3-Benzyloxy-6-pyridylpyridazine compounds and their preparation method and use

Abstract

The present invention discloses a class of 3-benzyloxy-6-pyridylpyridazine compounds (I) and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition thereof, and use thereof in preparing a drug for treating and / or preventing diseases by inhibiting monoamine oxidase B, metal ion complexation, or anti-neuroinflammation, including but not limited to vascular dementia, Alzheimer's disease, frontotemporal dementia, prion disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma; #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a class of 3-benzyloxy-6-pyridylpyridazine compounds (I) and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition thereof, and use thereof in preparing drugs for treating and / or preventing diseases by inhibiting monoamine oxidase B, metal ion complexation, or anti-neuroinflammation, including but not limited to vascular dementia, Alzheimer's disease, frontotemporal dementia, prion disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma. Background Art

[0002] Neurodegenerative diseases are a general term for diseases caused by the chronic, progressive degeneration of central nervous system tissues, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Their pathogenesis is closely linked to oxidative stress, neuroinflammation, and the resulting damage. Oxidative stress is mediated by reactive oxygen species (ROS) free radicals, including superoxide anions, hydrogen peroxide, and hydroxyl radicals. Under normal physiological conditions, ROS production levels are in a dynamic equilibrium with the body's antioxidant capacity. When ROS production exceeds cellular antioxidant capacity, oxidative stress occurs. The brain is particularly sensitive to oxidative stress, which can trigger a variety of neurological diseases. Other studies have found that vascular dementia, HIV-related dementia, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma are also closely related to the body's oxidative stress and neuroinflammation.

[0003] Vascular dementia (VD) is a clinical syndrome characterized by intellectual and cognitive impairment caused by various types of cerebrovascular disease, including ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, and acute and chronic hypoxic cerebrovascular disease. Due to its complex pathogenesis, there are currently no medications that can halt its progression. Clinical treatment focuses on improving cerebral blood circulation, brain metabolism, and enhancing brain nutrition.

[0004] Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and memory loss. Its incidence is increasing annually, making it second only to cardiovascular disease and cancer in terms of prevalence. With the accelerating aging of the global population, its incidence is showing a significant upward trend. It is estimated that over 50 million people worldwide suffer from dementia, with the total cost of treatment and care exceeding US$1 trillion in 2018. The number of patients is projected to increase to 152 million by 2050. AD manifests itself in clinical manifestations such as decreased memory, orientation, thinking, and judgment, as well as impaired daily living abilities, and can even lead to abnormal psychiatric and behavioral symptoms. This makes patient care challenging and places a heavy burden on society and families. Currently approved drugs for the treatment of mild / moderate AD include acetylcholinesterase (AChE) inhibitors and, for severe AD, N-methyl-D-aspartate (NMDA) receptor antagonists. However, clinical use has shown that these drugs can alleviate AD symptoms by increasing acetylcholine levels in patients or inhibiting the excitotoxicity of excitatory amino acids, but they cannot effectively prevent or reverse the course of the disease. In addition, they can cause serious side effects such as hallucinations, confusion, dizziness, nausea, and liver toxicity, resulting in less than ideal long-term efficacy. Therefore, there is an urgent need to develop new AD treatment drugs that can both improve AD symptoms and change the course of the disease.

[0005] AD is a disease caused by multiple factors, and its pathogenesis is complex and has not yet been fully elucidated. However, studies have shown that the decrease in acetylcholine levels in the patient's brain, excessive production and deposition of β-amyloid protein, platelet aggregation in cerebral blood vessels, metal ion metabolism disorders, Ca 2+ Multiple factors play a key role in the pathogenesis of AD, including imbalanced homeostasis, neurofibrillary tangles caused by tau protein hyperphosphorylation, excessive glutamate receptor activity, oxidative stress producing large amounts of reactive oxygen species (ROS) and free radicals, and neuroinflammatory responses. To address these pathogenic factors, researchers have employed a traditional "one-drug, one-target" drug design strategy, discovering a large number of highly active and selective drugs for a specific target, such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. However, these drugs suffer from a single target, numerous toxic side effects during clinical use, and poor long-term efficacy in AD patients.

