CN115724779B - Amidoalkyl disulfide compounds, preparation methods and uses thereof - Google Patents

Abstract

The invention discloses a class of amidoalkyl disulfide compounds (I) and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions and uses in preparing drugs for the treatment and/or prevention of nervous system-related diseases, including but not Limited to vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, Diseases such as neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma; .

Description

Amidoalkyl disulfide compounds, preparation methods and uses thereof

Technical field

The invention belongs to the field of medicinal chemistry and relates to a class of amidoalkyl disulfide compounds (I) and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions and uses in preparing drugs for the treatment and/or prevention of nervous system-related diseases. , including but not limited to 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 side effects Diseases such as thoracic sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.

Background technique

Neurodegenerative diseases refer to a general term for diseases caused by chronic progressive degeneration of central nervous system tissues, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Their pathogenesis is closely related to oxidative stress, neuroinflammation and corresponding damage. Oxidative stress is mediated by reactive oxygen species (ROS) free radicals, including superoxide anions, hydrogen peroxide and hydroxyl free radicals. Under normal physiological conditions, the level of ROS generation is in a dynamic equilibrium with the body’s antioxidant capacity. When the generation of ROS exceeds the antioxidant capacity of cells, oxidative stress will occur. The brain is particularly sensitive to oxidative stress, which can induce a variety of neurological diseases. Other studies have found that vascular dementia, HIV-related dementia, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma are also closely related to the body's oxidative stress and neuroinflammation.

Vascular Dementia (VD) is a disorder of intelligence and cognition caused by various types of cerebrovascular diseases (including ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, acute and chronic hypoxic cerebrovascular disease, etc.) Clinical syndrome of cognitive dysfunction. Due to the complex pathogenesis of vascular dementia, there are currently no drugs that can block the progression of the disease. Clinical treatment focuses on improving brain blood circulation, brain metabolism, and enhancing brain nutrition.

Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive impairment and memory impairment. Its incidence rate is increasing year by year, becoming second only to cardiovascular disease and High incidence of cancer. With the acceleration of the aging of the global population, its incidence rate has shown a significant upward trend. It is estimated that more than 50 million people worldwide are currently suffering from dementia, and the total cost of treatment and care exceeded US$1 trillion in 2018. The number of patients will increase to 152 million by 2050. Because the clinical manifestations of AD include decreased memory ability, orientation ability, thinking and judgment abilities, as well as reduced daily living abilities, and even abnormal mental and behavioral symptoms, it makes patient care more difficult and places a heavy burden on society and families. Drugs currently approved for the treatment of mild/moderate AD include acetylcholinesterase (AChE) inhibitors and N -methyl- D -aspartate (NMDA) receptor antagonists for the treatment of severe AD. However, clinical use shows that these drugs can alleviate AD symptoms by increasing acetylcholine levels in patients or inhibiting the excitotoxicity of excitatory amino acids, but they cannot effectively prevent or reverse the course of the disease, and can also cause hallucinations, confusion, dizziness, nausea, and liver toxicity. , loss of appetite and frequent bowel movements and other serious side effects, so the long-term efficacy is not ideal. Therefore, there is an urgent clinical need to develop new AD therapeutic drugs that can improve AD symptoms and change the course of the disease.

AD is a disease caused by multiple factors, and its pathogenesis is complex, and its pathogenesis has not yet been fully elucidated. However, studies have shown that decreased acetylcholine levels in the brain of patients, excessive production and deposition of β -amyloid protein, platelet aggregation in cerebral blood vessels, disordered metal ion metabolism, disordered Ca ²⁺ balance, and neurological disorders caused by excessive phosphorylation of tau -protein. Various factors such as fibrous tangles, excessive glutamate receptor activity, oxidative stress producing large amounts of reactive oxygen species (ROS) and free radicals, and neuroinflammatory responses play an important role in the pathogenesis of AD. In response to the above-mentioned pathogenic factors, researchers adopted the traditional "one drug, one target" drug design strategy and discovered a large number of drugs with high activity and high selectivity for a certain target, such as: cholinesterase inhibitors and N -methyl - D -aspartate receptor antagonists, etc. However, these drugs have problems such as single target, many toxic and side effects in clinical use, and poor long-term efficacy in AD patients.

