CN115724786A - Amide alkane dithiophthalimide compound, preparation method and application thereof - Google Patents
Amide alkane dithiophthalimide compound, preparation method and application thereof Download PDFInfo
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- CN115724786A CN115724786A CN202111022119.5A CN202111022119A CN115724786A CN 115724786 A CN115724786 A CN 115724786A CN 202111022119 A CN202111022119 A CN 202111022119A CN 115724786 A CN115724786 A CN 115724786A
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- Prior art keywords
- acid
- compound
- pharmaceutically acceptable
- acceptable salt
- amidoalkanedithiophthalimide
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Abstract
The invention discloses an amidoalkane dithiophthalimide 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 related diseases of the nervous system comprise but are not limited to vascular dementia, alzheimer disease, frontotemporal dementia, prion disease, lewy body dementia, parkinson disease, huntington's disease, HIV (human immunodeficiency Virus) related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, 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 an amidoalkane dithiophthalimide compound (I), 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 related diseases of the nervous system comprise vascular dementia, alzheimer disease, frontotemporal dementia, prion disease, lewy body dementia, parkinson disease, huntington's disease, HIV (human immunodeficiency Virus) related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, 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, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and the like are 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.
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. 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, 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 for the development of novel AD therapeutic drugs that have both improved AD 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, the research shows that the acetylcholine level in the brain of the patient is reduced,βOverproduction and deposition of amyloid, platelet aggregation in cerebral vessels, metabolic disorders of metal ions, ca 2+ Imbalance of balance,tauProtein hyperphosphorylationThe resulting neurofibrillary tangles, glutamate receptor hyperactivity, oxidative stress producing large amounts of Reactive Oxygen Species (ROS) and free radicals, and neuroinflammatory responses play a central role 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 neurodegenerative diseases, it is found that the occurrence and development of neurodegenerative diseases have the characteristics of multi-mechanism and multi-factor action, and different mechanisms are mutually associated and influenced, thereby forming a complex network regulation system in the occurrence and development process of the diseases. Obviously, the development of therapeutic drugs that can act simultaneously on multiple links in the pathological process of neurodegenerative diseases is the current necessity. Based on the above results, researchers have proposed a "multi-target-directed drug" 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 each single effect. 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. Therefore, the development of a neurodegenerative disease-resistant therapeutic drug having a novel chemical structure, a novel action mechanism, a multi-target action and low toxic and side effects is an important direction at present.
Disclosure of Invention
The invention aims to disclose an amidoalkane dithiophthalimide compound (I) and a pharmaceutically acceptable salt thereof.
The invention also aims to disclose a preparation method of the amidoalkane dithiophthalimide compound (I) and pharmaceutically acceptable salts thereof.
The invention also aims to disclose a pharmaceutical composition containing the amidoalkane dithiophthalimide compound (I) and pharmaceutically acceptable salts thereof.
The invention also aims to disclose that the amidoalkane dithiophthalimide compound (I) and the pharmaceutically acceptable salt thereof have multi-target effect and can be used for preparing the drugs for treating and/or preventing related diseases of the nervous system, including but not limited to vascular dementia, alzheimer disease, frontotemporal dementia, prion disease, lewy body dementia, parkinson disease, huntington disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, nerve injury caused by brain trauma and other diseases.
The chemical structural general formula of the amidoalkane dithiophthalimide compound (I) provided by the invention is as follows:
in the formula: m represents 1 to 5; n represents 1 to 5;
represents a natural or non-natural amino acid residue; r 2 And R 3 Each independently represents H, OH, SH, C 1 ~C 12 Alkyl radical, C 1 ~C 12 Alkoxy, CN, halogen, NR 4 R 5 Or C 1 ~C 12 An alkylthio group; r 4 And R 5 Each independently represent H, C 1 ~C 12 An alkyl group; NR (nitrogen to noise ratio) 4 R 5 Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r 2 And R 3 At any possible position on the phenyl ring; the term "natural or unnatural amino acid" refers to: glycine, L-or D-alanine, aminoisobutyric acid, gamma-aminobutyric acid, L-or D-valine, L-or D-proline, L-or D-lysine, L-or D-leucine, L-or D-Methionine, L-or D-serine, L-or D-O-benzylserine, L-or D-histidine, L-or D-tyrosine, L-or D-phenylglycine, L-or D-phenylalanine, L-or D-tryptophan, L-or D-aspartic acid, L-or D-glutamic acid; the "halogen" refers to F, cl, br or I.
