CN113185447B - Phthaloyl cysteamine compound, preparation method and application thereof - Google Patents
Phthaloyl cysteamine compound, preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a phthaloyl cysteamine compound (I) and pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition and a preparation method thereofThe application of the medicine for treating and/or preventing nervous system related diseases comprises, but is not limited to vascular dementia, alzheimer's disease, parkinson's disease, huntington's disease, HIV-related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic cerebral apoplexy, hemorrhagic cerebral apoplexy, nerve damage caused by brain trauma and the like;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a phthaloyl cysteamine 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, parkinson disease, huntington disease, HIV related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic cerebral apoplexy, hemorrhagic cerebral apoplexy, nerve injury caused by cerebral 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, vascular dementia, HIV-associated dementia, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, and nerve injury caused by brain trauma have been found to be closely related to oxidative stress and neuroinflammation 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. Recent studies have shown that VD patients exhibit impairment of cognitive function, often accompanied by abnormalities in the cholinergic system. The density of the hippocampal ChAT positive neurons and fibers of the VD patient is reduced, the ChAT activity of different parts in the brain is reduced, the concentration of acetylcholine in cerebrospinal fluid of the VD patient is obviously lower than the normal level, and the degree of the reduction of the concentration is positively related to the severity of dementia; cerebral ischemia can lead to increased activity of acetylcholinesterase in the brain; meanwhile, some acetylcholinesterase inhibitors are found to be capable of protecting neuron injury caused by ischemia and promoting nerve injury and recovery of brain function after cerebral ischemia.
Alzheimer's Disease (AD) is a central nervous system degenerative disease mainly composed of progressive cognitive disorder and memory impairment, and the incidence of which is in an increasing trend year by year, becoming a high-incidence 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 use has shown that these drugs can alleviate AD symptoms by increasing acetylcholine levels or inhibiting excitotoxicity of excitatory amino acids in patients, but notCan effectively prevent or reverse the course of 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 the problems of single action target point, more toxic and side effects in clinical use, poor long-term curative effect on AD patients and the like.
In recent years, along with the continuous elucidation of the pathogenesis of AD, the occurrence and development of AD are found to have the characteristics of multi-mechanism and multi-factor effect, and the different mechanisms are mutually related and influenced, so that a complex network regulation and control system in the occurrence and development process of AD is formed. Based on the above results, researchers have proposed a "multi-target drug" strategy to develop anti-neurodegenerative disease drugs. The expression "multi-target drug" refers to a compound in which a single chemical entity can act on multiple targets closely related to treatment in a network of the disease, and the actions on the targets can produce a synergistic effect so that the total effect is greater than the sum of the single effects, and the compound is also called as a "multi-functional" or "multi-potential" drug. The main differences of the multi-target medicine and multi-medicine combined application and the compound medicine are as follows: can reduce dosage, improve therapeutic effect, and avoid interaction between medicinesThe toxic and side effects brought by the method, uniform pharmacokinetic properties, convenient use and the like. Therefore, research and development of anti-neurodegenerative disease therapeutic drugs with novel chemical structures, novel action mechanisms, multi-target actions and low toxic and side effects are currently important directions. A large number of clinical studies have demonstrated that AChE inhibitors are effective in alleviating the symptoms of dementia patients and have a positive short-term therapeutic effect; therefore, it is generally necessary to preserve the AChE inhibitory activity of the compound (inhibiting the enzyme is critical for improving symptoms of dementia patients) and add one or more other targets or functions with pharmacological synergism on the basis of the AChE inhibitory activity to achieve the multi-target anti-dementia therapeutic effect when designing multi-target anti-dementia drugs. Obviously, the design and the discovery have the functions of inhibiting acetylcholinesterase and inhibiting acetylcholinesteraseβThe excessive generation and deposition of amyloid, antioxidant stress, metal ion complexation and anti-neuroinflammation multi-target anti-dementia drugs may break through the treatment of related dementia.