In recent years, with the continuous elucidation of the pathogenesis of neurodegenerative diseases, it has been found that the occurrence and development of neurodegenerative diseases are characterized by multi-mechanisms and multi-factors, and different mechanisms are interrelated and influence each other, forming this type of disease. Complex network regulatory systems in the occurrence and development of diseases. Obviously, the development of therapeutic drugs that can act on multiple links in the pathological process of neurodegenerative diseases at the same time is an inevitable choice at present. Based on the above results, the researchers proposed a "multi-target-directed drug" strategy to develop drugs against neurodegenerative diseases. The so-called "multi-target drug" refers to a single chemical entity that acts on multiple targets in the disease network at the same time, and can produce a synergistic effect on each target, making the total effect greater than the sum of the individual effects. The main difference between multi-target drugs, multi-drug combinations and compound drugs is that they can reduce the dosage of drugs, improve the therapeutic effect, avoid interactions between drugs and the resulting toxic and side effects, and have uniform pharmacokinetic properties. Ease of use etc. Therefore, it is currently an important direction to develop anti-neurodegenerative disease therapeutic drugs with new chemical structures, new mechanisms of action, multi-target effects, and low toxic and side effects.

Contents of the invention

The object of the present invention is to disclose a class of amidoalkyl disulfide compounds (I) and pharmaceutically acceptable salts thereof.

Another object of the present invention is to disclose the preparation method of this type of amide alkyl disulfide compound (I) and its pharmaceutically acceptable salt.

Another object of the present invention is to disclose pharmaceutical compositions containing such amidoalkane disulfide compounds (I) and pharmaceutically acceptable salts thereof.

Another object of the present invention is to disclose that the amidoalkyl disulfide compounds (I) and their pharmaceutically acceptable salts have multi-target effects and can be used in the preparation of drugs for the treatment and/or prevention of nervous system-related diseases, including but not limited to: Not limited to vascular dementia, Alzheimer's disease, frontotemporal dementia, Prion's disease, Lewy body dementia, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis , neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma and other diseases.

The general chemical structure formula of the amidoalkyl disulfide compound (I) disclosed in the present invention is:

In the formula:

Represents natural or unnatural amino acid residues; n represents 2-5; the "natural or unnatural amino acid" refers to: L- or D-alanine, aminoisobutyric acid, γ-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-α-glutamic acid, L-or D-γ-glutamic acid; but when n represents 2 or 3, /> Does not indicate L- or D-alanine residues.

The amidoalkyl disulfide compound (I) disclosed in the present invention can be prepared by the following method:

The corresponding aminoalkyl disulfide compound (1) and the amino acid compound (2) whose amino group is protected by Boc (tert-butyloxycarbonyl) are used as starting materials, and condensation is carried out under appropriate solvent and condensation agent conditions to obtain the corresponding amide intermediate (3); then the Boc protecting group is removed under acidic conditions to obtain the corresponding amide alkane disulfide compound (I); the reaction formula is as follows:

In the formula: the definitions of R and n are the same as the general chemical structure of the amidoalkyl disulfide compound (I); R ₁ represents the substituent in which the amino group in R is protected by Boc.

