CN117143074A - 3-benzyloxy-6-pyridylpyridazine compound as well as preparation method and application thereof - Google Patents

3-benzyloxy-6-pyridylpyridazine compound as well as preparation method and application thereof Download PDF

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CN117143074A
CN117143074A CN202311115184.1A CN202311115184A CN117143074A CN 117143074 A CN117143074 A CN 117143074A CN 202311115184 A CN202311115184 A CN 202311115184A CN 117143074 A CN117143074 A CN 117143074A
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benzyloxy
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pyridylpyridazines
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邓勇
陈军利
余光俊
张冰冰
黄远晨
钟凤
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Sichuan University
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Abstract

The invention discloses a 3-benzyloxy-6-pyridylpyridazines compound (I) and pharmaceutically acceptable salts thereof, a preparation method, a pharmaceutical composition and application thereof in preparing medicines 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, dementia with lewy bodies, parkinson's disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and other diseases;

Description

3-benzyloxy-6-pyridylpyridazine compound as well as preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a 3-benzyloxy-6-pyridylpyridazines compound (I) and pharmaceutically acceptable salts thereof, a preparation method, a pharmaceutical composition and application thereof in preparing medicines 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, dementia with lewy bodies, parkinson's disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, cerebral trauma-induced nerve injury and other diseases.
Background
Neurodegenerative diseases are the general names of diseases caused by chronic progressive degenerative changes of central nervous tissue, and include Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's disease (Huntington disease, HD), amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis, ALS), multiple sclerosis (Multiple sclerosis, MS) and the like, and the pathogenesis thereof is closely related to oxidative stress, neuroinflammation and corresponding injury. Oxidative stress is mediated by reactive oxygen (Reactive oxygen species, ROS) radicals, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, among others. Under normal physiological conditions, ROS production levels are in a state of dynamic equilibrium with the organism's antioxidant capacity, and Oxidative stress (Oxidative stress) occurs when ROS production exceeds the cell's antioxidant capacity, whereas the brain is particularly sensitive to Oxidative stress, thereby inducing various neurological diseases. In addition, it has been found that vascular dementia, HIV-related dementia, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve injury caused by brain trauma are also closely related to oxidative stress and nerve inflammation of the body.
Vascular dementia (Vascular Dementia, VD) is a clinical syndrome of intellectual and cognitive dysfunction caused by various types of cerebrovascular diseases including ischemic cerebrovascular diseases, hemorrhagic cerebrovascular diseases, acute and chronic hypoxic cerebrovascular diseases, etc. Due to the complex pathogenesis of vascular dementia, no medicine capable of blocking the development of the disease exists at present, and clinical treatment is mainly performed to improve the blood circulation and the brain metabolism of the brain and strengthen the nutrition of the brain.
Alzheimer's Disease (AD) is a central nervous system degenerative disease mainly composed of progressive cognitive disorder and memory impairment, and the incidence of which is in an increasing trend year by year, becoming a high-incidence disease next to cardiovascular disease and cancer. With the acceleration of the aging process of the global population, the incidence rate of the disease is obviously increased. It is estimated that over 5000 tens of thousands of people worldwide are currently suffering from dementia, and the total cost of treatment and care is over dollars 1 trillion in 2018, and the number of people suffering from dementia will increase to 1.52 billion by 2050. AD is clinically manifested by reduced memory, orientation, thinking and judgment, reduced daily life, even abnormal mental behavior symptoms, and the like, which makes patient care difficult and places a heavy burden on society and families. Currently approved drugs for the treatment of mild/moderate AD are acetylcholinesterase (AChE) inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists for the treatment of severe AD. Clinical application shows that the medicines can relieve AD symptoms by improving the level of acetylcholine in patients or inhibiting the excitotoxicity of excitatory amino acids, but can not effectively prevent or reverse the course of the disease, and can also cause serious toxic and side effects such as illusion, consciousness chaos, dizziness, nausea, hepatotoxicity and the like, so that the long-term curative effect is not ideal. Thus, there is a great clinical need to develop new therapeutic agents for AD that have both symptomatic improvement and altered course of disease.