[0006] Currently, two monoamine oxidases have been identified and characterized in the human body, including two subtypes, MAO-A and MAO-B, which are mainly responsible for the oxidative deamination of biogenic amines and monoamine neurotransmitters such as serotonin, dopamine, norepinephrine and phenylethylamine to regulate their concentrations and metabolism in the brain and peripheral tissues. MAO-B is mainly distributed in the outer membrane of mitochondria of glial cells and uses flavin adenine dinucleotide (FAD) as a coenzyme factor. It is the main enzyme in the brain for the oxidative deamination of dopamine. Recent studies have found that the expression of MAO-B in the brains of patients with AD or PD is abnormally increased. This enzyme can not only destroy cholinergic neurons and promote the formation of Aβ plaques and neurofibrillary tangles, but also significantly reduce the dopamine content in the brain. In addition, when MAO-B catalyzes deamination, H2O2 is also produced, and the generated H2O2 can react with endogenous Cu 2+ 、Fe 2+ Plasma generates hydroxyl radicals through the Fenton reaction, which in turn damage lipids, proteins, and nucleic acids, leading to mitochondrial dysfunction and ultimately neuronal cell death in the brain. Therefore, inhibiting the deamination activity of MAO-B can not only increase dopamine levels in the brain but also protect against oxidative stress and promote neuroprotection by reducing the production of free radicals and reactive oxygen species. Other studies have found that inhibiting MAO-B can also increase phenylethylamine levels in the brain, which in turn stimulates dopamine release and inhibits dopamine reuptake. Therefore, the discovery of selective MAO-B inhibitors is of great significance for the treatment and / or prevention of neurological diseases.

[0007] In recent years, as the pathogenic mechanisms of neurodegenerative diseases have been elucidated, it has been discovered that the onset and progression of neurodegenerative diseases are characterized by multiple mechanisms and factors. These mechanisms are interconnected and mutually influential, forming a complex network regulatory system in the onset and progression of these diseases. Clearly, the development of therapeutic agents that can simultaneously target multiple pathways in the pathological process of neurodegenerative diseases is a necessary step. Based on these findings, researchers have proposed a "multi-target drug" strategy for the development of anti-neurodegenerative disease drugs. A "multi-target drug" refers to a single chemical entity that simultaneously acts on multiple targets within the disease network, generating synergistic effects on each target, resulting in a total effect greater than the sum of the individual effects. The key differences between multi-target drugs and multidrug combinations and combination drugs include reduced dosage, improved therapeutic efficacy, avoidance of drug interactions and the resulting toxic side effects, uniform pharmacokinetic properties, and ease of use. Therefore, the development of anti-neurodegenerative disease drugs with novel chemical structures, novel mechanisms of action, multi-target effects, and reduced toxicity and side effects is a key focus. Summary of the Invention

[0008] The present invention aims to disclose a class of 3-benzyloxy-6-pyridylpyridazine compounds (I) and pharmaceutically acceptable salts thereof.

[0009] Another object of the present invention is to disclose a method for preparing the 3-benzyloxy-6-pyridylpyridazine compound (I) and its pharmaceutically acceptable salt.

[0010] Another object of the present invention is to disclose a pharmaceutical composition comprising the 3-benzyloxy-6-pyridylpyridazine compound (I) and a pharmaceutically acceptable salt thereof.

[0011] Another object of the present invention is to disclose that the 3-benzyloxy-6-pyridylpyridazine compound (I) and its pharmaceutically acceptable salt have multi-target effects and can be used to prepare drugs for treating and / or preventing diseases related to the nervous system, including but not limited to vascular dementia, Alzheimer's disease, frontotemporal dementia, prion disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.

[0012] The general chemical structure formula of the 3-benzyloxy-6-pyridylpyridazine compound (I) disclosed in the present invention is:

[0013]

[0014] In the formula: X represents O or S; R1 and R2 each independently represent H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, R1 and R2 are in any possible position of the benzene ring; R3 and R4 each independently represent H, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, CF3, CF3O, R5CONH, CN, halogen, or NR6R7; when X represents S, R3 and R4 do not represent H at the same time; R5 represents C1-C6 alkyl; R6 and R7 each independently represent H, C1-C6 alkyl; when NR6R7 forms a ring, it represents tetrahydropyrrolyl, morpholinyl or piperidinyl; R3 and R4 are in any possible position of the pyridine ring; the "halogen" refers to F, Cl, Br or I; however, the above-mentioned 3-benzyloxy-6-pyridylpyridazine compound (I) does not represent the following compounds:

[0015]

[0016] The 3-benzyloxy-6-pyridylpyridazine compound (I) disclosed in the present invention can be prepared by the following method: using the corresponding 3-chloro-6-pyridylpyridazine compound (1) as a starting material, reacting it with a benzyl alcohol or benzyl mercaptan compound (2) in a solvent under alkaline conditions to obtain the corresponding 3-benzyloxy-6-pyridylpyridazine compound (I), and the reaction formula is as follows:

[0017]

[0018] Wherein: the definitions of X, R1, R2, R3 and R4 are the same as those of the general chemical structure formula of 3-benzyloxy-6-pyridylpyridazine compound (I).

[0019] For the above-mentioned synthetic route, its specific preparation method is described as follows:

[0020] The solvent used in the reaction is: diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, 1,4-dioxane, benzene, toluene or acetonitrile, preferably: N,N-dimethylformamide, dichloromethane, tetrahydrofuran or toluene; the base used in the reaction is: alkali metal hydride, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate or alkaline earth metal carbonate, preferably: hydrogenated The molar feed ratio of lithium, sodium hydride, potassium hydroxide or potassium carbonate; 3-chloro-6-pyridylpyridazine compound (1): benzyl alcohol or benzyl mercaptan compound (2): base is 1.0:1.0-6.0:1.0-6.0, preferably 1.0:1.0-3.0:1.0-3.0; the reaction temperature is 0°C to 120°C, preferably room temperature to 100°C; the reaction time is 1 to 72 hours, preferably 2 to 36 hours.

[0021] The starting material of the present invention, 3-chloro-6-pyridylpyridazine compound (1), can be prepared by common techniques in the art, including but not limited to the methods disclosed in the following documents: 1. Yichun Shi, et al. Eur. J. Med. Chem. 2022, 230, 114098; 2. Binglun Lam. US4340733.

[0022] The pharmaceutical composition disclosed herein comprises a therapeutically effective amount of one or more 3-benzyloxy-6-pyridylpyridazine compounds (I), which may further contain one or more pharmaceutically acceptable carriers or excipients. The term "therapeutically effective amount" refers to the amount of a drug or agent that elicits a biological or medical response in a tissue, system, or animal targeted by a researcher or physician; the term "composition" refers to a product formed by mixing one or more substances or components; and the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that carries or transports a chemical substance. The pharmaceutical composition provided herein ideally comprises 2% to 99.5% by weight of the active ingredient in the 3-benzyloxy-6-pyridylpyridazine compound (I).

[0023] The 3-benzyloxy-6-pyridylpyridazine compound (I) disclosed in the present invention was screened for the following biological activities:

[0024] (1) Inhibitory activity of 3-benzyloxy-6-pyridylpyridazine compounds (I) against monoamine oxidase B

