, such as sodium glycolate starch. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

[0021] Solid oral compositions can be prepared using common methods such as mixing, filling, and tableting. Repeated mixing allows the active ingredient to be distributed throughout compositions that use a large amount of filler.

[0022] Oral liquid formulations may take the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be a dry product that can be reconstituted with water or other suitable carriers before use. Such liquid formulations may contain conventional additives such as suspending agents, such as sorbitol, syrups, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; emulsifiers, such as lecithin, dehydrated sorbitan monooleate, or gum arabic; non-aqueous carriers (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters such as glycerol, propylene glycol, or ethanol; preservatives, such as methylparaben or propylparaben or sorbic acid; and, if desired, conventional flavorings or colorings.

[0023] For injectable formulations, the prepared liquid unit contains the active ingredient of this invention and a sterile carrier. Depending on the carrier and concentration, this compound can be suspended or dissolved. Solution preparation typically involves dissolving the active ingredient in a carrier, filtering and sterilizing it before filling it into a suitable vial or ampoule, and then sealing it. Excipients such as a local anesthetic, preservative, and buffer can also be dissolved in this carrier. To improve its stability, the composition can be frozen after filling into the vial, and water can be removed under vacuum.

[0024] The compositions of the present invention may selectively incorporate suitable pharmaceutically acceptable carriers (various solid dosage forms, liquid dosage forms, gel dosage forms, sustained-release dosage forms, etc.) during the preparation of pharmaceutical formulations. These pharmaceutically acceptable carriers are selected from: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine ​​hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, sodium calcium EDTA, carbonates, acetates, phosphates or aqueous solutions of monovalent alkali metals, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerol, Twenty-80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, β-cyclodextrin, phospholipids, kaolin, talc, calcium stearate, magnesium stearate, etc.

[0025] Compared with the prior art, the present invention has the following beneficial effects: (1) The monoamine oxidase B inhibitor of the present invention has strong MAO-B inhibition and strong MAO-B selectivity: the half-maximal inhibitory concentration (IC50) of the compound for MAO-B is as follows: 50The concentration was 38 nmol / L, classifying it as a potent MAO-B inhibitor, with significantly superior activity compared to most existing coumarin derivatives; its IC50 for MAO-A was also determined. 50 Value, calculate the selectivity index (SI=IC) 50 (MAO-A) / IC 50 (MAO-B)) The results showed that SI>1000, indicating extremely high MAO-B selectivity, which can avoid the side effects caused by MAO-A inhibition; enzyme kinetic experiments confirmed that this compound is a reversible, competitive MAO-B inhibitor with a clear mechanism of action and higher safety.

[0026] (2) Excellent blood-brain barrier permeability: The compound has a suitable lipid-water partition coefficient (logP) and molecular weight, and moderate molecular rigidity, which allows it to pass through the blood-brain barrier well and efficiently enter the central nervous system to exert its effects, meeting the key drug-like requirements for the treatment of brain diseases. As determined by the parallel artificial membrane PAMPA method, its apparent permeability coefficient Pe>5.0×10 -6 cm / s, which meets the penetration standards for drugs in the central nervous system.

[0027] (3) Extremely low neurotoxicity: In vitro cytotoxicity evaluation was performed using human neuroblastoma cells SH-SY5Y. The results showed that the cell viability was >90% in the range of 0.01–10 μM; there was no significant cytotoxicity at high concentrations (≥10 μM); the half-maximal toxicity concentration (MCC) was 0.5%. 50 >100 μM, therapeutic index (TI=CC) 50 / IC 50 >2600; almost non-toxic or minimally toxic to nerve cells, with significantly better safety than similar reported compounds.

