CN110698445A - 3-aminoalkyl phthalide compounds, preparation method and application thereof - Google Patents
3-aminoalkyl phthalide compounds, preparation method and application thereof Download PDFInfo
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Abstract
The invention disclosesA novel 3-amine alkyl phthalide 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 the nervous system, wherein the diseases include but are not limited to vascular dementia, Alzheimer disease, Parkinson disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a novel 3-aminoalkyl phthalide compound (I), 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 diseases comprise but are not limited to vascular dementia, Alzheimer disease, Parkinson disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like.
Background
Alzheimer's disease (AD, senile dementia) is a degenerative disease of the central nervous system mainly caused by progressive cognitive impairment and memory impairment, and the incidence of Alzheimer's disease is on the rise year by year, and is a high-grade disease second to cardiovascular diseases and cancers, and is the fourth cause of death in advanced countries such as europe and america. According to the report of the world health organization, 10% of the elderly over 65 years old have intellectual disability, wherein one half of the elderly have dementia, and the incidence rate of the elderly over eighty-five years old is nearly 50%. The number of AD patients in China is about 600- > 700 thousands, and the morbidity exceeds 5%. With the accelerated aging process of the global population, the incidence rate of the Disease is in a clear rising trend, and according to the global influence of Alzheimer's Disease published in 2013 in 12 months by Alzheimer's Disease International: 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-DAspartic acid (NMDA) receptor antagonists, but clinical use shows that the drugs can relieve AD symptoms by increasing acetylcholine level or inhibiting excitotoxicity of excitatory amino acid in a patient body, but cannot effectively prevent or reverse the disease course, and can cause severe toxic and side effects such as hallucinations, conscious chaos, dizziness, headache, nausea, hepatotoxicity, inappetence, frequent stools 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 drugs have the problems of single action target, more toxic and side effects in clinical use, poor long-term curative effect on AD patients and the like.
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 Ligands" (MTDLs) strategy to develop anti-neurodegenerative drugs. By "multi-target ligand" is meant that a single chemical entity acts on multiple molecules in a disease network simultaneouslyThe effect of each target on each target can produce a synergistic effect, so that the total effect is larger than the sum of single effects, and the compounds are also called 'Multifunctional' or 'multipotent' medicines. 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, 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, when designing multi-target anti-AD drugs, the AChE inhibitory activity of the compound (inhibiting the enzyme is important for improving the symptoms of AD patients) is usually required to be kept, and one or more other targets or functions with pharmacological synergistic effect are added on the basis of the inhibition activity, so as to achieve the multi-target AD therapeutic effect [ 1, yellow Shufang and the like ] research progress of multi-target Alzheimer disease therapeutic drugs, China pharmaceutical chemistry journal 2011, 21(6): 433-434; 2. luo Sten et al, research progress of treating Alzheimer's disease by multi-target small molecule inhibitors, China journal of drug chemistry 2011, 21(6): 442-443). Obviously, the design and the discovery have the effects of inhibiting acetylcholinesterase and inhibitingβMulti-target AD therapeutics that are associated with excessive amyloid production and deposition, antioxidant stress, anti-platelet aggregation, and anti-neuritic response remain important research targets.
Disclosure of Invention
The invention aims to disclose a 3-amine alkyl phthalide compound (I) and pharmaceutically acceptable salt thereof;
the invention also discloses a preparation method of the 3-amine alkyl phthalide compound (I) and pharmaceutically acceptable salts thereof;
the invention also discloses a pharmaceutical composition containing the 3-amine alkyl phthalide compound (I) and pharmaceutically acceptable salts thereof;
the invention also aims to disclose that the 3-aminoalkyl phthalide compounds (I) and the pharmaceutically acceptable salts thereof have multi-target effect and can be used for preparing the drugs for treating and/or preventing related diseases of the nervous system, including but not limited to vascular dementia, Alzheimer disease, Parkinson disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and other diseases.
