CN109665969B - 3-methoxy-4-hydroxychalcone bis-Mannich base compound, and preparation method and application thereof - Google Patents
3-methoxy-4-hydroxychalcone bis-Mannich base compound, and preparation method and application thereof Download PDFInfo
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- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
The invention discloses a novel 3-methoxy-4-hydroxychalcone bis mannich base compound (I) and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicaments for treating and/or preventing related diseases of a nervous system, wherein the compounds include but are not limited to vascular dementia, alzheimer disease, parkinson disease, huntington disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury and other diseases caused by brain trauma;
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a novel 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) and pharmaceutically acceptable salts thereof, a preparation method thereof, a medicinal composition and application thereof in preparing medicaments for treating and/or preventing nervous system related diseases, wherein the diseases comprise vascular dementia, Alzheimer disease, Parkinson disease, Huntington's disease, HIV-related dementia disease, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like.
Background
Neurodegenerative diseases refer to a general term for diseases caused by chronic progressive degeneration of central nervous tissue, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and the pathogenesis of which is closely related to oxidative stress, neuroinflammation, and corresponding injury. Oxidative stress is mediated by Reactive Oxygen Species (ROS) radicals, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, among others. Under normal physiological conditions, the ROS production level and the body antioxidant capacity are in a dynamic balance state, when the ROS production exceeds the cell antioxidant capacity, Oxidative stress (Oxidative stress) occurs, and the brain is particularly sensitive to the Oxidative stress, so that various nervous system diseases are induced. In addition, researches show that vascular dementia, HIV-related dementia, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like are also related to oxidative stress and neuroinflammation of the body.
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 disease development exists at present, and the clinical treatment mainly aims at improving the brain blood circulation and brain metabolism and strengthening the brain nutrition. Recent studies have shown that VD patients often have abnormalities in the cholinergic system as well as impaired cognitive function. The density of ChAT positive neurons and fibers in the hippocampal region of a VD patient is reduced, the ChAT activity of different parts in the brain is reduced, the concentration of acetylcholine in cerebrospinal fluid of the VD patient is obviously lower than the normal level, and the degree of reduction of the concentration is positively correlated with the severity of dementia; cerebral ischemia can cause the activity of acetylcholinesterase in brain to rise; meanwhile, the acetylcholinesterase inhibitors are found to protect neuron damage caused by ischemia and promote nerve damage and brain function recovery after cerebral ischemia.
Alzheimer's disease (senile dementia) is a degenerative disease of the central nervous system mainly involving progressive cognitive impairment and memory impairment, and its incidence rate is increasing year by year, and it is a high-grade disease next to cardiovascular diseases and cancer, and it is the fourth cause of death in developed countries such as europe and the united states. With the accelerated aging process of the global population, the incidence rate is on the rising trend, according to Alzheimer's DiseaseInternational published in 2013, 12 months, "Global impact of Alzheimer's disease: 2013-2050 reports indicate that AD will become the biggest health challenge worldwide for decades in the future, and by 2030, the number of patients will rise from 4400 ten thousand in 2013 to 7600 ten thousand, and by 2050, the number will reach 1.35 hundred million which is surprising. Because AD is clinically manifested as hypomnesis, orientation ability, thinking and judgment ability, reduction of daily life ability, even abnormal mental behavior symptoms, and the like, the nursing difficulty of patients is large, and the heavy burden is brought to the society and families. Currently approved drugs for the treatment of light/moderate AD are acetylcholinesterase (AChE) inhibitors, and for the treatment of severe ADN-methyl-D-an aspartate (NMDA) receptor antagonist. Clinical application shows that the medicines can relieve AD symptoms by improving the acetylcholine level in a patient body or inhibiting excitotoxicity of excitatory amino acid, but cannot effectively prevent or reverse the course of disease, and can cause severe toxic and side effects such as hallucinations, consciousness chaos, dizziness, headache, nausea, hepatotoxicity, inappetence, frequent defecation and the like, so that the long-term curative effect is not ideal. Therefore, there is an urgent clinical need to develop a novel therapeutic agent for AD that has both improved symptoms and altered course of disease.