[0028] In short, this compound has the following advantages: 1. High activity and high selectivity: The IC50 of the compounds of this invention for MAO-B is [not specified in the original text]. 50 With a concentration as low as 38 nmol / L, it exhibits excellent inhibitory activity and a selectivity index for MAO-A >1000, resulting in extremely low risk of side effects. 2. Clear mechanism of action: It is a reversible competitive inhibitor, avoiding the long-term enzyme inhibition risk of irreversible inhibitors, and has higher safety. 3. Excellent blood-brain barrier permeability: It can efficiently enter the brain to exert MAO-B inhibitory effects, solving the problem of insufficient central delivery of existing inhibitors; 4. Extremely low neurotoxicity: It is almost non-toxic to SH-SY5Y neurons, has an extremely high therapeutic index, and significantly improves the safety of long-term use; 5. Wide range of applications: It can be used to treat a variety of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. It has high activity, high safety and good central delivery, and is more suitable for development into an oral drug for central nervous system diseases such as Parkinson's disease. It has important clinical value and market prospects. Attached Figure Description

[0030] Figure 1 The compound of this invention is anti-Aβ 1-42 Graph illustrating the neuroprotective effects of toxicity. Detection of the effects of compound 3B on Aβ in SH-SY5Y cells. 1-42 Induced toxicity and neuroprotective activity. Data represent the mean SD of three observations. Compared with Aβ 1-42 Compared with the control group, *p<0.05 and **p<0.01. Detailed Implementation

[0031] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand the present invention, but it is not intended to limit the present invention.

[0032] Unless otherwise specified, the experimental materials and reagents used in the embodiments of this invention are all consumables and reagents that are conventionally available from commercial sources.

[0033] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. Percentages and parts are by weight.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0035] In the pharmacological experiments of the following embodiments of the present invention, compound It is abbreviated as compound 3B.

[0036] Example 1: MAO-B Inhibitory Activity Assay

[0037] 1. Experimental Methods: The MAO-Glo™ Assay kit (Promega) was used according to the manufacturer's instructions. Different concentrations of the target compound (0.1 nM-10 μM) were co-incubated with MAO-B enzyme (0.5 U / mL) and fluorescent substrate at 37°C for 60 minutes. After adding the stop solution, the fluorescence intensity was measured, and the inhibition rate was calculated. The IC50 was fitted using GraphPad Prism software. 50 value.

[0038] 2. Experimental Results: IC50 of the target compound against MAO-B 50 The concentration was 38 nmol / L, and the IC50 of the positive control drug rasagiline was 38 nmol / L. 50 The concentration was 2.1 nmol / L, indicating that the activity of this compound is close to that of clinical drugs, classifying it as a potent MAO-B inhibitor; its IC50 for MAO-A was also determined. 50 >40 μM, with a selectivity index SI>1050, indicating extremely high selectivity.

[0039] Example 2: Evaluation of blood-brain barrier permeability (parallel artificial membrane PAMPA method)

[0040] 1. Experimental Methods: Porcine polar brain extract was prepared to a concentration of 20 mg / mL using dodecane. Five commercially available drugs (estradiol, clonidine, imipramine, progesterone, hydrocortisone), compound 3B, baicalein, and donepezil were initially dissolved in a small amount of DMSO solution. This solution was then diluted to a concentration of 25 μg / mL using a PBS:EtOH buffer solution of 7:3. 4 μL of porcine polar brain extract was added dropwise onto a lipophilic filter membrane in the recipient pore to simulate a biomembrane. 300 μL of the test compound solution was added to the donor pore, and 200 μL of the PBS:EtOH buffer solution of 7:3 was added to the recipient pore, ensuring the compound solution just contacts the phospholipid membrane. The recipient pore was then placed on top of the donor pore, forming a sandwich structure of donor pore-biomembrane-recipient pore. The tested drugs diffused passively from the donor pore through the phospholipid membrane to the recipient pore. The mixture was allowed to stand at room temperature for 16 hours. Five replicates were performed for each compound. The liquid in the donor and acceptor wells was removed, and the OD value at 450 nm was measured using a microplate reader. The effective permeability Pe (cm / s) of the compound was calculated using the following formula: Pe = −VdVa / [(Vd + Va)At]ln(1 – drug acceptor / drug receiver Where Vd is the volume of the donor pore, Va is the volume of the acceptor pore, A is the area of ​​the artificial phospholipid membrane, t represents the permeation time, and drug acceptor It is the absorbance of the fluid in the donor pore, drug receiver This is the absorbance of the acceptor pore, and the results are expressed as mean ± standard error (SE).