Disclosure of Invention
The invention aims to disclose a phthaloyl cysteamine compound (I) and pharmaceutically acceptable salts thereof;
the invention also aims to disclose a preparation method of the phthaloyl cysteamine compound (I) and pharmaceutically acceptable salts thereof;
it is a further object of the present invention to disclose pharmaceutical compositions comprising such phthaloyl cysteamides (I) and pharmaceutically acceptable salts thereof;
it is still another object of the present invention to disclose that the phthaloyl cysteamine compound (I) and pharmaceutically acceptable salts thereof have multi-target effect, and can be used for preparing medicines for treating and/or preventing nervous system related diseases, including but not limited to vascular dementia, alzheimer's disease, parkinson's disease, huntington's disease, HIV related dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.
The chemical structural general formula of the phthaloyl cysteamine compound (I) disclosed by the invention is as follows:
wherein: r represents- (CH) 2 )n-NR 1 R 2 Or (b)The method comprises the steps of carrying out a first treatment on the surface of the n represents 1-5, R 1 Represent C 1 ~C 12 An alkyl group; r is R 2 Represents benzyl or substituted benzyl; m represents 0 to 3, R 3 Represent C 1 ~C 12 Alkyl, benzyl or substituted benzyl;
R 4 and R is 5 Each independently represents H, OH, C 1 ~C 6 Alkoxy, CN, halogen or NR 6 R 7 But R is 4 And R is 5 Not simultaneously representing H; r is R 4 And R is 5 Any possible position on its benzene ring; r is R 6 And R is 7 Each independently represents H, C 1 ~C 6 An alkyl group; when NR is 6 R 7 When ring-formed, it represents tetrahydropyrrolyl or piperidinyl;
also indicate->Or->；
The compound is in R configuration, S configuration or any ratio mixture of R and S configuration;
the term "halogen" refers to F, cl, br or I; "substituted benzyl" refers to a benzyl group substituted on the phenyl ring with 1 to 4 groups selected from the group consisting of: F. cl, br, I, C 1-4 Alkyl, C 1-4 Alkoxy, NR 8 R 9 Trifluoromethyl, trifluoromethoxy, R 8 And R is 9 Each independently ofFloor representation C 1 ~C 12 Alkyl groups, these substituents being in any of the possible positions of the phenyl ring.
The phthaloyl cysteamine compound (I) provided by the invention can be prepared by the following method:
the corresponding phthaloyl cysteamine compound (I) is prepared by taking the corresponding phthaloyl cysteamine compound (1) and the corresponding primary amine compound (2) as starting materials and carrying out condensation reaction under the existence of a proper solvent and a condensing agent, wherein the reaction formula is as follows:
wherein: r, R 4 And R is 5 The definition of the compound is the same as the chemical structural general formula of the phthaloyl cysteamine compound (I);
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 (THF),N,N-dimethylformamide, 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: carbonyl Diimidazole (CDI) and chloroformic acidEthyl ester, dicyclohexylcarbodiimide (DCC), EDCI, DMTMM; compound (1): compound (2): the molar feed ratio of the condensing agent is 1.0:1.0 to 10.0: 1.0-10.0, preferably a molar feed ratio of 1.0:2.0 to 5.0:2.0 to 5.0; the condensation reaction temperature is 0-100 ℃, and the preferable reaction temperature is room temperature-60 ℃; the condensation reaction time is 1 to 72 hours, preferably 2 to 48 hours.
The phthaloyl cysteamine compound (I) obtained according to the above method can be prepared into pharmaceutically acceptable salts thereof with any suitable acid by a pharmaceutically conventional salifying 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 starting materials of the present invention, phthalylcysteine compound (1) and the corresponding primary amine compound (2), can be prepared using techniques existing or common in the art, including, but not limited to, the methods disclosed in the following documents: 1. simona Sestino. et al.European Journal of Medicinal Chemistry2019, 184, 111745；2、Q. Liu, et al. Bioorganic & Medicinal Chemistry, 23 (2015) 911-923。
The disclosed pharmaceutical compositions comprise a therapeutically effective amount of one or more phthaloyl cysteamine compounds (I) or pharmaceutically acceptable salts 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 phthaloyl cysteamine compound (I) or pharmaceutically acceptable salt thereof is taken as an active ingredient to account for 2 to 99.5 percent of the total weight.