The amidoalkane dithiophthalimide compound (I) provided by the invention can be prepared by the following method: taking a corresponding phthalimide alkyl thiol compound (1) as an initial raw material, reacting with 2,2-dithiodipyridine (2) in a solvent to obtain a phthalimide alkyl dithiopyridine compound (3), and then reacting with an amidoalkane thiol compound (4) to obtain a corresponding amidoalkane dithiophthalimide compound (I); the reaction formula is as follows:
in the formula:
、R 2 、R 3 m and n are defined as the chemical structural general formula of the amidoalkane dithiophthalimide compound (I).
For the above synthetic route, the specific preparation method is described as follows:
step A): the phthalimide alkyl thiol compound (1) reacts with 2,2-dithiodipyridine (2) in a solvent to obtain a phthalimide alkyl dithiopyridine compound (3); wherein the solvent used in the reaction is: c 1-8 Fatty alcohol, C 3-8 Aliphatic ketone, dichloromethane, chloroform,N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1,4-dioxane, ethylene glycol dimethyl ether or C 5-8 Alkanes, preferably solvents such as methanol, dichloromethane, 2-methyltetrahydrofuran, ethyl acetate, acetonitrile, toluene, or 1,4-dioxane; phthalimidyl alkyl thiol compound (1): 2,2-Dithiodipyridine (2) molar feedThe ratio is 1.0:1.0 to 10.0, and the preferable molar feed ratio is 1.0:1.0 to 5.0; the reaction temperature is 0 to 100 ℃, and the preferable reaction temperature is 20 to 80 ℃; the reaction time is 1 to 120 hours, preferably 2 to 72 hours.
Step B): reacting the phthalimide alkyl dithio pyridine compound (3) obtained in the step A) with an amidoalkane thiol compound (4) in a solvent to obtain a corresponding amidoalkane dithio phthalimide compound (I); wherein, the solvent used in the reaction is: c 1-8 Fatty alcohol, C 3-8 Aliphatic ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,4-dioxane, benzene, toluene, acetonitrile or C 5-8 Alkanes, preferred solvents are: chloroform, dichloromethane, acetone, acetonitrile, tetrahydrofuran or toluene; compound (3): the molar charge ratio of the compound (4) is 1.0:1.0 to 5.0, and the preferable molar feed ratio is 1.0:1.0 to 3.0; the reaction temperature is 0 to 80 ℃, and the preferable reaction temperature is room temperature to 60 ℃; the reaction time is 20 minutes to 48 hours, and the preferable reaction time is 1 to 24 hours.
The amidoalkanedithiophthalimide compound (I) obtained by the above method can be prepared into a pharmaceutically acceptable salt thereof by a conventional salt-forming method with any suitable acid: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C 1-6 Aliphatic 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, C 1-6 Alkyl 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, phthalimide alkyl mercaptan compounds (1) and amidoalkyl mercaptan compounds (4), may be prepared by techniques common 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、Fatome, Marc et al.European Journal of Medicinal Chemistry, 1988, 23(3), 257；3、Shair, Matthew D. et al.WO 2001057526。
The pharmaceutical composition disclosed by the invention comprises one or more amide alkane dithiophthalimide 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 amidoalkane dithiophthalimide compound (I) or the pharmaceutically acceptable salt thereof is taken as an active ingredient and accounts for 2-99.5 percent of the total weight.
