CN113105409B - 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound, preparation method and application thereof - Google Patents
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Abstract
The invention discloses a 2- (hydroxybenzyl) benzo [ d ]]Isothiazolones (I) and pharmaceutically acceptable salts thereof, preparation method, pharmaceutical composition and application thereof in 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, alzheimer's disease, HIV related dementia, HIV infection, and HIV infection,Amyotrophic lateral sclerosis, neuropathic pain, glaucoma, ischemic stroke, hemorrhagic stroke, and nerve injury caused by brain trauma;
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a 2- (hydroxybenzyl) benzo [ d ] isothiazolone 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'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 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, 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 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, thereby having long-term curative effectIs 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 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, research and development have novel chemical structure, novel action mechanism, multi-target action and low costThe anti-neurodegenerative disease treatment drug with toxic and side effects is an important direction at present. 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 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound (I) and pharmaceutically acceptable salts thereof.
The invention also aims at disclosing a preparation method of the 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound (I) and pharmaceutically acceptable salts thereof.
It is a further object of the present invention to disclose pharmaceutical compositions comprising such 2- (hydroxybenzyl) benzo [ d ] isothiazolones (I) and pharmaceutically acceptable salts thereof.
It is still another object of the present invention to disclose the use of the 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound (I) and pharmaceutically acceptable salts thereof having multi-target effect for preparing a medicament 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 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound (I) disclosed by the invention is as follows:
wherein:
x represents S or SO 2 ；
R 1 、R 2 And R is 3 Each independently represents H, OH, CF 3 O、C 1 ~C 6 Alkoxy or NR 7 R 8 ，R 7 And R is 8 Each independently represents C 1 ~C 6 An alkyl group; NR (NR) 7 R 8 Also represents tetrahydropyrrolyl or piperidinyl; but R is 1 、R 2 And R is 3 Not simultaneously representing H;
R 4 and R is 5 Each independently represents C 1 ~C 12 Alkyl, benzyl, substituted benzyl; NR (NR) 4 R 5 Also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, piperazinyl, C-substituted at the 4-position 1 ~C 6 Piperazinyl substituted by alkyl, piperazinyl substituted by benzyl or substituted benzyl at the 4-position;
R 1 、R 2 、R 3 、-CH 2 NR 4 R 5 and OH may be in any possible position on its corresponding benzene ring;
the term "substituted benzyl" refers to a benzyl group on the phenyl ring substituted with 1 to 4 groups selected from the group consisting of: F. cl, br, I, C 1-4 Alkyl, C 1-4 Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, any possible position of these substituents on the benzene ring of the benzyl group.
The 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound (I) disclosed by the invention can be prepared by the following method, and the reaction formula is as follows:
wherein: x, R 1 、R 2 、R 3 、R 4 And R is 5 Definition of (d) and 2- (hydroxybenzyl) benzo [ d ]]Isothiazolone compounds (I)The chemical structural general formula is the same.
In the form of the corresponding 2- (hydroxybenzyl) benzo [ d ]]Isothiazolone compound (1) as starting material, and formaldehyde and amine compound (HNR) 4 R 5 ) Mannich reaction to obtain the corresponding 2- (hydroxybenzyl) benzo [ d ]]Isothiazolones (I); wherein, the solvent used in the reaction is: c (C) 1-8 Fatty alcohol, ethyl acetate, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1, 4-dioxane, benzene, toluene, acetonitrile or C 5-8 Alkanes, preferably solvents are: methanol, ethanol, isopropanol,N,N-dimethylformamide, tetrahydrofuran, dichloromethane or toluene; compound (1): formaldehyde: the molar feed ratio of the amine compound is 1.0:1.0 to 10.0: 1.0-10.0, preferably a molar feed ratio of 1.0:1.0 to 5.0:1.0 to 5.0; the reaction temperature is 0-120 ℃, and the preferable reaction temperature is room temperature-100 ℃; the reaction time is 1 to 72 hours, preferably 2 to 48 hours.
2- (hydroxybenzyl) benzo [ d ] obtained according to the above process]The isothiazolone compound (I) and any appropriate acid can be prepared into pharmaceutically acceptable salts thereof by a pharmaceutically conventional salifying method, wherein the acid is as follows: 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.
