CN115724779B - Amide alkyl disulfide compound, preparation method and application thereof - Google Patents
Amide alkyl disulfide compound, preparation method and application thereof Download PDFInfo
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- CN115724779B CN115724779B CN202111022116.1A CN202111022116A CN115724779B CN 115724779 B CN115724779 B CN 115724779B CN 202111022116 A CN202111022116 A CN 202111022116A CN 115724779 B CN115724779 B CN 115724779B
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- acid
- compound
- pharmaceutically acceptable
- disease
- acceptable salt
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an amide alkane disulfide compound (I) and pharmaceutically acceptable salts thereof, a preparation method, a pharmaceutical composition and application thereof in preparing medicaments for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, alzheimer disease, frontotemporal dementia, prion 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, nerve injury caused by brain trauma and the like;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to an amide alkane disulfide compound (I) and pharmaceutically acceptable salts thereof, a preparation method and a pharmaceutical composition thereof, and application thereof in preparing medicaments for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, alzheimer's disease, frontotemporal dementia, prion 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, nerve injury caused by brain trauma and the like.
Background
Neurodegenerative diseases are the general names of diseases caused by chronic progressive degenerative changes of central nervous tissue, and include Alzheimer's Disease (AD), parkinson's Disease (PD), huntington's disease (Huntington disease, HD), amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis, ALS), multiple sclerosis (Multiple sclerosis, MS) and the like, and the pathogenesis thereof is closely related to oxidative stress, neuroinflammation and corresponding injury. Oxidative stress is mediated by reactive oxygen (Reactive oxygen species, ROS) radicals, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, among others. Under normal physiological conditions, ROS production levels are in a state of dynamic equilibrium with the organism's antioxidant capacity, and Oxidative stress (Oxidative stress) occurs when ROS production exceeds the cell's antioxidant capacity, whereas the brain is particularly sensitive to Oxidative stress, thereby inducing various neurological diseases. In addition, it has been found that vascular dementia, HIV-related dementia, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve injury caused by brain trauma are also closely related to oxidative stress and nerve inflammation of the body.
Vascular dementia (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 development of the disease exists at present, and clinical treatment is mainly performed to improve the blood circulation and the brain metabolism of the brain and strengthen the nutrition of the brain.
Alzheimer's Disease (AD) is a central nervous system degenerative disease mainly comprising progressive cognitive dysfunction and memory impairment, the incidence rate of which is in an increasing trend year by year,is a highly advanced disease next to cardiovascular disease and cancer. With the acceleration of the aging process of the global population, the incidence rate of the disease is obviously increased. It is estimated that over 5000 tens of thousands of people worldwide are currently suffering from dementia, and the total cost of treatment and care is over dollars 1 trillion in 2018, and the number of people suffering from dementia will increase to 1.52 billion by 2050. AD is clinically manifested by reduced memory, orientation, thinking and judgment, reduced daily life, even abnormal mental behavior symptoms, and the like, which makes patient care difficult and places a heavy burden on society and families. Drugs currently approved for the treatment of mild/moderate AD are acetylcholinesterase (AChE) inhibitors, as well as for the treatment of severe ADNMethyl-)D-an aspartate (NMDA) receptor antagonist. Clinical application shows that the medicines can relieve AD symptoms by improving the level of acetylcholine in patients or inhibiting the excitotoxicity of excitatory amino acids, but can not effectively prevent or reverse the course of the disease, and can also cause serious toxic and side effects such as illusion, consciousness chaos, dizziness, nausea, hepatotoxicity, inappetence, frequent stool and the like, so that the long-term curative effect is not ideal. Thus, there is a great clinical need to develop new therapeutic agents for AD that have both symptomatic improvement and altered course of disease.