The amidoalkane dithiophthalimide compound (I) and the pharmaceutically acceptable salt thereof disclosed by the invention are subjected to the following biological activity screening:
(1) Amidoalkane dithiophthalimide compounds (I) have inhibitory activity on acetylcholinesterase and butyrylcholinesterase
Adding 1.0 mmol/L thioacetylcholine 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, phosphate buffer solution of pH7.4 as homogenate medium) solution into 96-well plate, mixing, incubating at 37 deg.C for 15min, adding 5,5' -dithio-bis (2-nitrobenzoic acid) (DTNB) solution 0.2% into each well 30 μ L, developing, and measuring the color of each well at 405nm with enzyme-labeling instrumentOptical density (OD value), as compared with a blank well to which no sample to be tested was added, the inhibition rate of the compound to the enzyme (enzyme inhibition (%) = (1-sample group OD value/blank group OD value) × 100%) was calculated; 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 compound 50 . The determination result shows that the amidoalkane dithiophthalimide compound (I) disclosed in the embodiment of the invention has obvious inhibition effect on acetylcholinesterase and IC (integrated Circuit) of the compound 50 Is 0.02 mu M to 23.5 mu M. The determination result also shows that the inhibitory activity of the amidoalkane dithiophthalimide compound (I) on acetylcholinesterase is obviously higher than that of butyrylcholinesterase (the selectivity is more than 10 times). In addition, the measurement results also show that the IC of AChE inhibition by the clinically used rivastigmine 50 IC for butyrylcholinesterase inhibition at 16.5 μ M 50 Is 4.7 mu M; and phthalimide alkyl thiol compounds (1) and amidoalkane thiol compounds (4) used as raw materials for synthesizing amidoalkane dithiophthalimide compounds (I) have almost no inhibitory activity against acetylcholinesterase (acetylcholinesterase-inhibited IC) 50 Greater than 100 μ M).
(2) Antioxidant activity of amidoalkane dithiophthalimide compound (I) (ORAC-FL method)
Reference (Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331), namely: 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid(s) ((Trolox) 10-80. Mu. Mol/L of the buffer solution PBS pH7.4, 250 nmol/L of the buffer solution PBS pH7.4 for fluorescein (fluorescein), and 40 mmol/L of the buffer solution PBS pH7.4 for 2,2' -azobisisobutyramidine dihydrochloride (AAPH) before use. Adding 50-10 μmol/L compound solution and fluorescein solution into 96-well plate, mixing, incubating at 37 deg.C for 15min, adding AAPH solution to make total volume of 200 μ L per well, mixing, immediately placing in Varioskan Flash Multimode Reader (Thermo Scientific) instrument, exciting at 485 nmWavelength and 535 nm emission wavelength were measured continuously for 90 min. Calculating the area AUC under the fluorescence decay curve, wherein the AUC is 1-8 mu mol/LTroloxAs a standard, the result of the antioxidant activity of the compound is expressed asTroloxThe formula of the equivalent of (a) is: [ (AUC Sample-AUC blank)/(AUCTrolox-AUC blank)] ×[(concentration of Trolox/concentration of sample)]Each compound was assayed in 3 replicates each, each set of experiments was independently repeated three times. The determination result shows that the antioxidant activity of the amidoalkane dithiophthalimide compound (I) disclosed in the embodiment of the invention is 0.43-2.3 times of that of Trolox, which indicates that the compound has stronger antioxidant activity; as a result of the tests, it was also found that the starting materials used in the examples of the present invention, phthalimide alkyl thiol compounds (1) and amidoalkane thiol compounds (4), also had a certain antioxidant activity equivalent to that of the corresponding amidoalkane dithiophthalimide compounds (I); however, further studies on the structure-activity relationship found that the disulfide bond in the molecules of the amidoalkane dithiophthalimide compound (I) in the examples is replaced by-CH 2 CH 2 -substitution, under the condition that other substituents remain unchanged, the antioxidant activity of the obtained corresponding compound is obviously reduced, and the antioxidant activity of the obtained corresponding compound is reduced by at least 2-5 times; this study shows that disulfide bonds in the molecule are important to enhance the antioxidant activity of the compounds.