Starting material of the present invention-2- (hydroxybenzyl) benzo [ d ]]Isothiazolone compounds (1) can be prepared using techniques common in the art, including but not limited to the methods disclosed in the following documents: 1. liu D.et al.Bioorganic & Medicinal Chemistry, 2013, 21(11), 2960-2967；2、Pietka-Ottlik M. et al.Molecules, 2010, 15, 8214-8228；3、Ivanova J. et al.Bioorganic & Medicinal Chemistry, 2017, 25(13), 3583-3589。
The disclosed pharmaceutical compositions comprise a therapeutically effective amount of one or more 2- (hydroxybenzyl) benzo [ d ] isothiazolones (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 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound (I) or pharmaceutically acceptable salt thereof is taken as an active ingredient to account for 2-99.5% of the total weight.
The 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound (I) and pharmaceutically acceptable salts thereof disclosed by the invention are subjected to the following biological activity screening:
(1) Inhibitory Activity of 2- (hydroxybenzyl) benzo [ d ] isothiazolones (I) against acetylcholinesterase and butyrylcholinesterase
1.0 mmol/L of acetylcholine iodide or dibutyryl iodide (all purchased from Sigma Co.) 30. Mu.L of PBS buffer (pH 7.4), 20. Mu.L of test compound solution (DMSO content less than 1%) and 10. Mu.L of acetylcholinesterase (rat brain cortex 5% homogenized supernatant, pH7.4 phosphate buffer as homogenized medium) or butyrylcholinesterase (rat serum 25% supernatant, pH7.4 phosphate buffer as homogenized medium) were sequentially added to a 96-well plate, after the addition and homogenization, incubated at 37℃for 15min, 0.2% of 5,5' -dithiobis (2-nitrobenzoic acid) (DTNB, purchased from Sigma Co.) solution was added to each well for 30. Mu.L of color development, and each well was measured at 405nm with a microplate readerThe inhibition ratio of the compound to the enzyme (enzyme inhibition ratio (%) = (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 results show that the 2- (hydroxybenzyl) benzo [ d ] disclosed in the examples of the present invention]Isothiazolones (I) (except NR) 4 R 5 Out of compounds representing piperazinyl and morpholinyl) have a significant inhibitory effect on acetylcholinesterase, IC thereof 50 0.08 mu M-25.0 mu M; and 2- (hydroxybenzyl) benzo [ d ] of this type]The inhibition activity of isothiazolone compounds (I) on acetylcholinesterase is obviously higher than that of butyrylcholinesterase (the selectivity is more than 10 times), which indicates that the compounds disclosed by the invention have selective inhibition effect on acetylcholinesterase. Further structure-activity relationship research shows that the 2- (hydroxybenzyl) benzo [ d]In the chemical structural general formula of the isothiazolone compound (I), when R 1 、R 2 And R is 3 Simultaneously, when H is represented and other substituents are defined as the general formula of the chemical structure, the inhibitory activity of the represented compound on acetylcholinesterase is greatly reduced (IC 50 All greater than 100 μm); and 2- (hydroxybenzyl) benzo [ d ]]Mother nucleus 2- (hydroxybenzyl) benzo [ d ] of isothiazolone compound (I)]Isothiazolones [ R ] 1 、R 2 、R 3 X is defined as the chemical structural general formula of the compound (I); CH (CH) 2 NR 4 R 5 IC for inhibiting acetylcholinesterase, which is a compound wherein H, OH is located at the 2' -position, 3' -position or 4' -position 50 Are all larger than 100 mu M. In addition, experiments have found that when NR 4 R 5 The definition of the other substituents is the same as that of the general chemical structure of the piperazinyl or morpholinyl group (for example, 1-6, 1-7, 1-45, 1-46, 1-53, 1-54, 2-6, 2-7, 2-45, 2-46, 2-53, 2-54, 3-6, 3-7, 3-45, 3-46, 3-53, 3-54, 4-6, 4-7, 4-45, 4-46, 4-53, 4-54) are used as the main chainAcetylcholinesterase-inhibited IC 50 Values all greater than 100 [ mu ] M indicate NR 4 R 5 In the case of piperazinyl or morpholinyl, the compounds have little acetylcholinesterase inhibitory activity.
