CN105439876B - 2 hydroxylated chalcone aminated compounds, preparation method and use - Google Patents
2 hydroxylated chalcone aminated compounds, preparation method and use Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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Abstract
The invention discloses 2 new hydroxylated chalcone aminated compounds of a class（I）And its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and the purposes in treatment and/or prevention nervus retrogression relevant disease medicine is prepared, including but not limited to nerve degenerative 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
Technical field
The invention belongs to medicinal chemistry art, it is related to the new 2- hydroxylated chalcone aminated compounds of a class（I）And its pharmacy
Go up acceptable salt, its preparation method, pharmaceutical composition and prepare treatment and/or prevention nervus retrogression relevant disease medicine
In purposes, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementias
The nerve degenerative diseases such as disease, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Background technology
Alzheimer's disease（Alzheimer ' s disease, AD, senile dementia）Be one kind with progressive cognitive disorder
With memory damage based on central nervous system degenerative disease, its incidence of disease is in ascendant trend year by year, as being only second to the heart
The frequently-occurring disease of angiosis and cancer, has gone up as the 4th of the cause of death in developed countries such as America and Europes.According to world health
Organisation Report, global over-65s old man has 10% dysnoesia, wherein 1/2nd occur dull-witted, morbidity in more than 85 years old
Rate nearly 50%.In China AD patient numbers about 600-700 ten thousand, the incidence of disease is more than 5%.With adding for population in the world aging process
It hurry up, its incidence of disease is in obvious ascendant trend, is announced according to Alzheimer's Disease International in December, 2013
's《The global implication of Alzheimer's disease：2013-2050》Pointed out in report, AD will face most as the coming few decades whole world
Big Health challenges, to the year two thousand thirty, patient numbers will rise to 76,000,000 by 44,000,000 in 2013, to the year two thousand fifty, this numerical value
It is up to surprising 1.35 hundred million.Because AD clinical manifestations are that memory capability, capacity of orientation, thinking and judgement decline, and
Activity of daily living is reduced, or even abnormal Behavioral and psychological symptom etc. occurs, makes patient care difficulty larger, to society and family's band
Carry out heavy burden.The medicine that current approved is used to treat light/moderate AD has acetylcholinesterase（AChE）Inhibitor, Yi Jiyong
Treated in severe ADN- methyl-D- aspartic acid（NMDA）Receptor antagonist, but Clinical practice shows that these medicines can pass through
The exitotoxicity of levels of acetylcholine or suppression excitatory amino acid in patient's body is improved to alleviate AD symptoms, but can not be effective
Prevent or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, nausea, hepatotoxicity, poor appetite and
The serious toxic side effect such as stool frequency, thus long-term efficacy is not satisfactory.Therefore, clinically in the urgent need to research and development have new work
With the AD medicines of mechanism.
Disease caused by AD category many factors, pathogenesis is complicated, does not illustrate its pathogenesis, but research completely also so far
Show, the decline of patient's intracerebral levels of acetylcholine,βThe excessive generation of-amyloid and deposition, metal ion metabolism are disorderly
Disorderly, Ca2+Dysequilibrium,tauNeurofibrillary tangles, glutamate receptor activity are too high caused by-protein hyperphosphorylation, aoxidize and answer
Swash and produce a large amount of active oxygens（ROS）Play the part of weight in AD pathogenic process with many factors such as free radical and Neuroinflammation
Want role.For above-mentioned pathogenic factors, researcher is using traditional " target of a medicine one " drug design strategies, it was found that largely to certain
One target spot has the medicine of high activity and high selectivity, such as：Anticholinesterase andN- methyl-D- aspartate receptor antagonism
Agent etc., but these medicines are present that action target spot is single, Clinical practice toxic side effect is more, not good enough to the long-term efficacy of AD patient etc.
Problem.