The general chemical structure formula of the 3-amine alkyl phthalide compound (I) provided by the invention is as follows:
in the formula: x represents O, NR7Or S; a. the1-A2Represents CH-CH2Or C = CH; when A is1-A2When C = CH, the compound isZ-configuration,EA configuration of the formula orZA formula andE-mixtures of formula (la) configuration in any ratio; when A is1-A2Represents CH-CH2When the compound isRThe configuration,SConfiguration, orRConfiguration andSa mixture of the configurations in any ratio; n represents 1 to 12; r3And R4Each independently represents H, OH, SH, C1~C12Alkyl radical, C1~C12Alkoxy, CN, halogen, NR5R6Or C1~C12An alkylthio group; r5And R6Each independently representing H, C1~C12An alkyl group; NR (nitrogen to noise ratio)5R6Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r1Representation H, C1~C12An alkyl group; r2Is represented by C1~C12Alkyl, benzyl or substituted benzyl; NR (nitrogen to noise ratio)1R2Also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-position by C1~C12Piperidinyl substituted by alkyl, piperidinyl substituted by benzyl or substituted benzyl in the 4-position, piperazinyl, piperidinyl substituted by C in the 4-position1~C12Piperazinyl substituted with alkyl, piperazinyl substituted at the 4-position with benzyl or substituted benzyl; r7Representation H, C1~C12Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; the term "halogen" as defined above means F, Cl, Br, or I; "substituted phenyl" or "substituted benzyl" refers to a benzyl group on the phenyl ring substituted with 1-4 groups selected from the group consisting of: F. cl, Br, I, C1-4Alkyl radical, C1-4Alkoxy, NR8R9Trifluoromethyl, trifluoromethoxy, nitro, carboxyl, hydroxyl, cyano, R8And R9Each independently represents H or C1~C12Alkyl radical, NR8R9Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; these substituents may be in any possible position on the phenyl ring. However, the 3-amine alkyl phthalide compound (I) provided by the invention does not comprise the following compounds:
the 3-amine alkyl phthalide compound (I) provided by the invention can be prepared by the following method:
taking corresponding 3-bromide (1) as an initial raw material, and reacting with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine salt compound (2); the obtained compound 2 and an amine alkyl aldehyde compound (3) are subjected to Wittig reaction under proper solvent and alkaline conditions to obtain a corresponding compound (4)E/ZMixture of configurations (i.e.E/ZCompound I mixture of configuration); the mixture of the compound (4) can be separated and purified by silica gel column chromatography by a conventional method to respectively obtain corresponding compoundsEIs of the formulaZ-a compound of formula (la); the mixture of the compound (4) can be directly reduced by catalytic hydrogenation in a proper solvent without separation and purification to obtain a corresponding 3-amine alkyl phthalide compound (I) racemate; separating the corresponding 3-amine alkyl phthalide compound (I) raceme by using a conventional chiral chromatography to obtain a corresponding optical isomer; the reaction formula is as follows:
in the formula: x, R1、R2、R3、R4And n is defined as the same as the general chemical structure formula of the 3-amine alkyl phthalide compound (I).
For the above synthetic route, the specific preparation method is described as follows:
step A): reacting 3-bromide (1) with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine salt compound (2); wherein, the solvent used in the reaction is: c3-8An aliphatic ketone,N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1, 4-dioxane, ethylene glycol dimethyl ether or C5-8The alkane is preferably 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene or 1, 4-dioxane, the 3-bromide (1) is triphenylphosphine, the molar charge ratio is 1.0: 1.0 ~ 10.0.0, the preferred molar charge ratio is 1.0: 1.0 ~ 5.0.0, the reaction temperature is 40 ~ 150 ℃, the preferred reaction temperature is 60 ~ 120 ℃, and the reaction time is 1 ~ 120 hours, the preferred reaction time is 2 ~ 72 hours.
Step B): the 3-triphenylphosphine salt compound (2) obtained in the step A) and the amine alkyl aldehyde compound (3) are subjected to Wittig reaction in a proper solvent under the alkaline condition to obtain a corresponding compound (4)E/ZA mixture of configurations; wherein, the solvent used in the reaction is: c1-8Fatty alcohol, C3-8Aliphatic ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1, 4-dioxane, benzene, toluene, acetonitrile or C5-8Alkanes, preferred solvents are: chloroform, dichloromethane, acetone, acetonitrile, tetrahydrofuran or toluene; 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, organic tertiary or quaternary amines (e.g. triethylamine, tributylamine, trioctylamine, pyridine, tert-butyl amine, tert-butyl,N-methylmorpholine,NMethylpiperidine, triethylenediamine, tetrabutylammonium hydroxide), preferably potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide, compound (2) and compound (3) in a molar feed ratio of 1.0: 1.0 ~ 10.0.0: 1.0 ~ 10.0.0, preferably in a molar feed ratio of 1.0: 1.0 ~ 3.0.0: 1.0 ~ 5.0.0, at a reaction temperature of 0 ~ 120 ℃, preferably at room temperature ~ 100 ℃ at 100 ℃, for 20 minutes ~ 48 hours, preferably for 1 ~ 24 hours.