(3) Amidoalkane dithiophthalimide compounds (I) to Aβ 1-42 Inhibitory Activity of self-aggregation
Reference (Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331) by the method reported in the following: pretreated Aβ 1-42 Stock 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 2.5mM in DMSO, and 20. Mu.L of A was added to the stock solution before use, which was diluted with PBS (pH7.4)β 1-42 Solution + 20. Mu.L of test Compound solution, 20. Mu.L of Aβ 1-42 The solution + 20. Mu.L of PBS buffer (2% DMSO) was incubated in a 96-well plate at 37 ℃ for 24 hours,then 160. Mu.L of 50mM glycine-NaOH buffer (pH = 8.5) containing 5. Mu.M thioflavin T was added, and the fluorescence was measured immediately after shaking for 5 seconds with a multifunctional microplate reader at 446 nm excitation wavelength and 490nm emission wavelength; a. Theβ 1-42 + fluorescence value of test Compound recorded as IF i ，Aβ 1-42 The fluorescence value of + PBS buffer was designated as IF c The fluorescence value of the buffer solution containing only PBS was designated as IF 0 Compounds inhibiting Aβ 1-42 The inhibition rate of self-aggregation is: 100- (IF) i -IF 0 )/(IF c -IF 0 ) 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 amidoalkane dithiophthalimide compounds (I) disclosed in the embodiment of the invention are Aβ1-42 has obvious inhibition activity on self aggregation and is applied to A at the concentration of 20.0 mu Mβ1-42 self-aggregation inhibition rate is between 30.5% and 72.8%; and anti-AD drugs that are widely used clinically: donepezil, rivastigmine, memantine hydrochloride, and the starting materials used in the examples of the present invention, phthalimide alkyl thiol compound (1) and amidoalkyl thiol compound (4), were applied to A at a concentration of 25.0 μ Mβ1-42 have inhibition rate of self-aggregation less than 15.0%.
(4) Inhibitory Activity of Anirane Dithiophthalimide Compound (I) against neuroinflammation
(a) Effect of Compounds and Lipopolysaccharide (LPS) on BV-2 cell Activity
Preparing a cell suspension from logarithmic growth phase BV-2 cells, inoculating into a 96-well plate, placing at 37 deg.C, 5% 2 Culturing 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 at 37 ℃ and 5% CO 2 Continuously culturing in a cell culture box for 24h, adding MTT solution, incubating at 37 deg.C for 4h, discarding supernatant, adding 200 μ L DMSO solution into each well, slightly shaking for 10min, measuring OD at 490nm with enzyme-labeling instrument, and calculating different concentrations of each sampleThe OD values were averaged and the cell viability was calculated according to the following company: cell survival (%) = administration group OD mean/control group OD mean × 100%. The test results showed that all of the amidoalkanedithiophthalimide compounds (I), the phthalimidoalkylthiol compounds (1), the amidoalkanethiolate compounds (4), and LPS disclosed in the examples of the present invention did not exhibit cytotoxicity (inhibition rate less than that of less than 25. Mu.M) at a concentration of not more than 25. Mu.M<10%）。
(b) Effect of amidoalkane dithiophthalimide compound (I) on NO release of LPS-induced BV-2 cells
Preparing BV-2 cells in logarithmic growth phase into cell suspension, inoculating into 96-well plate, placing at 37 deg.C, and 5% CO 2 Culturing 24h in a cell culture box, changing to 90 μ L of fresh serum-free culture solution after cells adhere to the wall, respectively adding 10 μ L of each concentration compound to be tested, pre-incubating for 30 min, setting 3 parallel holes per concentration, and setting a blank control group; then LPS stimulation was added, 37 ℃ C., 5% CO 2 Continuously culturing 24h in the cell culture box, taking cell culture supernatants of different treatment groups, adding an equal volume of Griess reagent I and an equal volume of Griess reagent II, reacting for 10min at room temperature in a dark place, 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 a NO detection kit). Test results show that all the amidoalkane dithiophthalimide 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 25 mu M (the inhibition rate under the concentration of 5.0 mu M is over 28.0 percent), and have obvious dose-effect relationship; the amidoalkane dithiophthalimide compound (I) disclosed in the embodiment of the invention has remarkable anti-neuritis activity. It was also found that the starting material, amidoalkanethiol (4), used in the examples of the present invention also had significant anti-neuritic activity (inhibition of LPS-induced NO production by BV-2 cells at 5.0. Mu.M concentration was more than 30.0%).