In recent years, with constantly illustrating to AD pathogenesis, it is found that AD occurrence and development have many mechanism, multifactor
It is again interrelated between the characteristics of effect, different mechanisms to influence each other, constitute complicated network during AD occurrence and development
Regulator control system.Based on the above results, researcher proposes " Mutiple Targets targeted drug "（Multitarget-directed
Ligands, MTDLs）Strategy researches and develops anti-nerve degenerative diseases medicine.So-called " Mutiple Targets medicine " refers to that single chemistry is real
Multiple target spots that body is acted in disease network simultaneously, the effect to each target spot can produce cooperative effect, be more than gross effect each
Sum is answered in single-action, and such medicine is also referred to as " Multifunctional " or " Multipotential " medicine.Mutiple Targets medicine with it is many
Medicine use in conjunction and the main distinction of compound medicine are：Dosage can be reduced, therapeutic effect is improved, avoids between medicine
Interaction and the toxic side effect thus brought, homogeneous pharmacokinetic properties, be easy to use etc..Therefore, research and development tool
There are novel chemical structure, new mechanism of action, and the anti-nerve degenerative diseases treatment with multiple target effect, low toxicity side effect
Medicine not only conforms with the active demand of social senilization's process, and with good market prospects.In early-stage Study, we
For the acetylcholinesterase in AD pathogenic processes and oxidative stress factor, Scutellarein carbamic acid has been designed and synthesized
Ester derivative（CN101337956A、CN102603698A）, talan or ethane carbamate compound
（CN102816090A）, isoflavones carbamate compound（CN102827131A）, flavones alkyl amine compound
（CN103087024A）, siskin isoflavonoid alkyl amine compound（CN103113340A）, talan oxyalkyl amine chemical combination
Thing（CN103073440A）, though these compounds have preferable acetylcholine ester enzyme level and antioxidation activity, to Aβ 1-42
The suppression of self assemble（Inhibiting rate under 20.0 μM of concentration is respectively less than 65.0%）, to Cu2+The A of inductionβ 1-42The suppression of aggregation
（Inhibiting rate under 20.0 μM of concentration is respectively less than 65.0%）And to Cu2+The A of inductionβ 1-42The Disaggregating activity of aggregation（20.0
Depolymerization rate under μM concentration is respectively less than 60.0%）It is undesirable, cause curative effect of these compounds to AD in animal model to be owed
It is good.Therefore, design and find while having anti-acetylcholinesterase, anti-oxidation stress, complexing of metal ion, suppressionβ- amyloid
The excessive generation of albumen and deposition and Mutiple Targets AD medicines are still research direction important at present to activity in a balanced way.
The content of the invention
Present invention aims at disclose a class 2- hydroxylated chalcone aminated compounds（I）And its pharmaceutically acceptable salt；
Another object of the present invention is to disclose such 2- hydroxylated chalcone aminated compounds（I）And its it is pharmaceutically acceptable
The preparation method of salt；
A further object of the present invention is open comprising such 2- hydroxylated chalcone aminated compounds（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 2- hydroxylated chalcone aminated compounds（I）And its it is pharmaceutically acceptable
Salt has multiple target effect, available for the purposes in the medicine for preparing treatment and/or prevention nervus retrogression relevant disease, including
But it is not limited to vascular dementia, Alzheimer's, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis
The nerve degenerative diseases such as disease, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
2- hydroxylated chalcones aminated compounds disclosed in this invention（I）Chemical structure of general formula be：
In formula：R1Represent O (CH2)nNR5R6Or R5R6N, R1Can be in any possible position of phenyl ring；R2、R3And R4Each
Independently represent H or C1~C12Alkyl；R5Represent H, C1~C12Alkyl；R6Represent C1~C12Alkyl, benzyl, substituted benzyl, 1,2,3,
4- tetrahydro acridine -9- bases, the chloro- 1,2,3,4- tetrahydro acridines -9- bases of 6-, the chloro- 1,2,3,4- tetrahydro acridines -9- bases of 8- or 6,8- bis-
Chloro- 1,2,3,4- tetrahydro acridines -9- bases；R5R6N may also indicate thatN- demethylgalanthamine base, nafoxidine base, morpholinyl, piperazine
Piperidinyl, 4- by C1~C12Piperidyl that alkyl is replaced, 4- replaced by benzyl or substituted benzyl piperidyl, piperazinyl,
4- by C1~C12Piperazinyl that alkyl is replaced, the 4- piperazinyls that are replaced by benzyl or substituted benzyl；O(CH2)nNR5R6
It may also indicate that, m represents 0-10, R7Represent H, C1~C12Alkyl, benzyl or substituted benzyl；Above-mentioned art
Language " substituted benzyl " refers to the benzyl replaced on phenyl ring by the 1-4 groups being selected from the group：F、Cl、Br、I、C1-4Alkyl,
C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano group, these substituents can phenyl ring any possibility
Position.
