CN106810532B - A kind of amine alkoxy thioxanthene ketone class compound, preparation method and use - Google Patents

A kind of amine alkoxy thioxanthene ketone class compound, preparation method and use Download PDF

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CN106810532B
CN106810532B CN201611181250.5A CN201611181250A CN106810532B CN 106810532 B CN106810532 B CN 106810532B CN 201611181250 A CN201611181250 A CN 201611181250A CN 106810532 B CN106810532 B CN 106810532B
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acid
compound
pharmaceutically acceptable
thioxanthene ketone
ketone class
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CN106810532A (en
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邓勇
罗礼
曹忠诚
徐锐
宋青
张小玉
刘红艳
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/10—Dibenzothiopyrans; Hydrogenated dibenzothiopyrans
    • C07D335/12—Thioxanthenes
    • C07D335/14—Thioxanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D335/16—Oxygen atoms, e.g. thioxanthones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses a kind of novel amine alkoxy thioxanthene ketone class compound (I) and its pharmaceutically acceptable salt, preparation method, pharmaceutical composition and the purposes in preparation treatment and/or prevention nervus retrogression related disease drug, the including but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma；

Description

A kind of amine alkoxy thioxanthene ketone class compound, preparation method and use
Technical field
The invention belongs to field of medicinal chemistry, are related to a kind of novel amine alkoxy thioxanthene ketone class compound (I) and its pharmacy It goes up acceptable salt, preparation method, pharmaceutical composition and nervus retrogression related disease drug is treated and/or prevented in preparation In purposes, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementias The neurodegenerative diseases such as disease, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Background technique
Alzheimer's disease (Alzheimer ' s disease, AD, senile dementia) is one kind with progressive cognitive disorder With the central nervous system degenerative disease based on memory damage, disease incidence becomes in trend is risen year by year and is only second to the heart The high incidence disease of angiosis and cancer, having gone up in developed countries such as America and Europes is the 4th of the cause of death.According to world health Organisation Report, global over-65s old man have 10% dysnoesia, and wherein half occurs dull-witted, fall ill within 85 years old or more Rate nearly 50%.The AD patient numbers about 600-700 ten thousand in China, disease incidence are more than 5%.With adding for population in the world aging process Fastly, disease incidence is in obvious ascendant trend, is announced according to Alzheimer's Disease International in September, 2016 " World Alzheimer Report 2016 " report in point out, AD is good for the maximum that faces of the coming few decades whole world is become Health challenge, to the year two thousand thirty, patient numbers will rise to 76,000,000 by 47,000,000 in 2015, and to the year two thousand fifty, this numerical value will reach To surprising 1.31 hundred million.Due to AD clinical manifestation be memory capability, capacity of orientation, thinking and judgement decline and it is daily Viability reduces, or even abnormal Behavioral and psychological symptom occur etc., while it being also accompanied by significant depressive symptom, make patient care Difficulty is larger, brings heavy burden to society and family.The drug that approved is used to treat light/moderate AD at present has acetylcholine Esterase (AChE) inhibitor, and for severe AD treatmentNMethyl-DAspartic acid (NMDA) receptor antagonist, but it is clinical Using show these drugs can by improve patient's body levels of acetylcholine or inhibit excitatory amino acid exitotoxicity Alleviate AD symptom, but not can effectively prevent or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, evil The serious toxic side effect such as the heart, hepatotoxicity, loss of appetite and stool frequency, thus long-term efficacy is not satisfactory.Therefore, clinical On there is an urgent need to research and develop the AD therapeutic agent with novel mechanism of action.
