CN106810532A - One class amine alkoxy thioxanthene ketone class compound, Preparation Method And The Use - Google Patents

Abstract

The invention discloses a new type of amine alkoxythioxanthone compound (I) and its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and preparation of drugs for treating and/or preventing neurodegenerative related diseases Including but not limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma, etc. neurodegenerative diseases; .

Description

A class of amine alkoxythioxanthone compounds, its preparation method and use

technical field

The invention belongs to the field of medicinal chemistry, and relates to a new type of amine alkoxythioxanthone compound (I) and its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and its preparation for treating and/or preventing neurodegeneration Sex-related diseases, including but not limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neurological Pain, glaucoma and other neurodegenerative diseases.

Background technique

Alzheimer's disease (Alzheimer's disease, AD, senile dementia) is a degenerative disease of the central nervous system mainly characterized by progressive cognitive impairment and memory impairment. Vascular diseases and cancers are high-incidence diseases, which have risen to the fourth cause of death in developed countries such as Europe and the United States. According to the report of the World Health Organization, 10% of people over the age of 65 in the world have mental retardation, one-half of them develop dementia, and the incidence rate of people over the age of 85 is nearly 50%. The number of AD patients in my country is about 6-7 million, and the incidence rate exceeds 5%. With the acceleration of the aging process of the global population, its incidence has shown a clear upward trend. According to the "World Alzheimer Report 2016" report released by Alzheimer's Disease International in September 2016, AD will become the biggest disease facing the world in the next few decades. Health challenges. By 2030, the number of patients will rise from 47 million in 2015 to 76 million. By 2050, this value will reach a staggering 131 million. AD is clinically manifested as decreased memory, orientation, thinking and judgment, decreased ability to perform daily living, and even abnormal mental and behavioral symptoms, accompanied by significant depressive symptoms. The family is a heavy burden. Drugs currently approved for the treatment of mild/moderate AD include acetylcholinesterase (AChE) inhibitors, and N -methyl- D -aspartate (NMDA) receptor antagonists for the treatment of severe AD, but Clinical use shows that these drugs can relieve AD symptoms by increasing the level of acetylcholine in the patient's body or inhibiting the excitotoxicity of excitatory amino acids, but they cannot effectively prevent or reverse the course of the disease, and they can also cause hallucinations, confusion, dizziness, headache, nausea, liver Toxicity, loss of appetite and frequent stools and other serious side effects, so the long-term efficacy is not ideal. Therefore, there is an urgent clinical need to develop AD therapeutic drugs with novel mechanisms of action.

AD is a disease caused by a variety of factors, and its pathogenesis is complex. Its pathogenesis has not been fully elucidated yet, but studies have shown that the decrease in the level of acetylcholine in the brain of patients, the excessive production and deposition of β -amyloid protein, the disorder of metal ion metabolism, Ca ²⁺ imbalance, neurofibrillary tangles caused by hyperphosphorylation of tau -protein, increased activity of monoamine oxidase B (MAO-B), hyperactivity of glutamate receptors, oxidative stress producing large amounts of reactive oxygen species (ROS) and free Many factors, such as genetics and neuroinflammation, play an important role in the pathogenesis of AD. In addition, the latest research has found that most AD patients also have significant depressive symptoms, and depression can increase the deposition of β -amyloid in the brain and aggravate their cognitive dysfunction. In response to the above-mentioned pathogenic factors, researchers adopted the traditional "one drug, one target" drug design strategy, and discovered a large number of drugs with high activity and high selectivity for a certain target, such as: cholinesterase inhibitors and N -methyl - D -aspartate receptor antagonists, etc., but these drugs have problems such as a single target, more toxic and side effects in clinical use, and poor long-term curative effect on AD patients.