2- hydroxylated chalcones aminated compounds disclosed in this invention（I）It can be prepared by the following method and obtain：
In formula：R1、R2、R3And R4Definition and 2- hydroxylated chalcone aminated compounds（I）Chemical structure of general formula it is identical.
With corresponding compound of benzaldehyde category（1）With 2- hydroxy acetophenone class compounds（2）For initiation material, in solvent and
Direct polycondensation under alkalescence condition, obtains corresponding 2- hydroxylated chalcones aminated compounds（I）.Wherein, reacting alkali used is：Alkali metal
Hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline-earth metal
Bicarbonate, C1-8Alkali metal salt, trimethylamine class or the quaternary ammonium bases of alcohol（Such as：Triethylamine, tri-n-butylamine, trioctylamine, pyridine,N-
Methyl morpholine,N- methyl piperidine, triethylene diamine, TBAH）, preferably alkali is：Potassium hydroxide, sodium hydroxide, carbon
Sour potassium, triethylamine, pyridine or sodium methoxide；Reacting solvent for use is：C1-8Fatty alcohol, C3-8Aliphatic ketone, ether, tetrahydrofuran, 2-
Methyltetrahydrofuran,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, toluene,
Acetonitrile or C5-8Alkane, preferred solvent is：Methanol, ethanol, isopropanol,N,N- dimethylformamide, acetone, acetonitrile, tetrahydrochysene furan
Mutter, dichloromethane or toluene；Compound of benzaldehyde category（1）：2- hydroxy acetophenone class compounds（2）：The molar feed ratio of alkali is
1.0~10.0：1.0：1.0 ~ 10.0, preferably molar feed ratio is 1.0 ~ 4.0：1.0：1.2~6.0；Reaction temperature is 0 ~ 150 DEG C,
Preferable reaction temperature is room temperature ~ 100 DEG C；Reaction time is 1 ~ 120 hour, and preferred reaction time is 2 ~ 72 hours.
Initiation material --- the R of the present invention1Represent O (CH2)nNR5R6When compound of benzaldehyde category（1）Can be according to document
（Yong D.,et al. CN 201310054592.0）Institute's report method, with hydroxy benzaldehyde compound first with it is corresponding
Dibromide react, gained list bromide again with HNR5R6Produced through alkylated reaction.
The 2- hydroxylated chalcone aminated compounds of gained according to the method described above（I）Contain amino in molecule, the amino is in alkali
Property, its pharmaceutically acceptable salt, described acid can be made with any suitable sour salifying method by pharmaceutically routine
For：Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid（Such as：Formic acid, acetic acid, propionic acid etc.）, oxalic acid, benzoic acid, water
Poplar acid, maleic acid, fumaric acid, butanedioic acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Alkyl sulfonic acid（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 2- hydroxylated chalcones amines of therapeutically effective amount
Compound（I）Or its pharmaceutically acceptable salt, the pharmaceutical composition can be further containing one or more pharmaceutically acceptable
Carrier or excipient." therapeutically effective amount " refers to cause researcher or the targeted tissue of doctor, system or the life of animal
The amount of the medicine or medicament of thing or medicine reaction；" composition " refers to form by the way that more than one materials or component are mixed
Product；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, composition or carrier, such as：Liquid or
Solid-filling agent, diluent, excipient, solvent or packing material, they carry or transported certain chemical substance.The present invention is carried
Its preferable ratio of the pharmaceutical composition of confession is, 2- hydroxylated chalcone aminated compounds（I）Or its pharmaceutically acceptable salt is made
Gross weight is accounted for than 2%~99.5% for active component, and remainder is to account for gross weight than less than 98%.
2- hydroxylated chalcones aminated compounds disclosed in this invention（I）And its pharmaceutically acceptable salt carried out it is as follows
Bioactivity screening.