[0041] 2. Experimental Results. The experimental results are shown in Table 1.

[0042]

[0043] For BBB osmosis, the Pe value is 6.1 × 10⁻⁶. -6Compounds with a velocity of cm / s or higher exhibit good blood-brain barrier permeability, with a Pe value of 6.1 × 10⁻⁶. -6 cm / s and 4.1×10 -6 Compounds with a permeability between cm / s have general blood-brain barrier permeability and a Pe value less than 4.1 × 10⁻⁶. -6 cm / s indicates poor blood-brain barrier permeability. Compound 3B shows a Pe value of 17.6 × 10⁻⁶. -6 The value of cm / s indicates that compound 3B can easily penetrate the BBB, and its permeability is stronger than that of baicalin (<0) and donepezil (11.1×10⁻⁶). -6 (cm / s).

[0044] Example 3: SH-SY5Y Neurocytotoxicity Experiment Experimental methods:

[0045] SH-SY5Y cells (human myeloid neuroblastoma cell line) are derived from human neuroblastoma cell lines. They express tyrosine hydroxylase, dopamine 2β2 hydroxylase and dopamine transporter, which are specific to catecholamine neurons. They have neuronal cytoplasmic processes. This cell line is widely used in the study of the pathogenesis of nervous system diseases.

[0046] Preparation of complete cell culture medium: The cells are cultured in DMEM high-glucose high-lipid medium. Take a 50ml sterile centrifuge tube, add 10% serum (5ml) and 1% penicillin-antibody (500μL), and then add DMEM medium to make up to 50ml to complete the preparation of complete culture medium.

[0047] Cell culture environment: Place the cells in a culture incubator with 95% air and 5% carbon dioxide, at a temperature of 37℃ and a humidity of 70%-80%.

[0048] The MTT assay was used to detect the cytotoxicity of the compound on SH-SY5Y cells. Frozen cells were removed from liquid nitrogen, thawed in a water bath, and then placed in culture dishes with an appropriate amount of DMEM complete medium. During cell culture, the medium was changed regularly (the red color in the culture medium faded), and the cells were passaged (the cell density in the culture dish was approximately 90%). Once a sufficient cell density was reached, 96-well plates were seeded. Before seeding, the cell suspension was counted using a hemocytometer, and the cell suspension was diluted to 0.7 million cells / ml. 100 μL of cell suspension was added to each well of the 96-well plate, and the plates were incubated for 12 hours.

[0049] Weigh appropriate amounts of the compound and the positive control drugs baicalein and donepezil. Dissolve them with a small amount of DMSO, then dilute with DMEM complete medium to 100 μM, 50 μM, and 25 μM. Discard the original medium. Add 200 μL of the prepared compound solution to each well of a 96-well plate. Add the solution directly to the blank control group. Incubate the 96-well plates in an incubator for 48 hours. After 48 hours, add 10 μL of MTT and wrap the plates with aluminum foil. Incubate in the dark for another 4 hours. Remove the 96-well plates, aspirate and discard the culture medium. Purple crystals will appear at the bottom of the wells. Dissolve the crystals in 150 μL of DMSO solution and measure the absorbance at 450 nm using a microplate reader. Calculate the cell viability using the formula: Cell viability = A1 / A0, where A1 is the absorbance value of the cells at each concentration, and A0 is the absorbance value of the blank control group.

[0050] The experimental results are shown in Table 2.

[0051]

[0052] Conclusion: Compound 3B is almost non-toxic at a concentration of 25 μM.

[0053] Example 4: Neuroprotective effect of compound 3B Experimental methods:

[0054] Compound 3B was prepared into solutions of different concentrations (0, 6.25, 12.5, and 25 μM) using a small amount of DMSO as a dissolving agent and complete cell culture medium as a solvent. After pretreating SH-SY5Y cells with 200 μL of the prepared compound 3B solution for 5 hours, the culture medium was discarded using a pipette, and then 200 μL of 25 μM Aβ solution was added. 1-42 Cells were incubated for 24 hours, and cell viability was evaluated using the MTT assay. Baicalein and donepezil (25 μM) were used as positive control compounds.