In recent years, with the continuous elucidation of the pathogenic mechanism of AD, it has been found that the occurrence and development of AD have the characteristics of multi-mechanism and multi-factor effects. Network control system. Based on the above results, the researchers proposed a "Multitarget-directed Ligands (MTDLs) strategy to develop anti-neurodegenerative disease drugs. The so-called "multi-target drug" means that a single chemical entity acts on multiple targets in the disease network at the same time, and the effect on each target can produce a synergistic effect, making the total effect greater than the sum of the individual effects. It is a "Multifunctional" or "Multipotential" medicine. The main difference between multi-target drug, multi-drug combination and compound drug is that it can reduce the dosage, improve the therapeutic effect, avoid the interaction between drugs and the resulting toxic and side effects, uniform pharmacokinetic characteristics, Ease of use etc. Designed and found to inhibit monoamine oxidase A and B, anti-oxidative stress, anti- beta -amyloid overproduction and deposition, selective complexation of metal ions in the central tissue (especially Cu ²⁺ and Fe ²⁺ ), And a variety of multi-target AD therapeutic drugs with balanced biological activity intensity is the current research hotspot. Therefore, the research and development of anti-neurodegenerative disease drugs with new chemical structures, new mechanisms of action, multi-target (or multifunctional) effects, and low side effects not only meets the urgent needs of the aging society, but also has good market expectation.

Contents of the invention

The purpose of the present invention is to disclose a new class of amine alkoxythioxanthone compounds (I) and pharmaceutically acceptable salts thereof;

Another object of the present invention is to disclose the preparation method of the amine alkoxythioxanthone compound (I) and its pharmaceutically acceptable salt;

Another object of the present invention is to disclose a pharmaceutical composition comprising the amine alkoxythioxanthone compound (I) and a pharmaceutically acceptable salt thereof;

Another object of the present invention is to disclose that the amine alkoxythioxanthone compound (I) and its pharmaceutically acceptable salt have multi-target effects and can be used to prepare drugs for treating and/or preventing neurodegenerative related diseases Including but not limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma, etc. neurodegenerative disease.

The general chemical structure formula of the amine alkoxythioxanthone compound (I) disclosed by the present invention is:

In the formula: R represents -(CH ₂ )n-NR ₁ R ₂ , n represents 2-12, R ₁ represents H, C ₁ ~C ₁₂ alkyl; R ₂ represents C ₁ ~C ₁₂ alkyl, benzyl or Substituted benzyl; NR ₁ R ₂ can also represent tetrahydropyrrolyl, morpholinyl, piperidinyl, piperidinyl substituted by C ₁ ~ C ₁₂ alkyl at the 4-position, benzyl or substituted at the 4-position Piperidinyl substituted by benzyl, piperazinyl, piperazinyl substituted by C ₁ ~C ₁₂ alkyl at 4-position, piperazinyl substituted by benzyl or substituted benzyl at 4-position; R also Can represent , m represents 1-10, R ₃ represents H, C ₁ ~ C ₁₂ alkyl, benzyl or substituted benzyl; the above-mentioned term "substituted benzyl" means that the benzene ring is replaced by 1-4 selected from the following group Benzyl substituted by the group: F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano groups, and these substituents can be in any possible position of the benzene ring.

The amine alkoxythioxanthone compound (I) proposed by the present invention can be prepared by the following method:

(1) When R represents -(CH ₂ )n-NR ₁ R ₂ , and n represents 2-12:

In the formula: X represents Cl, Br, I; the definition of R ₁ , R ₂ , n is the same as that of the general chemical structure formula (I);

Step a): Using 1,3-dihydroxythioxanthone (1) as a starting material, react with a dihaloalkyl compound (2) under solvent and alkaline conditions to generate the corresponding 1-hydroxy-3-oxo Alkyl halide compounds (3);

Step b): reacting the intermediate 3 obtained in step a) with the organic amine compound (4) in a solvent to obtain the corresponding amine alkoxythioxanthone compound (I);

Its specific preparation method is described as follows:

In the step a), the alkali used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, _C1 Alkali metal salts of _-8 alcohols, organic tertiary amines or quaternary ammonium bases (such as: triethylamine, tributylamine, trioctylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylene diamine, tetrabutylammonium hydroxide), the preferred base is: potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, pyridine or sodium methoxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -di Methylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes, preferred solvents are: N,N -dimethylformamide, Acetone, acetonitrile, tetrahydrofuran or toluene; 1,3-dihydroxythioxanthone (1): dihaloalkyl compound (2): molar feed ratio of base is 1.0: 1.0~10.0: 1.0~10.0, preferably molar feed ratio 1.0: 1.0~5.0: 1.0~5.0; the reaction temperature is room temperature~150°C, preferably the reaction temperature is room temperature~120°C; the reaction time is 1~72 hours, the preferable reaction time is 2~24 hours;