Step C): directly reducing double bonds in a proper solvent by catalytic hydrogenation without separating and purifying the compound (4) mixture obtained in the step B) to obtain a corresponding 3-amine alkyl phthalide compound (I) racemate; wherein, the solvent used in the reaction is: c1-6Fatty alcohol, C3-8Aliphatic ketones, C1-6Fatty acid, C1-6Fatty acids with C1-6Esters formed from aliphatic alcohols, ethers (e.g., diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, etc.), benzene, toluene or xylene, aliphatic hydrocarbons (e.g., hexane, heptane, octane, etc.), preferably solvents such as: tetrahydrofuran, methanol, ethanol or isopropanol; the catalysts used for the catalytic hydrogenation were: raney Ni, PtO2、1%~30%Pd-C、1%~30% Pd(OH)2-C, preferably the catalyst is: raney Ni, PtO25 percent ~ 20 percent Pd-C, the mass ratio of the compound (4) to the catalyst is 1.0: 0.01 ~ 1.0.0, the reaction pressure is ~ 10.0.0 MPa under normal pressure, preferably ~ 2.0.0 MPa under normal pressure, the reaction temperature is ~ 150 ℃ at room temperature, preferably ~ 80 ℃ at room temperature, and the reaction time is 1 ~ 96 hours, preferably 2 ~ 50 hours.
The 3-amine alkyl phthalide 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: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C1-6Fatty carboxylic acid (such as 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, etc,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 starting materials of the present invention, 3-bromo compound (1) and amine alkyl aldehyde compound (3), can be prepared by techniques common in the art, including but not limited to the methods disclosed in the following documents: 1. guidong Z.et al.WO2011130478A1；2、Sakamoto F.et al.Chem. Pharm. Bull.1983, 31(8), 2698-2707；3、Chunzhi Z.et al.Chinese Journal of Organic Chemistry2014, 34, 1881-1888；4、Sugimoto H.et al.US 5100901；5、Mingyu W.et al.European Journal of Medicinal Chemistry2016, 121, 864-879。
The pharmaceutical composition disclosed by the invention comprises one or more 3-aminoalkyl phthalides (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-aminoalkyl phthalide compound (I) or the pharmaceutically acceptable salt thereof is taken as an active component and accounts for 2 to 99.5 percent of the total weight.
The 3-amine alkyl phthalide compound (I) and the pharmaceutically acceptable salt thereof disclosed by the invention are subjected to the following biological activity screening:
(1) inhibitory activity of 3-aminoalkylphthalides (I) on acetylcholinesterase and butyrylcholinesterase
Adding 1.0mmol of the mixture into a 96-well plate in sequence30 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 the test compound solution (DMSO content is less than 1%), and 10 μ L of acetylcholinesterase (5% supernatant from rat brain cortex, phosphate buffer solution with pH7.4 as homogenization medium) or butyrylcholinesterase (25% supernatant from rat serum, phosphate buffer solution with pH7.4 as homogenization medium) solution, mixing, incubating at 37 ℃ for 15min, adding 0.2% 5, 5' -dithio-bis (2-nitrobenzoic acid) (DTNB from Sigma) solution 30. mu.L to each well for color development, measuring optical density (OD value) of each well at 405nm with a microplate reader, the inhibition rate of the compound to the enzyme (enzyme inhibition (%) = (1-sample group OD value/blank group OD value) × 100%) was calculated as compared with the blank wells to which the sample to be tested was not added; 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 measurement result shows that the 3-amine alkyl phthalide compound (I) disclosed in the embodiment of the invention [ comprises: process for producing Compound (4)EA formula andZtarget of formula (I) ]has significant inhibitory effect on acetylcholinesterase and IC50Is 1.2X 10-3The further structure-activity relationship analysis of nM ~ 20.0.0 mu M shows that the 3-amine alkyl phthalide compound (I) molecules have certain carbon chain lengthEFormula (II) andZthe difference of the inhibition activity of the configuration of the