（1）2- hydroxylated chalcone aminated compounds（I）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, i.e.,：Pretreated Aβ 1-42Storing solution is made into DMSO, the PBS using preceding use pH7.4 is dilute
Release to 50 μM；Testing compound is made into 2.0 mM storing solutions with DMSO, is diluted to accordingly with pH7.4 PBS using preceding
Concentration, takes 20 μ L Aβ 1-42The A of the μ of solution+20 L testing compound solution, 20 μ Lβ 1-42The μ of solution+20 L PBS（Contain
2%DMSO）In 96 orifice plates, then 37 °C of incubation 24h add the glycine-NaOH for the 50mM that 160 μ L contain 5 μM of thioflavine Ts
Buffer solution（pH=8.5）, shake and surveyed immediately with multi-function microplate reader under 446 nm excitation wavelengths and 490 nm launch wavelengths after 5s
Determine fluorescent value；Aβ 1-42The fluorescent value of+testing compound is designated as IFi, Aβ 1-42The fluorescent value of+PBS is designated as IFc, comprise only
The fluorescent value of PBS is designated as IF0, compound suppression Aβ 1-42The inhibiting rate of self assemble is：100-(IFi-IF0)/(IFc-
IF0)*100；Select five to six concentration of compound, determine its inhibiting rate, and with the negative logarithm of the compound molar concentration with
Corresponding inhibiting rate linear regression, molar concentration when trying to achieve 50% inhibiting rate is the IC of the compound50Value.Each compound
Each concentration repetition measurement three times, using curcumin as positive control.Measurement result shows, the 2- hydroxyls disclosed in the embodiment of the present invention
Chalcone aminated compounds（I）To Aβ 1-42Self assemble is respectively provided with remarkable inhibiting activity, to A under 20.0 μM of concentrationβ 1-42From
The inhibiting rate of body aggregation is all higher than 65.0%, and inhibiting rate of the curcumin under same concentrations is 43.1%；And it is clinical widely used
Anti- AD medicines：Donepezil, Rivastigmine, memantine hydrochloride and compound（I）Parent nucleus --- 2- Hydroxylated Chalcones and Relateds
Compound【（1）R1=R2=R3=R4Compound represented by=H；（2）R1=R3=H, R2=R4=CH3Represented compound；（3）R1=
H, R2=R3=R4=CH3Represented compound】To A under 20.0 μM of concentrationβ 1-42The inhibiting rate of self assemble is respectively less than 20%.
（2）2- hydroxylated chalcone aminated compounds（I）The measure acted on complexing of metal ion
CuCl is dissolved with methanol2·2H2O、ZnCl2、FeSO4·7H2O、AlCl3And testing 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 mixture ultraviolet in the range of 200-600 nm on Varioskan Flash Multimode Reader instrument
Absorption curve, and using 100 μ L testing compound solutions and 100 μ L methyl alcohol mixed liquors as control, observation metal ion and to be measuredization
The Red Shift Phenomena of the maximum absorption band of compound mixed liquor and the intensity of maximum absorption band.Measurement result shows, the embodiment of the present invention
Disclosed in 2- hydroxylated chalcone aminated compounds（I）Show have strong complexing to metal ion.
（3）2- hydroxylated chalcone aminated compounds（I）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（2.0 mM）
With 200 μM of Aβ 1-42Storing solution is diluted to 75 μM, and 20 μ L Cu are taken respectively2+The μ L of solution+20 Aβ 1-42μ L to be measuredization of solution+20
Polymer solution, 20 μ L Cu2+The μ L of solution+20 Aβ 1-42The μ L HEPES buffer solutions of solution+20 and 60 μ L HEPES buffer solutions are in 96
In orifice plate, mix, then 37 °C of 24 h of incubation add the glycine-NaOH buffer for the 50mM that 190 μ L contain 5 μM of thioflavine Ts
（pH=8.5）, fluorescence is determined under 446nm excitation wavelengths and 490nm launch wavelengths with multi-function microplate reader immediately after shaking 5s
Value；Cu2++Aβ 1-42The fluorescent value of+testing compound is recorded as IFi, Cu2++Aβ 1-42The fluorescent value of+HEPES buffer solution is recorded as
IFc, the fluorescent value for comprising only HEPES buffer solution is recorded as IF0, compound is to Cu2+The A of inductionβ 1-42The inhibiting rate of aggregation is：
100-(IFi-IF0)/(IFc-IF0)*100.Each compound three multiple holes of each concentration mensuration, using curcumin as positive control.