The pathogenesis of AD is complex due to various factors, and the pathogenesis of AD is not completely elucidated yet. However, studies have shown that the level of acetylcholine in the brain of the patient is reduced,βExcessive production and deposition of amyloid, platelet aggregation in cerebral vessels, metal ion metabolism disorder, ca 2+ Dysbalance of,tauMany factors, such as neurofibrillary tangles, glutamate receptor hyperactivity, oxidative stress to produce large amounts of Reactive Oxygen Species (ROS) and free radicals, and neuroinflammatory reactions, caused by protein hyperphosphorylation play an important role in the pathogenesis of AD. For the above-mentioned pathogenesis, researchers have adopted the traditional "one drug one target" drug design strategy, and found a large number of drugs with high activity and high selectivity to a certain target, such as: cholinesterase inhibitorsNMethyl-)D-aspartate receptor antagonists and the like. However, the medicines have single action target point and more toxic and side effects in clinical useAnd poor long-term curative effect on AD patients.
In recent years, along with the continuous elucidation of the pathogenesis of neurodegenerative diseases, the occurrence and development of neurodegenerative diseases are found to have the characteristics of multi-mechanism and multi-factor actions, and the different mechanisms are mutually related and mutually influenced, so that a complex network regulation and control system in the occurrence and development process of the neurodegenerative diseases is formed. Obviously, the development of therapeutic drugs that can act simultaneously on multiple links in the pathological process of neurodegenerative diseases is a current necessary choice. Based on the above results, researchers have proposed a "multi-target targeted drug" strategy to develop anti-neurodegenerative disease drugs. By "multi-target drug" is meant a single chemical entity that acts on multiple targets in the disease network simultaneously, and the effects on each target can produce a synergistic effect such that the total effect is greater than the sum of the individual effects. The main differences of the multi-target medicine and multi-medicine combined application and the compound medicine are as follows: can reduce the dosage, improve the treatment effect, avoid the interaction between medicines and the toxic and side effect caused by the interaction, has uniform pharmacokinetic property, is convenient to use, and the like. Therefore, the development of the anti-neurodegenerative disease treatment drug with novel chemical structure, novel action mechanism, multi-target effect and low toxic and side effect is an important current direction.
Disclosure of Invention
The invention aims to disclose an amide alkane disulfide compound (I) and pharmaceutically acceptable salts thereof.
The invention also aims at disclosing a preparation method of the amid alkane disulfide compound (I) and pharmaceutically acceptable salts thereof.
It is a further object of the present invention to disclose pharmaceutical compositions comprising such amidedisulfur compounds (I) and pharmaceutically acceptable salts thereof.
It is still another object of the present invention to disclose the use of the amidedisulfur compounds (I) and pharmaceutically acceptable salts thereof for the preparation of a medicament 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 lateral sclerosis, neuropathic pain, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.
The chemical structural general formula of the amide alkyl disulfide compound (I) disclosed by the invention is as follows:
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-fluviographO-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 amide alkane disulfide compound (I) disclosed by the invention can be prepared by the following method:
taking a corresponding aminoalkyl disulfide compound (1) and an amino acid compound (2) with amino protected by Boc (tert-butyloxycarbonyl) as starting materials, and condensing under the condition of a proper solvent and a condensing agent to obtain a corresponding amide intermediate (3); then removing Boc protecting group under acidic condition to obtain corresponding amide alkyl disulfide compound (I); the reaction formula is as follows:
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 protected by Boc.