In the step b), the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketone, benzene, toluene, acetonitrile , C _1-8 alcohol, or C _5-8 alkane, the preferred solvent is: N,N -dimethylformamide, acetone, acetonitrile, tetrahydrofuran, ethanol or toluene; intermediate (3): organic amine compound (4 ) molar feeding ratio is 1.0:1.0~10.0, the preferred molar feeding ratio is 1.0:1.0~5.0; the reaction temperature is room temperature~150°C, the preferred reaction temperature is room temperature~120°C; the reaction time is 1~72 hours, the preferred reaction The time is 2 to 24 hours.

(2) When R indicates , when m means 1-10:

In the formula: X represents Cl, Br, I; the definitions of R ₃ and m are the same as those in the general chemical structure formula (I);

Using 1,3-dihydroxythioxanthone (1) as the starting material, react with 1-substituted-4-haloalkylpiperidine (5) under solvent and alkaline conditions to obtain the corresponding amine alkoxythioxanthone Xanthones (I);

Its specific preparation method is described as follows:

The base used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, organic tertiary amines or quaternary ammonium bases (e.g. triethylamine, tributylamine, trioctylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylenediamine, tetrabutylammonium hydroxide), or bases of C _1-8 alcohols Metal salt, the preferred base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine, or sodium methoxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformamide, dimethyl Sulfoxide, methylene chloride, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes, preferred solvents are: N,N -dimethylformamide, acetone, acetonitrile, tetrahydrofuran or toluene; 1,3-Dihydroxythioxanthone (1): 1-substituted-4-haloalkylpiperidine (5): The molar feed ratio of alkali is 1.0: 1.0~10.0: 1.0~10.0, preferably 1.0 : 1.0~3.0: 1.0~5.0; the reaction temperature is room temperature~150°C, preferably room temperature~120°C; the reaction time is 1~72 hours, preferably 2~24 hours.

The amine alkoxythioxanthone compound (I) obtained according to the above method contains an amino group in its molecule, which is basic and can be prepared with any suitable acid by a pharmaceutically conventional salt-forming method. Its pharmaceutically acceptable salt, the acid is: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C _1-6 fatty carboxylic acid (such as: formic acid, acetic acid, propionic acid, etc.), oxalic acid, benzoic acid, salicylic acid, horse Toric acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lipoic acid, C _1-6 alkyl sulfonic acid (such as: methylsulfonic acid, ethylsulfonic acid, etc.), camphorsulfonic acid, benzenesulfonic acid acid or p-toluenesulfonic acid.

The pharmaceutical composition disclosed in the present invention includes one or more amine alkoxythioxanthone compounds (I) or pharmaceutically acceptable salts thereof in a therapeutically effective amount, and the pharmaceutical composition may further contain one or more a pharmaceutically acceptable carrier or excipient. The "therapeutically effective amount" refers to the amount of the drug or agent that causes the biological or medical response of the tissue, system or animal targeted by the researcher or doctor; the "composition" refers to the combination of more than one substance or The mixed product; the "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition or carrier, such as: liquid or solid filler, diluent, excipient, solvent or encapsulation Substances that carry or transport a chemical substance. The ideal proportion of the pharmaceutical composition provided by the present invention is that the amine alkoxythioxanthone compound (I) or its pharmaceutically acceptable salt as the active ingredient accounts for 2% to 99.5% of the total weight, and the rest is Accounting for less than 98% of the total weight.

The amine alkoxythioxanthone compounds (I) and their pharmaceutically acceptable salts disclosed in the present invention were screened for their biological activity as follows.