For the above synthetic route, its specific preparation method is described as follows:

Step A): The amine alkyl disulfide compound (1) and the amino acid compound (2) whose amino group is protected by Boc are condensed under the action of an appropriate solvent and a condensing agent to obtain the corresponding amide intermediate (3); wherein, the reaction The solvents are: pyridine, N,N -dimethylformamide, dimethyl sulfoxide, C _3-8 fatty ketone, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 , 4-dioxane, ethylene glycol dimethyl ether, esters formed by C _1-6 fatty acids and C _1-6 fatty alcohols, methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, Acetonitrile or C _5-8 alkane, the preferred solvent is: tetrahydrofuran, dichloromethane, chloroform or acetonitrile; the condensation agent used is: carbonyldiimidazole (CDI), chloroformic acid C _1-8 fatty alcohol ester compounds (such as: chlorine Ethyl formate, tert-butyl chloroformate, benzyl chloroformate, etc.), N -ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), carbodiimide compounds (such as: Dicyclohexylcarbodiimide (referred to as DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (referred to as EDCI)), diethyl cyanophosphate (referred to as DEPC), 2-chloro-4,6-dimethoxy-1,3,5-triazine (abbreviated as CDMT), 4-(4,6-dimethoxy-1,3,5-chloride) Triazin-2-yl)-4-methylmorpholine salt (abbreviated as DMTMM), the preferred condensation agent is: CDI, ethyl chloroformate, DCC, EDCI, DMTMM; compound (1): compound (2): condensation The molar feeding ratio of the mixture is 1.0:2.0~8.0:2.0~8.0, and the preferred molar feeding ratio is 1.0:2.2~6.0:2.2~6.0; the condensation reaction temperature is 0~100°C, and the preferred reaction temperature is room temperature~60°C; condensation The reaction time is 1 to 72 hours, and the preferred reaction time is 2 to 48 hours.

Step B): The amide intermediate (3) obtained in step A) is removed from the Boc protecting group under acidic conditions to obtain the corresponding amide alkane disulfide compound (I); wherein, the acid used in the reaction is: hydrochloric acid, sulfuric acid, benzene Sulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, C _1-6 alkylsulfonic acid, phosphoric acid, perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or nitric acid, the preferred acid is hydrochloric acid, trifluoroacetic acid, p-toluene Sulfonic acid, methane sulfonic acid or ethane sulfonic acid; amide intermediate (3): the molar feeding ratio of acid is 1.0:0.1~10.0, the preferred molar feeding ratio is 1.0:0.3~5.0, the reaction temperature is 0~100℃ , the preferred reaction temperature is room temperature to 60°C; the reaction time is 1 to 60 hours, and the preferred reaction time is 2 to 48 hours.

The amidane disulfide compound (I) obtained according to the above method can be prepared into a pharmaceutically acceptable salt by a conventional pharmaceutical salt-forming method with any suitable acid. The acid is: hydrochloric acid, hydrobromic acid, Nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C _1-6 fatty carboxylic acid (such as formic acid, acetic acid, propionic acid, etc.), trifluoroacetic acid, stearic acid, parapeptic acid, oxalic acid, benzoic acid, phenylacetic acid, water Cylic 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 acid ( Such as: methylsulfonic acid, ethylsulfonic acid, etc.), camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 1,4-butanedisulfonic acid.

The pharmaceutical composition disclosed in the present invention includes a therapeutically effective amount of one or more amidane disulfide compounds (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may further contain one or more pharmaceutically acceptable salts. Acceptable carrier or excipient. The "therapeutically effective amount" refers to the amount of a drug or agent that causes a biological or medical response to the tissue, system or animal targeted by the researcher or physician; the "composition" refers to the amount of a drug or agent that is produced by combining more than one substance or composition The “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substance, composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or capsule. Substances that carry or transport certain chemicals. The ideal proportion of the pharmaceutical composition provided by the present invention is that the amidane disulfide compound (I) or its pharmaceutically acceptable salt as the active ingredient accounts for 2% to 99.5% of the total weight.