[0025] Recombinant human MAO-B was prepared into a 75 μg / mL sample solution using 100 mM potassium phosphate buffer at pH 7.4. 20 μL of the test compound solution and 80 μL of monoamine oxidase were added to a black 96-well plate, mixed, and incubated at 37°C in a dark place for 15 minutes. 200 μM Amplex Red reagent, 2 U / mL horseradish peroxidase, and 2 mM benzylamine were added to initiate the reaction. The reaction was incubated at 37°C for 20 minutes. Fluorescence emission intensity at 590 nm was measured on a multifunctional microplate reader with a fixed excitation wavelength of 545 nm. Potassium phosphate buffer was used instead of MAO-B as a blank. The inhibition rate of the compound against monoamine oxidase was calculated as follows: 100-(IF i ) / (IF c )*100, in the formula, IF i and IF c The difference between the fluorescence intensity in the presence of inhibitors and in the absence of inhibitors and the blank fluorescence intensity. Each compound was tested in 3 replicates each time, and each group of experiments was repeated three times independently. Five to six concentrations of the compound were selected, and their enzyme inhibition rate was determined. The negative logarithm of the molar concentration of the compound was linearly regressed with the enzyme inhibition rate, and the molar concentration at which the inhibition rate was 50% was obtained as the IC of the compound. 50 The results showed that the 3-benzyloxy-6-pyridylpyridazine compounds (I) disclosed in the examples of the present invention have significant inhibitory effects on MAO-B, and their IC 500.12nM~16.8μM (for example: Example compound 1-1-2 is 910.0nM, compound 1-1-3 is 0.58nM, compound 1-1-5 is 43.0nM, compound 1-1-6 is 14.0nM, compound 1-1-13 is 55.0nM, compound 1-1-30 is 30.0nM, compound 1-1-33 is 16.0nM, compound 1-1-39 is 1.2nM, compound Further structure-activity relationship studies found that when the 6-position substituent of the pyridazine nucleus of the 3-benzyloxy-6-pyridylpyridazine compound (I) was replaced by "H" while the 3-position benzyloxy group of the pyridazine nucleus remained unchanged, the MAO-B inhibitory activity of the corresponding compounds was greatly reduced, and their IC 50 The values ​​were all greater than 26.5 μM; when the "benzyloxy" at the 3-position of the pyridazine mother nucleus was replaced by "H" or "OH" and the pyridyl substituted at the 6-position of the pyridazine mother nucleus remained unchanged, the MAO-B inhibitory activities of the corresponding compounds were also greatly reduced, and their IC 50 The values ​​were all greater than 45.0 μM; the "benzyl" of the 3-benzyloxy group in the 3-benzyloxy group of the pyridazine compound (I) was shifted to the 2-N position of the pyridazine nucleus, and the MAO-B inhibition IC of the obtained 2-benzyl-6-pyridylpyridazine-3-one compound was 50 The values ​​were all greater than 50.0 μM.

[0026] (2) Complexation of 3-benzyloxy-6-pyridylpyridazine compounds (I) with metal ions

[0027] CuCl2·2H2O, ZnCl2, FeSO4, AlCl3, and the test compound were dissolved in methanol to form a 75 μmol / L solution. 100 μL of the test compound solution and 100 μL of the metal ion solution were added to a 96-well plate, mixed, and allowed to stand at room temperature for 30 minutes. The UV absorption curve of the mixture in the range of 200-600 nm was recorded on a Varioskan Flash Multimode Reader. The red shift of the maximum absorption peak of the metal ion and the test compound mixture and the intensity of the maximum absorption peak were observed using 100 μL of the test compound solution and 100 μL of methanol as controls. The measurement results showed that the 3-benzyloxy-6-pyridylpyridazine compound (I) disclosed in the examples of the present invention exhibited complexation with the above-mentioned metal ions; however, replacing the pyridyl group at the 6-position of the pyridazine nucleus with a phenyl group in the structure resulted in almost no complexation with the above-mentioned metal ions (the maximum absorption peak intensity of the test compound and metal ion mixture did not change significantly, and the maximum absorption peak did not exhibit a red shift). This study shows that the pyridyl group at the 6-position of the pyridazine nucleus in 3-benzyloxy-6-pyridylpyridazine compounds (I) has a significant effect on the metal ion complexation of the compounds.

[0028] (3) Inhibitory activity of 3-benzyloxy-6-pyridylpyridazine compounds (I) on neuroinflammation

[0029] (a) Effects of compounds and lipopolysaccharide (LPS) on BV-2 cell viability

[0030] BV-2 cells in the logarithmic growth phase were prepared into a cell suspension and inoculated into a 96-well plate. The cells were cultured in a 37°C, 5% CO2 cell culture incubator for 24 h. After the cells adhered, 90 μL of fresh serum-free culture medium was replaced. 10 μL of the test compound at each concentration was added and pre-incubated for 30 min. Three parallel wells were set up for each concentration, and a blank control group was set up. LPS was then added or not and the cells were cultured in a 37°C, 5% CO2 cell culture incubator for another 24 h. MTT solution was added and incubated at 37°C for 4 h. The supernatant was discarded and 200 μL of DMSO solution was added to each well. After gentle shaking for 10 min, the OD value was measured at 490 nm using a microplate reader. The mean OD value of each test sample at different concentrations was calculated, and the cell viability was calculated as follows: Cell viability (%) = mean OD value of the treatment group / mean OD value of the control group × 100%. The test results show that all 3-benzyloxy-6-pyridylpyridazine compounds (I) disclosed in the examples of the present invention showed no cytotoxicity (inhibition rate less than <10%) at a concentration not exceeding 30 μM.