(1) Inhibitory activity of amine alkoxythioxanthone compounds (I) on monoamine oxidase A and B

Use 100 mM pH 7.4 potassium phosphate buffer to make recombinant human MAO-A into 12.5 μg/mL sample solution, and MAO-B into 75 μg/mL sample solution. Add 20 μL of the test compound solution and 80 μL of monoamine oxidase to a black 96-well plate, mix well, incubate at 37°C in a dark place for 15 min, add 200 μM Amplex Red reagent, 2U/mL horseradish peroxidase, 2 Initiate the reaction with mM p-hydroxyphenylethylamine (inhibit MAO-A) or 2 mM benzylamine (inhibit MAO-B), incubate at 37°C for 20 min, and measure Fluorescence emission intensity at 590 nm, using potassium phosphate buffer instead of MAO-A or MAO-B as a blank; the formula for the inhibition rate of compounds inhibiting monoamine oxidase is: 100-(IF _i )/(IF _c )*100, where, IF _i and IF _c are the difference between the fluorescence intensity and the blank fluorescence intensity in the presence and absence of inhibitors, respectively. Each compound was measured in triplicate wells, and each group of experiments was repeated three times independently. Select five to six concentrations of the compound, measure its enzyme inhibition rate, and linearly regress the negative logarithm of the molar concentration of the compound and the enzyme inhibition rate to obtain the molar concentration when the 50% inhibition rate is the _IC50 of the compound . The measurement results show that the amine alkoxythioxanthone compound (I) disclosed in the examples of the present invention has a significant inhibitory effect on both MAO-A and MAO-B, wherein the IC ₅₀ for MAO-A inhibition is 0.3 µM~10.0 µM, the IC ₅₀ for MAO-B inhibition is 0.1 µM~10.0 µM.

(2) Inhibitory activity of amine alkoxythioxanthone compounds (I) on A β _1-42 self-aggregation

Refer to the method reported in the literature (Qiang, XM et al. Eur. J Med. Chem. 2014, 76, 314-331), that is, the pretreated A β _1-42 is made into a stock solution with DMSO, using Dilute to 50 μM with PBS buffer at pH 7.4 before use; make 2.5 mM stock solution of the compound to be tested with DMSO, dilute with PBS buffer at pH 7.4 to the corresponding concentration before use, take 20 μL of A β _1-42 solution+ 20 μL of the test compound solution, 20 μL of A β _1-42 solution + 20 μL of PBS buffer (containing 2% DMSO) were placed in a 96-well plate, incubated at 37°C for 24 hours, and then 160 μL of 50 mM thioflavin T containing 5 μM was added. Glycine-NaOH buffer solution (pH = 8.5), after shaking for 5 s, measure the fluorescence value with a multi-functional microplate _reader at the excitation wavelength of 446 nm and the emission wavelength of 490 nm; IF _i , the fluorescence value of A β _1-42 + PBS buffer is recorded as IF _c , the fluorescence value of only PBS buffer is recorded as IF ₀ , and the inhibition rate of the compound to inhibit A β _1-42 self-aggregation is: 100- (IF _i -IF ₀ )/(IF _c -IF ₀ )*100; five to six concentrations of the compound were selected, and the inhibition rate was determined. Each compound was tested three times at each concentration, and curcumin was used as a positive control. The measurement results show that the amine alkoxythioxanthone compounds (I) disclosed in the examples of the present invention have significant inhibitory activity on A β _1-42 self - _aggregation . The inhibition rates of aggregation were all greater than 40.0%; the control drugs used: 1,3-dihydroxythioxanthone (1) and curcumin had an inhibition rate of 9.5% and 36.2% for A β _1-42 self-aggregation at the same concentration .

(3) Determination of complexation between amine alkoxythioxanthone compounds (I) and metal ions

Dissolve CuCl ₂ 2H ₂ O, ZnCl ₂ , FeSO ₄ 7H ₂ O, AlCl ₃ and the test compound in methanol to make a 75 μmol/L solution, add 100 μL test compound solution and 100 μL metal Ionic solution, mix well, let stand at room temperature for 30 min, record the UV absorption curve of the mixture in the range of 200-600 nm on a multifunctional microplate reader, and use 100 μL of the compound solution to be tested and 100 μL of methanol mixture as controls, observe The red shift of the maximum absorption peak of the mixture of metal ions and the compound to be tested and the intensity of the maximum absorption peak. The measurement results show that the amine alkoxythioxanthone compounds (I) disclosed in the examples of the present invention all exhibit selective complexation for Cu ²⁺ and Fe ²⁺ , while for Zn ²⁺ and Al ^{3 +} Virtually no complexation.