formula on acetylcholinesterase is small, but the inhibition activity is reduced after the double bond in the molecule is reduced; in addition, the chiral configuration of the target has certain influence on the activity of inhibiting acetylcholinesterase, but the target still has obvious acetylcholinesterase inhibiting activity and IC50Are all smaller than 20.0 mu M. The determination result also shows that the inhibitory activity of the 3-aminoalkylphthalide compound (I) on acetylcholinesterase is obviously higher than that of butyrylcholinesterase (the selectivity is more than 100 times), which indicates that the compound disclosed by the invention has a selective inhibitory effect on acetylcholinesterase and indicates that the compound has low toxicity on peripheral systems. In addition, the measurement results also show that the clinically used rivastigmine can inhibit AChEMade IC50IC for butyrylcholinesterase inhibition at 10.5 μ M50Is 2.6 mu M; and IC of acetylcholinesterase inhibition by control Compound (II) (Y in the chemical formula represents O, NH or S, respectively) and control Compound (III) shown below50Are all larger than 150 mu M;
(2) 3-aminoalkylphthalides (I) to Aβ 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 of PBS buffer (containing 2% DMSO) in 96-well plate, 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 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; selecting five to six concentrations of the compound, and determining the inhibition rate; each compound was tested in triplicate at each concentration, with curcumin as a positive control. The measurement result shows that the 3-amine alkyl phthalide compound (I) disclosed in the embodiment of the invention [ comprises: process for producing Compound (4)EFormula (II) andZtarget of formula (II): pair Aβ 1-42The self-aggregation has obvious inhibition activity at 25.0 muFor A at M concentrationβ 1-42The inhibition rate of self-aggregation is between 20.0 and 55.0 percent; and anti-AD drugs widely used clinically: donepezil, rivastigmine, memantine hydrochloride, and the above control compound (II) (Y in the chemical structural formula represents O, NH or S, respectively) and control compound (III) were added to A at a concentration of 25.0 μ Mβ 1-42The inhibition rate of self-aggregation is less than 10%.
(3) Anti-platelet aggregation activity of 3-aminoalkylphthalide compound (I)
3 male rabbits were taken, locally anesthetized with lidocaine, and subjected to surgical isolation of carotid artery for blood collection, and 3.8% sodium citrate 1: 9 anticoagulating, centrifuging at 500 r/min for 10 min to obtain Platelet Rich Plasma (PRP), centrifuging the rest at 3000 r/min to obtain Platelet Poor Plasma (PPP), and performing platelet aggregation experiment by turbidimetry. mu.L of PRP and 30. mu.L of the test drug at different concentrations were added to the assay tube and incubated for 5 minutes, and the maximal aggregation rate was observed and recorded within 5 minutes using 30. mu.L of Adenosine Diphosphate (ADP) (final concentration of 10. mu. mol/L), 30. mu.L of thrombin (final concentration of 0.5U/mL) and 30. mu.L of Arachidonic Acid (AA) (final concentration of 1.0 mmol/L) as inducers. The inhibition (%) of each test compound was calculated using physiological saline (NS) as a control. The measurement result shows that the 3-amine alkyl phthalide compound (I) disclosed in the embodiment of the invention [ comprises: process for producing Compound (4)EFormula (II) andZthe target object has obvious inhibition effect on platelet aggregation induced by ADP, thrombin and AA, and the inhibition rate of the target object under the concentration of 50.0 mu M is more than 25.0%. And anti-AD drugs widely used clinically: the inhibition rate of the donepezil, the rivastigmine, the memantine hydrochloride, the control compound (II) (Y in the chemical structural formula represents O, NH or S respectively) and the control compound (III) on the platelet aggregation is less than 15.0 percent under the same concentration.