For the above synthetic route, the specific preparation method is described as follows:
step A): condensing an aminoalkyl disulfide compound (1) and an amino acid compound (2) with amino protected by Boc under the action of a proper solvent and a condensing agent to obtain a corresponding amide intermediate (3); wherein, the solvent used in the reaction is: pyridine (pyridine),N,N-dimethylformamide, dimethyl sulfoxide, 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 Alkanes, preferably solvents are: tetrahydrofuran, dichloromethane, chloroform or acetonitrile; the condensing agent is as follows: carbonyl Diimidazole (CDI), chloroformic acid C 1-8 Fatty alcohol ester compounds (such as ethyl chloroformate, tert-butyl chloroformate, benzyl chloroformate, etc.),Nethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), carbodiimides (e.g., dicyclohexylcarbodiimide (abbreviated as DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (abbreviated as EDCI)), diethyl cyanophosphate (DEPC), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (abbreviated as CDMT), chlorinated 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine salt (abbreviated as DMTMM), preferred condensing agents are: CDI, ethyl chloroformate, DCC, EDCI, DMTMM; 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, preferably a molar feed ratio of 1.0:2.2 to 6.0: 2.2-6.0; the condensation reaction temperature is 0-100 ℃, and the preferable reaction temperature is room temperature-60 ℃; the condensation reaction time is 1 to 72 hours, preferably 2 to 48 hours.
Step B): removing Boc protecting group from the amide intermediate (3) obtained in the step A) under acidic condition to obtain corresponding amide alkane disulfideAn object (I); wherein, the acid used in 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, preferably the acid is hydrochloric, trifluoroacetic, p-toluenesulfonic, methanesulfonic or ethanesulfonic acid; amide intermediate (3): the molar feed ratio of the acid is 1.0: 0.1-10.0, preferably a molar feed ratio of 1.0: 0.3-5.0, wherein the reaction temperature is 0-100 ℃, and the preferable reaction temperature is room temperature-60 ℃; the reaction time is 1 to 60 hours, preferably 2 to 48 hours.
The amidedisulfation compound (I) obtained according to the above method can be prepared into pharmaceutically acceptable salts thereof with any suitable acid by a pharmaceutically conventional salt-forming method, wherein the acid is: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid, C 1-6 Fatty 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 Alkylsulfonic acids (e.g., methylsulfonic acid, ethylsulfonic acid, etc.), camphorsulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 1, 4-butanesulfonic acid.
The disclosed pharmaceutical compositions comprise a therapeutically effective amount of one or more amidoalkanedisulfide compounds (I) or a pharmaceutically acceptable salt thereof, which may further comprise one or more pharmaceutically acceptable carriers or excipients. The "therapeutically effective amount" refers to the amount of a drug or agent that causes a biological or medical response to a tissue, system or animal targeted by a researcher or doctor; the term "composition" refers to a product formed by mixing more than one substance or component; the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or carrier, such as: liquid or solid fillers, diluents, excipients, solvents or encapsulating substances that carry or transport a chemical substance. The ideal proportion of the pharmaceutical composition provided by the invention is that the amidoalkanedisulfide compound (I) or the pharmaceutically acceptable salt thereof is used as an active ingredient to account for 2 to 99.5 percent of the total weight.
The disclosed amidoalkanedisulfide compound (I) and pharmaceutically acceptable salts thereof perform the following biological activity screening:
(1) Antioxidant Activity of the amidedisulfur Compound (I) (ORAC-FL method)
The determination was carried out by the method reported in the 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 (Trolox) was formulated as a 10-80. Mu. Mol/L solution with PBS buffer at pH7.4, fluorescein (fluoscein) was formulated as a 250 nmol/L solution with PBS buffer at pH7.4, and 2,2' -azobisisobutylamidine dihydrochloride (AAPH) was formulated as a 40 mmol/L solution with PBS buffer at pH7.4 prior to use. 50-10 mu mol/L of the compound solution and the fluorescein solution are added into a 96-well plate, uniformly mixed, incubated at 37 ℃ for 15min, AAPH solution is added to ensure that the total volume of each well is 200 mu L, uniformly mixed, immediately placed into a Varioskan Flash Multimode Reader (Thermo Scientific) instrument, and continuously measured for 90 min at 485 nm excitation wavelength and 535 nm emission wavelength. Calculating the area AUC under a fluorescence attenuation curve, wherein Trolox with 1-8 mu mol/L is used as a standard, a sample to be detected is not added as a blank, and the antioxidant activity result of the compound is expressed as the equivalent of Trolox, and the calculation formula is as follows: [ (AUC Sample-AUC blank)/(AUC Trolox-AUC blank)]×[(concentration of Trolox/concentration of sample)]Each compound was assayed 3 replicate wells at a time and each set of experiments was independently repeated three times. The measurement result shows that the antioxidant activity of the amidoalkane disulfide compound (I) disclosed in the embodiment of the invention is 0.56-2.0 times that of Trolox, which indicates that the compound has stronger antioxidant activity; the test results also found that the S atom in the amidedisulfur compound (I) in the examples was replaced with CH 2 Alternatively, the corresponding compounds obtained have little antioxidant activity (all of which have an antioxidant strength of less than 0.12 times that of Trolox).