(4) Inhibitory activity of amine alkoxythioxanthones (I) on Cu ²⁺ -induced aggregation of Aβ _1-42

Make a 75 μM solution of CuCl ₂ with HEPES buffer, dilute the compound stock solution (2.5 mM) and 200 μM Aβ _1-42 stock solution to 75 μM with HEPES buffer, take 20 μL Cu ²⁺ solution + 20 μL respectively A β _1-42 solution + 20 μL test compound solution, 20 μL Cu ²⁺ solution + 20 μL A β _1-42 solution + 20 μL HEPES buffer and 60 μL HEPES buffer in a 96-well plate, mix well, and incubate at 37°C for 24 h, then add 190 μL of 50 mM glycine-NaOH buffer solution (pH=8.5) containing 5 μM Thioflavin T, shake for 5 s, and immediately measure the fluorescence value with a multifunctional microplate reader at an excitation wavelength of 446 nm and an emission wavelength of 490 nm; Cu ^{2 +} +A β _1-42 +The fluorescence value of the compound to be tested is recorded as IF _i , the fluorescence value of Cu ²⁺ +A β _1-42 +HEPES buffer is recorded as IF _c , and the fluorescence value of the buffer containing only HEPES is recorded as IF ₀ , the inhibition rate of the compound on Cu ²⁺ -induced A β _1-42 aggregation is: 100-(IF _i -IF ₀ )/(IF _c -IF ₀ )*100. Three replicate wells were measured for each concentration of each compound, and curcumin was used as a positive control. The measurement results show that the amine alkoxythioxanthone compound (I) disclosed in the examples of the present invention has an inhibition rate of more than 75.0% on Cu ²⁺ -induced aggregation of Aβ _1-42 at a concentration of 25.0 μM; and The inhibition rate of curcumin at the same concentration was 62.1%, and that of 1,3-dihydroxythioxanthone (1) was only 31.4%.

(5) Antioxidant activity of amine alkoxythioxanthones (I) (ORAC-FL method)

Determination with reference to the method reported in the literature (Qiang, XM et al. Eur. J Med. Chem. 2014, 76, 314-331), namely: 6-hydroxy-2,5,7,8-tetramethylchromane -2-Carboxylic acid ( Trolox ) was made into a 10-80 μmol/L solution with pH 7.4 PBS buffer, and fluorescein was made into a 250 nmol/L solution with pH 7.4 PBS buffer, 2 , 2'-Azobisisobutylamidine dihydrochloride (AAPH) was made into a 40 mmol/L solution with PBS buffer at pH 7.4 before use. Add 50-10 μmol/L compound solution and fluorescein solution to the 96-well plate, mix well, incubate at 37°C for 15 minutes, add AAPH solution to make the total volume of each well 200 μL, mix well, and immediately place in the multifunctional In a microplate reader, continuous measurement was performed for 90 min at an excitation wavelength of 485 nm and an emission wavelength of 535 nm. Calculate the AUC of the area under the fluorescence decay curve, wherein the Trolox of 1-8 μmol/L is used as the standard, and the sample to be tested is not added as a blank, and the antioxidant activity of the compound is expressed as the equivalent of Trolox , and its calculation formula is: [(AUC Sample-AUC blank)/(AUC Trolox -AUC blank)]´[(concentrationof Trolox /concentration of sample)], each compound was measured in three replicate wells, and each group of experiments was repeated three times independently. The measurement results show that the antioxidant activity of the amine alkoxythioxanthone compound (I) disclosed in the examples of the present invention is 0.5-2.0 times that of Trolox , indicating that this type of compound has strong antioxidant activity.

detailed description

The present invention can 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 can understand that various changes and modifications can be made in the present invention without departing from the spirit and scope of the present invention.