The phthaloyl cysteamide compound (I) and pharmaceutically acceptable salt thereof disclosed by the invention are subjected to the following biological activity screening:
(1) Inhibition activity of phthaloyl cysteamide compound (I) on acetylcholinesterase and butyrylcholinesterase
Adding 30 mu L of 1.0mmol/L of thioacetylcholine iodide or thiobutyrylcholine iodide, 40 mu L of PBS buffer with pH7.4, 20 mu L of compound solution to be tested (DMSO content is less than 1%) and 10 mu L of acetylcholinesterase (rat brain cortex 5% homogenized supernatant, phosphate buffer with pH7.4 is taken as homogenized medium) or butyrylcholinesterase (rat serum 25% supernatant, pH7.4 phosphate buffer is taken as homogenized medium) sequentially into a 96-well plate, incubating for 15min at 37 ℃ after adding, adding 30 mu L of 5,5' -dithio-bis (2-nitrobenzoic acid) (DTNB) solution into each well, developing color, measuring the optical density (OD value) of each well at 405nm by an enzyme marker, and calculating the inhibition rate of the compound to enzyme (enzyme inhibition rate (%) = (1-sample group OD value/blank group OD value) ×100%); selecting five to six concentrations of the compound, measuring the enzyme inhibition rate, and obtaining the molar concentration of the compound which is the IC of the compound when the 50% inhibition rate is obtained by linear regression of the negative logarithm of the molar concentration of the compound and the inhibition rate of the enzyme 50 . The measurement result shows that the phthaloyl cysteamine compound (I) disclosed in the embodiment of the invention has obvious inhibition effect on acetylcholinesterase and IC thereof 50 25.0nM to 15.0 [ mu ] M (for example, 1.55 [ mu ] M for example, 4.52 [ mu ] M for example, 1-2-19, 5.40 [ mu ] M for example, 4.52 [ mu ] M for example, 1-2-11, and 8.45 [ mu ] M for example), and found that the chiral configuration of the compound (I) had no significant effect on the inhibitory activity of acetylcholinesteraseAnd is known. Further structure-activity relationship research shows that the phthaloyl cysteamine compound (I) is used for preparing HSCH in the molecule 2 The fragment is replaced by H, and when other substituents are kept unchanged, the obtained phthaloyl glycinamide compound still has inhibitory activity on acetylcholinesterase, and the activity is not obviously different; indicating that in this class of compound molecules "mercaptomethyl (HSCH) 2 The (-) "fragment does not inhibit the acetylcholinesterase pharmacophore. In the molecule of the phthaloyl cysteamine compound (I), when R 1 And R is 2 At the same time represent C 1 ~C 12 Alkyl, IC for inhibiting acetylcholinesterase obtained by the compound when other substituents are kept unchanged 50 Are all larger than 80 mu M. The measurement result also shows that the inhibition activity of the phthaloyl cysteamide compound (I) on acetylcholinesterase is obviously higher than that of the butyrylcholinesterase (the selectivity is more than 50 times greater), which indicates that the compound disclosed by the invention has a selective inhibition effect on acetylcholinesterase, and the toxicity of the compound on a peripheral system is smaller. In addition, the measurement results also show that the clinically used rivastigmine inhibits the AChE IC 50 IC for butyrylcholinesterase inhibition at 15.5. Mu.M 50 3.8 mu M; in addition, the phthaloyl cysteine compound (1) and the corresponding primary amine compound (2) used in the embodiment of the invention have weak inhibitory activity on acetylcholinesterase (IC for inhibiting acetylcholinesterase) 50 Are all greater than 100 μm).