(4) Inhibitory Activity of 3-Aminoalkylphthalide Compound (I) against neuroinflammation
(a) Effect of Compounds and Lipopolysaccharide (LPS) on BV-2 cell Activity
Logarithmic growth phaseThe BV-2 cells are prepared into cell suspension to be inoculated on a 96-pore plate, and the cell suspension is placed at 37 ℃ and 5 percent CO2Culturing for 24h in a cell culture box, changing to 90 μ L of fresh serum-free culture solution after the cells adhere to the wall, respectively adding 10 μ L of each concentration compound to be tested, pre-incubating for 30 min, and setting a blank control group for each concentration of 3 parallel holes; then, with or without LPS, the mixture was left at 37 ℃ with 5% CO2Continuously culturing for 24h in a cell culture box, adding MTT solution, incubating for 4h at 37 ℃, discarding supernatant, adding 200 mu of LDMSO solution into each hole, slightly oscillating for 10 min, measuring OD (optical density) at 490 nm by using an enzyme-labeling instrument, calculating the mean value of the measured OD values of different concentrations of each tested sample, and calculating the cell survival rate according to the following companies: cell survival (%) = administration group OD mean/control group OD mean × 100%. The test results show that all 3-aminoalkylphthalides (I) disclosed in the examples of the present invention [ include: process for producing Compound (4)EFormula (II) andZtarget of formula (I) and LPS showed no cytotoxicity (inhibition rate less than 25 μ M) at concentrations not exceeding 25 μ M<5%）。
(b) Influence of 3-aminoalkylphthalides (I) on NO release from LPS-induced BV-2 cells
Preparing BV-2 cells in logarithmic growth phase into cell suspension, inoculating the cell suspension in a 96-well plate, placing the plate at 37 ℃ and 5% CO2Culturing for 24h in a cell culture box, changing to 90 μ L of fresh serum-free culture solution after the cells adhere to the wall, respectively adding 10 μ L of each concentration compound to be tested, pre-incubating for 30 min, and setting a blank control group for each concentration of 3 parallel holes; then LPS stimulation was added and the mixture was left at 37 ℃ with 5% CO2And (3) continuously culturing for 24h in the cell culture box, taking cell culture supernatants of different treatment groups, adding a Griess reagent I with the same volume and a Griess reagent II with the same volume, carrying out a dark reaction at room temperature for 10 min, and measuring absorbance at 540 nm to detect the level of NO in the cell supernatants (the specific operation is carried out according to the instruction of the NO detection kit). The test results show that all 3-aminoalkylphthalides (I) disclosed in the examples of the present invention [ include: process for producing Compound (4)EFormula (II) andZthe target compound with the formula (I) shows stronger inhibition on the NO generation of BV-2 cells induced by LPS in the concentration range of 0.5 mu M to 25 mu M (the inhibition rate at the concentration of 2.5 mu M is all over20.0 percent over) and has obvious dose-effect relationship; and their inhibitory activity was significantly enhanced as compared with the above-mentioned control compound (II) (Y in the chemical structural formula thereof represents O, NH or S, respectively) and control compound (III) at the same concentration (n =6,P<0.05), which shows that the 3-amine alkyl phthalide compound (I) disclosed in the embodiment of the invention has remarkable anti-neuritis activity. The test also further finds that the chiral center of the compound (I) has no significant influence on the anti-neuritic activity of the compound.
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 1 general procedure for preparation of Compound (4)
Adding 2.0 mmol of corresponding 3-bromide (1), 2.4 mmol of triphenylphosphine and 20 ml of toluene into a reaction bottle, heating, refluxing and stirring for reaction for 12-24.0 hours (tracking the reaction process by TLC); after the reaction is finished, cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake by toluene and petroleum ether in sequence, and drying to obtain the corresponding 3-triphenylphosphine salt compound (2), wherein the yield is 60.0-88.0%, and the chemical structures are all subjected to reaction1H-NMR confirmation;
adding 1.0mmol of the 3-triphenylphosphine salt compound (2), 1.3mmol of the amine alkyl aldehyde compound (3) and 30 ml of dichloromethane prepared in the previous step into a reaction bottle, stirring uniformly, adding 1.5 mmol of triethylamine, and stirring at room temperature for reaction for 12-24.0 hours (tracking the reaction process by TLC); after the reaction, the solvent was distilled off under reduced pressure, 30 mL of deionized water was added to the residue, the pH of the reaction solution was adjusted to strong acidity with 10% hydrochloric acid aqueous solution, the pH of the reaction solution was adjusted to weak acidity with saturated sodium bicarbonate aqueous solution, extraction was carried out three times with 120 mL of methylene chloride, the organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and filtered, the solvent was distilled off under reduced pressure, and the residue was the residue of Compound (4)E/ZConfiguration mixture, yield: 35.6% -85.0%); separating and purifying the obtained mixture with silica gel column chromatography to obtain corresponding compoundsEIs of the formulaZA compound of formula (I) having the chemical structure1H-NMR and ESI-MS.