(2) Amide Alkyldisulfide Compound (I) pair Aβ1-42 self-aggregation inhibitory Activity
Reference (Qiang, X.M. et al Eur. J Med. Che)m.2014, 76, 314-331), i.e.: pretreated Aβ1-42 were stock made up with DMSO and diluted to 50. Mu.M with PBS buffer pH7.4 prior to use; the test compound was prepared as a stock solution of 2.5. 2.5 mM in DMSO, diluted to the corresponding concentration in PBS buffer pH7.4 before use, and 20. Mu.L of A was takenβ1-42 solution+20. Mu.L of test compound solution, 20. Mu.L of Aβ1-42 solutions+20. Mu.L of PBS buffer (containing 2% DMSO) in 96-well plates, incubated at 37℃for 24h, then 160. Mu.L of 50mM glycine-NaOH buffer (pH=8.5) containing 5. Mu.M thioflavin T was added, and immediately after shaking for 5s, fluorescence values were determined with a multifunctional microplate reader at 446nm excitation wavelength and 490nm emission wavelength; a is thatβThe fluorescence value of the 1-42+ test compound is recorded as IF i ,AβThe fluorescence value of 1-42+PBS buffer is shown as IFc, and the fluorescence value of PBS buffer alone is shown as IF 0 Compounds inhibit AβThe inhibition rate of the self aggregation of 1-42 is as follows: 100- (IF) i -IF 0 )/(IFc-IF 0 ) 100; selecting five to six concentrations of the compound and determining the inhibition thereof; each concentration of each compound was repeated three times with curcumin as positive control. The measurement results show that the amidoalkanedisulfide compound (I) disclosed in the examples of the present invention has a molecular structure corresponding to that of Aβ1-42 self-aggregation has obvious inhibition activity on A at 20.0 mu M concentrationβ1-42 self aggregation inhibition rate is 28.5% -62.0%; and the anti-AD drugs widely used clinically: donepezil, rivastigmine, memantine hydrochloride, and the starting amine alkyl disulfide compound (1) used for the reaction of a at a concentration of 20.0 μmβ1-42 each have an inhibition rate of aggregation of less than 16.0%; the test results also found that the S atom in the amidedisulfur compound (I) in the examples was replaced with CH 2 Alternatively, the corresponding compound pair A is obtainedβThe inhibition rate of 1-42 self-aggregation is obviously reduced (the inhibition rate is less than 20%).