(2) Antioxidant Activity of the phthaloyl cysteamides (I) (ORAC-FL method)
Reference (Qiang, X.M).et al.Eur. J Med. Chem.2014, 76, 314-331), i.e.: 6-hydroxy-2, 5,7, 8-tetramethylchromane-2-carboxylic acidTrolox) 10-80. Mu. Mol/L of the solution was prepared with PBS buffer pH7.4, 250 nmol/L of fluorescein (fluoroscein) was prepared with PBS buffer pH7.4, and 40 mmol/L of 2,2' -azobisisobutylamidine dihydrochloride (AAPH) was prepared with PBS buffer pH7.4 before use. 50-10. Mu. Mol/L of the compound solution and fluorescence were added to a 96-well plateThe plain solution was mixed well, incubated at 37℃for 15min, AAPH solution was added to make the total volume per well 200. Mu.L, mixed well, immediately placed in Varioskan Flash Multimode Reader instrument and measured continuously for 90 min at 485 nm excitation wavelength and 535 nm emission wavelength. Calculate the area under the fluorescence decay curve AUC, wherein the area under the fluorescence decay curve AUC is 1-8 mu mol/LTroloxAs a standard, the antioxidant activity of the compound was expressed asTroloxThe equivalent weight of (2) is calculated as: [ (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 phthaloyl cysteamine compound (I) disclosed in the embodiment of the invention isTroloxThe compound has stronger antioxidant activity as shown by 0.5 to 3.0 times. Analysis of structure-activity relationship shows that the chiral configuration of the compound has little effect on the antioxidant activity; but will phthaloyl cysteamine compound (I) in the molecule of "HSCH 2 The segment is replaced by H, and when other substituents are kept unchanged, the antioxidant activity of the obtained phthaloyl glycinamide compound is obviously reduced, and the antioxidant activity is reduced by at least 3-10 times; the results indicate that "mercaptomethyl" in the molecule (HSCH 2 The (-) "fragment is important for enhancing the antioxidant activity of the compound.
(3) Determination of complexation of phthaloyl cysteamine compound (I) with metal ions
Dissolving CuCl with methanol 2 ·2H 2 O、ZnCl 2 、FeSO 4 ·7H 2 O、AlCl 3 And the compound to be tested is prepared into a 75 mu mol/L solution, 100 mu L of the compound to be tested and 100 mu L of the metal ion solution are added into a 96-well plate, uniformly mixed, kept stand at room temperature for 30 min, an ultraviolet absorption curve of the mixture in the range of 200-600 nm is recorded on a Varioskan Flash Multimode Reader instrument, and 100 mu L of the compound to be tested and 100 mu L of the methanol mixed solution are used as a reference to observe the red shift phenomenon of the maximum absorption peak and the intensity of the maximum absorption peak of the metal ion and the compound to be tested mixed solution. The measurement result shows that the inventionThe phthaloyl cysteamides (I) disclosed in the examples all exhibit a specific activity on Cu 2+ 、Fe 2+ Selective complexation; while "HSCH" in the molecule 2 The "fragment" is replaced by "H", and the resulting phthaloyl glycinamide compound has no complexation to all the four metal ions, while the other substituents remain unchanged.
(4) Inhibitory Activity of phthaloyl cysteamine 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 the phthaloyl cysteamine compounds (I) and LPS disclosed in the examples of the present invention do not show cytotoxicity at a concentration of not more than 25. Mu.M (inhibition rate is less than<5%）。
(b) Effect of phthaloyl cysteamide-based Compounds (I) on LPS-induced release of NO by BV-2 cells
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 box is continuously cultivated for 24h, and the cell is not taken outEqual volumes of Griess reagent I and Griess reagent II were added to the cell culture supernatants of the same treatment group, reacted at room temperature in the dark for 10min, and absorbance was measured at 540 nm to detect NO levels in the cell supernatants (specific procedures were performed according to NO detection kit instructions). Test results show that all the phthaloyl cysteamine compounds (I) disclosed in the embodiment of the invention show strong inhibition effect on LPS-induced NO generation of BV-2 cells in the concentration range of 0.5 mu M to 20 mu M (the inhibition rate at the concentration of 5.0 mu M is more than 35.0%), and have obvious dose-effect relationship; and their inhibitory activity is higher than that of the control compound at the same concentration (molecular "HSCH" in the molecule 2 The fragment is replaced by H, and the inhibition rate of other substituents is obviously enhanced (the inhibition rate of the control compound at the concentration of 5.0 mu M is less than 15.0%), so that the phthaloyl cysteamine compound (I) disclosed in the embodiment of the invention has obvious anti-neuroinflammation activity.