AD is a disease caused by various factors and its pathogenesis is repeatedThe pathogenesis of this is not yet fully elucidated. However, studies have shown that patients have reduced levels of acetylcholine, excessive production and deposition of beta-amyloid, platelet aggregation in cerebral vessels, disturbed metal ion metabolism, ca 2+ Many factors such as imbalance, neurofibrillary tangles due to tau-protein hyperphosphorylation, glutamate receptor hyperactivity, oxidative stress to produce large amounts of Reactive Oxygen Species (ROS) and free radicals, and neuroinflammatory reactions play an important role in the pathogenesis of AD. For the above-mentioned pathogenesis, researchers have adopted the traditional "one drug one target" drug design strategy, and found a large number of drugs with high activity and high selectivity to a certain target, such as: cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and the like. However, the medicines have the problems of single action target point, more toxic and side effects in clinical use, poor long-term curative effect on AD patients and the like.
Currently, two monoamine oxidase enzymes (Monoamine oxidases) have been identified and characterized in humans, including two subtypes MAO-A and MAO-B, which are primarily responsible for oxidative deamination of biogenic amines and monoamine neurotransmitters such as 5-hydroxytryptamine, dopamine, norepinephrine and phenethylamine to regulate their concentration and metabolism in the brain and surrounding tissues. MAO-B is mainly distributed in the outer mitochondrial membrane of glial cells, takes Flavin Adenine Dinucleotide (FAD) as a coenzyme factor, and is a main enzyme for oxidative deamination of dopamine in the brain. In recent years, the research shows that the expression quantity of MAO-B in the brain of an AD or PD patient is abnormally increased, and the enzyme can destroy cholinergic neurons, promote the generation of Abeta plaque and neurofibrillary tangles and obviously reduce the content of dopamine in the brain; in addition, H is also produced at the same time as MAO-B is catalytically deaminated 2 O 2 And H is generated 2 O 2 Can be combined with endogenous Cu 2+ 、Fe 2+ The plasma generates hydroxyl radicals through the Fenton reaction (Fenton reaction), which in turn can damage lipids, proteins and nucleic acids, thereby causing mitochondrial dysfunction and ultimately leading to brain neuronal cell death. Therefore, inhibiting deamination of MAO-B can increase dopamine content in brain, and can reduce free radical and active oxygen productionTo antioxidant stress and neuroprotection; in addition, the inhibition of MAO-B has been found to increase the content of phenethylamine in the brain, which in turn stimulates dopamine release and inhibits dopamine reuptake. Thus, selective inhibitors of MAO-B have been found to be of great importance in the treatment and/or prevention of neurological related disorders.
In recent years, along with the continuous elucidation of the pathogenesis of neurodegenerative diseases, the occurrence and development of neurodegenerative diseases are found to have the characteristics of multi-mechanism and multi-factor actions, and the different mechanisms are mutually related and mutually influenced, so that a complex network regulation and control system in the occurrence and development process of the neurodegenerative diseases is formed. Obviously, the development of therapeutic drugs that can act simultaneously on multiple links in the pathological process of neurodegenerative diseases is a current necessary choice. Based on the above results, researchers have proposed a "multi-target targeted drug" strategy to develop anti-neurodegenerative disease drugs. By "multi-target drug" is meant a single chemical entity that acts on multiple targets in the disease network simultaneously, and the effects on each target can produce a synergistic effect such that the total effect is greater than the sum of the individual effects. The main differences of the multi-target medicine and multi-medicine combined application and the compound medicine are as follows: can reduce the dosage, improve the treatment effect, avoid the interaction between medicines and the toxic and side effect caused by the interaction, has uniform pharmacokinetic property, is convenient to use, and the like. Therefore, the development of the anti-neurodegenerative disease treatment drug with novel chemical structure, novel action mechanism, multi-target effect and low toxic and side effect is an important current direction.