EXAMPLE 23 general procedure for the preparation of Aminoalkylphthalide Compound (I)
Adding 1.0mmol of the compound (4) mixture prepared according to the method in the embodiment 1 and 25 ml of ethanol into a reaction bottle, uniformly stirring, adding 10% Pd/C40 mg, introducing hydrogen for three times of replacement, introducing hydrogen at room temperature and normal pressure, stirring for reaction for 2.0-24.0 hours (tracking the reaction process by TLC), after the reaction is finished, evaporating the solvent under reduced pressure, and purifying the residue by silica gel column chromatography (eluent: dichloromethane: methanol = 20-30: 1 v/v) to obtain the corresponding 3-aminoalkyl phthalide compound (I), wherein the yield is 60.5-92.0%, and the chemical structures are all subjected to TLC1H-NMR、13C-NMR and ESI-MS confirmation; the purities of the obtained target substances are more than 97.0 percent through HPLC. The target prepared by the method has the following structure:
note: in the table R1And R2When they share a single cell, they represent the substituent-NR1R2”；
Of partial compounds1The H-NMR data are as follows:
1H NMR (CDCl3): 7.35-7.27 (m, 4H), 7.26-7.24 (m, 2H), 6.96 (s, 1H), 5.46(t,J= 7.6 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 3H), 3.55 (s, 2H), 2.50 (q,J=7.6 Hz, 2H), 2.49 (t,J= 7.6 Hz, 2H), 2.21 (s,3H), 1.81−1.75 (m, 2H)；
1H NMR (CDCl3): 7.30 (s, 1H), 7.29-7.26 (m, 5H), 7.21 (s, 1H), 5.71 (t,J= 8.4 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.57 (s, 2H), 2.60 (q,J= 8.4 Hz,2H), 2.57-2.53 (m, 2H), 2.26 (s,3H), 1.84 (t,J= 7.2 Hz, 2H)；
1H NMR (CDCl3): 7.32-7.25 (m, 6H), 6.80 (s, 1H), 5.37 (dd,J= 3.6, 7.6Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.52 (s, 2H), 2.41 (t,J= 6.8 Hz, 2H),2.22 (s,3H), 2.04-1.99 (m, 1H), 1.73-1.69 (m, 1H), 1.62-1.58 (m, 2H), 1.54-1.47 (m, 2H)；
1H NMR (CDCl3): 7.67 (d,J= 7.6 Hz, 1H), 7.33 (t,J= 7.6 Hz, 1H), 7.24(s, 1H), 7.04 (s, 1H), 6.98 (t,J= 7.6 Hz, 1H), 6.89 (d,J= 7.6 Hz, 1H),5.53 (t,J= 8.0 Hz, 1H), 4.24 (s, 2H), 4.03 (s, 3H), 3.96 (s, 3H), 3.86 (s,3H), 3.07 (q,J= 8.0 Hz, 2H), 2.96 (t,J= 6.8 Hz, 2H) , 2.48 (q,J= 7.2Hz, 2H), 2.21-2.17 (m, 2H), 1.44 (t,J= 7.2 Hz, 3H);
1H NMR (CDCl3): 7.46 (d,J= 7.6 Hz, 1H), 7.29 (s, 1H), 7.25 (t,J= 7.6Hz, 1H), 7.20 (s, 1H), 6.90 (t,J= 7.6 Hz, 1H), 6.84 (d,J= 7.6 Hz, 1H),5.67 (t,J= 8.0 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.78 (s, 5H), 2.78-2.70(m, 4H), 2.62 (q,J= 7.6 Hz, 2H), 1.98-1.88 (m, 2H), 1.16 (t,J= 7.6 Hz,3H)；
1H NMR (CDCl3): 7.44 (d,J= 7.6 Hz, 1H), 7.27 (s, 1H), 7.23 (t,J= 7.6Hz, 1H), 6.94 (t,J= 7.6 Hz, 1H), 6.86 (d,J= 7.6 Hz, 1H), 6.81 (s, 1H),5.35 (dd,J= 3.6, 7.6 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.82 (s, 3H),3.71 (s, 2H), 2.63 (q,J= 6.8 Hz, 2H), 2.55 (t,J= 7.2 Hz, 2H), 2.04-1.99(m, 1H), 1.73-1.64 (m, 3H), 1.56-1.47 (m, 2H), 1.12 (t,J= 6.8 Hz, 3H)；
1H NMR (CDCl3): 7.24 (s, 1H), 7.02 (s, 1H), 5.52 (t,J= 7.6 Hz, 1H),4.01 (s, 3H), 3.95 (s, 3H), 2.62-2.55 (m, 6H), 2.49 (q,J= 7.6 Hz, 2H),1.92-1.85 (m, 2H), 1.75-1.72 (m, 4H), 1.55-1.50 (m, 2H)；
1H NMR (CDCl3): 7.30 (s, 1H), 7.22 (s, 1H), 5.73 (t,J= 8.0 Hz, 1H),4.03 (s, 3H), 3.97 (s, 3H), 2.59 (q,J= 7.6 Hz, 2H), 2.47 (t,J= 7.2 Hz,6H), 1.87-1.80 (m, 2H), 1.64-1.60 (m, 4H), 1.48-1.45 (m, 2H)；
1H NMR (CDCl3): 7.26 (s, 1H), 6.89 (s, 1H), 5.40 (dd,J= 3.2, 8.0 Hz,1H), 4.01 (s, 3H), 3.94 (s, 3H), 2.95-2.90 (m, 4H), 2.78 (t,J= 8.0 Hz, 2H),2.20-2.12 (m, 1H), 1.95-1.88 (m, 6H), 1.80-1.71 (m, 1H), 1.61-1.45 (m, 4H)。