AD is a disease caused by various factors, the pathogenesis of the AD is complex, and the pathogenesis of the AD is not completely clarified so far. However, studies have shown that the patient has a decreased acetylcholine level in the brain,βOverproduction and deposition of amyloid, platelet aggregation in cerebral vessels, metabolic disorders of metal ions, Ca2+Imbalance of balance,tauNeurofibrillary tangles caused by protein hyperphosphorylation, glutamate receptor hyperactivity, large amounts of Reactive Oxygen Species (ROS) and free radicals produced by oxidative stress, and various factors such as neuroinflammatory responses play important roles in the pathogenesis of AD. In view of the above pathogenic factors, researchers have found a large number of drugs with high activity and high selectivity to a target by using the traditional "one drug one target" drug design strategy, such as: cholinesterase inhibitors andN-methyl-DAspartate receptor antagonists and the like. However, the medicines have single action target, more toxic and side effects in clinical use and are used for treating AAnd D, the long-term curative effect of the patient is poor.
In recent years, with the continuous elucidation of the pathogenic mechanism of AD, the occurrence and development of AD have the characteristics of multi-mechanism and multi-factor action, and different mechanisms are mutually associated and influenced to form a complex network regulation and control system in the occurrence and development process of AD. Obviously, the development of therapeutic drugs that can act simultaneously on multiple links in the pathological process of AD is the current necessity. Based on the above results, researchers have proposed a "multi-target-directed drugs" (MTDLs) strategy to develop anti-neurodegenerative drugs. By "multi-target drug" is meant that a single chemical entity acts on multiple targets in a disease network simultaneously, and the effect on each target can produce a synergistic effect, such that the total effect is greater than the sum of the individual effects, such compounds also being referred to as "Multifunctional" or "Multipotential" drugs. The main differences of the multi-target point medicine and the multi-medicine combined application and the compound medicine are as follows: can reduce the dosage, improve the treatment effect, avoid the interaction between the medicaments and the toxic and side effect caused by the interaction, have uniform pharmacokinetic characteristic, and are convenient to use, and the like. Therefore, the research and development of the neurodegenerative disease resisting treatment drug which has a novel chemical structure, a novel action mechanism, a multi-target effect and low toxic and side effects not only meets the urgent need of the social aging process, but also has good market prospect. A large number of clinical studies have proved that AChE inhibitors can effectively relieve the symptoms of AD patients, and the short-term treatment effect is positive; therefore, in designing multi-target anti-AD drugs, it is generally necessary to retain the AChE inhibitory activity of the compound (inhibition of this enzyme is important for improving the symptoms of AD patients) and to add one or more other targets or functions with pharmacological synergy to achieve multi-target AD therapeutic effects. Obviously, the design and the discovery have the effects of inhibiting acetylcholinesterase and inhibitingβThe overproduction and deposition of amyloid, antioxidant stress and multi-target AD therapeutics against monoamine oxidase-B remain important research directions at present.
Disclosure of Invention
The invention aims to disclose a novel 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) and a pharmaceutically acceptable salt thereof.
The invention also aims to disclose a preparation method of the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) and pharmaceutically acceptable salts thereof.
The invention also discloses a pharmaceutical composition containing the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) and a pharmaceutically acceptable salt thereof.
The invention also aims to disclose that the 3-methoxy-4-hydroxychalcone bis mannich base compound (I) and the pharmaceutically acceptable salt thereof have multi-target effect, and can be used for preparing the drugs for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, alzheimer disease, parkinson disease, huntington disease, HIV-related dementia disease, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like.
The general chemical structure formula of the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) provided by the invention is as follows:
in the formula: r1、R2、R3And R4Each independently represents C1~C12Alkyl, benzyl, substituted benzyl, NR1R2Or NR3R4Also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-position by C1~C12Piperidinyl substituted by alkyl, piperidinyl substituted by benzyl in the 4-position, 4-thiopiperidinyl, piperazinyl, C in the 4-position1~C12Piperazinyl substituted by alkyl, piperazinyl substituted by benzyl or substituted benzyl at the 4-position, wherein OH on the B ring in the molecule is at any possible position of the corresponding benzene ring; the "substituted benzyl" refers to a benzyl group substituted on the phenyl ring with 1 to 4 groups selected from the group consisting of: F. cl、Br、I、C1-4Alkyl radical, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, these substituents being in any possible position on the phenyl ring of the benzyl group.
