CN113185447A - Phthaloyl cysteamine compound, preparation method and use thereof - Google Patents

Phthaloyl cysteamine compound, preparation method and use thereof Download PDF

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CN113185447A
CN113185447A CN202110490147.3A CN202110490147A CN113185447A CN 113185447 A CN113185447 A CN 113185447A CN 202110490147 A CN202110490147 A CN 202110490147A CN 113185447 A CN113185447 A CN 113185447A
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acid
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phthaloyl
pharmaceutically acceptable
acceptable salt
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邓勇
余光俊
刘卓龄
强晓明
徐一丹
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Sichuan University
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Abstract

The invention discloses a phthaloyl cysteine amide 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'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

Phthaloyl cysteamine compound, preparation method and use thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a phthaloyl cysteine amide 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 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
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 closely 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 blood circulation and the brain metabolism of the brain and strengthening the brain nutrition. Recent studies have shown that VD patients exhibit impaired cognitive function and are often accompanied by abnormalities in the cholinergic system. 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, AD) is a degenerative disease of the central nervous system mainly involving progressive cognitive impairment and memory impairment, and its incidence rate is on the rise year by year, and it is a high-grade disease second to cardiovascular disease and cancer. With the accelerated aging process of the global population, the incidence rate of the disease is in a remarkably rising trend. It is estimated that more than 5000 million people suffer from dementia worldwide, the total amount of treatment and care cost exceeds 1 trillion dollars in 2018, and the number of patients will increase to 1.52 billion by 2050. The clinical manifestations of AD include memory, orientation, thinking and judgmentThe ability of the patient is reduced, the daily life ability of the patient is reduced, even abnormal psychobehavioral symptoms and the like occur, the nursing difficulty of the patient is high, and the patient bears heavy burden on 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, 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 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. Based on the above results, researchers proposed "multiple target spotsDrug "strategy to develop anti-neurodegenerative drugs. By "multi-target drug" is meant that a single chemical entity can act on multiple targets in the disease network that are closely related to treatment, 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, and such compounds are also referred to as "Multifunctional" or "multi-potential" 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, research and development of neurodegenerative disease-resistant therapeutic drugs with novel chemical structures, novel action mechanisms, multi-target effects and low toxic and side effects are currently important directions. A large number of clinical studies have proved that AChE inhibitors can effectively relieve the symptoms of patients with dementia, and the short-term treatment effect is positive; therefore, in designing multi-target anti-dementia drugs, it is usually necessary to retain the AChE inhibitory activity of the compound (inhibiting the enzyme is crucial to improving the symptoms of dementia patients), and to add one or more other targets or functions with pharmacological synergistic effects on the basis of the AChE inhibitory activity, so as to achieve multi-target anti-dementia therapeutic effects. Obviously, the design and the discovery have the effects of inhibiting acetylcholinesterase and inhibitingβThe overproduction and deposition of amyloid, oxidative stress, metal ion complexation and multi-target anti-dementia drugs against neuritis may make a breakthrough in the treatment of associated dementia.
Disclosure of Invention
The invention aims to disclose a class of phthaloyl cysteamine compounds (I) and pharmaceutically acceptable salts thereof;
the invention also discloses a preparation method of the phthaloyl cysteamine compound (I) and pharmaceutically acceptable salt thereof;
still another object of the present invention is to disclose a pharmaceutical composition comprising such phthaloyl cysteamine compounds (I) and pharmaceutically acceptable salts thereof;
the invention also aims to disclose that the phthaloyl cysteamine compound (I) and the pharmaceutically acceptable salt thereof have multi-target function 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 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 chemical structural general formula of the phthaloyl cysteamine compound (I) disclosed by the invention is as follows:
Figure 100002_DEST_PATH_IMAGE001
in the formula: r represents- (CH)2)n-NR1R2Or
Figure 100002_DEST_PATH_IMAGE002
(ii) a n represents 1-5, R1Is represented by C1~C12An alkyl group; r2Represents benzyl or substituted benzyl; m represents 0-3, R3Is represented by C1~C12Alkyl, benzyl or substituted benzyl;
R4and R5Each independently represents H, OH, C1~C6Alkoxy, CN, halogen or NR6R7However, R4And R5Does not simultaneously represent H; r4And R5At any possible position on the phenyl ring; r6And R7Each independently representing H, C1~C6An alkyl group; when NR is6R7When cyclized, it represents a tetrahydropyrrolyl group or a piperidinyl group;
Figure 100002_DEST_PATH_IMAGE003
and also shows
Figure 100002_DEST_PATH_IMAGE004
Or
Figure 100002_DEST_PATH_IMAGE005
；
The compound is in an R configuration, an S configuration or a mixture of the R configuration and the S configuration in any proportion;
the term "halogen" as defined above means F, Cl, Br or I; "substituted benzyl" refers to benzyl groups on the phenyl ring substituted with 1 to 4 groups selected from: F. cl, Br, I, C1-4Alkyl radical, C1-4Alkoxy, NR8R9Trifluoromethyl, trifluoromethoxy, R8And R9Each independently represents C1~C12Alkyl, these substituents being in any possible position of the phenyl ring.