AD belongs to disease caused by many factors, and pathogenesis is complicated, does not illustrate its pathogenesis completely also so far, but study Show patient's intracerebral levels of acetylcholine decline,βThe excessive generation and deposition, metal ion metabolism of amyloid protein are disorderly Disorderly, Ca2+Dysequilibrium,tauNeurofibrillary tangles caused by protein hyperphosphorylation, monoamine oxidase B (MAO-B) activity increase By force, glutamate receptor activity is excessively high, oxidative stress generates a large amount of active oxygens (ROS) and free radical and Neuroinflammation etc. are more Kind factor is played an important role in the pathogenic process of AD.In addition, current research finds that there is also significant by most of AD patients Depressive symptom, depression can increase intracerebralβThe deposition of amyloid protein simultaneously aggravates its cognition dysfunction.For above-mentioned morbidity Factor, researcher is using traditional " one target of a medicine " drug design strategies, it was found that largely to a certain target spot have high activity and Highly selective drug, such as: anticholinesterase andNMethyl-DAspartate receptor agonist etc., but these drugs are deposited The problems such as action target spot is single, clinical use toxic side effect is more, not good enough to the long-term efficacy of AD patient.
In recent years, with constantly illustrating to AD pathogenesis, it is found that the occurrence and development of AD have multimachine system, multifactor It is the characteristics of effect, again interrelated between different mechanisms to influence each other, constitute complicated network during AD occurrence and development Regulator control system.Based on the above results, researcher proposes " multiple target point targeted drug " (Multitarget-directed Ligands, MTDLs) strategy researches and develops anti-neurodegenerative disease drug.So-called " multiple target point drug " refers to that single chemistry is real Body acts on multiple target spots in disease network simultaneously, can produce synergistic effect to the effect of each target spot, is greater than gross effect each Single-action the sum of is answered, and such medicine is also referred to as " Multifunctional " or " Multipotential " drug.Multiple target point drug and more Medicine use in conjunction and the main distinction of compound medicine are: can reduce dosage, improve therapeutic effect, avoid between drug Interaction and thus bring toxic side effect, uniform pharmacokinetic properties, be easy to use etc..It designs and finds have simultaneously Have and inhibits monoamine oxidase A and B, anti-oxidation stress, resistsβExcessive generation and the deposition, selective complexation maincenter of amyloid protein Metal ion (especially Cu in tissue2+And Fe2+), and the multiple target point AD medicine that multiple biological activities intensity is more balanced Object is current research hotspot.Therefore, research and development have novel chemical structure, novel mechanism of action, and have multiple target point (or It is multi-functional) effect, less toxic side effect anti-neurodegenerative disease therapeutic agent not only conform with the urgent of social senilization's process Demand, and there are good market prospects.
Summary of the invention
Present invention aims at open a kind of novel amine alkoxy thioxanthene ketone class compounds (I) and its pharmaceutically acceptable Salt；
Another object of the present invention is to disclose such amine alkoxy thioxanthene ketone class compound (I) and its pharmaceutically acceptable The preparation method of salt；
Another object of the present invention is to open comprising such amine alkoxy thioxanthene ketone class compound (I) and its pharmaceutically may be used The pharmaceutical composition of the salt of receiving；
Still a further object of the present invention is to disclose such amine alkoxy thioxanthene ketone class compound (I) and its pharmaceutically acceptable Salt has multiple target effect, can be used for preparing the purposes in the drug for the treatment of and/or prevention nervus retrogression related disease, including But it is not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis The neurodegenerative diseases such as disease, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
The general formula of the chemical structure of amine alkoxy thioxanthene ketone class compound (I) disclosed in this invention are as follows:
In formula: R expression-(CH2)n-NR1R2, n expression 2-12, R1Indicate H, C1~C12Alkyl；R2Indicate C1~C12Alkyl, benzyl Base or substituted benzyl；NR1R2May also indicate that nafoxidine base, morpholinyl, piperidyl, 4- by C1~C12Piperidines replaced alkyl Base, the 4- piperidyls replaced benzyl or substituted benzyl, piperazinyl, 4- by C1~C12Piperazinyl replaced alkyl, 4- Position piperazinyl replaced benzyl or substituted benzyl；R may also indicate that, m expression 1-10, R3Expression H, C1~C12Alkyl, benzyl or substituted benzyl；Above-mentioned term " substituted benzyl " refer to by phenyl ring by 1-4 groups selected from the group below Replaced benzyl: F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyanogen Base, these substituent groups can be in any possible positions of phenyl ring.