The amidoalkyl disulfide compound (I) and its pharmaceutically acceptable salt disclosed in the present invention have been screened for biological activity as follows:

(1) Antioxidant activity of amidoalkane disulfide compounds (I) (ORAC-FL method)

Determine according to the method reported in the literature (Qiang, XM et al. Eur. J Med. Chem. 2014, 76, 314-331), namely: 6-hydroxy-2,5,7,8-tetramethylchromane -2-Carboxylic acid (Trolox) is made into a 10-80 μmol/L solution with PBS buffer at pH 7.4, and fluorescein is made into a 250 nmol/L solution with PBS buffer at pH 7.4, 2 , 2'-Azobisisobutylamidine dihydrochloride (AAPH) is prepared into a 40 mmol/L solution with PBS buffer at pH 7.4 before use. Add 50-10 μmol/L compound solution and fluorescein solution to the 96-well plate, mix well, and incubate at 37°C for 15 minutes. Add AAPH solution to make the total volume of each well 200 μL, mix well, and immediately place it in the Varioskan Flash MultimodeReader (Thermo Scientific) instrument, continuous measurement at 485 nm excitation wavelength and 535 nm emission wavelength for 90 min. Calculate the area under the fluorescence decay curve AUC, with 1-8 μmol/L Trolox as the standard and no sample to be tested as the blank. The antioxidant activity result of the compound is expressed as the equivalent of Trolox. The calculation formula is: [(AUC Sample-AUC blank)/(AUC Trolox-AUC blank)]×[(concentration of Trolox/concentrationof sample)], each compound was measured in 3 replicate wells, and each set of experiments was repeated three times independently. The measurement results show that the antioxidant activity of the amide alkyl disulfide compound (I) disclosed in the embodiments of the present invention is 0.56 to 2.0 times that of Trolox, indicating that this type of compound has strong antioxidant activity; the test results also found that the implementation The S atom in the amidane disulfide compound (I) in the example is replaced with _CH2 , and the corresponding compound has almost no antioxidant activity (its antioxidant strength is less than 0.12 times that of Trolox).

(2) Inhibitory activity of amidoalkane disulfide compounds (I) against Aβ1-42 self-aggregation

The determination was carried out according to the method reported in the literature (Qiang, Dilute to 50 μM with PBS buffer of pH 7.4 before use; prepare the compound to be tested into a 2.5 mM stock solution with DMSO. Dilute to the corresponding concentration with PBS buffer of pH 7.4 before use. Take 20 μL of A β 1-42 solution + 20 μL of the compound solution to be tested, 20 μL of A β 1-42 solution + 20 μL of PBS buffer (containing 2% DMSO) were placed in a 96-well plate and incubated at 37°C for 24 h, then 160 μL of 50 mM thioflavin T containing 5 μM was added. Glycine-NaOH buffer (pH=8.5), shake for 5 seconds and immediately use a multifunctional microplate reader to measure the fluorescence value at an excitation wavelength of 446 nm and an emission wavelength of 490 nm; the fluorescence value of A β 1-42 + the compound to be tested is recorded as IF _i , the fluorescence value of Aβ1-42 +PBS buffer is recorded as IFc, the fluorescence value of only PBS buffer is recorded as _IF0 , the inhibition rate of compound inhibiting Aβ1-42 self-aggregation: 100-(IF _i -IF ₀ )/(IFc-IF ₀ )*100; select five to six concentrations of the compound and determine its inhibition rate; repeat the test three times for each concentration of each compound, using curcumin as a positive control. The measurement results show that the amidoalkane disulfide compound (I) disclosed in the embodiments of the present invention has significant inhibitory activity on the self-aggregation of Aβ1-42 , and the inhibition rate on the self-aggregation of Aβ1-42 at a concentration of 20.0 µM Between 28.5% and 62.0%; and anti-AD drugs widely used in clinical practice: donepezil, rivastigmine, memantine hydrochloride, and the starting raw material amine alkyl disulfide compound (1) at a concentration of 20.0 µM. The inhibition rate of β 1-42 self-aggregation was less than 16.0%; the test results also found that the S atom in the amidane disulfide compound (I) in the embodiment was replaced with CH ₂ , and the corresponding compound obtained had an inhibitory effect on A β 1-42 The inhibition rates of self-aggregation were significantly reduced (the inhibition rates were less than 20%).