The phthaloyl cysteamine compound (I) provided by the invention can be prepared by the following method:
the corresponding phthaloyl cysteine compound (1) and the 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 phthaloyl cysteine amide compound (I), and the reaction formula is as follows:
Figure 100002_DEST_PATH_IMAGE006
in the formula: r, R4And R5The definition of (A) is the same as the chemical structural general formula of the phthaloyl cysteine 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: tetrahydrofuran, tetrahydrofuran,N,N-dimethylformamide, dichloromethane, chloroform or acetonitrile; the condensing agent used was: carbonyl Diimidazole (CDI), chloroformic acid C1-8Fatty alcohol ester compounds (e.g. ethyl chloroformate, tert-butyl chloroformate)Esters, benzyl chloroformate, etc.)),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), preferably condensing agents: 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 0-100 ℃, and the preferable reaction temperature is room temperature-60 ℃; the condensation reaction time is 1-72 hours, and the preferable reaction time is 2-48 hours.
The phthaloyl cysteamine compound (I) obtained according to the above method can be prepared into pharmaceutically acceptable salts thereof by a pharmaceutically conventional salt-forming method with any suitable acid: 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, phthaloyl cysteine compound (1) and the corresponding primary amine compound (2), can be prepared by techniques known or customary in the art, including but not limited to the methods disclosed in the following documents: 1. simona sestto. et al.European Journal of Medicinal Chemistry2019, 184, 111745；2、Q. Liu, et al. Bioorganic & Medicinal Chemistry, 23 (2015) 911-923。
The pharmaceutical composition disclosed by the invention comprises one or more phthaloyl cysteamine 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 phthaloyl cysteamine 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 invention discloses a phthaloyl cysteamine compound (I) and pharmaceutically acceptable salt thereof, which are subjected to the following biological activity screening:
(1) inhibitory Activity of phthalimide Compound (I) on Acetylcholinesterase and Butyrylcholinesterase
Adding 1.0mmol/L thioacetyl choline iodide or thiobutyrylcholine iodide 30 μ L, PBS buffer solution of pH7.4 40 μ L, test compound solution 20 μ L (DMSO content is less than 1%) and acetylcholinesterase 10 μ L (rat brain cortex 5% homogenate supernatant, phosphate buffer solution of pH7.4 as homogenate medium) or butyrylcholinesterase (rat serum 25% supernatant, pH7.4 phosphate buffer solution as homogenate medium) into 96-well plate, mixing, incubating at 37 deg.C for 15min, adding 0.2% 5, 5' -dithio-bis (2-nitrobenzoic acid) (DTNB) solution 30 μ L to each well for color development, measuring optical density (OD value) of each well at 405nm with 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, and performing linear regression by using the negative logarithm of the molar concentration of the compound and the enzyme inhibition rate to obtainThe molar concentration at 50% inhibition is the IC of the compound50. The test result shows that the phthaloyl cysteine amide compound (I) disclosed in the embodiment of the invention has obvious inhibition effect on acetylcholinesterase, and the IC of the compound50Is 25.0nM to 15.0 [ mu ] M (for example, 1.55 [ mu ] M for example compound 1-2-19, 4.52 [ mu ] M for compound 1-2-1, 5.40 [ mu ] M for compound 1-2-11, 8.45 [ mu ] M for compound 1-2-2), and the influence of the chiral configuration of compound (I) on the inhibitory activity of acetylcholinesterase is found to be insignificant. Further structural-activity relationship research shows that the 'HSCH' in the molecule of the phthaloyl cysteine amide compound (I)2The fragment is replaced by H, and when other substituents