Amine alkoxy thioxanthene ketone class compound (I) proposed by the invention can be prepared by the following method to obtain:
(1) as R expression-(CH2)n-NR1R2, when n indicates 2-12:
In formula: X indicates Cl, Br, I；R1、R2, the definition of n it is identical as general formula of the chemical structure (I)；
Step a): with 1,3- dihydroxy thioxanthones (1) be starting material, under solvent and alkaline condition with Dihaloalkyl Object (2) reaction is closed, corresponding 1- hydroxyl -3- oxyalkyl halogen compound (3) is generated；
Step b): the intermediate 3 obtained by step a) reacts in a solvent with organic amine compound (4), obtains corresponding amine Alkoxy thioxanthene ketone class compound (I)；
Its specific preparation method is described as follows:
In the step a), alkali used is reacted are as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonic acid Salt, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, trimethylamine class Or quaternary ammonium bases (such as: triethylamine, tri-n-butylamine, trioctylamine, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene diamine, four fourths Base ammonium hydroxide), preferred alkali are as follows: potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, pyridine or sodium methoxide；Reaction Solvent for use are as follows: ether, tetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, C3-8Aliphatic ketone, Benzene, toluene, acetonitrile or C5-8Alkane, preferred solvent are as follows:N,NDimethylformamide, acetone, acetonitrile, tetrahydrofuran or toluene；1, 3- dihydroxy thioxanthones (1): Dihaloalkyl compound (2): the molar feed ratio of alkali is 1.0:1.0 ~ 10.0:1.0 ~ 10.0, excellent Selecting molar feed ratio is 1.0:1.0 ~ 5.0:1.0 ~ 5.0；Reaction temperature is room temperature ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 ℃；Reaction time is 1 ~ 72 hour, and preferred reaction time is 2 ~ 24 hours；
In the step b), react solvent for use are as follows: ether, tetrahydrofuran,N,NDimethylformamide, dimethyl are sub- Sulfone, methylene chloride, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane, preferred solvent are as follows:N,NDimethyl Formamide, acetone, acetonitrile, tetrahydrofuran, ethyl alcohol or toluene；Intermediate (3): the molar feed ratio of organic amine compound (4) For 1.0:1.0 ~ 10.0, preferably molar feed ratio is 1.0:1.0 ~ 5.0；Reaction temperature is room temperature ~ 150 DEG C, preferable reaction temperature For room temperature ~ 120 DEG C；Reaction time is 1 ~ 72 hour, and preferred reaction time is 2 ~ 24 hours.
(2) when R is indicated, when m indicates 1-10:
In formula: X indicates Cl, Br, I；R3, the definition of m it is identical as general formula of the chemical structure (I)；
With 1,3- dihydroxy thioxanthones (1) be starting material, under solvent and alkaline condition with 1- substitution -4- alkylhalide group piperazine Pyridine (5) reaction, obtains corresponding amine alkoxy thioxanthene ketone class compound (I)；
Its specific preparation method is described as follows:
React alkali used are as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline-earth metal carbon Hydrochlorate, alkali metal hydrogencarbonate, alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases are (such as: triethylamine, tri-n-butylamine, three Octylame, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene diamine, tetrabutylammonium hydroxide) or C1-8The alkali metal salt of alcohol, It is preferred that alkali are as follows: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide；React solvent for use are as follows: ether, four Hydrogen furans,N,NDimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile or C5-8 Alkane, preferred solvent are as follows:N,NDimethylformamide, acetone, acetonitrile, tetrahydrofuran or toluene；1,3- dihydroxy thioxanthones (1): 1- substitution -4- alkyl halide phenylpiperidines (5): the molar feed ratio of alkali is 1.0:1.0 ~ 10.0:1.0 ~ 10.0, preferably mole is fed intake Than for 1.0:1.0 ~ 3.0:1.0 ~ 5.0；Reaction temperature is room temperature ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C；When reaction Between be 1 ~ 72 hour, preferred reaction time be 2 ~ 24 hours.