Measurement result shows, the 2- hydroxylated chalcone aminated compounds disclosed in the embodiment of the present invention（I）It is right under 20.0 μM of concentration
Cu2+The A of inductionβ 1-42The inhibiting rate of aggregation is all higher than 80.0%, and inhibiting rate of the curcumin under same concentrations is 54.0%；And change
Compound（I）Parent nucleus --- 2- Hydroxylated Chalcones and Related compounds【（1）R1=R2=R3=R4Compound represented by=H；（2）R1=R3=
H, R2=R4=CH3Represented compound；（3）R1=H, R2=R3=R4=CH3Represented compound】Suppression under same concentrations
Rate is less than 20.0%.
（4）2- hydroxylated chalcone aminated compounds（I）To Cu2+The A of inductionβ 1-42The Disaggregating activity of aggregation
Take 20 μ L Cu2+The μ L of solution+20 Aβ 1-42Solution is in 96 orifice plates, and 37 °C of incubation 24h add 20 μ L test compounds
Thing solution（Cu2+、Aβ 1-42Ultimate density with testing compound is 20 μM）, 24h is incubated again at 37 °C, then adds 190 μ
L contains 50 mM of 5 μM of thioflavine Ts glycine-NaOH buffer（pH=8.5）, multi-function microplate reader is used immediately after shaking 5s
Fluorescent value is determined under 446 nm excitation wavelengths and 490 nm launch wavelengths；With the HEPES buffer solution of pH=6.6（20 mM）For ginseng
Than Cu2++Aβ 1-42The fluorescent value of+testing compound is recorded as IFi, Cu2++Aβ 1-42The fluorescent value of+HEPES buffer solution is recorded as
IFc, compound is to Cu2+The A of inductionβ 1-42The calculation formula of the depolymerization rate of aggregation is：100-(IFi)/(IFc)*100.Eachization
Compound three multiple holes of each concentration mensuration, using curcumin as positive control.Measurement result shows, disclosed in the embodiment of the present invention
2- hydroxylated chalcone aminated compounds（I）To Cu under 20.0 μM of concentration2+The A of inductionβ 1-42The depolymerization rate of aggregation is all higher than
70.0%, depolymerization rate of the curcumin under same concentrations is 56.5%, and compound（I）Parent nucleus compound --- 2- hydroxyls Cha Er
Ketone compounds【（1）R1=R2=R3=R4Compound represented by=H；（2）R1=R3=H, R2=R4=CH3Represented compound；（3）
R1=H, R2=R3=R4=CH3Represented compound】Depolymerization rate under same concentrations is respectively less than 20.0%.
（5）2- hydroxylated chalcone aminated compounds（I）Antioxidation activity（ORAC-FL methods）
Reference literature（Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331）Reported
Method be measured, i.e.,：6- hydroxyl -2,5,7,8- tetramethyl primary colours alkane -2- carboxylic acids（Trolox）With pH7.4 PBS
It is made into 10-80 μm of ol/L solution, fluorescein（fluorescein）It is made into 250 nmol/L's with pH7.4 PBS
Solution, 2,2 '-azo diisobutyl amidine dihydrochloride（AAPH）With pH7.4 PBS it is made into 40 mmol/L's using preceding
Solution.Into 96 orifice plates, 50-10 μm of ol/L of addition compound solution and luciferin solution, is mixed, 37 °C of incubation 15min, plus
Enter AAPH solution, it is 200 μ L to make every hole cumulative volume, mixes, is immediately placed on Varioskan Flash Multimode Reader
In instrument, the min of METHOD FOR CONTINUOUS DETERMINATION 90 under 485 nm excitation wavelengths and 535 nm launch wavelengths.Calculate below fluorescence decay curve
Product AUC, wherein with 1-8 μm of ol/L'sTroloxIt is used as standard, to be not added with testing sample as blank, the antioxidation activity of compound
Results expression isTroloxEquivalent, its calculation formula is：[(AUC Sample-AUC blank)/(AUCTrolox-AUC
blank)]´[(concentration of Trolox/ concentration of sample)], each compound is surveyed every time
Fixed 3 multiple holes, every group of experiment is independent in triplicate.Measurement result shows, the 2- hydroxyls Cha Er disclosed in the embodiment of the present invention
Ketone aminated compounds（I）Antioxidation activity beTrolox1.0-15.0 times, illustrate that such compound has strong anti-oxidation work
Property.