[0031] (b) Effects of compounds on LPS-induced NO release in BV-2 cells

[0032] BV-2 cells in the logarithmic growth phase were prepared into a cell suspension and inoculated into a 96-well plate. The cells were cultured in a 37°C, 5% CO2 cell culture incubator for 24 h. After the cells adhered, 90 μL of fresh serum-free culture medium was replaced. 10 μL of the test compound at each concentration was added and pre-incubated for 30 min. Three parallel wells were set for each concentration, and a blank control group was also set up. LPS (1.0 μg / ml) was then added for stimulation. The cells were cultured in a 37°C, 5% CO2 cell culture incubator for another 24 h. The cell culture supernatant of the different treatment groups was taken, and an equal volume of Griess reagent I and an equal volume of Griess reagent II were added. The cells were reacted in the dark at room temperature for 10 min. The absorbance at 540 nm was measured to detect the NO level in the cell supernatant (the specific operation was carried out according to the instructions of the NO detection kit). The test results showed that all 3-benzyloxy-6-pyridylpyridazine compounds (I) disclosed in the examples of the present invention showed a strong inhibitory effect on LPS-induced NO production in BV-2 cells in the concentration range of 0.5 μM to 25 μM (the inhibition rate at a concentration of 15.0 μM was more than 40.0%), and had a significant dose-effect relationship; indicating that 3-benzyloxy-6-pyridylpyridazine compounds (I) have significant anti-neuroinflammatory activity. DETAILED DESCRIPTION

[0033] The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention.

[0034] Example 1 General method for preparing 3-benzyloxy-6-pyridylpyridazine compounds (I)

[0035] Benzyl alcohol or benzyl mercaptan compound (2) (3.0 mmol), sodium hydride (4.0 mmol) and tetrahydrofuran (35 ml) were added to a reaction flask, stirred at room temperature for 10 minutes, and then 3-chloro-6-pyridylpyridazine compound (1) (2.0 mmol) was added. The reaction was continued at room temperature for 2.0 to 24.0 hours (the reaction progress was monitored by TLC). After the reaction, the solvent was evaporated under reduced pressure, deionized water (30 ml) was added to the residue, and the mixture was extracted with ethyl acetate (90 ml) three times. The organic layers were combined and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: acetone-petroleum ether = 1:8 v / v) to obtain the corresponding 3-benzyloxy-6-pyridylpyridazine compound (I) with a yield of 28.3%-65.6%. The chemical structures of the compounds were determined by 1 H-NMR, 13C-NMR and ESI-MS confirmed that the purity of the obtained target product was greater than 96.0% as determined by HPLC. The structure of the target product prepared by the above general method is as follows:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043] Some compounds 1 H-NMR and 13 The C-NMR data are as follows:

[0044]

[0045] 1 HNMR(CDCl3):8.67(d,J=4.8Hz,1H),8.57(d,J=8.0Hz,1H),8.50(d,J=9.2Hz,1H),7.84(td,J=8.0,2.0Hz,1H),7. 51(dd,J=8.8,5.6Hz,2H),7.35(dd,J=8.0,4.8Hz,1H),7.13(d,J=9.2Hz,1H),7.09(t,J=8.8Hz,2H),5.56(s,2H). 13 CNMR(CDCl3):164.7,162.7,155.0,153.5,149.1,137.1,132.2,130.3,128.0,124.1,120.8,117.9,115.5,68.5;

[0046]

[0047] 1HNMR(CDCl3):8.63(dd,J=8.4,5.6Hz,1H),8.49(d,J=9.2Hz,1H),8.31(dd,J=10.4,2.4Hz,1H),7.51(dd,J=8.8,5.6Hz,2H),7.13(d,J=9.2Hz,1H),7.09(t,J=8.8Hz,3H),5.62(s,2H). 13 CNMR(CDCl3):169.5,165.0,162.7,156.8,154.0,151.5,132.1,130.4,128.1,118.0,115.5,112.1,108.6,68.7;

[0048]