Contain amino in amine alkoxy thioxanthene ketone class compound (I) molecule of gained according to the method described above, which is in alkali Property, its pharmaceutically acceptable salt, the acid can be made by pharmaceutically conventional salifying method with any suitable acid Are as follows: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid (such as: formic acid, acetic acid, propionic acid), oxalic acid, benzoic acid, water Poplar acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Alkyl sulfonic acid is (such as: methyl sulphur Acid, ethylsulfonic acid etc.), camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
Pharmaceutical composition disclosed in this invention includes one or more amine alkoxy thioxanthene ketone class of therapeutically effective amount Object (I) or its pharmaceutically acceptable salt are closed, which can be further containing one or more pharmaceutically acceptable Carrier or excipient." therapeutically effective amount ", which refers to, causes researcher or targeted tissue, system or the life of animal of doctor The amount of the drug or medicament of object or medicine reaction；" composition " refers to by mixing more than one substances or component Product；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable substance, composition or carrier, such as: liquid or Solid-filling agent, diluent, excipient, solvent or packing substance, they carry or transport certain chemical substance.The present invention is mentioned Its ideal ratio of the pharmaceutical composition of confession is that amine alkoxy thioxanthene ketone class compound (I) or its pharmaceutically acceptable salt are made Total weight is accounted for than 2%~99.5% for active constituent, and rest part is to account for total weight than 98% or less.
Amine alkoxy thioxanthene ketone class compound (I) disclosed in this invention and its pharmaceutically acceptable salt have carried out as follows Bioactivity screening.
(1) inhibitory activity of the amine alkoxy thioxanthene ketone class compound (I) to monoamine oxidase A and B
Recombined human MAO-A is made into 12.5 μ g/mL sample liquids with 7.4 kaliumphosphate buffer of pH of 100 mM, by MAO-B It is made into 75 μ g/mL sample liquids.20 μ L of testing compound solution, 80 μ L of monoamine oxidase are added into 96 orifice plate of black, mixes Even, 37 °C are incubated for 15 min in the place of being protected from light, and 200 μM of Amplex Red reagents, 2U/mL horseradish peroxidase, 2 mM are added Uteramin (inhibiting MAO-A) or 2 mM benzene methanamines (inhibiting MAO-B) initiation reaction, 37 °C of 20 min of incubation, in more function In energy microplate reader, to fix 545 nm of excitation wavelength, fluorescent emission intensity at 590 nm is surveyed, MAO- is replaced with kaliumphosphate buffer A or MAO-B is blank；The inhibiting rate calculation formula of compound inhibition monoamine oxidase are as follows: 100- (IFi)/(IFc) * 100, formula In, IFiAnd IFcRespectively there is the difference of the fluorescence intensity and blank fluorescence intensity under inhibitor and no inhibitor.Each compound 3 multiple holes of measurement every time, every group of experiment are independent in triplicate.Five to six concentration for selecting compound, measure its enzyme inhibition rate, And with the inhibiting rate linear regression of the negative logarithm of the compound molar concentration and enzyme, molar concentration when acquiring 50% inhibiting rate is i.e. For the IC of the compound50.Measurement result shows the amine alkoxy thioxanthene ketone class compound (I) disclosed in the embodiment of the present invention The effect of significantly inhibiting is all had to MAO-A and MAO-B, wherein the IC inhibited to MAO-A50It is 0.3 μM ~ 10.0 μM, to MAO- The IC that B inhibits50It is 0.1 μM ~ 10.0 μM.