are kept unchanged, the obtained phthaloyl glycinamide compound still has inhibitory activity on acetylcholinesterase, and the activity is not obviously different; shows that the mercapto methyl (HSCH) in the molecule of the compound2- "fragments are not inhibitory acetylcholinesterase pharmacophores. In the molecule of the phthaloyl cysteamine compound (I), when R is1And R2Simultaneously represents C1~C12Alkyl, the IC of the resulting compound for acetylcholinesterase inhibition remaining unchanged with the other substituents50Are all larger than 80 mu M. The determination result also shows that the inhibitory activity of the phthaloyl cysteamine compound (I) on acetylcholinesterase is obviously higher than that of butyrylcholinesterase (the selectivity is more than 50 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 IC of AChE inhibition by the clinically used rivastigmine50IC for butyrylcholinesterase inhibition at 15.5 μ M50Is 3.8 mu M; in addition, the phthaloyl cysteine compound (1) and the corresponding primary amine compound (2) used in the examples of the present invention have weak acetylcholinesterase inhibitory activity (acetylcholinesterase inhibitory IC)50Are all larger than 100 mu M).
(2) Antioxidant activity of phthalimide compound (I) (ORAC-FL method)
Reference toLiterature (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. Adding 50-10 mu mol/L compound solution and fluorescein solution into a 96-well plate, mixing uniformly, incubating for 15min at 37 ℃, adding AAPH solution to make the total volume of each well 200 mu L, mixing uniformly, immediately placing in a Varioskan Flash Multimode Reader, and continuously measuring for 90 min under 485 nm excitation wavelength and 535 nm emission wavelength. 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 test result shows that the antioxidant activity of the phthaloyl cysteine amide compound (I) disclosed in the embodiment of the invention isTrolox0.5-3.0 times of the total amount of the compound, which shows that the compound has stronger antioxidant activity. The analysis of structure-activity relationship shows that the chiral configuration of the compound has almost no influence on the antioxidant activity; but the 'HSCH' in the molecule of the phthaloyl cysteamine compound (I)2The fragment is replaced by H, and when other substituents are kept unchanged, the antioxidant activity of the obtained phthaloyl glycinamide compound is obviously reduced, and the antioxidant activity of the compound is reduced by at least 3-10 times; the results show that the "mercaptomethyl group" (HSCH) in the molecule2- "fragments are important for enhancing the antioxidant activity of the compound.
(3) Determination of complexation of phthaloyl cysteamine compound (I) with metal ion
Dissolving CuCl with methanol2·2H2O、ZnCl2、FeSO4·7H2O、AlCl3And a to-be-detected compound, preparing a solution of 75 mu mol/L, adding 100 mu L of the to-be-detected compound solution and 100 mu L of the metal ion solution into a 96-well plate, uniformly mixing, standing for 30 min at room temperature, recording an ultraviolet absorption curve of the mixture in the range of 200-600 nm on a Varioskan Flash Multimode Reader, and observing the red shift phenomenon of the maximum absorption peak and the intensity of the maximum absorption peak of the mixed solution of the metal ion and the to-be-detected compound by taking 100 mu L of the to-be-detected compound solution and 100 mu L of methanol mixed solution as a reference. The test results show that the phthaloyl cysteamine compounds (I) disclosed in the invention examples all show Cu resistance2+、Fe2+Selective complexation; to convert the "HSCH" in the molecule2The "fragment" is replaced by "H", and the phthaloyl glycinamide compound obtained has no complexing effect on any of the four metal ions mentioned above, when the other substituents are left unchanged.
