CN109265362B - 2, 5-dihydroxy terephthalamide compounds, preparation method and application thereof - Google Patents
2, 5-dihydroxy terephthalamide compounds, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 2, 5-dihydroxy terephthalamide 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 diseases comprise but are 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;
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a novel 2, 5-dihydroxy terephthalamide compound (I), 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 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 leading cause of death in developed countries such as europe and america. 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-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-D-Asparagus fernAn amino acid receptor antagonist, 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 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 inhibitingβMulti-target AD therapeutics with overproduction and deposition of amyloid, antioxidant stress and anti-neuritic response remain important research directions today.
Disclosure of Invention
The invention aims to disclose a 2, 5-dihydroxy terephthalamide compound (I) and pharmaceutically acceptable salts thereof;
the invention also discloses a preparation method of the 2, 5-dihydroxy terephthalamide compounds (I) and pharmaceutically acceptable salts thereof;
the invention also discloses a pharmaceutical composition containing the 2, 5-dihydroxy terephthalamide compound (I) and pharmaceutically acceptable salts thereof;
the invention also aims to disclose that the 2, 5-dihydroxy terephthalamide compounds (I) and the pharmaceutically acceptable salts thereof have multi-target effect and can be used for preparing the medicines for treating and/or preventing nervous system related diseases, such as 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.
The general chemical structure formula of the 2, 5-dihydroxy terephthalamide compound (I) provided by the invention is as follows:
in the formula: r represents- (CH)2)n-NR1R2N represents 1-12, R1Is represented by 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; r also represents
M represents 0-10, R3Representation H, C1~C12Alkyl, benzyl or substituted benzyl; the term "substituted benzyl" as defined above 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, NR4R5Trifluoromethyl, trifluoromethoxy, amino, hydroxy or cyano, R4And R5Each independently represents C1~C12Alkyl radical, NR4R5But also tetrahydropyrrolyl, morpholinyl or piperidinyl, these substituents being in any possible position of the phenyl ring.
The 2, 5-dihydroxy terephthalamide compound (I) provided by the invention can be prepared by the following method, and has the following reaction formula:
in the formula: the definition of R is the same as the general formula of the chemical structure of the 2, 5-dihydroxy terephthalamide compound (I).
For the above synthetic route, the specific preparation method is described as follows:
2, 5-dihydroxy terephthalic acid (1) and corresponding primary amine compound (2) are taken as starting materials, and are subjected to condensation reaction in the presence of a proper solvent and a condensing agent to prepare corresponding 2, 5-dihydroxy terephthalic acid amide compound (I); wherein, the solvent used in the reaction is: pyridine, pyridine,N,N-dimethylformamide, dimethyl sulfoxide, C3-8Aliphatic ketone, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, C1-6Fatty acids with C1-6Esters of fatty alcohols, dichloromethane, chloroform, 1, 2-dichloroethane, benzene, toluene, acetonitrile or C5-8Alkanes, preferred solvents are: pyridine, tetrahydrofuran,N,N-dimethylformamide, dichloromethane, chloroform or acetonitrile; the condensing agent used was: carbonyl Diimidazole (CDI), chlorineFormic acid C1-8Fatty alcohol ester compounds (such as ethyl chloroformate, tert-butyl chloroformate and benzyl chloroformate),NEthoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), carbodiimide-based compounds (e.g. dicyclohexylcarbodiimide (DCC for short), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI for short)), diethyl cyanophosphate (DEPC), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT for short), 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine chloride (DMTMM for short), wherein the anion in DMTMM is chlorine, bromine, perchlorate, fluoroborate, methane sulfonate, benzene sulfonate, p-toluene sulfonate, camphor sulfonate, amino sulfonate, preferred condensing agents are: carbonyldiimidazole (CDI), ethyl chloroformate, Dicyclohexylcarbodiimide (DCC), EDCI, DMTMM; compound (1): compound (2): the molar charge ratio of the condensing agent is 1.0: 1.0-10.0: 1.0-10.0, and preferably, the molar feed ratio is 1.0: 2.0-5.0: 2.0 to 5.0; the condensation reaction temperature is 0-130 ℃, and the preferable reaction temperature is room temperature-80 ℃; the condensation reaction time is 1-72 hours, and the preferable reaction time is 2-48 hours.