(2) Antioxidant Activity of 2- (hydroxybenzyl) benzo [ d ] isothiazolones (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 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 at 485 nm excitation wavelength and 535 nm emission wavelength for 90 min. 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 results show that the 2- (hydroxybenzyl) benzo [ d ] disclosed in the examples of the present invention]The antioxidant activity of isothiazolone compound (I) isTrolox0.9-3.2 times of the total weight of the total composition, which shows that the compound has strong antioxidant activity.
(3) Determination of complexation of 2- (hydroxybenzyl) benzo [ d ] isothiazolones (I) with Metal ions
Dissolving CuCl with methanol 2 ·2H 2 O、ZnCl 2 、FeSO 4 ·7H 2 O、AlCl 3 And a compound to be tested, preparing a 75 mu mol/L solution, adding 100 mu L of the compound to be tested into a 96-well plateAnd (3) uniformly mixing the compound solution and 100 mu L of metal ion solution, standing at room temperature for 30 min, recording an ultraviolet absorption curve of the mixture in a range of 200-600 nm on a Varioskan Flash Multimode Reader (Thermo Scientific) instrument, and observing the red shift phenomenon of the maximum absorption peak and the intensity of the maximum absorption peak of the mixed solution of the metal ion and the compound to be tested by taking 100 mu L of the compound to be tested and 100 mu L of the methanol mixed solution as a reference. The measurement results show that the 2- (hydroxybenzyl) benzo [ d ] disclosed in the examples of the present invention]Isothiazolones (I) all show Cu 2+ And Fe (Fe) 2+ Has selective complexation.
(4) 2- (hydroxybenzyl) benzo [ d ]]Isothiazolone compound (I) pair Aβ 1-42 Inhibition of self-aggregation
Reference (Qiang, X.M).et al.Eur. J Med. Chem.2014, 76, 314-331), i.e.: pretreated Aβ 1-42 Stock solutions were made up with DMSO and diluted to 50 μm 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 takenβ 1-42 Solution +20. Mu.L of test compound solution, 20. Mu.L of Aβ 1-42 Solution +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, the fluorescence value was determined with a multifunctional microplate reader at 446 nm excitation wavelength and 490 nm emission wavelength; a is thatβ 1-42 The fluorescence value of the +test compound is recorded as IF i ，Aβ 1-42 Fluorescence values of +PBS buffer were recorded as IF c The fluorescence value of the buffer containing PBS alone was recorded as IF 0 Compounds inhibit Aβ 1-42 The inhibition rate of self aggregation is as follows: 100- (IF) i -IF 0 )/(IF c -IF 0 ) 100; five to six concentrations of the compound were selected, their inhibition was determined, each concentration was repeated three times for each compound, and curcumin was used as a positive control. The measurement results show that the 2- (hydroxybenzyl) benzo [ d ] disclosed in the examples of the present invention]Isothiazolone compound (I) pairAβ 1-42 Self-aggregation has obvious inhibition activity on A at the concentration of 50.0 mu Mβ 1-42 The inhibition rate of self aggregation is more than 40.0 percent; the inhibition rate of curcumin at the same concentration is 45.3%, and the anti-AD medicament widely used clinically: donepezil, rivastigmine, memantine hydrochloride, 2- (hydroxybenzyl) benzo [ d ] of compound (I)]Isothiazolones [ R ] 1 、R 2 、R 3 X is defined as the chemical structural general formula of the compound (I); CH (CH) 2 NR 4 R 5 Represents H, OH in the 2' -position, 3' -position or 4' -position at a concentration of 50.0 mu M for Aβ 1-42 The inhibition rate of self aggregation is less than 15 percent.
(5) Influence of 2- (hydroxybenzyl) benzo [ d ] isothiazolones (I) on scopolamine-induced mouse memory acquisition disorder
SPF grade ICR male mice, 25-30g, were randomly divided into: normal group, model group, positive control group, and high-low dose group (21.0 mg/kg, 7.0mg/kg, 2.3 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 the administration, normal mice are intraperitoneally injected with normal saline, and the other animals are respectively injected with scopolamine (5 mg/kg) with the administration 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 mouse is placed at the tail end of one arm, freely passes through the maze for 8 min, the times of entering each arm and the alternation times are recorded, and the alternation rate is calculated according to the following formula: the alternation ratio = [ alternation number/(total entry number-2) ]. Times.100, the result was expressed as mean ± standard deviation, and the difference between groups was analyzed by single factor variance analysis. The results of the assay show that the tested 2- (hydroxybenzyl) benzo [ d ] isothiazolone compounds (I) (examples 1-5, 2-8 and 3-5) have a dose-dependent improving effect on scopolamine induced mice acquired memory impairment under the experimental conditions, are statistically different (p < 0.01) compared with the model group, and have significantly higher activity than the clinical drug rivastigmine (p < 0.01) at the same molar concentration.