(4) Inhibitory Activity of phthalimide 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 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, 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 10min, measuring OD (optical density) at 490nm 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 all the phthalimide compounds (I) and LPS disclosed in the examples of the present invention showed no cytotoxicity (inhibition rate less than that of the compound) at a concentration of not more than 25. mu.M<5%）。
(b) Effect of phthalimide compounds (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 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 10min, 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 all the phthaloyl cysteamine compounds (I) disclosed in the embodiment of the invention show stronger inhibition on the generation of BV-2 cell NO induced by LPS in the concentration range of 0.5 mu M to 20 mu M (the inhibition rate under the concentration of 5.0 mu M is more than 35.0 percent), and have obvious dose-effect relationship; and their inhibitory activity was comparable to that of the control compound (in the molecule, "HSCH")2Compounds in which "fragment" was replaced with "H" and other substituents remained unchanged) were significantly enhanced (the inhibition rate of the control compounds at a concentration of 5.0 μ M was less than 15.0%), indicating that the phthaloyl cysteinamide compound (I) disclosed in the examples of the present invention has significant anti-neuritic activity.
(5) Influence of phthaloyl cysteamine compound (I) on mouse memory acquisition disorder caused by scopolamine
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; 45 min after administration, normal mice were injected with normal saline in the abdominal cavity, and the other animals were injected with scopolamine (3.0 mg/kg) in an administration volume of 0.1ml/10 g; after 30 min of molding, the mice were placed in the non-electrostimulated Y maze for behavioral testing. When tested, willMice were placed at the end of one arm, allowed to freely walk in the maze for 8 minutes, and the number of entries and alternations into each arm were recorded, and the rate of alternation was calculated according to the following formula: alternation rate% = [ alternation times/(total number of entries-2)]X 100, results are expressed as mean ± standard deviation, and differences between groups were analyzed using one-way anova. The test result shows that the tested phthaloyl cysteamine compound (I) (example compound 1-2-19, compound 1-2-1 and compound 1-2-11) has dose-dependent improvement effect on mouse acquired memory disorder caused by scopolamine under the experimental condition, and has statistical difference compared with the model group (thep<0.001) and the activity is obviously higher than that of the clinical medicine rivastigmine (at the same molar concentration)p<0.01）。
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 the preparation of phthalimide compounds (I)