The 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) provided by the invention can be prepared by the following method:
in the formula: r1～R4And the definition of the position of the hydroxyl on the B ring is the same as the chemical structural general formula of the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I).
Taking corresponding 3-methoxy-4-hydroxy-5-amine methyl acetophenone compound (1) and hydroxybenzaldehyde Mannich base compound (2) as initial raw materials, and directly condensing under the conditions of solvent and alkali to obtain corresponding 3-methoxy-4-hydroxy chalcone bis Mannich base compound (I). Wherein the alkali used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, C1-8Alkali metal salts of alcohols, organic tertiary or quaternary amines (e.g. triethylamine, tributylamine, trioctylamine, pyridine, tert-butyl amine, pyridine, tert-butyl amine, pyridine, tert-butyl amine, pyridine, tert-butyl amine, tert-butyl,N-methylmorpholine,NMethylpiperidine, triethylenediamine, tetrabutylammonium hydroxide), the preferred bases being: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine or pyridine; the solvent used in the reaction is: c1-8Fatty alcohol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide, dichloromethane, chloroform, 1, 4-dioxane, benzene, toluene or acetonitrile, preferably in the presence of a solvent: methanol, ethanol, isopropanol,N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane or toluene; 3-methoxy-4-hydroxy-5-aminomethyl acetophenones compound (1): hydroxybenzaldehyde mannich base compounds (2): the molar charge ratio of alkali is 1.0: 1.0-3.0: 1.0-20.0, and preferably, the molar feed ratio is 1.0: 1.0-2.0: 1.0 to 10.0; reaction ofThe temperature is 0-150 ℃, and the preferable reaction temperature is room temperature-120 ℃; the reaction time is 1-120 hours, and the preferable reaction time is 2-72 hours.
The starting materials of the invention, namely 3-methoxy-4-hydroxy-5-amine methyl acetophenone compound (1) and hydroxybenzaldehyde Mannich base compound (2), can be prepared by the technique which is common in the field, namely: the compound is prepared by taking corresponding 3-methoxy-4-hydroxyacetophenone or hydroxybenzaldehyde compounds as substrates and performing conventional Mannich reaction with formaldehyde (or paraformaldehyde) and corresponding secondary amine compounds under the catalysis of acid.
The 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) obtained by the method contains amino which is basic, and can be prepared into pharmaceutically acceptable salts thereof by a pharmaceutically conventional salt forming method with any suitable acid, wherein the acid is as follows: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C1-6Aliphatic carboxylic acids (e.g. formic acid, acetic acid, propionic acid, etc.), 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, C1-6Alkyl sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 1, 4-butanedisulfonic acid.
The pharmaceutical composition disclosed by the invention comprises one or more 3-methoxy-4-hydroxychalcone bis-Mannich base compounds (I) or pharmaceutically acceptable salts thereof with a therapeutically effective amount, and the pharmaceutical composition can further contain one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of a drug or agent that elicits a biological or medicinal response in a tissue, system, or animal targeted by a researcher or physician; the term "composition" refers to a product formed by mixing more than one substance or component; the "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or vehicle, such as: liquid or solid fillers, diluents, excipients, solvents or encapsulating substances, which carry or transport certain chemical substances. The ideal proportion of the pharmaceutical composition provided by the invention is that the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) or the pharmaceutically acceptable salt thereof is taken as an active ingredient and accounts for 5-99.5% of the total weight, and the rest is less than 95% of the total weight.
The 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) and pharmaceutically acceptable salts thereof disclosed by the invention are subjected to the following biological activity screening.