(2) amine alkoxy thioxanthene ketone class compound (I) is to Aβ 1-42The inhibitory activity of self assemble
Reference literature (Qiang, X.M.et al.Eur. J Med. Chem.2014,76,314-331) reported Method be measured, it may be assumed that pretreated Aβ 1-42It is made into stock solution with DMSO, using preceding dilute with the PBS buffer solution of pH7.4 It releases to 50 μM；Untested compound is made into 2.5 mM stock solutions with DMSO, is diluted to accordingly using preceding with the PBS buffer solution of pH7.4 Concentration takes the A of 20 μ Lβ 1-42The A of the testing compound solution of+20 μ L of solution, 20 μ Lβ 1-42The PBS buffer solution of+20 μ L of solution (contains 2%DMSO) in 96 orifice plates, 37 °C are incubated for for 24 hours, and the glycine-NaOH for the 50mM that 160 μ L contain 5 μM of thioflavine Ts is then added Buffer (pH=8.5) is surveyed under 446 nm excitation wavelengths and 490 nm launch wavelengths with multi-function microplate reader immediately after shaking 5s Determine fluorescent value；Aβ 1-42The fluorescent value of+untested compound is denoted as IFi, Aβ 1-42The fluorescent value of+PBS buffer solution is denoted as IFc, contain only The fluorescent value of PBS buffer solution is denoted as IF0, compound inhibition Aβ 1-42The inhibiting rate of self assemble are as follows: 100- (IFi-IF0)/(IFc- IF0)*100；Five to six concentration for selecting compound, measure its inhibiting rate, each each concentration repetition measurement of compound three times, with Curcumin is positive control.Measurement result shows the amine alkoxy thioxanthene ketone class compound (I) disclosed in the embodiment of the present invention To Aβ 1-42Self assemble all has remarkable inhibiting activity, to A under 25.0 μM of concentrationβ 1-42The inhibiting rate of self assemble is all larger than 40.0%；Control drug used: 1,3- dihydroxy thioxanthones (1) and curcumin are under same concentrations to Aβ 1-42The suppression of self assemble Rate processed is respectively 9.5% and 36.2%.
(3) measurement of amine alkoxy thioxanthene ketone class compound (I) and complexing of metal ion effect
CuCl is dissolved with methanol2·2H2O、ZnCl2、FeSO4·7H2O、AlCl3And untested compound, it is made into 75 μm of ol/L Solution, 100 μ L testing compound solutions and 100 μ L metal ion solutions are added into 96 orifice plates, mix, be stored at room temperature 30 Min records ultraviolet absorption curve of the mixture within the scope of 200-600 nm on multi-function microplate reader, and to be measured with 100 μ L Compound solution and 100 μ L methyl alcohol mixed liquors are control, observe the maximum absorption band of metal ion and untested compound mixed liquor Red Shift Phenomena and maximum absorption band intensity.Measurement result shows the amine alkoxy thioxanthene disclosed in the embodiment of the present invention Ketone compounds (I) are shown to Cu2+And Fe2+With selective complexation effect, and to Zn2+And Al3+Make almost without complexing With.
(4) amine alkoxy thioxanthene ketone class compound (I) is to Cu2+The A of inductionβ 1-42The inhibitory activity of aggregation
By CuCl275 μM of solution are made into HEPES buffer solution, with HEPES buffer solution by compound stock solution (2.5 mM) With 200 μM of Aβ 1-42Stock solution is diluted to 75 μM, takes 20 μ L Cu respectively2++ 20 μ L A of solutionβ 1-42+ 20 μ L to be measuredization of solution Polymer solution, 20 μ L Cu2++ 20 μ L A of solutionβ 1-42+ 20 μ L HEPES buffer solution of solution and 60 μ L HEPES buffer solutions are in 96 It in orifice plate, mixes, then the glycine-NaOH buffer for the 50mM that 190 μ L contain 5 μM of thioflavine Ts is added in 37 °C of 24 h of incubation (pH=8.5) measure fluorescence under 446nm excitation wavelength and 490nm launch wavelength with multi-function microplate reader immediately after shaking 5s Value；Cu2++Aβ 1-42The fluorescent value of+untested compound is recorded as IFi, Cu2++Aβ 1-42The fluorescent value of+HEPES buffer solution is recorded as IFc, the fluorescent value for containing only HEPES buffer solution is recorded as IF0, compound is to Cu2+The A of inductionβ 1-42The inhibiting rate of aggregation are as follows: 100-(IFi-IF0)/(IFc-IF0)*100.Each each three multiple holes of concentration mensuration of compound, using curcumin as positive control. Measurement result shows that the amine alkoxy thioxanthene ketone class compound (I) disclosed in the embodiment of the present invention is right under 25.0 μM of concentration Cu2+The A of inductionβ 1-42The inhibiting rate of aggregation is all larger than 75.0%；And inhibiting rate of the curcumin under same concentrations is 62.1%, 1, Inhibiting rate of the 3- dihydroxy thioxanthones (1) under same concentrations is only 31.4%.