2.0 mmol of phthaloyl cysteine compound (1), 2.6 mmol of corresponding primary amine compound (2) and 15 ml of tetrahydrofuran are sequentially added into a reaction bottle, the mixture is uniformly stirred at room temperature, 3.0 mmol of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4.0 mmol of triethylamine are added, and the mixture is continuously stirred at room temperature for reaction for 6 to 36 hours (the reaction process is tracked 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 by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, purifying the residue by using silica gel column chromatography (eluent: dichloromethane: methanol = 5-20: 1 v/v) to obtain the corresponding phthaloyl half-cystine amide compound (I), wherein the yield is 45.3% -82.5%, and the chemical structures of the compounds are all obtained by using1H-NMR、13C-NMR and ESI-MS confirmation; the purities of the obtained target substances are more than 96 through HPLC.0 percent. The following target substances are prepared by the general method:
(1) when R represents- (CH)2)n-NR1R2The target compound has the following structure:
Figure DEST_PATH_IMAGE007
Figure DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE009
Figure DEST_PATH_IMAGE010
Figure DEST_PATH_IMAGE011
Figure DEST_PATH_IMAGE012
Figure DEST_PATH_IMAGE013
Figure DEST_PATH_IMAGE014
；
Figure DEST_PATH_IMAGE015
Figure DEST_PATH_IMAGE016
Figure DEST_PATH_IMAGE017
；
(2) when R represents
Figure 657452DEST_PATH_IMAGE002
The target compound has the following structure:
Figure DEST_PATH_IMAGE018
Figure DEST_PATH_IMAGE019
Figure DEST_PATH_IMAGE020
Figure DEST_PATH_IMAGE021
Figure DEST_PATH_IMAGE022
Figure DEST_PATH_IMAGE023
Figure DEST_PATH_IMAGE024
；
NMR data for some of the compounds were as follows:
Figure DEST_PATH_IMAGE025
1H NMR (CDCl3): 7.71 (brs, 1H), 7.32-7.29 (m, 3H), 7.28 (s, 2H), 7.17 (d, J = 6.8 Hz, 2H), 4.77 (dd, J = 5.2 Hz, 10.4 Hz, 1H), 3.96 (s, 6H), 3.44-3.27 (m, 6H), 2.49-2.43 (m, 2H), 2.08 (s, 3H), 1.69 (t, J = 6.0 Hz, 2H); 13C NMR (CDCl3):168.0, 167.3, 154.1, 137.2, 129.1, 128.4, 127.4, 125.0, 105.4, 62.4, 56.7, 56.6, 55.4, 41.5, 39.5, 24. 9, 23.8;
Figure DEST_PATH_IMAGE026
1H NMR (CDCl3): 7.32-7.25 (m, 7H), 6.44 (brs, 1H), 4.75 (dd, J = 5.6, 10.4 Hz, 1H,), 3.98 (s, 6H), 3.63 (s, 2H), 3.45-3.20 (m, 4H), 2.57-2.49 (m, 4H), 1.55-1.43 (m, 2H), 1.05 (t, 3H, J = 6.8 Hz);
Figure DEST_PATH_IMAGE027
1H NMR (CDCl3): 8.11 (brs, 1H), 7.28 (d, J = 6.8 Hz, 1H), 7.22 (s, 2H), 7.15 (d, J = 6.8 Hz, 1H), 6.90 (t, J = 6.8 Hz, 2H), 4.75 (dd, J = 5.2, 10.4 Hz, 1H), 3.97 (s, 6H), 3.82 (s, 3H), 3.62-3.25 (m, 6H), 2.67-2.59 (m, 2H), 2.14 (s, 3H), 1.80 (t, J = 6.0 Hz, 2H); 13C NMR (CDCl3): 168.0, 167.3, 157.8, 153.9, 131.4, 131.3, 129.3, 125.0, 120.4, 110.7, 105.3, 56.5, 56.4, 55.7, 55.4, 55.3, 41.1, 39.3, 24.4, 23.8;
Figure DEST_PATH_IMAGE028
1H NMR (CDCl3): 7.95 (brs, 1H), 7.37-7.31 (m, 2H), 7.28 (s, 2H), 6.96 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.76 (dd, J = 5.2, 10.4 Hz, 1H), 3.96 (s, 6H), 3.88 (s, 2H), 3.87 (s, 3H), 3.40-3.24 (m, 4H), 2.83-2.73 (m, 4H), 1.92 (t, J = 6.0 Hz, 2H), 1.18 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3):168.2, 167.9, 158.0, 154.0, 132.0, 131.9, 130.1, 125.3, 120.8, 110.9, 105.5, 56.6, 56.4, 55.5, 50.6, 50.4, 46.8, 38.1, 24.2, 24.0, 9.4;
Figure DEST_PATH_IMAGE029
1H NMR (CDCl3): 7.57 (d, J = 7.2 Hz, 1H), 7.29 (s, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 4.76 (dd, J= 5.2, 10.4 Hz, 1H), 3.97 (s, 6H), 3.91 (s, 2H), 3.42-3.25 (m, 4H), 2.81-2.65 (m, 4H), 2.64 (s, 6H), 1.87 (t, J = 6.0 Hz, 2H), 1.13 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3): 168.2, 167.8, 154.0, 153.5, 130.9, 129.0, 125.2, 124.1, 119.9, 105.5, 56.6, 51.5, 50.4, 46.8, 45.4, 37.8, 29.7, 24.7, 24.0, 9.6;
Figure DEST_PATH_IMAGE030
1H NMR (CDCl3): 7.88 (brs, 1H), 7.30 (s, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 2H), 4.78 (dd, J = 5.2, 10.4 Hz, 1H), 3.98 (s, 6H), 3.80 (s, 2H), 3.40-3.25 (m, 4H), 2.97 (s, 6H), 2.84-2.74 (m, 4H), 1.94 (t, J= 6.0 Hz, 2H), 1.23 (t, J = 6.8 Hz, 3H);