(1) 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) has inhibitory activity on acetylcholinesterase and butyrylcholinesterase
Adding 30 μ L of thioacetyl choline iodide or thiobutyrylcholine iodide (all from Sigma), 40 μ L of PBS buffer solution with pH7.4, 20 μ L of test compound solution (DMSO content is less than 1%) and 10 μ L of acetylcholinesterase (rat brain cortex 5% homogenate supernatant, pH7.4 phosphate buffer solution as homogenate medium) or butyrylcholinesterase (rat serum 25% supernatant, pH7.4 phosphate buffer solution as homogenate medium) into a 96-well plate in sequence, incubating at 37 deg.C for 15min after adding, adding 0.2% of 5, 5' -dithio-bis (2-nitrobenzoic acid) (DTNB, from Sigma) solution 30 μ L for developing color, measuring optical density (OD value) of each well at 405nm with an enzyme reader, comparing with blank wells without test sample, calculating the inhibition rate (enzyme inhibition rate) = (1-blank sample group (%) =value/OD value) × 100 OD value) of compound on enzyme %); selecting five to six concentrations of the compound, measuring the enzyme inhibition rate, performing linear regression by using the negative logarithm of the molar concentration of the compound and the enzyme inhibition rate, and obtaining the molar concentration when the 50% inhibition rate is obtained as the IC of the compound50. The determination result shows that the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) disclosed in the embodiment of the invention has a remarkable inhibition effect on acetylcholinesterase, and the IC of the compound50The particle size is 1.2 nM-12.0 [ mu ] M; and the inhibitory activity of the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) on acetylcholinesterase is obviously higher than that on butyrylcholinesterase (the selectivity is more than 10 times), which shows that the inventionThe disclosed compounds have selective inhibitory effects on acetylcholinesterase. The determination result also shows that the parent nucleus of the 3-methoxy-4-hydroxy chalcone bis-Mannich base compound (I) -dihydroxy chalcone compound (namely: CH)2NR1R2And CH2NR3R4Compounds which simultaneously represent H and represent the OH of the B ring at any possible position of the corresponding benzene ring), and hydroxybenzaldehyde Mannich bases compounds (2) acetylcholinesterase-inhibiting IC50Are all larger than 100 mu M. In further research, the inventor also found that in the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I), if CH is substituted2NR1R2Or CH2NR3R4When one of the two compounds is replaced by H, the inhibitory activity of the corresponding compound on acetylcholinesterase is obviously reduced (at least by more than 3 times).
(2) Antioxidant activity of 3-methoxy-4-hydroxychalcone bis mannich base compound (I) (ORAC-FL method)
Reference (Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-: 6-hydroxy-2, 5,7, 8-tetramethylchromane-2-carboxylic acid (C)Trolox) The solution was adjusted to 10-80. mu. mol/L with PBS buffer solution of pH7.4, the solution was adjusted to 250 nmol/L with PBS buffer solution of pH7.4 for fluorescein (fluorescein), and the solution was adjusted to 40 mmol/L with PBS buffer solution of pH7.4 for 2, 2' -azobisisobutylamidine dihydrochloride (AAPH) before use. The compound solution and the fluorescein solution were added to a 96-well plate at 50-10. mu. mol/L, mixed, incubated at 37 ℃ for 15min, and AAPH solution was added to make the total volume per well 200. mu.L, mixed, immediately placed in a Varioskan Flash Multimode Reader (Thermo Scientific) instrument, and continuously measured at 485 nm excitation wavelength and 535 nm emission wavelength for 90 min. Calculating the area AUC under the fluorescence decay curve, wherein the area AUC is 1-8 mu mol/LTroloxAs a standard, taking a sample not to be tested as a blank, and expressing the antioxidant activity result of the compound asTroloxThe formula of the equivalent of (a) is: [ (AUC Sample-AUC blank)/(AUCTrolox-AUC blank)] ×[(concentration of Trolox/concentration of sample)]Each compound was assayed in 3 replicates each, each set of experiments was independently repeated three times. The determination result shows that the antioxidant activity of the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) disclosed in the embodiment of the invention isTrolox1.6-4.0 times of the total amount of the compound, which shows that the compound has strong antioxidant activity.