(5) Effect of phthaloyl cysteamide compound (I) on mouse memory acquisition disorder caused by scopolamine
SPF grade ICR male mice, 25-30g, were randomly divided into: normal group, model group, positive control group, and high-low dose group (15.0 mg/kg, 2.5 mg/kg) of test agent, 10 animals per group. The tested medicine is administrated by one-time gastric lavage, and the administration volume of the blank group and the model group is 0.1ml/10g; 45 min after administration, normal mice were intraperitoneally injected with physiological saline, and the other animals were each injected with scopolamine (3.0 mg/kg) at a volume of 0.1ml/10g; after molding for 30 min, mice were placed into a non-electrically stimulated Y maze for behavioral testing. During the test, the mice are placed at the tail end of one arm, allowed to freely pass through the maze for 8 minutes, the times of entering each arm and the alternation times are recorded, and the alternation rate is calculated according to the following formula: alternation ratio% = [ alternation number/(total entry number-2)]X 100, results are expressed as mean ± standard deviation, and the differences between groups are analyzed by one-way variance analysis. The measurement results show that under the experimental conditions, the phthaloyl cysteamine compound (I) (examples 1-2-19, 1-2-1 and 1-2-11) tested is a compound of the formula (I)The scopolamine induced mouse acquired memory disorder has the dose-dependent improving effect, and compared with a model group, the scopolamine induced mouse acquired memory disorder has statistical differencep<0.001 And the activity is obviously higher than that of the clinical medicine rivastigmine at the same molar concentrationp<0.01）。
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. 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 phthaloyl cysteamine-based Compound (I)
2.0 mmol of phthaloyl cysteine compound (1), 2.6 mmol of corresponding primary amine compound (2) and 15 ml tetrahydrofuran are sequentially added into a reaction bottle, 3.0 mmol of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4.0 mmol of triethylamine are added after the mixture is stirred uniformly at room temperature, and the mixture is stirred at room temperature for reaction for 6-36 hours (the reaction progress is tracked by TLC). After the reaction, the solvent was distilled off under reduced pressure, 40 mL dichloromethane was added to the residue, followed by 20 mL deionized water, 20 mL saturated NaHCO 3 Washing the organic layer with water solution and 20 mL saturated NaCl water solution, drying the organic layer with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, purifying the residue by silica gel column chromatography (eluent: dichloromethane: methanol=5-20:1 v/v) to obtain the corresponding phthaloyl cysteamide compound (I), the yield is 45.3-82.5%, and the chemical structure is the same as that of the phthaloyl cysteamide compound (I) 1 H-NMR、 13 C-NMR and ESI-MS corroboration; the purity of the obtained target is greater than 96.0% as determined by HPLC. The following target substances are obtained by adopting the general method:
(1) When R represents- (CH) 2 )n-NR 1 R 2 The target compound had the following structure:
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(2) When R representsThe structure of the target compound is as follows:
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NMR data for some compounds were as follows:
1 H NMR (CDCl 3 ): 7.71 (brs, 1H), 7.32-7.29 (m, 3H), 7.28 (s, 2H), 7.17 (d, J = 6.8 Hz, 2H), 4.77 (dd, J = 5.2 Hz, 10.4 Hz, 1H), 3.96 (s, 6H), 3.44-3.27 (m, 6H), 2.49-2.43 (m, 2H), 2.08 (s, 3H), 1.69 (t, J = 6.0 Hz, 2H); 13 C NMR (CDCl 3 ):168.0, 167.3, 154.1, 137.2, 129.1, 128.4, 127.4, 125.0, 105.4, 62.4, 56.7, 56.6, 55.4, 41.5, 39.5, 24. 9, 23.8;