The 2, 5-dihydroxy terephthalamide compound (I) obtained by the method contains amino in the side chain, the amino is basic, and can be prepared into pharmaceutically acceptable salts thereof by any suitable acid through a pharmaceutically conventional salt forming method, 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 starting materials of the present invention, 2, 5-dihydroxyterephthalic acid (1) and the corresponding primary amine compound (2), can be prepared by techniques known or customary in the artMethods disclosed in, but not limited to, the following documents are included: 1. l, Hintermann,et al. Synthesis, 14 (2008) 2303-2306.；2、Q. Liu, et al.Bioorganic & Medicinal Chemistry, 23 (2015) 911-923。
the pharmaceutical composition disclosed by the invention comprises one or more 2, 5-dihydroxy terephthalamide 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 2, 5-dihydroxy terephthalamide compound (I) or the pharmaceutically acceptable salt thereof is taken as an active ingredient and accounts for 2-99.5% of the total weight.
The 2, 5-dihydroxy terephthalamide compound (I) and pharmaceutically acceptable salts thereof disclosed by the invention are subjected to the following biological activity screening.
(1) Inhibitory activity of 2, 5-dihydroxy terephthalamide compounds (I) on acetylcholinesterase and butyrylcholinesterase
Adding sequentially 1.0 mmol/L thioacetylcholine iodide or thiobutyrylcholine iodide (all from Sigma) 30. mu.L, pH7.4 PBS buffer solution 40. mu.L, test compound solution 20. mu.L (DMSO content less than 1%) and 10. mu.L 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) solution into 96-well plate, mixing, incubating at 37 deg.C for 15min, adding 0.2% 5, 5' -dithio-bis (2-nitrobenzoic acid) (DTNB, from Sigma) solution 30. mu.L to each wellMeasuring the optical density (OD value) of each hole at 405nm by using a microplate reader, and comparing the optical density with a blank hole without the sample to be measured, and calculating the inhibition rate of the compound on the enzyme (enzyme inhibition rate (%) = (1-sample group OD value/blank group OD value) × 100%); 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 2, 5-dihydroxy terephthalamide compounds (I) disclosed in the embodiment of the invention have obvious inhibition effect on acetylcholinesterase and IC (integrated Circuit) thereof50The value is 0.01-20.0 [ mu ] M; and the inhibitory activity of the 2, 5-dihydroxy terephthalamide compounds (I) on acetylcholinesterase is obviously higher than that of butyrylcholinesterase (the selectivity is more than 100 times), which shows that the compounds disclosed by the invention have selective inhibitory action on acetylcholinesterase, and shows that the compounds have low toxicity on peripheral systems. In addition, the measurement results also show that the IC of AChE inhibition by the clinically used rivastigmine50IC for butyrylcholinesterase inhibition at 10.5 μ M50Is 2.6 mu M; and 2, 5-dihydroxyterephthalic acid (1) and corresponding primary amine compound (2) as starting materials for synthesizing the target product of the invention [ wherein R is as defined in the general formula of the chemical structure of 2, 5-dihydroxyterephthalic acid amide compound (I) ], and the following control compound (II) for acetylcholinesterase-inhibiting IC50Are all larger than 150 mu M;
(2) antioxidant activity of 2, 5-dihydroxyterephthalamide compounds (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) Using PBS buffer solution with pH7.4 to prepare 10-80 mu mol/L solution, using PBS buffer solution with pH7.4 for fluorescein (fluorescein)The buffer solution was prepared to be 250 nmol/L, and 2, 2' -azobisisobutylamidine dihydrochloride (AAPH) was prepared to be 40 mmol/L in PBS buffer solution (pH 7.4) 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 measurement result shows that the antioxidant activity of the 2, 5-dihydroxy terephthalamide compounds (I) disclosed in the embodiment of the invention isTrolox0.6-4.0 times of the total amount of the compound, which shows that the compound has stronger antioxidant activity.
(3) 2, 5-dihydroxy terephthalic acid amide compound (I) p 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 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 1-42+ PBS bufferFluorescence value of the washing solution was recorded 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 results show that the 2, 5-dihydroxy terephthalamide compounds (I) disclosed in the embodiment of the invention are opposite to Aβ 1-42The self-aggregation has obvious inhibitory activity on A at the concentration of 20.0 mu Mβ 1-42The inhibition rate of self-aggregation is more than 70.0 percent; and anti-AD drugs widely used clinically: donepezil, rivastigmine, memantine hydrochloride, 2, 5-dihydroxyterephthalic acid (1) and the corresponding primary amine compound (2), and control compound (II) were applied to A at a concentration of 25.0 μ Mβ 1-42The inhibition rate of self-aggregation is less than 10%.