(5) Amidoalkane dithiophthalimide compound (I) to NaNO 2 Resulting mouse study recordEffect of memory consolidation disorder
Sodium nitrite (NaNO) 2 ) Can oxidize hemoglobin in red blood cells to methemoglobin, and has high dosage of NaNO 2 Can remarkably reduce the content of reduced small molecules (GSH) and reductase systems (SOD, GPx and GR) in vivo, further cause lipid peroxidation and protein carbonylation to cause oxidative stress, so that NaNO 2 The induced mouse model is often used for in vivo activity screening of candidate drugs against oxidative stress.
SPF grade ICR mice, half male and female, with initial body weight of 18-22 g, were randomly divided into: normal group, model group, positive control group (donepezil hydrochloride), high, medium and low dosage group of the test drug, 10 of each group. Before the bench jump test, the corresponding compound is respectively administered to the mice of each group (2 times per day, 12 hours at intervals, and 4 days), the normal group and the mice of the model group are respectively administered with physiological saline with the same volume, and the high, medium and low dose groups of the tested drugs are respectively administered with corresponding physiological saline solution (25.0 mg/kg, 10.0 mg/kg, 4.0 mg/kg); placing the mouse in a diving platform instrument for adaptation for 3 minutes 1.0 hour after the second administration on the third day, then placing the mouse on a circular platform, training for 5 minutes by introducing 36V alternating current, and recording the time of the mouse jumping off the platform for the first time as a training latency; after training, mice in each group except the normal group were injected with NaNO subcutaneously 2 Physiological saline solution (90.0 mg/kg); and (3) 1 hour after the last administration of the drug in the next day, testing the mouse by using a jump platform instrument, recording the time of the mouse jumping off the platform for the first time as a testing latency period, and taking the number of times of electric shock of the platform jumping off within 5 minutes as the number of times of errors. And (3) after the behavioral test is finished, cutting the head of the mouse to take the brain, separating the cerebral cortex of the mouse on an ice layer, homogenizing according to the test requirement, and using the homogenized supernatant for measuring the content of Malondialdehyde (MDA) and SOD (superoxide dismutase) of the cerebral cortex of the mouse.
The test result shows that the tested amidoalkane dithiophthalimide compound (I) (the example compounds 1-2-4, 2-1-4, 2-2-4 and 3-1-4) has NaNO 2 The mice have dose-dependent improvement effect on learning and memory consolidation disorder (prolonging the latent period and reducing the error frequency), and have statistical difference compared with the model groupIso (A), (B)p<0.001 And the activity is obviously stronger than that of the clinically used donepezil hydrochloride (b) under the same dosagep<0.01 ); at the same time, the disulfide bond in the corresponding amidoalkane dithiophthalimide compound (I) is replaced by-CH 2 CH 2 Substitution, under conditions in which the other substituents remain unchanged, of the corresponding compound obtained towards NaNO 2 The activity of the compound for causing the mouse learning and memory consolidation disorder is equivalent to that of donepezil hydrochloride. In addition, the determination result also shows that the tested amidoalkane dithiophthalimide compound (I) can reduce the MDA content of the cerebral cortex of the mouse to different degrees under high, medium and low doses, improves the SOD activity, has dose dependence, and has the activity which is obviously higher than that of donepezil hydrochloride (I) under the same dosep<0.001 -CH for disulfide bond in molecule 2 CH 2 -the corresponding compound after substitution; therefore, the amidoalkane dithiophthalimide compound (I) disclosed in the embodiment of the invention can relieve the problem caused by NaNO 2 Induced central oxidative stress in mice.