Figure DEST_PATH_IMAGE031
1H NMR (CDCl3): 7.31-7.24 (m, 7H), 6.44 (brs, 1H), 4.76 (dd, J = 5.6, 10.4 Hz, 1H), 3.98 (s, 6H), 3.59 (s, 2H), 3.45-3.21 (m, 4H), 2.54-2.48 (m, 4H), 1.57-1.46 (m, 4H), 1.04 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3):168.1, 167.6, 154.2, 138.1, 129.1, 128.2, 127.1, 124.9, 105.5, 57.6, 57.1, 56.6, 52.3, 46.9, 39.5, 27.0, 24.1, 23.8, 11.1;
Figure DEST_PATH_IMAGE032
1H NMR (CDCl3): 7.43 (d, J = 7.2 Hz, 1H), 7.29 (s, 2H), 7.27 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 4.78 (dd, J= 5.6, 10.4 Hz, 1H), 3.98 (s, 6H), 3.83 (s, 3H), 3.80 (s, 2H), 3.49-3.24 (m, 4H), 2.76-2.64 (m, 4H), 1.71-1.66 (m, 2H), 1.59-1.54 (m, 2H), 1.16 (t, J = 6.4 Hz, 3H); 13C NMR (CDCl3):168.2 167.7, 157.8, 154.1, 131.4, 129.3, 125.1, 120.6, 110.5, 105.5, 57.0, 56.6, 55.4, 52.2, 50.6, 47.1, 39.0, 26.7, 24.0, 22.9, 10.2;
Figure DEST_PATH_IMAGE033
1H NMR (CDCl3): 7.66 (d, J = 7.6 Hz, 1H), 7.30 (s, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 4.80 (dd, J= 5.2, 10.4 Hz, 1H), 3.97 (s, 6H), 3.93 (s, 2H), 3.53-3.23 (m, 4H), 2.82-2.74 (m, 4H), 2.66 (s, 6H), 1.76-1.68 (m, 2H), 1.58-1.53 (m, 2H), 1.16 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3): 168.2, 167.8, 154.0, 153.3, 130.9, 129.0, 125.1, 124.0, 119.7, 105.5, 56.9, 56.5, 52.2, 51.5, 46.8, 45.3, 38.8, 26.5, 24.1, 22.6, 9.7。
EXAMPLE 2 general Process for the preparation of salts of phthalimide Compounds (I) with an acid
Adding 1.0mmol of the phthaloyl cysteamine compound (I) obtained according to the embodiment 1 and 25 ml of methanol into a reaction bottle, stirring uniformly, adding 3.0 mmol of corresponding acid, heating up, refluxing, stirring, reacting for 20 minutes, cooling to room temperature after the reaction is finished, evaporating the solvent under reduced pressure, and separating and purifying by a conventional method to obtain the salt of the phthaloyl cysteamine compound (I), wherein the chemical structure of the salt is obtained by1H NMR andESI-MS corroborates.

Claims (8)

1. A kind of phthaloyl cysteamine compound or its pharmacy acceptable salt, characterized by that the chemical structure general formula of this kind of compound is shown as (I):
Figure DEST_PATH_IMAGE001
in the formula: r represents- (CH)2)n-NR1R2Or
Figure DEST_PATH_IMAGE002
(ii) a n represents 1-5, R1Is represented by C1~C12An alkyl group; r2Represents benzyl or substituted benzyl; m represents 0-3, R3Is represented by C1~C12Alkyl, benzyl or substituted benzyl;
R4and R5Each independently represents H, OH, C1~C6Alkoxy, CN, halogen or NR6R7However, R4And R5Does not simultaneously represent H; r4And R5At any possible position on the phenyl ring; r6And R7Each independently representing H, C1~C6An alkyl group; when NR is6R7When cyclized, it represents a tetrahydropyrrolyl group or a piperidinyl group;
Figure DEST_PATH_IMAGE003
and also shows
Figure DEST_PATH_IMAGE004
Or
Figure DEST_PATH_IMAGE005
；
The compound is in R-configuration, S-configuration or a mixture of R-configuration and S-configuration in any proportion;
the term "halogen" as mentioned above means F, Cl, Br orI; "substituted benzyl" refers to benzyl groups on the phenyl ring substituted with 1 to 4 groups selected from: F. cl, Br, I, C1-4Alkyl radical, C1-4Alkoxy, NR8R9Trifluoromethyl, trifluoromethoxy, R8And R9Each independently represents C1~C12Alkyl, these substituents being in any possible position of the phenyl ring.