1 H NMR (CDCl 3 ): 7.32-7.25 (m, 7H), 6.44 (brs, 1H), 4.75 (dd, J = 5.6, 10.4 Hz, 1H,), 3.98 (s, 6H), 3.63 (s, 2H), 3.45-3.20 (m, 4H), 2.57-2.49 (m, 4H), 1.55-1.43 (m, 2H), 1.05 (t, 3H, J = 6.8 Hz);
1 H NMR (CDCl 3 ): 8.11 (brs, 1H), 7.28 (d, J = 6.8 Hz, 1H), 7.22 (s, 2H), 7.15 (d, J = 6.8 Hz, 1H), 6.90 (t, J = 6.8 Hz, 2H), 4.75 (dd, J = 5.2, 10.4 Hz, 1H), 3.97 (s, 6H), 3.82 (s, 3H), 3.62-3.25 (m, 6H), 2.67-2.59 (m, 2H), 2.14 (s, 3H), 1.80 (t, J = 6.0 Hz, 2H); 13 C NMR (CDCl 3 ): 168.0, 167.3, 157.8, 153.9, 131.4, 131.3, 129.3, 125.0, 120.4, 110.7, 105.3, 56.5, 56.4, 55.7, 55.4, 55.3, 41.1, 39.3, 24.4, 23.8;
1 H NMR (CDCl 3 ): 7.95 (brs, 1H), 7.37-7.31 (m, 2H), 7.28 (s, 2H), 6.96 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.76 (dd, J = 5.2, 10.4 Hz, 1H), 3.96 (s, 6H), 3.88 (s, 2H), 3.87 (s, 3H), 3.40-3.24 (m, 4H), 2.83-2.73 (m, 4H), 1.92 (t, J = 6.0 Hz, 2H), 1.18 (t, J = 6.8 Hz, 3H); 13 C NMR (CDCl 3 ):168.2, 167.9, 158.0, 154.0, 132.0, 131.9, 130.1, 125.3, 120.8, 110.9, 105.5, 56.6, 56.4, 55.5, 50.6, 50.4, 46.8, 38.1, 24.2, 24.0, 9.4;
1 H NMR (CDCl 3 ): 7.57 (d, J = 7.2 Hz, 1H), 7.29 (s, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 4.76 (dd, J= 5.2, 10.4 Hz, 1H), 3.97 (s, 6H), 3.91 (s, 2H), 3.42-3.25 (m, 4H), 2.81-2.65 (m, 4H), 2.64 (s, 6H), 1.87 (t, J = 6.0 Hz, 2H), 1.13 (t, J = 6.8 Hz, 3H); 13 C NMR (CDCl 3 ): 168.2, 167.8, 154.0, 153.5, 130.9, 129.0, 125.2, 124.1, 119.9, 105.5, 56.6, 51.5, 50.4, 46.8, 45.4, 37.8, 29.7, 24.7, 24.0, 9.6;
1 H NMR (CDCl 3 ): 7.88 (brs, 1H), 7.30 (s, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 2H), 4.78 (dd, J = 5.2, 10.4 Hz, 1H), 3.98 (s, 6H), 3.80 (s, 2H), 3.40-3.25 (m, 4H), 2.97 (s, 6H), 2.84-2.74 (m, 4H), 1.94 (t, J= 6.0 Hz, 2H), 1.23 (t, J = 6.8 Hz, 3H);
1 H NMR (CDCl 3 ): 7.31-7.24 (m, 7H), 6.44 (brs, 1H), 4.76 (dd, J = 5.6, 10.4 Hz, 1H), 3.98 (s, 6H), 3.59 (s, 2H), 3.45-3.21 (m, 4H), 2.54-2.48 (m, 4H), 1.57-1.46 (m, 4H), 1.04 (t, J = 6.8 Hz, 3H); 13 C NMR (CDCl 3 ):168.1, 167.6, 154.2, 138.1, 129.1, 128.2, 127.1, 124.9, 105.5, 57.6, 57.1, 56.6, 52.3, 46.9, 39.5, 27.0, 24.1, 23.8, 11.1;
1 H NMR (CDCl 3 ): 7.43 (d, J = 7.2 Hz, 1H), 7.29 (s, 2H), 7.27 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 4.78 (dd, J= 5.6, 10.4 Hz, 1H), 3.98 (s, 6H), 3.83 (s, 3H), 3.80 (s, 2H), 3.49-3.24 (m, 4H), 2.76-2.64 (m, 4H), 1.71-1.66 (m, 2H), 1.59-1.54 (m, 2H), 1.16 (t, J = 6.4 Hz, 3H); 13 C NMR (CDCl 3 ):168.2 167.7, 157.8, 154.1, 131.4, 129.3, 125.1, 120.6, 110.5, 105.5, 57.0, 56.6, 55.4, 52.2, 50.6, 47.1, 39.0, 26.7, 24.0, 22.9, 10.2;
1 H NMR (CDCl 3 ): 7.66 (d, J = 7.6 Hz, 1H), 7.30 (s, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 4.80 (dd, J= 5.2, 10.4 Hz, 1H), 3.97 (s, 6H), 3.93 (s, 2H), 3.53-3.23 (m, 4H), 2.82-2.74 (m, 4H), 2.66 (s, 6H), 1.76-1.68 (m, 2H), 1.58-1.53 (m, 2H), 1.16 (t, J = 6.8 Hz, 3H); 13 C NMR (CDCl 3 ): 168.2, 167.8, 154.0, 153.3, 130.9, 129.0, 125.1, 124.0, 119.7, 105.5, 56.9, 56.5, 52.2, 51.5, 46.8, 45.3, 38.8, 26.5, 24.1, 22.6, 9.7。
EXAMPLE 2 general preparation of phthaloyl cysteamine Compound (I) and acid salt formation
Adding 1.0mmol of the phthaloyl cysteamine compound (I) obtained in the embodiment 1 and methanol 25 ml into a reaction bottle, stirring uniformly, adding 3.0 mmol of corresponding acid, heating, refluxing, stirring for 20 minutes, cooling to room temperature after the reaction is finished, evaporating the solvent under reduced pressure, and separating and purifying by a conventional method to obtain the salt of the phthaloyl cysteamine compound (I), wherein the chemical structure of the salt is as follows 1 H NMR and ESI-MS corroborations.