Disclosure of Invention
The invention aims to disclose a 3-benzyloxy-6-pyridylpyridazine compound (I) and pharmaceutically acceptable salts thereof.
The invention also aims to disclose a preparation method of the 3-benzyloxy-6-pyridylpyridazine compound (I) and pharmaceutically acceptable salts thereof.
It is a further object of the present invention to disclose pharmaceutical compositions comprising such 3-benzyloxy-6-pyridylpyridazines (I) and pharmaceutically acceptable salts thereof.
It is still another object of the present invention to disclose the use of the 3-benzyloxy-6-pyridylpyridazines (I) and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and/or prophylaxis of neurological related disorders, including but not limited to vascular dementia, alzheimer's disease, frontotemporal dementia, prion's disease, dementia with lewy bodies, parkinson's disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke and neurological damage caused by brain trauma.
The chemical structural general formula of the 3-benzyloxy-6-pyridylpyridazine compound (I) disclosed by the invention is as follows:
wherein: x represents O or S; r is R 1 And R is 2 Each independently represents H, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 1 ～C 6 Alkylthio, halogen, R 1 And R is 2 At any possible position of its benzene ring; r is R 3 And R is 4 Each independently represents H, OH, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 1 ～C 6 Alkylthio, CF 3 、CF 3 O、R 5 CONH, CN, halogen, Or NR (NR) 6 R 7 The method comprises the steps of carrying out a first treatment on the surface of the When X represents S, R 3 And R is 4 Not simultaneously representing H; r is R 5 Represent C 1 ～C 6 An alkyl group; r is R 6 And R is 7 Each independently represents H, C 1 ～C 6 An alkyl group; when NR is 6 R 7 Ring-forming represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r is R 3 And R is 4 At any possible position of the pyridine ring; the "halogenThe element "refers to F, cl, br or I; however, the 3-benzyloxy-6-pyridylpyridazines (I) do not represent the compounds shown below:
the 3-benzyloxy-6-pyridylpyridazine compound (I) disclosed by the invention can be prepared by the following method: the corresponding 3-chloro-6-pyridylpyridazines (1) are used as starting materials and react with benzyl alcohol or benzyl mercaptan compounds (2) in a solvent and under alkaline conditions to obtain corresponding 3-benzyloxy-6-pyridylpyridines (I), and the reaction formula is as follows:
wherein: x, R 1 、R 2 、R 3 And R is 4 The definition of the compound is the same as that of the chemical structural general formula of the 3-benzyloxy-6-pyridylpyridazine compound (I).
For the above synthetic route, the specific preparation method is described as follows:
the solvents used in the reaction are: diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, 1, 4-dioxane, benzene, toluene or acetonitrile, preferably the solvents are: n, N-dimethylformamide, dichloromethane, tetrahydrofuran or toluene; the alkali used in the reaction is as follows: alkali metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates or alkaline earth metal carbonates, preferably the bases are: lithium hydride, sodium hydride, potassium hydroxide or potassium carbonate; 3-chloro-6-pyridylpyridazines (1): benzyl alcohol or benzyl mercaptan compound (2): the molar feed ratio of the alkali is 1.0:1.0 to 6.0:1.0 to 6.0, preferably a molar feed ratio of 1.0:1.0 to 3.0:1.0 to 3.0; the reaction temperature is 0-120 ℃, preferably the reaction temperature is room temperature-100 ℃; the reaction time is 1 to 72 hours, preferably 2 to 36 hours.
The starting material of the present invention, 3-chloro-6-pyridylpyridazines (1), can be prepared by techniques common 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.
The disclosed pharmaceutical compositions comprise a therapeutically effective amount of one or more 3-benzyloxy-6-pyridylpyridazines (I), which may further comprise one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of a drug or agent that causes a biological or medical response to a tissue, system or animal targeted by a researcher or doctor; the term "composition" refers to a product formed by mixing more than one substance or component; the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or carrier, such as: liquid or solid fillers, diluents, excipients, solvents or encapsulating substances that carry or transport a chemical substance. The ideal proportion of the pharmaceutical composition provided by the invention is that the 3-benzyloxy-6-pyridylpyridazine compound (I) is 2% -99.5% of the total weight as the active ingredient.