(5) antioxidant activity (ORAC-FL method) of amine alkoxy thioxanthene ketone class compound (I)
Reference literature (Qiang, X.M.et al.Eur. J Med. Chem.2014,76,314-331) reported Method be measured, it may be assumed that 6- hydroxyl -2,5,7,8- tetramethyl primary colours alkane -2- carboxylic acids (Trolox) use pH7.4 PBS buffer solution It is made into the solution of 10-80 μm of ol/L, fluorescein (fluorescein) is made into 250 nmol/L's with the PBS buffer solution of pH7.4 Solution, 2,2 '-azo diisobutyl amidine dihydrochlorides (AAPH) are made into 40 mmol/L's with the PBS buffer solution of pH7.4 using preceding Solution.The compound solution and luciferin solution of 50-10 μm of ol/L are added into 96 orifice plates, mixes, 37 °C of incubation 15min add Enter AAPH solution, make every 200 μ L of hole total volume, mixes, be immediately placed in multi-function microplate reader, in 485 nm excitation wavelengths With 90 min of METHOD FOR CONTINUOUS DETERMINATION under 535 nm launch wavelengths.Area AUC under fluorescence decay curve is calculated, wherein with 1-8 μm of ol/L 'sTroloxAs standard, sample to be tested is not added as blank, the antioxidant activity results expression of compound isTroloxWork as Amount, its calculation formula is: [(AUC Sample-AUC blank)/(AUCTrolox-AUC blank)]´ [(concentration of Trolox/ concentration of sample)], each compound measures 3 again every time Hole, every group of experiment are independent in triplicate.Measurement result shows the amine alkoxy thioxanthene ketone class disclosed in the embodiment of the present invention Close object (I) antioxidant activity beTrolox0.5-2.0 times, illustrate such compound have strong anti-oxidative activity.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention is not limited to Following embodiments.One of skill in the art, can be right it is understood that under the premise of without departing substantially from the spirit and scope of the present invention The present invention carries out various change and modification.
Embodiment 1
R expression-(CH2)n-NR1R2, when n indicates 2-12, method is led in the preparation of amine alkoxy thioxanthene ketone class compound (I)
(1) 2.0 mmol of 1,3- dihydroxy thioxanthones, 30 ml acetonitriles, 7.0 mmol Carbon Dioxides are added in reaction flask (2) 7.0 mmol of potassium and dibromo alkyl compound, temperature rising reflux be stirred to react 3.0~12.0 hours (reaction process TLC with Track)；After reaction, it filters while hot, a small amount of acetonitrile washs filter cake, and solvent and excessive dibromo alkyl chemical combination is evaporated off in filtrate decompression Object, residue are purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate=30:1 v/v), obtain 1- hydroxyl -3- oxyalkyl Halogen compound (3), yield 76.2%-88.0%；
Above-mentioned 1- hydroxyl -3- oxyalkyl halogen compound (3) full dose is dissolved in 30 ml ethyl alcohol, it is organic that 6.0 mmol are added Aminated compounds (4), temperature rising reflux are stirred to react 6.0~16.0 hours (reaction process is tracked with TLC)；After reaction, subtract Pressure solvent is evaporated off, 50 ml methylene chloride are added in residue, successively with 20 ml, 5% sodium hydrate aqueous solution and 20 ml go from Sub- water washing, organic layer filter after being dried over anhydrous sodium sulfate, evaporating solvent under reduced pressure, residue through column chromatographic purifying (eluent: Petroleum ether-ethyl acetate=30:1 v/v), obtain corresponding amine alkoxy thioxanthene ketone class compound (I), yield 72.0%-90.6%, Its chemical structure passes through1H-NMR、13The purity of C-NMR and ESI-MS confirmation, gained object is all larger than through HPLC measurement 97.0%.The object structure being prepared using above-mentioned logical method is as follows:
2 R of embodiment is indicated, when m indicates 1-10, amine alkoxy thioxanthene ketone class compound (I) Prepare logical method