(3) 3-methoxy-4-hydroxy chalcone bis-Mannich base compounds (I) to Ab 1-42Inhibitory Activity of self-aggregation
Reference (Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-: pretreated Aβ 1-42Stock solutions were prepared in DMSO, and diluted to 50. mu.M in PBS buffer, pH7.4, before use; the test compound was diluted to a concentration of 2.5 mM in DMSO, and 20. mu.L of A was added to the stock solution before use, which was diluted with PBS (pH7.4)β 1-42Solution + 20. mu.L of test Compound solution, 20. mu.L of Aβ 1-42Solution +20 μ L PBS buffer (containing 2% DMSO) in 96-well plates, incubated at 37 ℃ for 24h, then 160 μ L of 50mM glycine-NaOH buffer (pH = 8.5) containing 5 μ M thioflavin T was added, and fluorescence was measured immediately after shaking for 5s with a multifunctional plate reader at 446 nm excitation wavelength and 490 nm emission wavelength; a. theβ 1-42+ the fluorescence value of the test compound is recorded as IFi，Aβ 1-42The fluorescence value of + PBS buffer was designated as IFcThe fluorescence value of the buffer solution containing only PBS was designated as IF0Compounds inhibiting Aβ 1-42The inhibition rate of self-aggregation is: 100- (IF)i-IF0)/(IFc-IF0) 100, x; five to six concentrations of compound were selected and their inhibition was determined, three replicates per compound concentration, with curcumin as a positive control. The determination result shows that the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) disclosed in the embodiment of the invention is opposite to Aβ 1-42The self-aggregation has obvious inhibitory activity on A at the concentration of 25.0 mu Mβ 1-42The inhibition rate of self-aggregation is more than 50.0 percent; the inhibition rate of curcumin under the same concentration is 41.3%, and the curcumin is an anti-AD drug widely used clinicallyAn object: donepezil, rivastigmine, memantine hydrochloride, parent nucleus of compound (I) -dihydroxy chalcone compound (namely: CH)2NR1R2And CH2NR3R4Simultaneously represents the H, and the compound represented when the OH of the B ring is positioned at any possible position of the corresponding benzene ring), and the hydroxybenzaldehyde Mannich base compound (2) is used for A under the concentration of 25.0 mu Mβ 1-42The inhibition rate of self-aggregation is less than 15 percent.
(4) Inhibitory activity of 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) on monoamine oxidase A and B
Recombinant human MAO-A was prepared as A sample solution at 12.5. mu.g/mL using 100 mM potassium phosphate buffer pH7.4, and MAO-B was prepared as A sample solution at 75. mu.g/mL. Adding 20 mu L of A compound solution to be detected and 80 mu L of monoamine oxidase into A black 96-well plate, uniformly mixing, incubating for 15min at 37 ℃ in A dark place, adding 200 mu M Amplex Red reagent, 2U/mL horseradish peroxidase, 2 mM p-hydroxyphenylethylamine (inhibiting MAO-A) or 2 mM benzylamine (inhibiting MAO-B) to initiate A reaction, incubating for 20 min at 37 ℃, and measuring the fluorescence emission intensity at 590 nm on A multifunctional enzyme-linked immunosorbent assay (ELISA) instrument by using A fixed excitation wavelength of 545 nm, wherein potassium phosphate buffer solution is used for replacing MAO-A or MAO-B as A blank; the inhibition rate of the compound for inhibiting monoamine oxidase is calculated by the following formula: 100- (IF)i)/(IFc) 100 of the formula, IFiAnd IFcThe difference between the fluorescence intensity in the presence and absence of inhibitor and the blank fluorescence intensity, respectively. Each compound was assayed in 3 replicates each, each experiment being independently repeated three times. Selecting five to six concentrations of the compound, measuring the enzyme inhibition rate, performing linear regression by using the negative logarithm of the molar concentration of the compound and the enzyme inhibition rate, and obtaining the molar concentration when the 50% inhibition rate is obtained as the IC of the compound50. The determination result shows that the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) disclosed in the embodiment of the invention has a remarkable inhibition effect on MAO-B, and IC (integrated Circuit) of the compound50The particle size is 0.05 to 15.0 mu M; IC for MAO-A inhibition50Are all higher than 30.0 mu M, which indicates that the compound disclosed by the invention has selective inhibition effect on MAO-B. It has also been found that in this class of CharlesIn the ketone bis-Mannich base compounds (I), if CH is substituted2NR1R2Or CH2NR3R4When one of the two compounds is replaced by H, the inhibitory activity of the corresponding compound to MAO-B is obviously reduced (at least by more than 2 times); in addition, hydroxybenzaldehyde Mannich bases (2) IC for MAO-B inhibition50Are all higher than 80.0 mu M.