The 3-benzyloxy-6-pyridylpyridazines compound (I) disclosed by the invention is subjected to the following biological activity screening:
(1) Inhibitory Activity of 3-benzyloxy-6-pyridylpyridazines (I) on monoamine oxidase B
Recombinant human MAO-B was formulated as 75. Mu.g/mL sample solution with 100mM potassium phosphate buffer pH 7.4. Adding 20 mu L of a compound solution to be detected into a black 96-well plate, uniformly mixing, incubating at 37 ℃ for 15min at a dark place, adding 200 mu M of an Amplex Red reagent, 2U/mL of horseradish peroxidase and 2mM of phenylmethylamine to initiate reaction, incubating at 37 ℃ for 20min, and measuring fluorescence emission intensity at 590nm by fixing excitation wavelength 545nm on a multifunctional enzyme-labeled instrument, wherein a potassium phosphate buffer solution is used as a blank instead of MAO-B; the inhibition rate of the compound for inhibiting monoamine oxidase is calculated as follows: 100- (IF) i )/(IF c ) 100, wherein, IF i And IF (IF) c The difference between the fluorescence intensity in the presence and absence of inhibitor and the blank fluorescence intensity, respectively. Each compound was assayed each time3 duplicate wells, each set of experiments was independently repeated three times. Selecting five to six concentrations of the compound, measuring the enzyme inhibition rate, and obtaining the molar concentration of the compound which is the IC of the compound when the 50% inhibition rate is obtained by linear regression of the negative logarithm of the molar concentration of the compound and the inhibition rate of the enzyme 50 . The measurement result shows that the 3-benzyloxy-6-pyridylpyridazines compound (I) disclosed in the embodiment of the invention has remarkable inhibition effect on MAO-B, and IC thereof 50 0.12nM to 16.8. Mu.M (e.g., 910.0nM for example 1-1-2, 0.58nM for 1-1-3, 43.0nM for 1-1-5, 14.0nM for 1-1-6, 55.0nM for 1-1-13, 30.0nM for 1-1-30, 16.0nM for 1-1-33, 1.2nM for 1-1-39, 24.0nM for 1-3-2, 2.3nM for 1-3-4, 21.0nM for 1-4-2, and 1.9nM for 1-4-12); further research on structure-activity relationship shows that when the 6-substituent-pyridyl group of the pyridazine mother nucleus of the 3-benzyloxy-6-pyridylpyridazine compound (I) is replaced by H, the MAO-B inhibition activity of the corresponding compound is greatly reduced when the 3-benzyloxy of the pyridazine mother nucleus is kept unchanged, and IC thereof 50 Values are all greater than 26.5. Mu.M; when the 3-benzyloxy group of the pyridazine mother nucleus is replaced by H or OH, and the 6-substituted pyridyl of the pyridazine mother nucleus is kept unchanged, the MAO-B inhibition activity of the corresponding compound is also greatly reduced, and the IC thereof 50 Values are all greater than 45.0. Mu.M; the "benzyl" of 3-position benzyloxy in the 3-benzyloxy-6-pyridylpyridazine compound (I) molecule is shifted to the 2-position "N" of the pyridazine mother nucleus, and MAO-B inhibition IC of the obtained 2-benzyl-6-pyridylpyridazin-3-one compound 50 The values are also all greater than 50.0. Mu.M.