(3) Inhibitory Activity of Amidoalkanedisulfide Compound (I) on neuroinflammation
(a) Effect of Compounds and Lipopolysaccharide (LPS) on BV-2 cell Activity
Inoculating BV-2 cells in logarithmic growth phase into 96-well plate, and placing at 37deg.C and 5% CO 2 Culturing in a cell culture box for 24 hours, changing into 90 mu L of fresh culture solution without serum after cells are attached, respectively adding 10 mu L of each concentration of compound to be tested, pre-incubating for 30 min, setting 3 parallel holes of each concentration, and setting a blank control group; then, with or without LPS, the mixture is placed at 37 ℃ and 5% CO 2 Culturing in a cell culture incubator for 24 hours, adding MTT solution, incubating at 37 ℃ for 4 hours, discarding supernatant, adding 200 mu LDMSO solution into each hole, slightly oscillating for 10 minutes, measuring OD value at 490nm by using an enzyme-labeling instrument, calculating the average value of the OD values measured at different concentrations of each sample, and calculating the cell survival rate according to the following companies: cell viability (%) = mean OD of dosing group/mean OD of control group x 100%. The test results show that all of the amidoalkanedisulfide compounds (I) and the starting material (1) used in the examples of the present invention show no cytotoxicity at a concentration of not more than 30. Mu.M (inhibition ratio is smaller than<10%)。
(b) Effect of the amid alkyl thiol ketal Compounds (I) on LPS-induced BV-2 cell Release of NO
Inoculating BV-2 cells in logarithmic growth phase into 96-well plate, and placing at 37deg.C and 5% CO 2 Culturing 24-h in a cell culture box, changing into 90 mu L of fresh culture solution without serum after cells are attached, adding 10 mu L of each concentration of compound to be tested, pre-incubating for 30 min, setting 3 parallel holes of each concentration, and setting a blank control group; then LPS is added for stimulation, and the mixture is placed at 37 ℃ and 5 percent CO 2 The cell culture was continued in a cell incubator for 24. 24h, the cell culture supernatants from the different treatment groups were taken, an equal volume of Griess reagent I and an equal volume of Griess reagent II were added, reacted at room temperature in the dark for 10min, and absorbance was measured at 540. 540 nm to detect the NO level in the cell supernatant (specific procedure was performed according to the NO detection kit instructions). The test results show that all the amidoalkanedisulfide compounds (I) disclosed in the embodiment of the invention have strong inhibition effect on LPS-induced BV-2 cell NO generation (inhibition rate at the concentration of 5.0 mu M exceeds 30.0%) in the concentration range of 0.5 mu M to 25 mu M, and have obvious dose-effect relationship, so that the amidoalkanedisulfide compounds (I) disclosed in the embodiment of the invention have remarkable anti-neuroinflammation activity. Research also shows that the inventionThe starting material, aminoalkyldisulphide compound (1), used in the examples also has a remarkable anti-neuroinflammatory activity (inhibition of LPS-induced NO production by BV-2 cells at a concentration of 5.0. Mu.M is all greater than 16.0%).
(4) Amide Alkyldisulphide Compound (I) versus NaNO 2 Influence of the learning and memory consolidation disorder in mice
Sodium nitrite (NaNO) 2 ) Can oxidize hemoglobin in red blood cells into methemoglobin, and has high dosage of NaNO 2 Can significantly reduce in vivo reduced small molecule (GSH) and reductase system (SOD, GPx, GR), thereby causing lipid peroxidation and protein carbonylation, resulting in oxidative stress, thus NaNO 2 The induced mouse model is often used for in vivo activity screening of antioxidant stress drug candidates.
SPF grade ICR mice, male and female halves, had an initial body weight of 18-22 g and were randomly divided into: normal group, model group, positive control group (donepezil hydrochloride), high, medium and low dose groups of the tested drug, 10 in each group. Before the bench jump test, the corresponding compound is respectively administered to each group of mice (2 times a day, an interval of 12 hours lasts for 4 days), normal group mice and model group mice 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 solutions (25.0 mg/kg, 10.0 mg/kg and 4.0 mg/kg); 1.0 hour after the second administration on the third day, placing the mice on a diving tower instrument for adaptation for 3 minutes, then placing the mice on a round platform, training for 5 minutes by supplying 36V alternating current, and recording the time of the mice for jumping off the platform for the first time as a training latency period; naNO was subcutaneously injected into mice of each group except the normal group after training 2 Physiological saline solution (90.0 mg/kg); the mice were tested again 1 hour after the last dose of the next day with a diving tower instrument, and the time the mice were first lifted off the platform was recorded as the test latency and the number of times the platform was shocked within 5 minutes as the number of errors. After the behavioural test is finished, the mouse is broken off to take out brain, the mouse cerebral cortex is separated on the ice layer, then homogenate is carried out according to the test requirement, and the homogenate supernatant is used for measuring the content of Malondialdehyde (MDA) and SOD in the mouse cerebral cortex.