(3) Inhibitory activity of amidane disulfide compound (I) on neuroinflammation

(a) Effects of compounds and lipopolysaccharide (LPS) on BV-2 cell activity

Take BV-2 cells in the logarithmic growth phase and prepare a cell suspension and inoculate them in a 96-well plate. Place them in a 37°C, 5% CO ₂ cell incubator and culture them for 24 hours. After the cells have adhered, replace them with 90 μL of fresh serum-free culture medium. Add 10 μL of the compound to be tested at each concentration and pre-incubate for 30 min. There are 3 parallel wells for each concentration, and a blank control group is set up. Then, LPS is added or not, and cultured in a 37°C, 5% CO ₂ cell incubator for 24 hours. Add MTT solution and incubate at 37°C for 4 hours. Discard the supernatant. Add 200 μL DMSO solution to each well. After shaking slightly for 10 minutes, measure the OD value at 490 nm with a microplate reader. Calculate the OD value measured at different concentrations of each test sample. The mean value, and calculate the cell survival rate according to the following company: cell survival rate (%) = mean OD value of the treatment group/mean OD value of the control group × 100%. The test results show that all the amide alkyl disulfide compounds (I) disclosed in the examples of the present invention and the starting material used - the amine alkyl disulfide compound (1) did not show cytotoxicity at a concentration of no more than 30 μM ( The inhibition rate is less than <10%).

(b) Effect of amidoalkylthiol ketals (I) on LPS-induced NO release from BV-2 cells

Take the BV-2 cells in the logarithmic growth phase and prepare a cell suspension and inoculate them in a 96-well plate. Place them in a 37°C, 5% CO ₂ cell incubator and culture them for 24 hours. After the cells adhere, they are replaced with fresh culture medium without serum for 90 hours. μL, add 10 μL of the compound to be tested at each concentration and pre-incubate for 30 min, 3 parallel wells for each concentration, and set a blank control group; then add LPS for stimulation, and continue culturing for 24 h in a 37°C, 5% CO ₂ cell incubator , take the cell culture supernatant of different treatment groups, add an equal volume of Griess reagent I and an equal volume of Griess reagent II, react at room temperature for 10 minutes in the dark, and measure the absorbance at 540 nm to detect the NO level in the cell supernatant (specific The operation is carried out according to the instructions of the NO detection kit). The test results show that all amidane disulfide compounds (I) disclosed in the embodiments of the present invention show strong inhibition of LPS-induced NO production in BV-2 cells in the concentration range of 0.5 μM to 25 μM (at 5.0 The inhibition rates at μM concentrations exceeded 30.0%) and had an obvious dose-effect relationship, indicating that the amidoalkane disulfide compound (I) disclosed in the embodiments of the present invention has significant anti-neuroinflammatory activity. The study also found that the starting material - amine alkyl disulfide compound (1) used in the embodiments of the present invention also has significant anti-neuroinflammatory activity (the inhibition rate of NO production in LPS-induced BV-2 cells at a concentration of 5.0 μM was both more than 16.0%).

(4) Effects of amidane disulfide compound (I) on learning and memory consolidation impairment in mice caused by NaNO ₂

Sodium nitrite (NaNO ₂ ) can oxidize hemoglobin in red blood cells into methemoglobin, and high doses of NaNO ₂ can significantly reduce the content of reducing small molecules (GSH) and reductase systems (SOD, GPx, GR) in the body. This in turn causes lipid peroxidation and protein carbonylation, leading to oxidative stress. Therefore, NaNO2 _- induced mouse models are often used for in vivo activity screening of candidate anti-oxidative stress drugs.