[0049] 1 HNMR(CDCl3):8.84-8.83(m,2H),8.48(d,J=9.2Hz,1H),7.56(d,J=5.2Hz,1H),7.52(dd,J=8.4,5.2 Hz,2H),7.16(d,J=9.2 Hz,1H),7.10(t,J=8.4 Hz,2H),5.64(s,2H). 13 CNMR(CDCl3):165.2,162.8,155.0,153.4,150.1,131.9,130.5,127.9,125.1,122.7,121.6,118.2,116.4,115.6,68.8;

[0050]

[0051] 1 HNMR(CDCl3):8.49(d,J=9.2 Hz,1H),8.30(d,J=6.0 Hz,1H),7.87(d,J=2.8Hz,1H),7.50(dd,J=8.8,5.4 Hz,2H),7.11-7.06(m,3H),6.56(dd,J=6.0,2.8 Hz,1H),5.61(s,2H),3.09(s,6H). 13 CNMR(CDCl3):164.6,162.7,155.6,155.1,153.3,149.2,132.3,130.3,128.3,117.8,115.5,107.2,103.4,68.4,39.3;

[0052]

[0053] 1 HNMR(CDCl3):8.48(d,J=9.2 Hz,1H),8.30(d,J=6.0 Hz,1H),8.03(d,J=2.8Hz,1H),7.50(dd,J=8.8,5.6 Hz,2H),7.08(t,J=9.2 Hz,3H),6.70(dd,J=6.0,2.8 Hz,1H),5.60(s,2H),3.46(brs,4H),1.67(brs,6H). 13 CNMR(CDCl3):164.6,162.7,155.6,155.6,153.8,149.6,132.3,130.3,128.3,117.8,115.5,108.7,105.0,68.4,47.4,25.2,24.5;

[0054]

[0055] 1 HNMR(DMSO-d6):10.52(s,1H),8.70(d,J=2.4 Hz,1H),8.55(dd,J=5.6,1H),8.44(d,J=9.2,1H),7.69(dd,J=5.6,2.4 Hz,1H),7.64-7.58(m,2H),7.39(dd,J=9.2,2.8 Hz,1H),7.25(t,J=8.8 Hz,2H),5.59(s,2H),2.15(s,3H). 13 CNMR(DMSO-d6):170.2,165.1,162.4,155.1,154.3,150.7,147.4,133.2,131.2,128.4,118.3,115.7,114.0,109.7,68.3,24.7;

[0056]

[0057] 1 HNMR(DMSO-d6):10.37(s,1H),8.86(d,J=2.4 Hz,1H),8.40(d,J=9.2 Hz,2H),8.22(dd,J=8.8,2.4 Hz,1H),7.59(dd,J=8.8,5.6 Hz,2H),7.37(d,J=9.2 Hz,1H),7.24(t,J=8.8 Hz,2H),5.57(s,2H),2.12(s,3H);

[0058]

[0059] 1 HNMR(DMSO-d6):10.56(s,1H),8.37(d,J=9.2Hz,1H),8.15(d,J=8.0Hz,1H),8.10(d,J=8.0Hz,1H),7.95(t,J=8 .0Hz,1H),7.59(dd,J=8.4,5.6Hz,2H),7.45(d,J=9.2Hz,1H),7.24(t,J=8.8Hz,2H),5.58(s,2H),2.14(s,3H). 13 CNMR(DMSO-d6):169.4,164.5,161.9,154.3,151.8,151.4,139.5,132.8,130.7,127.8,117.9,115.3,115.2113.9,67.9,24.0.

[0060] Example 2 General method for preparing 3-benzyloxy-6-pyridylpyridazine compound (I) by forming salt with acid

[0061] 1.0 mmol of 3-benzyloxy-6-pyridylpyridazine compound (I) obtained in Example 1 and 20 ml of methanol were added to a reaction flask, stirred evenly, and then 2.5 mmol of the corresponding acid was added. The mixture was stirred at room temperature for 30 minutes, and then the solvent was evaporated under reduced pressure. The residue was purified to obtain a salt of 3-benzyloxy-6-pyridylpyridazine compound (I). Its chemical structure is shown in FIG. 1 The results were confirmed by H NMR and ESI-MS.