EXAMPLE 33 general procedure for salt formation of Aminoalkylphthalide Compound (I) with acid
Adding 1.0mmol of 3-aminoalkyl phthalide compound (I) obtained in the above example 1 and example 2 and 25 ml of acetone into a reaction bottle, stirring uniformly, adding 2.5 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, and separating and purifying by a conventional method to obtain the salt of 3-aminoalkyl phthalide compound (I), wherein the chemical structure of the salt is obtained by1H NMR and ESI-MS.
Claims (8)
1. A3-amine alkyl phthalide compound or pharmaceutically acceptable salt thereof is characterized in that the chemical structural general formula of the compound is shown as (I):
in the formula: x represents O, NR7Or S; a. the1-A2Represents CH-CH2Or C = CH; when A is1-A2When C = CH, the compound isZ-configuration,EA configuration of the formula orZA formula andE-mixtures of formula (la) configuration in any ratio; when A is1-A2Represents CH-CH2When the compound isRThe configuration,SConfiguration, orRConfiguration andSa mixture of the configurations in any ratio; n represents 1 to 12; r3And R4Each independently represents H, OH, SH, C1~C12Alkyl radical, C1~C12Alkoxy, CN, halogen, NR5R6Or C1~C12An alkylthio group; r5And R6Each independently representing H, C1~C12An alkyl group; NR (nitrogen to noise ratio)5R6Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r1Representation H, C1~C12An alkyl group; r2Is represented by C1~C12Alkyl, benzyl or substituted benzyl; NR (nitrogen to noise ratio)1R2Also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-position by C1~C12Piperidinyl substituted by alkyl, piperidinyl substituted by benzyl or substituted benzyl in the 4-position, piperazinyl, piperidinyl substituted by C in the 4-position1~C12Piperazinyl substituted with alkyl, piperazinyl substituted at the 4-position with benzyl or substituted benzyl; r7Representation H, C1~C12Alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl; the term "halogen" as defined above means F, Cl, Br, or I; "substituted phenyl" or "substituted benzyl" refers to a benzyl group on the phenyl ring substituted with 1-4 groups selected from the group consisting of: F. cl, Br, I, C1-4Alkyl radical, C1-4Alkoxy, NR8R9Trifluoromethyl, trifluoromethoxy, nitro, carboxyl, hydroxyl, cyano, R8And R9Each independently represents H or C1~C12Alkyl radical, NR8R9Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; these substituents may be in any possible position of the phenyl ring;
however, the 3-aminoalkylphthalides (I) do not include the following compounds:
2. the 3-aminoalkylphthalides according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a mixture of the 3-aminoalkylphthalides with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, 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. A process for the preparation of a 3-aminoalkylphthalide compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2, wherein the compound is prepared by:
in the formula: x, R1、R2、R3、R4And n is defined as the same as the general chemical structure formula of the 3-amine alkyl phthalide compound (I);
step A): taking corresponding 3-bromide (1) as an initial raw material, and reacting with triphenylphosphine in a proper solvent to obtain a corresponding 3-triphenylphosphine salt compound (2);