SPF grade ICR mice, half male and half female, with an initial weight of 18-22 grams, were randomly divided into: normal group, model group, positive control group (donepezil hydrochloride), and test drug high, medium and low dose groups, with 10 mice in each group. Before the platform test, the mice in each group were given the corresponding compounds (twice a day, with an interval of 12 hours, for 4 days). The mice in the normal group and the model group were given the same volume of normal saline. The mice in the high, medium and low dose groups of the test drug were The corresponding drug physiological saline solution (25.0 mg/kg, 10.0 mg/kg, 4.0 mg/kg) was administered respectively; 1.0 hours after the second administration on the third day, the mice were placed on the jumping platform to adapt for 3 minutes, and then again Place it on a circular platform and train with 36V alternating current for 5 minutes. Record the time when the mice jump off the platform for the first time as the training latency period. After training, mice in each group except the normal group were subcutaneously injected with NaNO ₂ physiological saline solution ( 90.0 mg/kg); 1 hour after the last dose the next day, the mice were tested using a jumping platform, and the time when the mice jumped off the platform for the first time was recorded as the test latency, and the time when the mice jumped off the platform within 5 minutes was The number of electric shocks was taken as the number of errors. After the behavioral test, the mice were decapitated and their brains were removed, and the cerebral cortex of the mice was separated on ice, and then homogenized according to the test requirements. The supernatant of the homogenate was used for malondialdehyde (MDA) and SOD content determination.

The measurement results show that the tested amidane disulfide compound (I) (Example Compounds 2-4, 2-16, 2-18) can effectively inhibit _NaNO2- induced learning and memory consolidation impairment in mice at high, medium and low doses. It has an improvement effect (prolonging the incubation period and reducing the number of errors), and has statistical differences compared with the model group ( p <0.001), and its activity is significantly higher than the corresponding amine alkyl disulfide compound (1) at the same dose ( p <0.001 ), which is also stronger than the clinical drug donepezil hydrochloride at the same dose ( p <0.01). In addition, the measurement results also show that the tested amidane disulfide compound (I) can reduce the MDA content of the mouse cerebral cortex to varying degrees and increase the SOD activity in a dose-dependent manner at high, medium and low doses. Its effect is also significantly higher than that of the corresponding amine alkyl disulfide compound (1) at the same dose ( p <0.001); therefore, the amide alkyl disulfide compound (I) disclosed in the embodiments of the present invention can alleviate the symptoms caused by NaNO ₂ Central oxidative stress in mice.

Detailed ways

The present invention can be further described through 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 can be made to the present invention without departing from the spirit and scope of the invention.

Example 1 General method for preparing amide intermediate (3)

Add 2.0 mmol amine alkyl disulfide compound (1), 5.0 mmol corresponding amino acid compound with Boc-protected amino acid compound (2) and 30 ml dichloromethane in sequence to the reaction bottle. Stir evenly at room temperature and then add 1-ethyl- Add 5.0 mmol of 3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 5.0 mmol of triethylamine and continue stirring at room temperature for 4 to 40 hours (the reaction progress is followed by TLC). After the reaction, the solvent was evaporated under reduced pressure, 70 mL of dichloromethane was added to the residue, and washed with 30 mL of deionized water, 30 mL of saturated Na ₂ CO ₃ aqueous solution, and 30 mL of saturated NaCl aqueous solution, and the organic layer was washed with anhydrous sulfuric acid. After drying over sodium, it is filtered, and the solvent is evaporated under reduced pressure. The residue is the amide intermediate (3), which can be used in the next reaction without purification.

Example 2 General method for the preparation of amidane disulfide compound (I)

Dissolve the amide intermediate (3) (approximately 2.0 mmol) obtained in Example 1 in 30 ml of methylene chloride, add 6.0 mmol of trifluoroacetic acid under cooling, stir and react at room temperature for 3 to 20.0 hours (the reaction progress is tracked by TLC) After the reaction, add 50 mL deionized water, adjust the pH of the reaction solution to alkaline with saturated Na ₂ CO ₃ aqueous solution, extract it three times with 100 mL dichloromethane, combine the organic layers and wash with saturated sodium chloride aqueous solution. Dry anhydrous Na ₂ SO ₄ and then filter. The solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol = 15~30/1 v/v) to obtain the corresponding target. compound (total yield in two steps: 50.3% to 84.8%), its structure was confirmed by ¹ H-NMR, ¹³ C-NMR and ESI-MS, and the purity of the compound was greater than 97.0% as determined by HPLC; it was prepared by the above general method The target structure is as follows:

.