Claims

1. A class of 3-benzyloxy-6-pyridylpyridazine compounds and pharmaceutically acceptable salts thereof, characterized in that The chemical structure of this type of compound is shown in the formula (I): In the formula: X represents O or S; R1 and R2 each independently represent H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogen, R1 and R2 are in any possible position of the benzene ring; R3 and R4 each independently represent H, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, CF3, CF3O, R5CONH, CN, halogen, or NR6R7; when X represents S, R3 and R4 do not represent H at the same time; R5 represents C1-C6 alkyl; R6 and R7 each independently represent H, C1-C6 alkyl; when NR6R7 forms a ring, it represents tetrahydropyrrolyl, morpholinyl or piperidinyl; R3 and R4 are in any possible position of the pyridine ring; the "halogen" refers to F, Cl, Br or I; however, the above-mentioned 3-benzyloxy-6-pyridylpyridazine compound (I) does not represent the following compounds:

2. The 3-benzyloxy-6-pyridylpyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that X represents O; R1 and R2 each independently represent H, methyl, methoxy, methylthio, F, Cl or Br; R1 and R2 are in any possible position of their benzene ring; R3 and R4 each independently represent H, methyl, CF3, methoxy, CF3O, methylthio, CN, OH, NH2, N(CH3)2, N(C2H5)2, CH3CONH, tetrahydropyrrolyl, morpholinyl, piperidinyl, F, Cl, Br, However, the 3-benzyloxy-6-pyridylpyridazine compound does not represent the following compounds:

3. The 3-benzyloxy-6-pyridylpyridazine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that X represents S; R1 and R2 each independently represent H, methyl, methoxy, methylthio, F, Cl or Br; R1 and R2 are in any possible position of their benzene ring; R3 and R4 each independently represent H, methyl, CF3, methoxy, CF3O, methylthio, CN, OH, NH2, N(CH3)2, N(C2H5)2, CH3CONH, tetrahydropyrrolyl, morpholinyl, piperidinyl, F, Cl or Br, but R3 and R4 do not represent H at the same time; the 3-benzyloxy-6-pyridylpyridazine compound does not represent the following compounds:

4. The 3-benzyloxy-6-pyridylpyridazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that The pharmaceutically acceptable salts are prepared by reacting such 3-benzyloxy-6-pyridylpyridazine compounds with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, aminosulfonic acid, trifluoroacetic acid, stearic acid, pamoic acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C 1-6 Salts of alkylsulfonic acid, camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 1,4-butanedisulfonic acid.

5. A method for preparing a 3-benzyloxy-6-pyridylpyridazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that The compound can be prepared by the following method: Wherein: X, R1 to R4 are defined in the same manner as the general chemical structure of 3-benzyloxy-6-pyridylpyridazine compound (I); The corresponding 3-chloro-6-pyridylpyridazine compound (1) is used as a starting material, and reacted with a benzyl alcohol or benzyl mercaptan compound (2) in a solvent under alkaline conditions to obtain the corresponding 3-benzyloxy-6-pyridylpyridazine compound (I); and then reacted with an acid through a conventional salt-forming method to obtain a pharmaceutically acceptable salt thereof.

6. The method for preparing 3-benzyloxy-6-pyridylpyridazine compounds or pharmaceutically acceptable salts thereof according to claim 5, characterized in that The base used in the reaction is: alkali metal hydride, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate or alkaline earth metal carbonate; the solvent used in the reaction is: diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, 1,4-dioxane, benzene, toluene or acetonitrile.

7. The method for preparing 3-benzyloxy-6-pyridylpyridazine compounds or pharmaceutically acceptable salts thereof according to claim 5, characterized in that The molar feed ratio of 3-chloro-6-pyridylpyridazine compound (1): benzyl alcohol or benzyl mercaptan compound (2): base is 1.0:1.0-6.0:1.0-6.0; the reaction temperature is 0°C-120°C; and the reaction time is 1-72 hours.

8. A pharmaceutical composition characterized in that The invention comprises the 3-benzyloxy-6-pyridylpyridazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the 3-benzyloxy-6-pyridylpyridazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for preparing a drug for treating and / or preventing diseases by inhibiting monoamine oxidase B, metal ion complexation or anti-neuroinflammation.

10. The use of the 3-benzyloxy-6-pyridylpyridazine compound or a pharmaceutically acceptable salt thereof according to claim 9, characterized in that The diseases are: vascular dementia, Alzheimer's disease, frontotemporal dementia, prion disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.

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