(1) 2.0 mmol of 1,3- dihydroxy thioxanthones, 30 ml acetonitriles, 3.0 mmol Carbon Dioxides are added in reaction flask Potassium and 2.5 mmol 1- substitution -4- alkyl halide phenylpiperidines (5), temperature rising reflux is stirred to react 6.0~16.0 hours, and (reaction process is used TLC tracking)；After reaction, it filters while hot, a small amount of acetonitrile washs filter cake, and solvent is evaporated off in filtrate decompression, and residue is chromatographed through column It purifies (eluent: petroleum ether-ethyl acetate=30:1 v/v), obtains corresponding amine alkoxy thioxanthene ketone class compound (I), yield 70.8%-86.0%, chemical structure pass through1H-NMR、13C-NMR and ESI-MS confirmation, the purity of gained object are surveyed through HPLC Surely it is all larger than 97.0%.The object structure being prepared using above-mentioned logical method is as follows:
3 amine alkoxy thioxanthene ketone class compound (I) of embodiment and acid are prepared at salt leads to method
The amine alkoxy thioxanthene ketone class compound (I) 2.0 of -2 gained in accordance with the above-mentioned embodiment 1 is added in reaction flask 50 ml of mmol and acetone, is stirring evenly and then adding into that 6.0 mmol are sour accordingly, and temperature rising reflux is stirred to react 20 minutes, reaction knot It is cooled to room temperature after beam, evaporating solvent under reduced pressure, residue acetone recrystallization, filters the solid of precipitation to get amine alkoxy thiophene The salt of xanthones compound (I), chemical structure warp1H NMR and ESI-MS confirmation.

Claims (10)

1. a kind of amine alkoxy thioxanthene ketone class compound or its pharmaceutically acceptable salt, it is characterised in that the change of such compound It is shown to learn general structure such as (I):
In formula: R expression-(CH2)n-NR1R2, n expression 2-12, R1Indicate H, C1~C12Alkyl；R2Indicate C1~C12Alkyl, benzyl or Substituted benzyl；NR1R2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4- by C1~C12Piperidyl replaced alkyl, 4- Position piperidyl replaced benzyl or substituted benzyl, piperazinyl, 4- by C1~C12Piperazinyl replaced alkyl, 4- quilt Piperazinyl replaced benzyl or substituted benzyl；R is also illustrated that, m expression 1-10, R3Indicate H, C1~C12 Alkyl, benzyl or substituted benzyl；Above-mentioned " substituted benzyl " refers to the benzyl replaced 1-4 groups selected from the group below on phenyl ring Base: F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano, these take Any possible position of the Dai Jike in phenyl ring.
2. amine alkoxy thioxanthene ketone class compound as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that The pharmaceutically acceptable salt is such amine alkoxy thioxanthene ketone class compound and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphorus Acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, Lipoic acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid salt.
3. the preparation of amine alkoxy thioxanthene ketone class compound or its pharmaceutically acceptable salt as described in claim any one of 1-2 Method, it is characterised in that the compound can be prepared by following two method:
Method one: as R expression-(CH2)n-NR1R2, when n indicates 2-12:
In formula: X indicates Cl, Br, I；R1、R2, the definition of n it is identical as general formula of the chemical structure (I)；
Step a): with 1,3- dihydroxy thioxanthones (1) be starting material, under solvent and alkaline condition with Dihaloalkyl compound (2) it reacts, generates corresponding 1- hydroxyl -3- oxyalkyl halogen compound (3)；
Step b): the intermediate 3 obtained by step a) reacts in a solvent with organic amine compound (4), obtains corresponding amine alcoxyl Base thioxanthene ketone class compound (I)；
Method two: when R is indicated, when m indicates 1-10:
In formula: X indicates Cl, Br, I；R3, the definition of m it is identical as general formula of the chemical structure (I)；
With 1,3- dihydroxy thioxanthones (1) be starting material, under solvent and alkaline condition with 1- substitution -4- alkyl halide phenylpiperidines (5) it reacts, obtains corresponding amine alkoxy thioxanthene ketone class compound (I)；
Using amino is contained in amine alkoxy thioxanthene ketone class compound (I) molecule of above two method gained, which is in alkali Property, its pharmaceutically acceptable salt can be made by pharmaceutically conventional salifying method with any suitable acid.