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
Preparation method of 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound (I)
2- (hydroxybenzyl) benzo [ d ]]1.0 mmol of isothiazolone compound (1) was dissolved in 8 ml ethanol, 3.0 mmol of paraformaldehyde and the corresponding amine compound (HNR 4 R 5 ) 3.0 mmol, heating, refluxing and stirring the reaction for 2-48 hours (the reaction progress is followed by TLC), after the reaction is finished, the solvent is distilled off under reduced pressure, 50 ml dichloromethane is added to the residue, the residue is washed with 20 ml saturated brine, the organic layer is dried over anhydrous sodium sulfate and filtered, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: petroleum ether-ethyl acetate=1:3 v/v) to obtain corresponding 2- (hydroxybenzyl) benzo [ d]The isothiazolone compound (I) has a yield of 36.0-80.5%, and the chemical structure thereof is all that is obtained by 1 H-NMR、 13 The purity of the obtained target product is greater than 96.0% by HPLC (high performance liquid chromatography) as confirmed by C-NMR and ESI-MS. The structure of the target object prepared by the general method is as follows:
of part of the compounds 1 The H-NMR data are as follows:
1 H NMR (CDCl 3 ): 7.44 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.87 ( s, 1H), 6.80 (s, 1H), 6.75 (d, J = 7.6 Hz, 1H), 4.96 (s, 2H), 3.94 ( s, 6H), 3.66 (s, 2H), 2.35 (s, 6H); 13 C NMR (CDCl 3 ): 165.4, 158.3, 153.5, 148.6, 137.3, 134.0, 129.0, 121.3, 118.7, 116.9, 115.9, 107.0, 101.4, 62.1, 56.3, 56.2, 47.3, 44.3；
1 H NMR (CDCl 3 ): 7.40 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.81 ( s, 1H), 6.76 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 4.92 (s, 2H), 3.90 (s, 6H), 3.62 (s, 2H), 2.69 (m, 4H), 1.15 (m, 6H)；
1 H NMR (CDCl 3 ): 7.38 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.88 (s, 2H), 6.77 (d, J = 7.6 Hz, 1H), 4.95 (s, 2H), 3.94 (s, 5H), 3.90 (s, 3H), 2.82 (brs, 4H), 1.91 (brs, 4H); 13 C NMR (CDCl 3 ): 165.4, 157.9, 153.6, 148.6, 137.8, 134.0, 129.7, 120.7, 119.0, 116.7, 116.0, 106.9, 101.5, 56.6, 56.3, 56.2, 53.2, 47.3, 23.4；
1 H NMR (CDCl 3 ): 7.44 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.80 (s, 1H), 6.75 (d, J = 7.6 Hz, 1H), 4.95 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.69 (s, 2H), 2.64-2.54 (brs, 4H), 1.67-1.49 (m, 4H), 1.25 (brs, 2H); 13 C NMR (CDCl 3 ): 165.3, 158.2, 153.5, 148.6, 137.2, 134.0, 129.2, 121.0, 118.7, 116.9, 115.9, 107.0, 101.4, 61.2, 56.3, 56.2, 53.7, 47.3, 25.5, 23.7；
1 H NMR (CDCl 3 ): 7.41 (s, 1H), 7.31 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.81 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 3.87 (s, 2H), 2.77 (brs, 4H), 1.90 (brs, 4H)；
1 H NMR (CDCl 3 ): 7.41 (s, 1H), 7.31 (s, 1H), 6.94-6.92 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 4.81 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 3.64 (s, 2H), 2.64-2.49 (brs, 4H), 1.63-1.61 (m, 4H), 1.49 (brs, 2H); 13 C NMR (CDCl 3 ): 159.1, 158.2, 154.5, 153.9, 135.4, 128.7, 121.3, 120.7, 118.7, 115.9, 109.6, 105.8, 102.5, 61.7, 56.8, 56.7, 53.8, 42.3, 25.7, 23.9。
example 2 2 (hydroxybenzyl) benzo [ d ] isothiazolone Compound (I) salt formation with acid preparation method
The 2- (hydroxybenzyl) benzo [ d ] obtained according to example 1 above was introduced into a reaction flask]2.0 mmol of isothiazolone compound (I) and 30. 30 ml of acetone, adding 7.0 mmol of corresponding acid after stirring uniformly, heating, refluxing and stirring for reaction for 30 minutes, cooling to room temperature after the reaction is finished, decompressing and distilling off the solvent, recrystallizing the residue by using acetone, and filtering the precipitated solid to obtain 2- (hydroxybenzyl) benzo [ d ]]Salts of isothiazolones (I) having a chemical structure 1 H NMR and ESI-MS corroborations.