(4) Inhibitory activity of 2, 5-dihydroxyterephthalamide compound (I) on neuroinflammation
(a) Effect of Compounds and Lipopolysaccharide (LPS) on BV-2 cell Activity
Preparing BV-2 cells in logarithmic growth phase into cell suspension, inoculating the cell suspension in a 96-well plate, placing the 96-well plate at 37 ℃ in 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, with or without LPS, the mixture was placed at 37 ℃ in 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 showed that neither 2, 5-dihydroxyterephthalamide compound (I) nor LPS disclosed in the examples of the present invention exhibited cytotoxicity at a concentration of not more than 25. mu.M: (Suppression ratio of less than<5%）。
(b) Effect of 2, 5-dihydroxy-terephthalic acid amide compound (I) on LPS-induced NO release from 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 96-well plate at 37 ℃ in 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). Test results show that the 2, 5-dihydroxy terephthalamide compounds (I) disclosed in the embodiment of the invention all show strong inhibition on LPS-induced BV-2 cell NO generation in the concentration range of 0.5 mu M to 25 mu M (the inhibition rate under the concentration of 2.5 mu M is over 25.0 percent), and have obvious dose-effect relationship; and their inhibitory activity was significantly enhanced compared to 2, 5-dihydroxyterephthalic acid (1) at the same concentration (inhibition rate at 2.5 μ M concentration was less than 5.0%) (n =3,p <0.01), which shows that the 2, 5-dihydroxy terephthalamide compound (I) disclosed in the embodiment of the invention has remarkable anti-neuritis 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. 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 12 general procedure for preparation of 5-dihydroxy-terephthalamide Compound (I)
3.0 mmol of 2, 5-dihydroxyterephthalic acid (1), 9.0 mmol of the corresponding primary amine compound (2) and 15 ml of tetra-tert-butyl alcohol were added in sequence to a reaction flaskAnd (3) uniformly stirring tetrahydrofuran at room temperature, adding 9.0 mmol of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 12.0 mmol of triethylamine, and continuously stirring at room temperature for reacting for 10-32 hours (tracking the reaction process by TLC). After the reaction was completed, the solvent was distilled off under reduced pressure, and 40 mL of methylene chloride was added to the residue, followed by 20 mL of deionized water and 20 mL of saturated NaHCO3Washing the aqueous solution with 20 mL of saturated NaCl aqueous solution, drying the organic layer with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove the solvent, purifying the residue by silica gel column chromatography (eluent: acetone: dichloromethane = 2-3: 1 v/v) to obtain the corresponding 2, 5-dihydroxy terephthalamide compounds (I), wherein the yield is 30.0-80.0%, and the chemical structures are all obtained by1H-NMR、13C-NMR and ESI-MS confirmation; the purities of the obtained target substances are more than 97.0 percent through HPLC. The following target substances are prepared by the general method:
(1) when R represents- (CH)2)n-NR1R2The target compound 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): 11.80 (brs, 2H), 8.76 (brs, 2H), 7.33-7.26 (m, 10H), 6.87 (s, 2H), 3.64 (s, 4H), 3.55-3.45 (m, 4H), 2.65-2.60 (m, 4H), 2.39 (s, 6H), 1.86-1.79 (m, 4H);
1H NMR (CDCl3): 11.50 (brs, 2H), 9.23 (brs, 2H), 7.31-7.27 (m, 4H), 6.94-6.91 (m, 4H), 6.84 (d, J = 8.0 Hz, 2H), 3.76 (s, 4H), 3.68 (s, 6H), 3.51-3.47 (m, 4H), 2.85-2.75 (m, 4H), 2.43 (s, 6H), 1.95-1.84 (m, 4H);
1H NMR (CDCl3): 11.80 (brs, 2H), 9.07 (brs, 2H), 7.30-7.26 (m, 4H), 6.94-6.90 (m, 4H), 6.84 (d, J = 8.4 Hz, 2H), 3.75 (s, 4H), 3.70 (s, 6H), 3.47-3.44 (m, 4H), 2.80-2.70 (m, 8H), 1.90-1.78 (m, 4H), 1.16 (t, J = 6.4 Hz, 6H);
1H NMR (CDCl3): 8.59 (brs, 2H), 7.27-7.24 (m, 4H), 7.03 (s, 2H), 6.92 (t, J = 7.2 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 3.76 (s, 6H), 3.67 (s, 4H), 3.38-3.34 (m, 4H), 2.52-2.48 (m, 4H), 2.30 (s, 6H), 1.73-1.67 (m, 8H);
1H NMR (CDCl3): 7.99 (brs, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.26-7.23 (m, 2H), 7.06 (s, 2H), 6.92 (t, J = 7.2 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.79 (s, 6H), 3.76 (s, 4H), 3.37 (t, J = 6.0 Hz, 4H), 2.71 (q, J = 6.8 Hz, 4H), 2.62 (t, J = 6.0 Hz, 4H), 1.71-1.65 (m, 8H), 1.12 (t, J = 6.8 Hz, 6H, 2 × CH3);