Claims (7)
1. The phthaloyl cysteamine compounds or pharmaceutically acceptable salts thereof are characterized in that the chemical structural general formula of the compounds is shown as (I):
wherein: r represents- (CH) 2 )n-NR 1 R 2 Or (b)n represents 1-5, R 1 Represents methyl or ethyl; r is R 2 Represents benzyl or substituted benzyl; m represents 0 to 3, R 3 Represents methyl, ethyl, benzyl or substituted benzyl;
R 4 and R is 5 Each independently represents H, OH, C 1 ～C 6 Alkoxy, halogen or NR 6 R 7 But R is 4 And R is 5 Not simultaneously representing H; r is R 4 And R is 5 Any possible position on its benzene ring; r is R 6 And R is 7 Each independently represents H, methyl; when NR is 6 R 7 Represents a tetrahydropyrrole group when ring-formed;
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The compound is in R-configuration, S-configuration or any ratio mixture of R-and S-configuration;
the term "halogen" refers to F, cl, br or I; "substituted benzyl" refers to a benzyl group substituted on the phenyl ring with 1 to 4 groups selected from the group consisting of: F. cl, br, I, methyl, methoxy, NR 8 R 9 Trifluoromethyl, trifluoromethoxy, R 8 And R is 9 Each independently represents methyl, these substituents being in any of the possible positions of the phenyl ring thereof.
2. The phthaloyl cysteamide compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a mixture of the phthaloyl cysteamide 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.
3. The process for the preparation of phthaloyl cysteamides or pharmaceutically acceptable salts thereof according to any one of claims 1-2, wherein the compounds are prepared by the following process:
wherein: r, R 4 And R is 5 The definition of the compound is the same as the chemical structural general formula of the phthaloyl cysteamine compound (I);
the corresponding phthaloyl cysteamine compound (1) and the corresponding primary amine compound (2) are used as starting materials, and the corresponding phthaloyl cysteamine compound (I) can be prepared through condensation reaction under the existence of a solvent and a condensing agent; the phthaloyl cysteamine compound (I) obtained by the method contains amino in the molecule, the amino is alkaline, and pharmaceutically acceptable salts thereof are prepared by a pharmaceutically conventional salification method with any appropriate acid; the condensing agent is as follows: carbonyl diimidazole, chloroformic acid C 1-8 Fatty alcohol ester compound, N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diethyl cyanophosphate, or chlorinated 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl)-4-methylmorpholine salt.
4. The process for preparing phthaloyl cysteamide compounds or pharmaceutically acceptable salts thereof according to claim 3, wherein the solvent used in 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 Alkanes.
5. A process for the preparation of phthaloyl cysteamides or pharmaceutically acceptable salts thereof according to claim 3, wherein compound (1): compound (2): the molar feed ratio of the condensing agent is 1.0:1.0 to 10.0:1.0 to 10.0; the condensation reaction temperature is 0-100 ℃; the condensation reaction time is 1-72 hours.
6. A pharmaceutical composition comprising a phthaloyl cysteamine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, and one or more pharmaceutically acceptable carriers or excipients.
7. Use of a phthaloyl cysteamide compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating neurological related disorders such as: vascular dementia, alzheimer's disease, parkinson's disease, huntington's disease, HIV-associated dementia, multiple sclerosis, amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, and nerve damage caused by brain trauma.
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