4. the preparation method of amine alkoxy thioxanthene ketone class compound as claimed in claim 3 or its pharmaceutically acceptable salt, It is characterized in that in the step a) of method one, reacts alkali used are as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal Carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, triethylamine, Tri-n-butylamine, trioctylamine, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene diamine or tetrabutylammonium hydroxide；Used in reaction Solvent are as follows: ether, tetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, C3-8Aliphatic ketone, benzene, Toluene, acetonitrile or C5-8Alkane；1,3- dihydroxy thioxanthones (1): Dihaloalkyl compound (2): the molar feed ratio of alkali is 1.0: 1.0 ~ 10.0:1.0 ~ 10.0；Reaction temperature is room temperature ~ 150 DEG C；Reaction time is 1 ~ 72 hour.
5. the preparation method of amine alkoxy thioxanthene ketone class compound as claimed in claim 3 or its pharmaceutically acceptable salt, Be characterized in that in the step b) of method one, react solvent for use are as follows: ether, tetrahydrofuran,N,NDimethylformamide, dimethyl Sulfoxide, methylene chloride, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane；Intermediate (3): organic amine The molar feed ratio of compound (4) is 1.0:1.0 ~ 10.0；Reaction temperature is room temperature ~ 150 DEG C；Reaction time is 1 ~ 72 hour.
6. the preparation method of amine alkoxy thioxanthene ketone class compound as claimed in claim 3 or its pharmaceutically acceptable salt, It is characterized in that in method two, reacts alkali used are as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkali Earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, triethylamine, tri-n-butylamine, trioctylamine, pyridine,NMethyl Morpholine,NMethyl piperidine, triethylene diamine, tetrabutylammonium hydroxide or C1-8The alkali metal salt of alcohol；React solvent for use are as follows: second Ether, tetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile Or C5-8Alkane；1,3- dihydroxy thioxanthones (1): 1- substitution -4- alkyl halide phenylpiperidines (5): the molar feed ratio of alkali be 1.0:1.0 ~ 10.0:1.0 ~ 10.0；Reaction temperature is room temperature ~ 150 DEG C；Reaction time is 1 ~ 72 hour.
7. a kind of pharmaceutical composition, it is characterised in that comprising such as the described in any item amine alkoxy thioxanthene ketone class of claim 1-2 Compound or its pharmaceutically acceptable salt.
8. pharmaceutical composition as claimed in claim 7, it is characterised in that the pharmaceutical composition further contains one or more Pharmaceutically acceptable carrier or excipient.
9. pharmaceutical composition as claimed in claim 7 or 8, it is characterised in that the amine alkoxy thioxanthene ketone class compound or its Pharmaceutically acceptable salt accounts for total weight than 5%~99.5% as active constituent.
10. as the described in any item amine alkoxy thioxanthene ketone class compounds of claim 1-2 or its pharmaceutically acceptable salt exist Purposes in preparation treatment and/or prevention nervus retrogression related disease drug, this kind of nervus retrogression related disease are as follows: blood vessel Property dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis or progressive ridge Marrow lateral schlerosis.
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GB1195752A (en) * 1967-02-10 1970-06-24 Sterling Drug Inc Xanthene and Thioxanthene Derivatives
WO1996036347A1 (en) * 1995-05-17 1996-11-21 Eli Lilly And Company Use of leukotriene antagonists for alzheimer's disease
WO2005077899A2 (en) * 2004-02-04 2005-08-25 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use

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US7365193B2 (en) * 2004-02-04 2008-04-29 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use

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Publication number Priority date Publication date Assignee Title
GB1195752A (en) * 1967-02-10 1970-06-24 Sterling Drug Inc Xanthene and Thioxanthene Derivatives
WO1996036347A1 (en) * 1995-05-17 1996-11-21 Eli Lilly And Company Use of leukotriene antagonists for alzheimer's disease
WO2005077899A2 (en) * 2004-02-04 2005-08-25 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use

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