Example 1

When R represents -(CH ₂ )n-NR ₁ R ₂ , and n represents 2-12, the preparation method of amine alkoxythioxanthone compound (I)

Add 2.0 mmol of 1,3-dihydroxythioxanthone (1), 30 ml of acetonitrile, 7.0 mmol of anhydrous potassium carbonate and 7.0 mmol of dibromoalkyl compound (2) into the reaction flask, heat up and reflux and stir for 3.0 to 12.0 hours (The reaction process is tracked by TLC); after the reaction is completed, filter while hot, wash the filter cake with a small amount of acetonitrile, evaporate the filtrate to remove solvent and excess dibromoalkyl compound under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: Petroleum ether-ethyl acetate=30:1 v/v) to obtain 1-hydroxy-3-oxoalkyl halide compound (3), with a yield of 76.2%-88.0%;

Dissolve the above-mentioned 1-hydroxy-3-oxoalkyl halide compound (3) in 30 ml of ethanol, add 6.0 mmol of organic amine compound (4), heat up and reflux and stir for 6.0-16.0 hours (track the reaction process with TLC) ; After the reaction was finished, the solvent was evaporated under reduced pressure, and 50 ml of methylene chloride was added to the residue, followed by washing with 20 ml of 5% aqueous sodium hydroxide solution and 20 ml of deionized water, and the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether-ethyl acetate=30:1 v/v) to obtain the corresponding amine alkoxythioxanthone compound (I). The yields ranged from 72.0% to 90.6%. The chemical structures were confirmed by ¹ H-NMR, ¹³ C-NMR and ESI-MS. The purity of the obtained target compounds were all greater than 97.0% as determined by HPLC. The structure of the target object prepared by the above-mentioned general method is as follows:

Example 2 R means , when m represents 1-10, the preparation general method of amine alkoxy thioxanthone compound (I)

Add 2.0 mmol of 1,3-dihydroxythioxanthone (1), 30 ml of acetonitrile, 3.0 mmol of anhydrous potassium carbonate and 2.5 mmol of 1-substituted-4-haloalkylpiperidine (5) into the reaction flask, and heat up to reflux Stir the reaction for 6.0 to 16.0 hours (the reaction progress is tracked by TLC); after the reaction is completed, filter while it is hot, wash the filter cake with a small amount of acetonitrile, evaporate the filtrate to remove the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether- Ethyl acetate=30:1 v/v), the corresponding amine alkoxythioxanthone compound (I) was obtained, the yield was 70.8%-86.0%, and its chemical structure was verified by ¹ H-NMR and ¹³ C-NMR Confirmed by ESI-MS, the purity of the obtained target substance was greater than 97.0% as determined by HPLC. The structure of the target object prepared by the above-mentioned general method is as follows:

Example 3 General method for the preparation of amine alkoxythioxanthone compound (I) and acid salt formation

Add 2.0 mmol of the amine alkoxythioxanthone compound (I) obtained according to the above-mentioned Example 1-2 and 50 ml of acetone into the reaction flask, stir evenly, add 6.0 mmol of the corresponding acid, heat up and reflux and stir for 20 minutes, After the reaction, cool to room temperature, evaporate the solvent under reduced pressure, recrystallize the residue with acetone, and filter the precipitated solid to obtain the salt of amine alkoxythioxanthone compound (I), whose chemical structure has been verified by ¹ H NMR and Confirmed by ESI-MS.

Claims (10)