step B): the 3-triphenylphosphine salt compound (2) obtained in the step A) and the corresponding amino alkyl aldehyde compound (3) are subjected to Wittig reaction in a solvent under the alkaline condition to obtain the corresponding compound (4)E/ZA mixture of configurations; the mixture is separated and purified by silica gel column chromatography by conventional method to respectively obtain correspondingEIs of the formulaZ-a compound of formula (la);
step C): reducing the double bond of the compound (4) obtained in the step B) in a proper solvent through catalytic hydrogenation to obtain a corresponding 3-amine alkyl phthalide compound (I) racemate; separating the corresponding 3-aminoalkyl phthalide compound (I) racemate by using a conventional chiral chromatography to obtain a corresponding optical isomer;
the 3-amine alkyl phthalide compound (I) obtained by the method contains amino which is basic, and can be prepared into pharmaceutically acceptable salts with any suitable acid by a pharmaceutically conventional salt forming method.
4. The method for preparing 3-aminoalkylphthalide compounds or pharmaceutically acceptable salts thereof according to claim 3, wherein the solvent used in the reaction in step A) is: c3-8An aliphatic ketone,N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1, 4-dioxane, ethylene glycol dimethyl ether or C5-8The molar charge ratio of alkane, 3-bromide (1) and triphenylphosphine is 1.0: 1.0 ~ 10.0.0, the reaction temperature is 40 ~ 150 ℃ and 150 ℃, and the reaction time is 1 ~ 120 hours and 120 hours.
5. The method for preparing 3-aminoalkylphthalide compounds or pharmaceutically acceptable salts thereof according to claim 3, wherein the solvent used in the reaction in step B) is: c1-8Fatty alcohol, C3-8Aliphatic ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1, 4-dioxane, benzene, toluene, acetonitrile or C5-8An alkane; 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,NMethylpiperidine, triethylenediamine, tetrabutylammonium hydroxide, compound (2), compound (3), and base in a molar ratio of 1.0: 1.0 ~ 10.0.0: 1.0 ~ 10.0.0, and a reaction temperatureThe reaction temperature is 0 ~ 120 deg.C, and the reaction time is 20 min ~ 48 h.
6. The method for preparing 3-aminoalkylphthalide compounds or pharmaceutically acceptable salts thereof according to claim 3, wherein the solvent used in the reaction in step C) is: c1-6Fatty alcohol, C3-8Aliphatic ketones, C1-6Fatty acid, C1-6Fatty acids with C1-6Esters formed from fatty alcohols, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene or xylene, hexane, heptane, octane; the catalysts used for the catalytic hydrogenation were: raney Ni, PtO2、1%~30%Pd-C、1%~30% Pd(OH)2The mass ratio of the compound (4) to the catalyst is 1.0: 0.01 ~ 1.0.0, the reaction pressure is ~ 10.0.0 MPa at normal pressure, the reaction temperature is ~ 150 ℃ at room temperature, and the reaction time is 1 ~ 96 hours.
7. A pharmaceutical composition comprising a 3-aminoalkylphthalide compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2, together with one or more pharmaceutically acceptable carriers or excipients.
8. Use of a 3-aminoalkylphthalide compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 2 in the manufacture of a medicament for the treatment and/or prophylaxis of neurological-related disorders: 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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