Example 3 General preparation method of salt formation between amidane disulfide compound (I) and acid

1.0 mmol of the amidoalkane disulfide compound (I) obtained in Example 2 and 35 ml of methanol were added to a reaction flask. After stirring evenly, 3.0 mmol of the corresponding acid was added. After stirring at room temperature for 20 minutes, the solvent was evaporated under reduced pressure. The residue was recrystallized to obtain a salt of the amidoalkane disulfide compound. Its chemical structure was confirmed by ¹ H NMR and ESI-MS.

Claims (8)

1. An amidedisulfur compound or pharmaceutically acceptable salt thereof, which is characterized in that the chemical structural general formula of the compound is shown as (I):

wherein:

represents a natural or unnatural amino acid residue; n represents 2 to 5; the term "natural or unnatural amino acid" refers to: 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-benzyl serine, 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-alpha-glutamic acid, L-or D-gamma-glutamic acid; but when n represents 2 or 3, < >>Does not represent an L-or D-alanine residue; the above amide alkanedisulfide compound (I) does not include the following:

2. an amidedisulfur compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinResidues selected from the group consisting of L-alanine, L-valine, L-tyrosine, L-phenylalanine, and L-gamma-glutamic acid.

3. An amidedisulfur compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a mixture of such amidedisulfur compound with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C _1-6 Fatty 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 alkylsulfonic acid, camphorsulfonic acid, naphthalene sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or 1, 4-butanesulfonic acid.

4. A process for the preparation of an amidedisulfation compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein said compound is obtainable by the following process:

wherein: r and n are defined as the same as the chemical structural general formula of the amidoalkanedisulfide compound (I); r is R ₁ Represents a substituent of the amino group in R after being protected by Boc;

step A): condensing the corresponding aminoalkyl disulfide compound (1) and amino acid compound (2) with amino protected by Boc under the conditions of solvent and condensing agent to obtain corresponding amide intermediate (3);

step B): removing Boc protecting groups from the amide intermediate (3) obtained in the step A) under an acidic condition to obtain a corresponding amide alkane disulfide compound (I);

the amide alkanedisulfide compound (I) obtained according to the above-mentioned method is then subjected to conventional salt formation with an acid to obtain a pharmaceutically acceptable salt thereof.

5. The process for preparing an amidedisulfide compound or a pharmaceutically acceptable salt thereof as claimed in claim 4, wherein in the step A), the solvent used for the reaction is: pyridine, N-dimethylformamide, dimethyl sulfoxide and C _3-8 Aliphatic ketone, diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether and C _1-6 Fatty acid and C _1-6 Esters of fatty alcohols, dichloromethane, chloroform, 1, 2-dichloroethane, benzene, toluene, acetonitrile or C _5-8 An alkane; the condensing agent is as follows: carbonyl diimidazole, chloroformic acid C _1-8 Fatty alcohol ester compounds, N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, carbodiimide compounds, 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 feed ratio of the condensing agent is 1.0:2.0 to 8.0:2.0 to 8.0; the condensation reaction temperature is 0-100 ℃; the condensation reaction time is 1-72 hours.

6. The process for the preparation of an amidedisulfide compound or a pharmaceutically acceptable salt thereof as claimed in claim 4, wherein in the step B), the acid used for the reaction is: hydrochloric acid, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, C _1-6 Alkyl sulfonic, phosphoric, perchloric, trifluoroacetic, trifluoromethanesulfonic or nitric acids; amide intermediate (3): the molar feed ratio of the acid is 1.0:0.1 to 10.0, and the reaction temperature is 0 to 100 ℃; the reaction time is 1 to 60 hours.

7. A pharmaceutical composition comprising an amidedisulfation compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

8. Use of an amidedisulfur compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 in the manufacture of a medicament for the treatment and/or prevention of neurological related disorders: vascular dementia, alzheimer's disease, frontotemporal dementia, prion's disease, dementia with Lewy bodies, parkinson's disease, huntington's disease, HIV-associated dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.