(2) Complexation of 3-benzyloxy-6-pyridylpyridazines (I) with metal ions
Dissolving CuCl with methanol 2 ·2H 2 O、ZnCl 2 、FeSO 4 、AlCl 3 And the compound to be tested is prepared into a 75 mu mol/L solution, 100 mu L of the compound to be tested and 100 mu L of the metal ion solution are added into a 96-well plate, uniformly mixed, kept stand at room temperature for 30min, the ultraviolet absorption curve of the mixture in the range of 200-600nm is recorded on a Varioskan Flash Multimode Reader instrument, and 100 mu L of the compound to be tested and 1 mu L of the compound to be tested are addedThe 00. Mu.L of methanol mixed solution is used as a control, and the red shift phenomenon of the maximum absorption peak and the intensity of the maximum absorption peak of the mixed solution of the metal ions and the compound to be tested are observed. The measurement result shows that the 3-benzyloxy-6-pyridylpyridazines compound (I) disclosed in the example of the invention shows complexation effect on the metal ions; the pyridyl at the 6-position of the pyridazine mother nucleus in the structure is replaced by phenyl, and the obtained corresponding compound has almost no complexation with the metal ions (the maximum absorption peak intensity of the mixed solution of the compound to be tested and the metal ions has no obvious change, and the maximum absorption peak has no red shift phenomenon). The study shows that the pyridyl group at the 6-position of the pyridazine mother nucleus in the 3-benzyloxy-6-pyridylpyridazine compound (I) has a remarkable influence on the metal ion complexation of the compound.
(3) Inhibitory Activity of 3-benzyloxy-6-pyridylpyridazines (I) on neuroinflammation
(a) Effect of Compounds and Lipopolysaccharide (LPS) on BV-2 cell Activity
Inoculating BV-2 cells in logarithmic growth phase into 96-well plate, and placing at 37deg.C and 5% CO 2 Culturing in a cell culture box for 24 hours, changing into 90 mu L of fresh culture solution without serum after cells are attached, respectively adding 10 mu L of each concentration of compound to be tested, pre-incubating for 30min, setting 3 parallel holes of each concentration, and setting a blank control group; then, with or without LPS, the mixture is placed at 37 ℃ and 5% CO 2 The culture was continued for 24 hours in a cell incubator, MTT solution was added, incubated at 37℃for 4 hours, the supernatant was discarded, 200. Mu.L of DMSO solution was added to each well, after a gentle shaking for 10 minutes, OD values were measured at 490nm with an ELISA reader, the mean of the OD values measured at different concentrations for each sample was calculated, and the cell viability was calculated as follows: cell viability (%) = mean OD of dosing group/mean OD of control group x 100%. The test results show that all 3-benzyloxy-6-pyridylpyridazines (I) disclosed in the examples of the invention do not show cytotoxicity (inhibition ratio is less than<10％)。
(b) Effect of Compounds on LPS-induced release of NO by BV-2 cells
Inoculating BV-2 cells in logarithmic growth phase into 96-well plate, and placing at 37deg.C and 5% CO 2 Culturing in cell culture boxChanging into 90 mu L of fresh culture solution without serum after cell adhesion for 24 hours, adding 10 mu L of each concentration of compound to be tested, pre-incubating for 30 minutes, setting 3 parallel holes of each concentration, and setting a blank control group at the same time; then LPS (1.0. Mu.g/ml) was added for stimulation, and the mixture was left at 37℃with 5% CO 2 Culturing in a cell culture incubator for 24 hours, taking cell culture supernatants of different treatment groups, adding an equal volume of Griess reagent I and an equal volume of Griess reagent II, reacting for 10 minutes at room temperature in a dark place, and measuring absorbance at 540nm to detect the NO level in the cell supernatant (specific operation is performed according to the instruction of a NO detection kit). Test results show that all 3-benzyloxy-6-pyridylpyridazines compounds (I) disclosed in the embodiment of the invention show strong inhibition effect on BV-2 cell NO generation induced by LPS in the concentration range of 0.5 mu M to 25 mu M (inhibition rate at 15.0 mu M is more than 40.0%), and have obvious dose-effect relationship; the 3-benzyloxy-6-pyridylpyridazine compound (I) has remarkable anti-neuroinflammation activity.
Detailed Description
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 invention without departing from the spirit and scope thereof.