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 phthalimidoalkyldithiophopyridines (3)
Adding 2.0 mmol of corresponding phthalimide alkyl thiol compounds (1), 4.0 mmol of 2,2-dithiodipyridine (2) and dichloromethane 20 ml into a reaction bottle, and stirring at room temperature for reaction for 4-32 hours (the reaction process is tracked by TLC); after the reaction is finished, the solvent is evaporated under reduced pressure, and the residue is separated and purified by silica gel column chromatography to obtain the corresponding phthalimide alkyl dithiopyridine compound (3), wherein the yield is 63.5-92.8 percent, and the chemical structures are all obtained by 1 H-NMR and ESI-MS.
EXAMPLE 2 general method for preparing amidoalkanedithiophthalimide Compound (I)
1.0 mmol of phthalimide alkyl dithiopyridine compound (3), 1.2 mmol of amidoalkyl thiol compound (4) and 25 ml prepared by the method of example 1 were added to a reaction flask in this order, and the mixture was stirred at room temperature for reaction for 2 to 24 hours (the progress of the reaction was followed by TLC); after the reaction is finished, the solvent is evaporated under reduced pressure, and the residue is separated and purified by silica gel column chromatography to obtain the corresponding amidoalkane dithiophthalimide compound (I), wherein the yield is 56.0-78.5 percent, and the chemical structures are all obtained by 1 H-NMR、 13 C-NMR and ESI-MS confirmation; the purities of the obtained target substances are more than 96.0 percent through HPLC. The target prepared by the method has the following structure:
EXAMPLE 3 general preparation of amidoalkane dithiophthalimide Compounds (I) by salt formation with acid
Adding 1.0 mmol of the amidoalkane dithiophthalimide compound (I) obtained in the example 2 and 25 ml of methanol into a reaction bottle, stirring uniformly, adding 2.5 mmol of corresponding acid, stirring at room temperature for reaction for 30 minutes, decompressing and evaporating to remove the solvent, and recrystallizing the residue to obtain the salt of the amidoalkane dithiophthalimide compound (I), wherein the chemical structure of the salt is shown in the specification 1 H NMR and ESI-MS.
Claims (10)
1. An amide alkyl dithiophthalimide compound or a pharmaceutically acceptable salt thereof is characterized in that the chemical structural general formula of the compound is shown as (I):
in the formula: m represents 1 to 5; n represents 1 to 5;
represents a natural or non-natural amino acid residue; r is 2 And R 3 Each independently represents H, OH, SH, C 1 ~C 12 Alkyl radical, C 1 ~C 12 Alkoxy, CN, halogen, NR 4 R 5 Or C 1 ~C 12 An alkylthio group; r 4 And R 5 Each independently represent H, C 1 ~C 12 An alkyl group; NR (nitrogen to noise ratio) 4 R 5 Also represents tetrahydropyrrolyl, morpholinyl or piperidinyl; r 2 And R 3 At any possible position on the phenyl ring; the term "natural or unnatural amino acid" refers to: glycine, L-or D-alanine, aminoisobutyric acid, gamma-aminobutyric acid, L-or D-valine, L-or D-proline, L-or D-lysine, L-or D-leucine, L-or D-methionine, L-or D-serine, L-or D-O-benzylserine, L-or D-histidine, L-or D-tyrosine, L-or D-phenylglycine, L-or D-phenylalanine, L-or D-tryptophan, L-or D-aspartic acid, L-or D-glutamic acid; the "halogen" refers to F, cl, br or I.
2. The amidoalkanedithiophthalimide compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of
Preferably a residue selected from L-alanine, L-valine, L-leucine or L-phenylalanine.
3. The amidoalkanedithiophthalimide compound or the pharmaceutically acceptable salt thereof of claim 1, wherein R is 2 And R 3 Preferably H, OCH 3 、OH、SCH 3 、F、Me 2 N or tetrahydropyrrole.