(5) Influence of 3-methoxy-4-hydroxychalcone bis Mannich base Compounds (I) on mouse memory acquisition disorder caused by scopolamine (taking example Compounds 2-3 as examples)
SPF grade ICR male mice, 25-30g, randomly divided into: normal group, model group, positive control group, test drug high-low dose group (15.0 mg/kg, 2.5 mg/kg), each group of 10 animals. The tested medicine is given by one-time intragastric administration, the solvent of 0.5 percent CMC-Na is given to the blank group and the model group, and the administration volumes are both 0.1ml/10 g; injecting normal saline into abdominal cavity of normal group mice 45 min after administration, and injecting scopolamine (5 mg/kg) into other groups of animals, wherein the administration volume is 0.1ml/10 g; after 30 min of molding, the mice were placed in the non-electrostimulated Y maze for behavioral testing. During testing, a mouse is placed at the tail end of one arm, the mouse freely passes through the maze for 8 min, the times of entering each arm and the alternation times are recorded, and the alternation rate is calculated according to the following formula: alternation rate% = [ number of alternations/(total number of entries-2) ] × 100, results are expressed as mean ± standard deviation, and differences between groups were analyzed by one-way variance. The test result shows that under the experimental condition, the tested 3-methoxy-4-hydroxychalcone bis mannich base compound (I) (example compound 2-3) has a dose-dependent improvement effect on mouse acquired memory disorder caused by scopolamine, and has statistical difference (p is less than 0.01) compared with a model group, and the activity of the compound is remarkably higher than that of a clinical drug rivastigmine (p is less than 0.01) under the same molar concentration.
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. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.
EXAMPLE 13 general preparation of methoxy-4-hydroxychalcone bis Mannich base Compounds (I)
Adding 2.0 mmol of corresponding 3-methoxy-4-hydroxy-5-amine methyl acetophenone compounds (1), 2.5 mmol of corresponding hydroxybenzaldehyde Mannich base compounds (2) and 30 ml of ethanol into a reaction bottle, uniformly stirring, dropwise adding 15.0 mmol of 30% KOH aqueous solution, and stirring at room temperature for reaction for 2.0-48.0 hours (tracking the reaction process by TLC); after the reaction is finished, cooling to room temperature, adjusting the pH of a reaction solution to be strongly acidic by using a 10% hydrochloric acid aqueous solution, adjusting the pH of the reaction solution to be weakly alkaline by using a saturated sodium bicarbonate aqueous solution, distilling off ethanol under reduced pressure, adding 80 mL of deionized water into a residual solution, extracting with 240 mL of dichloromethane for three times, combining organic layers, washing with a saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, distilling off a solvent under reduced pressure, and purifying residues by column chromatography (eluent: dichloromethane: acetone =6:1 v/v) to obtain the corresponding 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I), wherein the yield is 30.0-62.2%, and the chemical structures are all purified by using dichloromethane: acetone =6:1 v/v)1H-NMR、13C-NMR and ESI-MS confirmation; the purities of the obtained target substances are more than 96.5 percent through HPLC. The target prepared by the method has the following structure:
of partial compounds1The H-NMR data are as follows:
1H NMR (CDCl3): 7.69 (d, J = 15.6 Hz, 1H), 7.51 (s, 1H), 7.49 (d, J = 15.6 Hz, 1H), 7.38 (s, 1H), 7.11 (s, 1H), 7.01-6.97 (m, 2H), 3.94 (s, 3H), 3.79 (s, 2H), 3.74 (s, 2H), 2.68-2.59 (m, 8H), 1.14-1.08 (m, 12H)；
1H NMR (CDCl3): 7.72 (d, J = 15.6 Hz, 1H), 7.54 (s, 1H), 7.51 (d, J = 15.6 Hz, 1H), 7.40 (s, 1H), 7.15 (s, 1H), 7.04-6.99 (m, 2H), 3.96 (s, 3H), 3.79 (s, 2H), 3.71 (s, 2H), 2.64 (brs, 8H), 1.69-1.66 (m, 8H), 1.51 (brs, 4H)。
EXAMPLE 23 general preparation of salt formation of methoxy-4-hydroxychalcone bis Mannich base Compound (I) with an acid
Adding 2.0 mmol of the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I) obtained in the embodiment 1 and 50 ml of acetone into a reaction bottle, stirring uniformly, adding 8.0 mmol of corresponding acid, heating, refluxing, stirring, reacting for 20 minutes, cooling to room temperature after the reaction is finished, evaporating under reduced pressure to remove the solvent, recrystallizing the residue with acetone, and filtering the precipitated solid to obtain the salt of the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I), wherein the chemical structure of the salt is obtained by1H NMR and ESI-MS.