The measurement results show that the tested amidoalkanedisulfide compound (I) (example compounds 2-4, 2-16, 2-18) has high, medium and low dosages on NaNO 2 The mice caused by the study and memory consolidation disorder have the effects of improving (prolonging the latency period and reducing the error frequency), and have statistical differences compared with the model groupp<0.001 And the activity is obviously higher than that of the corresponding aminoalkyl disulfide compound (1) at the same dosagep<0.001 Is also stronger than the clinic drug donepezil hydrochloride under the same dosagep<0.01). In addition, the measurement result also shows that the tested amidoalkyl disulfide compound (I) can reduce MDA content of the cerebral cortex of the mice to different degrees at high, medium and low doses, and improve SOD activity, has dose dependency, and has the effect which is obviously higher than that of the corresponding amidoalkyl disulfide compound (1) at the same dosep<0.001 A) is provided; thus, the amidedisulfur compounds (I) disclosed in the examples of the present invention can alleviate NaNO 2 The 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. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.
EXAMPLE 1 general preparation of amide intermediate (3)
2.0 mmol of the aminoalkyl disulfide compound (1), 5.0 mmol of the amino acid compound (2) with the corresponding amino group protected by Boc and 30 ml methylene dichloride are sequentially added into a reaction bottle, 5.0 mmol of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 5.0 mmol of triethylamine are added after the mixture is stirred uniformly at room temperature, and the reaction is continued to be carried out at room temperature for 4-40 hours (the reaction progress is tracked by TLC). After the reaction was completed, the solvent was distilled off under reduced pressure, 70 mL methylene chloride was added to the residue, followed by 30 mL deionized water, 30 mL saturated Na 2 CO 3 Washing with water solution and 30 mL saturated NaCl water solution, drying the organic layer with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and collecting residue as amide intermediate(3) Can be used in the next reaction without purification.
EXAMPLE 2 preparation of amidedisulfur Compound (I)
The amide intermediate (3) (about 2.0 mmol) obtained in example 1 was dissolved in 30 ml dichloromethane, 6.0 mmol of trifluoroacetic acid was added thereto under cooling, and the reaction was stirred at room temperature for 3 to 20.0 hours (the progress of the reaction was followed by TLC); after the reaction was completed, 50 mL deionized water was added and saturated Na was used 2 CO 3 The pH of the reaction solution was adjusted to be alkaline by the aqueous solution, the mixture was extracted with 100 mL dichloromethane three times, the organic layer was combined, washed with saturated aqueous sodium chloride solution, and dried over anhydrous Na 2 SO 4 Drying, filtering, evaporating solvent under reduced pressure, purifying the residue by silica gel column chromatography (eluent: dichloromethane/methanol=15-30/1 v/v) to obtain corresponding target product (total yield of two steps: 50.3% -84.8%), and subjecting the structure to chromatography 1 H-NMR、 13 C-NMR and ESI-MS confirm that the purity of the compound is more than 97.0% by HPLC; the structure of the target object prepared by the general method is as follows:
。
EXAMPLE 3 salt formation of the amidedisulfur Compound (I) with an acid
1.0 mmol of the amidedithio compound (I) obtained in example 2 and 35. 35 ml of methanol were charged into a reaction vessel, stirred uniformly, then 3.0 mmol of the corresponding acid was added, stirred at room temperature for 20 minutes, and then distilled under reduced pressureRemoving solvent, recrystallizing residue to obtain salt of amidoalkanedisulfide compound, and its chemical structure 1 H NMR and ESI-MS corroborations.
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.
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