4. The amidoalkanedithiophthalimide compound or the pharmaceutically acceptable salt thereof of claim 1, wherein m is preferably 1 or 2,n is preferably 1, 2 or 3.
5. The amidoalkanedithiophthalimide compound or the pharmaceutically acceptable salt thereof of claims 1-4, wherein the pharmaceutically acceptable salt is the reaction of the amidoalkanedithiophthalimide compound with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C 1-6 Aliphatic carboxylic acid, trifluoroacetic acid, stearic acid, pamoic acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C 1-6 Salts of alkyl sulfonic acids, camphor sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, or 1,4-butane sulfonic acid.
6. A process for the preparation of an amidoalkanedithiophthalimide compound or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1 to 5, which comprises:
in the formula:
、R 2 、R 3 m and n are defined as the chemical structural general formula of the amidoalkane dithiophthalimide compound (I);
step A): reacting the corresponding phthalimide alkyl thiol compound (1) with 2,2-dithiodipyridine (2) in a solvent to obtain a phthalimide alkyl dithiopyridine compound (3);
step B): reacting the phthalimide alkyl dithio pyridine compound (3) obtained in the step A) with an amidoalkane thiol compound (4) to obtain a corresponding amidoalkane dithio phthalimide compound (I);
the amidoalkane dithiophthalimide compound (I) obtained by the method can be prepared into pharmaceutically acceptable salts by a conventional salt forming method with acid.
7. The process for producing an amidoalkanedithiophthalimide compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein in the step A), the solvent used in the reaction is: c 1-8 Fatty alcohol, C 3-8 Aliphatic ketone, dichloromethane, chloroform,N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, diethyl ether, benzene, toluene, acetonitrile, 1,4-dioxane, ethylene glycol dimethyl ether or C 5-8 An alkane; phthalimidyl alkyl thiol compound (1): 2,2-dithiodipyridine (2) molar feed ratio is 1.0:1.0 to 10.0; the reaction temperature is 0 to 100 ℃; the reaction time is 1 to 120 hours.
8. The process for producing an amidoalkanedithiophthalimide compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein in the step B), the solvent used in the reaction is: c 1-8 Fatty alcohol, C 3-8 Aliphatic ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,4-dioxane, benzene, toluene, acetonitrile or C 5-8 An alkane; compound (3): the molar charge ratio of the compound (4) is 1.0:1.0 to 5.0; the reaction temperature is 0 to 80 ℃; the reaction time is 20 minutes to 48 hours.
9. A pharmaceutical composition comprising an amidoalkanedithiophthalimide compound or a pharmaceutically acceptable salt thereof as claimed in any of claims 1 to 5, and one or more pharmaceutically acceptable carriers or excipients.
10. Use of an amidoalkanedithiophthalimide compound or a pharmaceutically acceptable salt thereof as claimed in any of claims 1 to 5 for the preparation of a medicament for the treatment and/or prevention of a nervous system-related disease which is: vascular dementia, alzheimer's disease, frontotemporal dementia, prion's disease, dementia with Lewy bodies, parkinson's disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage due to brain trauma.
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| CN107205994A (en) * | 2014-11-26 | 2017-09-26 | 克塔巴西斯制药有限公司 | Aliphatic acid cysteamine conjugate and their purposes as the activator of autophagy |
| CN109912448A (en) * | 2019-04-03 | 2019-06-21 | 四川大学 | A kind of benzamido group Flurbiprofen amides compound, preparation method and use |
| CN113185447A (en) * | 2021-05-06 | 2021-07-30 | 四川大学 | Phthaloyl cysteamine compound, preparation method and use thereof |
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| CN107205994A (en) * | 2014-11-26 | 2017-09-26 | 克塔巴西斯制药有限公司 | Aliphatic acid cysteamine conjugate and their purposes as the activator of autophagy |
| CN109912448A (en) * | 2019-04-03 | 2019-06-21 | 四川大学 | A kind of benzamido group Flurbiprofen amides compound, preparation method and use |
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