Example 13 preparation of benzyloxy-6-pyridylpyridazines (I)
Benzyl alcohol or benzyl mercaptan compound (2) (3.0 mmol), sodium hydride (4.0 mmol) and tetrahydrofuran (35 ml) are added into a reaction bottle, and after stirring at room temperature for 10 minutes, 3-chloro-6-pyridylpyridazine compound (1) (2.0 mmol) is added, and the reaction is continued at room temperature with stirring for 2.0 to 24.0 hours (the reaction progress is followed by TLC); after the reaction, the solvent is distilled off under reduced pressure, deionized water (30 ml) is added into the residue, the mixture is extracted for three times by ethyl acetate (90 ml), the organic layer is combined and then washed by saturated sodium chloride aqueous solution, dried by anhydrous sodium sulfate and filtered, the solvent is distilled off under reduced pressure, the residue is purified by silica gel column chromatography (eluent: acetone-petroleum ether=1:8v/v), and the corresponding 3-benzyloxy-6-pyridylpyridazines compound (I) is obtained, the yield is 28.3% -65.6%, and the chemical knot is formedAll the channels of the structure 1 H-NMR、 13 The purity of the obtained target product is greater than 96.0% by HPLC (high performance liquid chromatography) as confirmed by C-NMR and ESI-MS. The structure of the target object prepared by the general method is as follows:
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of part of the compounds 1 H-NMR 13 The C-NMR data are as follows:
1 HNMR(CDCl 3 ):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(CDCl 3 ):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；
1 HNMR(CDCl 3 ):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(CDCl 3 ):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；
1 HNMR(CDCl 3 ):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(CDCl 3 ):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；
1 HNMR(CDCl 3 ):8.49(d,J＝9.2 Hz,1H),8.30(d,J＝6.0 Hz,1H),7.87(d,J＝2.8 Hz,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(CDCl 3 ):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；
1 HNMR(CDCl 3 ):8.48(d,J＝9.2 Hz,1H),8.30(d,J＝6.0 Hz,1H),8.03(d,J＝2.8 Hz,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(CDCl 3 ):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；
1 HNMR(DMSO-d 6 ):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-d 6 ):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；
1 HNMR(DMSO-d 6 ):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)；
1 HNMR(DMSO-d 6 ):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-d 6 ):169.4,164.5,161.9,154.3,151.8,151.4,139.5,132.8,130.7,127.8,117.9,115.3,115.2 113.9,67.9,24.0。
example 23 salt formation of benzyloxy-6-pyridylpyridazines (I) with acids
The reaction flask was charged with the above examples1.0mmol of the 3-benzyloxy-6-pyridylpyridazines compound (I) obtained in 1 and 20ml of methanol, adding 2.5mmol of corresponding acid after stirring uniformly, stirring at room temperature for reaction for 30 minutes, evaporating solvent under reduced pressure, purifying residues to obtain salts of the 3-benzyloxy-6-pyridylpyridazines compound (I), and obtaining chemical structures of the salts 1 H NMR and ESI-MS corroborations.