2. The compound of claim 1, wherein the pharmaceutically acceptable salt is a mixture of the 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 phthalimide compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-2, wherein the compound is obtainable by:
Figure DEST_PATH_IMAGE006
in the formula: r, R4And R5The definition of (A) is the same as the chemical structural general formula of the phthaloyl cysteine amide compound (I);
the corresponding phthaloyl cysteine compound (1) and the corresponding primary amine compound (2) are taken as initial raw materials, and the corresponding phthaloyl cysteine amide compound (I) can be prepared by condensation reaction in the presence of a solvent and a condensing agent; the phthaloyl cysteamine compound (I) obtained by the method contains amino in the molecule, the amino is alkaline, and the compound and any proper acid can be prepared into pharmaceutically acceptable salt by a pharmaceutically conventional salifying method.
4. The process for preparing a phthalimide compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the reaction is carried out using a solvent comprising: 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.
5. The process for preparing a phthalimide compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the condensing agent used in the reaction is: 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 or 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine chloride salt.
6. A process for the preparation of a phthalimide compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the 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 0-100 ℃; the condensation reaction time is 1-72 hours.
7. A pharmaceutical composition comprising a phthaloyl cysteamine compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
8. Use of a phthaloyl cysteamine compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating and/or preventing a nervous system related disease: 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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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115724786A (en) * 2021-09-01 2023-03-03 四川大学 Amide alkane dithiophthalimide compound, preparation method and application thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010219A1 (en) * 1995-09-11 1997-03-20 Fujisawa Pharmaceutical Co., Ltd. Benzimidazole derivatives and their use in the prevention and/or the treatment of bone diseases
WO2001022951A2 (en) * 1999-09-24 2001-04-05 Bayer Aktiengesellschaft Use of substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives for the treatment of multiple sclerosis
CN103524515A (en) * 2012-07-03 2014-01-22 浙江海正药业股份有限公司 Benzodioxide derivatives with acetylcholinesterase inhibitory activity and preparation method and use thereof
CN105777614A (en) * 2016-04-01 2016-07-20 南阳师范学院 Cyclamine alkylamide ferulate compound as well as preparation method and application thereof
CN105837497A (en) * 2016-04-01 2016-08-10 南阳师范学院 4-carbamate-3-methoxy cinnamic acid cyclamine alkyl amide compound, and preparation method and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997010219A1 (en) * 1995-09-11 1997-03-20 Fujisawa Pharmaceutical Co., Ltd. Benzimidazole derivatives and their use in the prevention and/or the treatment of bone diseases
WO2001022951A2 (en) * 1999-09-24 2001-04-05 Bayer Aktiengesellschaft Use of substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives for the treatment of multiple sclerosis
CN103524515A (en) * 2012-07-03 2014-01-22 浙江海正药业股份有限公司 Benzodioxide derivatives with acetylcholinesterase inhibitory activity and preparation method and use thereof
CN105777614A (en) * 2016-04-01 2016-07-20 南阳师范学院 Cyclamine alkylamide ferulate compound as well as preparation method and application thereof
CN105837497A (en) * 2016-04-01 2016-08-10 南阳师范学院 4-carbamate-3-methoxy cinnamic acid cyclamine alkyl amide compound, and preparation method and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HENG ZHANG,等: "Phthalimide‐(N‐alkylbenzylamine) cysteamide hybrids as multifunctional agents against Alzheimer\'s disease: Design, synthesis, and biological evaluation", CHEMICAL BIOLOGY & DRUG DESIGN, vol. 98, no. 04, pages 493 - 500 *
刘文虎;等: "多靶点药物及其研发", 药学进展, vol. 35, no. 02, pages 49 - 57 *
王祎明: "同型半胱氨酸与急性缺血性脑血管患者预后的相关性", 血栓与止血学, vol. 23, no. 01, pages 58 - 60 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115724786A (en) * 2021-09-01 2023-03-03 四川大学 Amide alkane dithiophthalimide compound, preparation method and application thereof
CN115724786B (en) * 2021-09-01 2024-01-30 四川大学 Amidedithiophthalimide compound, preparation method and application thereof

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