Claims (7)
1. A2- (hydroxybenzyl) benzo [ d ] isothiazolone compound or pharmaceutically acceptable salt thereof is characterized in that the chemical structural general formula of the compound is shown as (I):
wherein: x represents S or SO 2 ；R 1 、R 2 And R is 3 Each independently represents H, OH, CF 3 O、C 1 ~C 6 Alkoxy or NR 7 R 8 ，R 7 And R is 8 Each independently represents C 1 ~C 6 An alkyl group; NR (NR) 7 R 8 Also represents tetrahydropyrrolyl or piperidinyl; but R is 1 、R 2 And R is 3 Not simultaneously representing H; r is R 4 And R is 5 Each independently ofFloor representation C 1 ~C 12 Alkyl, benzyl, substituted benzyl; NR (NR) 4 R 5 Also represents tetrahydropyrrolyl, piperidinyl, C in the 4-position 1 ~C 6 Piperazinyl substituted by alkyl, piperazinyl substituted by benzyl or substituted benzyl at the 4-position; r is R 1 、R 2 、R 3 、-CH 2 NR 4 R 5 And OH may be in any possible position on its corresponding benzene ring; the "substituted benzyl" refers to a benzyl group substituted on the benzene ring with 1 to 4 groups selected from the group consisting of: F. cl, br, I, C 1-4 Alkyl, C 1-4 Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, any possible position of these substituents on the benzene ring of the benzyl group.
2. 2- (hydroxybenzyl) benzo [ d ] according to claim 1]Isothiazolones or pharmaceutically acceptable salts thereof, characterized in that said pharmaceutically acceptable salts are such 2- (hydroxybenzyl) benzo [ d ]]Isothiazolone compound, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sulfamic acid and 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. A process for the preparation of a 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 wherein the compound is obtainable by the process comprising:
wherein: x, R 1 、R 2 、R 3 、R 4 And R is 5 Definition of (c) and 2- (hydroxybenzyl) benzeneAnd [ d ]]The chemical structural general formula of the isothiazolone compound (I) is the same;
in the form of the corresponding 2- (hydroxybenzyl) benzo [ d ]]Isothiazolone compound (1) as starting material, formaldehyde and HNR in solvent 4 R 5 Mannich reaction to obtain the corresponding 2- (hydroxybenzyl) benzo [ d ]]The isothiazolone compound (I) and acid are subjected to a pharmaceutically conventional salifying method to prepare pharmaceutically acceptable salts.
4. A process as claimed in claim 3, wherein the 2- (hydroxybenzyl) benzo [ d ]]The preparation method of isothiazolone compounds or pharmaceutically acceptable salts thereof is characterized in that the solvents used in the reaction are as follows: c (C) 1-8 Fatty alcohol, ethyl acetate, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1, 4-dioxane, benzene, toluene, acetonitrile or C 5-8 Alkanes.
5. A process for the preparation of 2- (hydroxybenzyl) benzo [ d ] isothiazolone compounds or pharmaceutically acceptable salts thereof according to claim 3, characterized in that compound (1): formaldehyde: the molar feed ratio of the amine compound is 1.0:1.0 to 10.0:1.0 to 10.0; the reaction temperature is 0-120 ℃; the reaction time is 1-72 hours.
6. A pharmaceutical composition comprising a 2- (hydroxybenzyl) benzo [ d ] isothiazolone 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 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the manufacture of a medicament for the treatment and/or prevention of neurological related disorders: 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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