Claims (10)

1. The 3-benzyloxy-6-pyridylpyridazines and pharmaceutically acceptable salts thereof are characterized in that the chemical structural general formula of the compounds is shown as (I):
wherein: x represents O or S; r is R 1 And R is 2 Each independently represents H, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 1 ～C 6 Alkylthio, halogen, R 1 And R is 2 At any possible position of its benzene ring; r is R 3 And R is 4 Each independently represents H, OH, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, C 1 ～C 6 Alkylthio, CF 3 、CF 3 O、R 5 CONH, CN, halogen, Or NR (NR) 6 R 7 The method comprises the steps of carrying out a first treatment on the surface of the When X represents S, R 3 And R is 4 Not simultaneously representing H; r is R 5 Represent C 1 ～C 6 An alkyl group; r is R 6 And R is 7 Each independently represents H, C 1 ～C 6 An alkyl group; when NR is 6 R 7 Ring-forming represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r is R 3 And R is 4 At any possible position of the pyridine ring; the halogen refers to F, cl, br or I; but the above 3-benzylThe oxy-6-pyridylpyridazines (I) do not represent compounds as shown below:
2. 3-benzyloxy-6-pyridylpyridazines according to claim 1, characterized in that X represents O; r is R 1 And R is 2 Each independently represents H, methyl, methoxy, methylthio, F, cl or Br; r is R 1 And R is 2 At any possible position of its benzene ring; r is R 3 And R is 4 Each independently represents H, methyl, CF 3 Methoxy, CF 3 O, methylthio, CN, OH, NH 2 、N(CH 3 ) 2 、N(C 2 H 5 ) 2 、CH 3 CONH, tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-methylpiperazinyl, F, cl, br,But the 3-benzyloxy-6-pyridylpyridazines do not represent the following compounds:
3. 3-benzyloxy-6-pyridylpyridazines according to claim 1, characterized in that X represents S; r is R 1 And R is 2 Each independently represents H, methyl, methoxy, methylthio, F, cl or Br; r is R 1 And R is 2 At any possible position of its benzene ring; r is R 3 And R is 4 Each independently represents H, methyl, CF 3 Methoxy, CF 3 O, methylthio, CN, OH, NH 2 、N(CH 3 ) 2 、N(C 2 H 5 ) 2 、CH 3 CONH, tetrahydropyrroleRadicals, morpholinyl, piperidinyl, 4-methylpiperazinyl, F, cl or Br, but R 3 And R is 4 Not simultaneously representing H; the 3-benzyloxy-6-pyridylpyridazines do not represent the following compounds:
4. a 3-benzyloxy-6-pyridylpyridazine compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a mixture of such 3-benzyloxy-6-pyridylpyridazine compound and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C 1-6 Fatty carboxylic 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, naphthalene sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 1, 4-butanesulfonic acid.
5. A process for the preparation of 3-benzyloxy-6-pyridylpyridazines or pharmaceutically acceptable salts thereof according to any one of claims 1 to 4, characterised in that the compound is obtainable by:
wherein: x, R 1 ～R 4 The definition of the compound is the same as that of a 3-benzyloxy-6-pyridylpyridazine compound (I);
the corresponding 3-chlorine-6-pyridyl pyridazine compound (1) is used as a starting material and reacts with benzyl alcohol or benzyl mercaptan compound (2) in a solvent and under alkaline conditions to obtain the corresponding 3-benzyloxy-6-pyridyl pyridazine compound (I); and then the mixture is subjected to conventional salification with acid to obtain pharmaceutically acceptable salts thereof.
6. The process for preparing 3-benzyloxy-6-pyridylpyridazines or pharmaceutically acceptable salts thereof according to claim 5, wherein the base used for the reaction is: alkali metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates or alkaline earth metal carbonates; the solvents used in the reaction are: diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, chloroform, N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, 1, 4-dioxane, benzene, toluene or acetonitrile.
7. The process for producing 3-benzyloxy-6-pyridylpyridazines or pharmaceutically acceptable salts thereof according to claim 5, characterized in that 3-chloro-6-pyridylpyridazines (1): benzyl alcohol or benzyl mercaptan compound (2): the molar feed ratio of the alkali is 1.0:1.0 to 6.0:1.0 to 6.0; the reaction temperature is 0-120 ℃; the reaction time is 1-72 hours.
8. A pharmaceutical composition comprising a 3-benzyloxy-6-pyridalyl-pyridazine compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
9. Use of a 3-benzyloxy-6-pyridylpyridazine compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prophylaxis of diseases by inhibition of monoamine oxidase B, metal ion complexation or anti-neuroinflammation.
10. Use of a 3-benzyloxy-6-pyridylpyridazine compound according to claim 9 or a pharmaceutically acceptable salt thereof, characterized in that the disease is: vascular dementia, alzheimer's disease, frontotemporal dementia, prion's disease, dementia with Lewy bodies, parkinson's disease, huntington's disease, HIV-associated dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.
CN202311115184.1A 2023-08-31 2023-08-31 3-benzyloxy-6-pyridylpyridazine compound as well as preparation method and application thereof Pending CN117143074A (en)

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