Claims (7)
1. A3-methoxy-4-hydroxychalcone bis-Mannich base compound or a pharmaceutically acceptable salt thereof is characterized in that the chemical structure general formula of the compound is shown as (I):
in the formula: r1、R2、R3And R4Each independently represents methyl, ethyl, benzyl, NR1R2Or NR3R4Also tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-methylpiperidinyl, 4-benzylpiperidinyl, 4-thiopiperidinyl, piperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-benzylpiperazinyl, 4- ((methoxy) benzyl) piperazinyl, OH on the B ring of the molecule in any possible position of the corresponding phenyl ring.
2. The 3-methoxy-4-hydroxychalcone bis-mannich base compound or the pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the pharmaceutically acceptable salt is the 3-methoxy-4-hydroxychalcone bis-mannich base compound mixed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid and C1-6Aliphatic 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, C1-6Salts of alkylsulfonic acids, camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 1, 4-butanedisulfonic acid.
3. The method for preparing 3-methoxy-4-hydroxychalcone bis mannich bases or pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 2, characterized in that the compounds are prepared by the following method:
in the formula: r1～R4And the definition of the hydroxyl position on the B ring is the same as the chemical structural general formula of the 3-methoxy-4-hydroxychalcone bis-Mannich base compound (I);
directly condensing corresponding 3-methoxy-4-hydroxy-5-amine methyl acetophenone compounds (1) and hydroxybenzaldehyde Mannich base compounds (2) serving as initial raw materials under the conditions of a solvent and alkalinity to obtain corresponding 3-methoxy-4-hydroxy chalcone bis Mannich base compounds (I); the 3-methoxy-4-hydroxychalcone bis-Mannich base compound obtained by the method contains amino in the molecule, the amino is basic, and the pharmaceutically acceptable salt can be prepared by any suitable acid through a pharmaceutically conventional salt forming method.
4. The method for preparing 3-methoxy-4-hydroxychalcone bis mannich bases or pharmaceutically acceptable salts thereof as claimed in claim 3, wherein the base used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, C1-8Alkali metal salts of alcohols, triethylamine, tributylamine, trioctylamine, pyridine,N-methylmorpholine,N-methylpiperidine, triethylenediamine, or tetrabutylammonium hydroxide; the solvent used in the reaction is: c1-8Fatty alcohol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1, 4-dioxane, benzene, toluene or acetonitrile.
5. The method for preparing 3-methoxy-4-hydroxychalcone bis mannich base compounds or pharmaceutically acceptable salts thereof according to claim 3, wherein the 3-methoxy-4-hydroxy-5-aminomethylphenones compound (1): hydroxybenzaldehyde mannich base compounds (2): the molar charge ratio of alkali is 1.0: 1.0-3.0: 1.0 to 20.0; the reaction temperature is 0-150 ℃; the reaction time is 1-120 hours.
6. A pharmaceutical composition comprising the 3-methoxy-4-hydroxychalcone bis mannich base compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2 and one or more pharmaceutically acceptable carriers or excipients.
7. The use of 3-methoxy-4-hydroxychalcone bis mannich bases as claimed in any one of claims 1 to 2 or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment and/or prevention of neurological related diseases: vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, and nerve damage due to brain trauma.
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