1H NMR (CDCl3): 8.56 (brs, 2H), 8.00 (brs, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.29 (s, 2H), 7.24 (t, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 7.2 Hz, 2H), 3.88 (s, 4H), 3.40-3.37 (m, 4H), 2.73-2.64 (m, 8H), 2.64 (s, 12H), 1.67-1.62 (m, 8H), 1.11 (t, J = 6.8 Hz, 6H);
1H NMR (CDCl3): 8.61 (brs, 4H), 7.30 (s, 2H), 7.22 (d, J = 8.4 Hz, 4H), 6.63 (d, J = 8.4 Hz, 4H), 3.80 (s, 4H), 3.40 (t, J = 5.6 Hz, 4H), 2.90 (s, 12H), 2.77 (q, J = 6.8 Hz, 4H), 2.70 (t, J = 6.8 Hz, 4H), 1.82-1.72 (m, 4H), 1.68-1.58 (m, 4H), 1.19 (t, J = 6.8 Hz, 6H)。
(2) when R represents
The target compound has the following structure:
EXAMPLE 22 general procedure for salt formation of 5-dihydroxy-terephthalamide Compound (I) with acid
Adding 2.0 mmol of the 2, 5-dihydroxy terephthalamide compound (I) obtained in the example 1 and 35 ml of acetone into a reaction bottle, stirring uniformly, adding 6.0 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, and recrystallizing the residue to obtain the salt of the 2, 5-dihydroxy terephthalamide compound (I) and the acid, wherein the chemical structure of the salt is shown in the specification1H NMR and ESI-MS.
Claims (6)
1. A2, 5-dihydroxy terephthalamide compound or pharmaceutically acceptable salt thereof is characterized in that the chemical structure general formula of the compound is shown as (I):
in the formula: r represents- (CH)2)n-NR1R2Or
N represents 1-12, R1Is represented by C1~C12An alkyl group; r2Is represented by C1~C12Alkyl, benzyl or substituted benzyl; when NR is1R2When cyclized, it represents tetrahydropyrrolyl, morpholinyl, piperidinyl, or a 4-position substituted by C1~C12Piperidinyl substituted by alkyl, 4-by benzyl or substituted benzylSubstituted piperidinyl, piperazinyl, 4-position by C1~C12Piperazinyl substituted with alkyl, piperazinyl substituted at the 4-position with benzyl or substituted benzyl; m represents 0-10, R3Is represented by C1~C12Alkyl, benzyl or substituted benzyl; the term "substituted benzyl" as defined above 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, NR4R5Trifluoromethyl, trifluoromethoxy, R4And R5Each independently represents C1~C12Alkyl, these substituents being in any possible position of the phenyl ring.
2. The 2, 5-dihydroxy terephthalamide compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a mixture of the 2, 5-dihydroxy terephthalamide compound 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 2, 5-dihydroxy terephthalamide compound or its pharmaceutically acceptable salt according to any one of claims 1 to 2, which is obtainable by:
in the formula: the definition of R is the same as the general formula of the chemical structure of the 2, 5-dihydroxy terephthalamide compound (I);
2, 5-dihydroxy terephthalic acid (1) and corresponding primary amine compound (2) are taken as starting materials and are subjected to condensation reaction in the presence of a proper solvent and a condensing agent to prepare the corresponding 2, 5-dihydroxy terephthalic acid amide compound (I).
4. A process for producing 2, 5-dihydroxyterephthalic acid amides or pharmaceutically acceptable salts thereof according to claim 3, wherein the solvent used in the reaction is: pyridine, pyridine,N,N-dimethylformamide, dimethyl sulfoxide, C3-8Aliphatic ketone, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, C1-6Fatty acids with C1-6Esters of fatty alcohols, dichloromethane, chloroform, 1, 2-dichloroethane, benzene, toluene, acetonitrile or C5-8An alkane; the condensing agent used was: carbonyl diimidazole, chloroformic acid C1-8Fatty alcohol ester compounds,N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diethyl cyanophosphate, 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine chloride; compound (1): compound (2): the molar charge ratio of the condensing agent is 1.0: 1.0-10.0: 1.0 to 10.0; the condensation reaction temperature is 0-130 ℃; the condensation reaction time is 1-72 hours.
5. A pharmaceutical composition comprising a 2, 5-dihydroxyterephthalic acid amide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, and one or more pharmaceutically acceptable carriers or excipients.
6. Use of a 2, 5-dihydroxyterephthalamide-based compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, for the production of a medicament for the treatment and/or prophylaxis of neurological-related diseases which are: 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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