1. A class of amine alkoxythioxanthone compounds or pharmaceutically acceptable salts thereof, characterized in that the general chemical structure of the compounds is as shown in (I): In the formula: R represents -(CH ₂ )n-NR ₁ R ₂ , n represents 2-12, R ₁ represents H, C ₁ ~C ₁₂ alkyl; R ₂ represents C ₁ ~C ₁₂ alkyl, benzyl or Substituted benzyl; NR ₁ R ₂ can also represent tetrahydropyrrolyl, morpholinyl, piperidinyl, piperidinyl substituted by C ₁ ~ C ₁₂ alkyl at the 4-position, benzyl or substituted at the 4-position Piperidinyl substituted by benzyl, piperazinyl, piperazinyl substituted by C ₁ ~C ₁₂ alkyl at 4-position, piperazinyl substituted by benzyl or substituted benzyl at 4-position; R also Can represent , m represents 1-10, R ₃ represents H, C ₁ ~ C ₁₂ alkyl, benzyl or substituted benzyl; the above-mentioned "substituted benzyl" means that the benzene ring is replaced by 1-4 groups selected from the group below Benzyl substituted by group: F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano , these substituents can be at any possible position of the benzene ring. 2. The amine alkoxy thioxanthone compound or its pharmaceutically acceptable salt as claimed in claim 1, characterized in that said pharmaceutically acceptable salt is such amine alkoxy thioxanthone Compounds with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C _1-6 fatty carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, Salts of lipoic acid, _C1-6 alkylsulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. 3. The method for preparing the amine alkoxythioxanthone compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-2, characterized in that the compound can be prepared by the following two methods: Method 1: When R represents -(CH ₂ )n-NR ₁ R ₂ , and n represents 2-12: In the formula: X represents Cl, Br, I; the definition of R ₁ , R ₂ , n is the same as that of the general chemical structure formula (I); Step a): Using 1,3-dihydroxythioxanthone (1) as a starting material, react with a dihaloalkyl compound (2) under solvent and alkaline conditions to generate the corresponding 1-hydroxy-3-oxo Alkyl halide compounds (3); Step b): reacting the intermediate 3 obtained in step a) with the organic amine compound (4) in a solvent to obtain the corresponding amine alkoxythioxanthone compound (I); Method 2: When R means , when m means 1-10: In the formula: X represents Cl, Br, I; the definitions of R ₃ and m are the same as those of the general chemical structure formula (I); Using 1,3-dihydroxythioxanthone (1) as the starting material, react with 1-substituted-4-haloalkylpiperidine (5) under solvent and alkaline conditions to obtain the corresponding amine alkoxythioxanthone Xanthones (I); The amine alkoxythioxanthone compound (I) obtained by the above two methods contains an amino group in its molecule, which is basic and can be prepared with any suitable acid by a pharmaceutically conventional salt-forming method. acceptable salt. 4. the preparation method of amine alkoxy thioxanthone compound or its pharmaceutically acceptable salt as claimed in claim 3, it is characterized in that in the step a) of method one, the alkali used in reaction is: alkali metal hydroxide , alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal salts of C _1-8 alcohols, triethylamine, tributylamine, tri Octylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylenediamine, or tetrabutylammonium hydroxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformamide, di Methyl sulfoxide, methylene chloride, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes; 1,3-dihydroxythioxanthone (1): dihaloalkyl compounds (2 ): The molar feeding ratio of alkali is 1.0:1.0~10.0:1.0~10.0; the reaction temperature is room temperature~150°C; the reaction time is 1~72 hours. 5. the preparation method of amine alkoxy thioxanthone compound or its pharmaceutically acceptable salt as claimed in claim 3, it is characterized in that in the step b) of method one, the solvent used for reaction is: ether, tetrahydrofuran, N , N -dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile, C _1-8 alcohols, or C _5-8 alkanes; intermediates ( 3): The molar feed ratio of the organic amine compound (4) is 1.0:1.0~10.0; the reaction temperature is room temperature~150°C; the reaction time is 1~72 hours. 6. the preparation method of amine alkoxy thioxanthone compound or its pharmaceutically acceptable salt as claimed in claim 3 is characterized in that in method two, the alkali used in reaction is: alkali metal hydroxide, alkaline earth metal hydrogen Oxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, triethylamine, tributylamine, trioctylamine, pyridine, N -methylmorpholine, N- Methylpiperidine, triethylenediamine, tetrabutylammonium hydroxide, or alkali metal salts of C _1-8 alcohols; the solvents used for the reaction are: ether, tetrahydrofuran, N,N -dimethylformamide, dimethyl sulfoxide , dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes; 1,3-dihydroxythioxanthone (1): 1-substituted-4-haloalkylpiperidine (5): The molar feeding ratio of alkali is 1.0:1.0~10.0:1.0~10.0; the reaction temperature is room temperature~150°C; the reaction time is 1~72 hours. 7. A pharmaceutical composition characterized by comprising the amine alkoxythioxanthone compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-2. 8. The pharmaceutical composition according to claim 7, characterized in that the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers or excipients. 9. The pharmaceutical composition according to claim 7 or 8, characterized in that the amine alkoxythioxanthone compound or a pharmaceutically acceptable salt thereof as an active ingredient accounts for 5% to 99.5% of the total weight. 10. Use of the amine alkoxythioxanthone compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-2 in the preparation of medicines for the treatment and/or prevention of neurodegenerative related diseases, such The neurodegenerative related disease is: vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, or glaucoma.