[0055] The experimental results are shown in Figure 1 .

[0056] according to Figure 1 The results show that, compared with untreated cells, cells treated with Aβ... 1-42 The cell viability after treatment decreased to 44%, while compound 3B exhibited good neuroprotective effects in the concentration range of 6.25-25 μM (6.25 μM: 60% ± 0.67; 12.5 μM: 63% ± 1.56; 25 μM: 66% ± 0.67), and this protective effect increased with increasing compound concentration. Furthermore, this neuroprotective effect was slightly higher than that of the positive control compounds baicalein (60% ± 0.89) and donepezil (60% ± 0.22). These findings strongly suggest that compound 3B can effectively inhibit Aβ.1-42 It reduces toxicity and better protects nerve cells.

[0057] Example 5: In vivo toxicity test in mice

[0058] Twelve healthy, newly adult Kunming mice, weighing approximately 18-22g, were selected, with an equal number of males and females. The mice were divided into experimental and control groups and pre-fed in an SPF-grade animal facility for 6 days to allow them to better adapt to the new environment. After 6 days, the mice were fasted but allowed free access to water overnight. The mice were then weighed, and compound 3B was administered to the experimental group at a dose of 2 g / kg. Compound 3B was then prepared into a suspension at a concentration of 30 μL / g using physiological saline. The control group was administered the corresponding dose of physiological saline via gavage. Mice mortality was observed at 6 h, 48 h, and 30 days. During this period, the mice's behavior, motor function, nervous system, respiratory system, digestive and absorptive systems, and skin and fur were examined and recorded. The results of the acute toxicity test in mice are shown in Table 3.

[0059]

[0060] Based on the results in the table, we can draw the following conclusions: Regarding behavior and motor function, mice showed reduced activity initially after administration, but subsequently returned to normal, and were able to quickly receive and respond to appropriate stimuli. Regarding the nervous system, mice exhibited no abnormal movements and were able to react to sudden sounds with a startle reflex. Regarding the respiratory system, observations of respiration and respiratory rate revealed normal breathing and a normal respiratory rate. Regarding the digestive and absorptive system, mice maintained a normal diet after administration, and their weight gradually increased. Furthermore, no abnormalities were observed in the skin and fur of the mice after administration. In conclusion, compound 3B is non-toxic to mice at a dose of 2 g / kg.

[0061] Example 6 Preparation of pharmaceutical composition (tablets)

[0062] 1. Tablet formulation (per tablet): 3,5-Dimethoxy-N-(7-methoxy-2-oxo-2H-chromene-3-yl)benzamide (compound 3B): 50 mg Microcrystalline cellulose: 120 mg Crospovidone: 10 mg Magnesium stearate: 2 mg Hydroxypropyl methylcellulose: 5 mg 2. Preparation method: Mix the active ingredients with microcrystalline cellulose and crospovidone evenly, prepare a soft mass with hydroxypropyl methylcellulose aqueous solution, granulate, dry, and sizing the mass. Add magnesium stearate, mix, and compress into tablets to obtain the final product.

[0063] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A monoamine oxidase B inhibitor, characterized in that, The monoamine oxidase B inhibitor comprises the structural formula […]. Compounds thereof or their pharmaceutically acceptable salts thereof.

2. The use of the monoamine oxidase B inhibitor according to claim 1 in the preparation of a drug for treating Parkinson's disease.

3. The use of the monoamine oxidase B inhibitor according to claim 1 in the preparation of a drug for treating Alzheimer's disease.

4. The use of the monoamine oxidase B inhibitor according to claim 1 in the preparation of a drug for treating neurodegenerative diseases.

5. The application according to claim 4, characterized in that, The neurodegenerative disease mentioned is Huntington's disease or amyotrophic lateral sclerosis (ALS).

6. The use of the monoamine oxidase B inhibitor according to claim 1 in the preparation of an antidepressant drug.

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains a therapeutically effective amount of the monoamine oxidase B inhibitor of claim 1 and a pharmaceutically acceptable carrier.

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