（6）Acetylcholinesterase and butyrylcholine esterase inhibitory activity
1.0 mmol/L acetylthiocholine iodides or iodine bisulfide are sequentially added into 96 orifice plates for BuCh（It is purchased from
Sigma companies）30 μ L, pH7.4 μ L of PBS 40, the μ L of testing compound solution 20（DMSO contents are less than 1%）With 10
μ L acetylcholinesterases（Rat brain cortex 5% is homogenized supernatant, and pH7.4 phosphate buffer makees homogenate medium）Or BuCh
Esterase（The supernatant of rat blood serum 25%, pH7.4 phosphate buffers make homogenate medium）Solution, is finished after mixing, 37 DEG C of incubations
15min, 5,5 '-two thio-bis- (the 2- nitrobenzoic acids) of addition 0.2% into each hole（DTNB, purchased from Sigma companies）Solution
30 μ L are developed the color, and the optical density in each hole at 405nm is determined with ELIASA（OD values）, compared with the blank well for being not added with testing sample, counted
Calculate inhibiting rate of the compound to enzyme（Enzyme inhibition rate (%)=(1- sample sets OD values/blank group OD values) × 100%）；Select compound
Five to six concentration, determine its enzyme inhibition rate, and linearly return with the inhibiting rate of the negative logarithm of the compound molar concentration and enzyme
Return, molar concentration when trying to achieve 50% inhibiting rate is the IC of the compound50.Measurement result shows that institute is public in the embodiment of the present invention
The 2- hydroxylated chalcone aminated compounds opened（I）The effect of significantly inhibiting is respectively provided with to acetylcholinesterase, its IC50For 0.01 μM ~
50.0 µM；And compound（I）The suppression that inhibitory activity to acetylcholinesterase is significantly higher than to butyrylcholine esterase is lived
Property, illustrate that compound disclosed in this invention has selective inhibitory to acetylcholinesterase.Being also shown that of measurement result
Compound（I）Parent nucleus --- 2- Hydroxylated Chalcones and Related compounds【（1）R1=R2=R3=R4Compound represented by=H；（2）R1=R3=
H, R2=R4=CH3Represented compound；（3）R1=H, R2=R3=R4=CH3Represented compound】To acetylcholine ester enzyme level
IC50It is all higher than 500 μM.
（7）To AβCause the influence of cognition dysfunction in Model of Dementia in Rats（Illustrated by taking compound 2-1 as an example）
Wistar rats（10 week old）280 grams or so of body weight, is randomly divided into：Control group and dull-witted moulding group, dull-witted moulding
Group animal is anaesthetized with yellow Jackets（40mg/kg,i.p.）After be fixed on the I-C type rat stereotaxic instruments of river gulf, routinely disappear
Skin is cut after poison, exposure bregma is slowly injected into state of aggregation A with micro syringe to rats with left hippocampusβ 1-42（Aβ 1-42Storage
Standby liquid normal saline dilution is to 2.0 μ g/ μ L, and 37 °C are incubated 24h）5.0 μ L, let the acupuncture needle remain at a certain point 5 minutes so that AβAbundant disperse, Ran Houhuan
Slowly pin is removed to sew up a wound.Control group gives isometric physiological saline.In injection AβNext day, dull-witted moulding group rat is randomly divided into
5 groups：Model group, by reagent are high（9.9mg/kg）, in（3.3mg/kg）, it is low（1.0mg/kg）More than dosage group and positive control how piperazine
Together（5mg/kg）Group, every group 8, gastric infusion（Control group and model group give isometric solvent）, 1 day 1 time, continuous 4 weeks；
The ability of learning and memory for determining rat on the 3rd week with Morris water mazes is administered.Measurement result shows, compared with control group, is crazy about
The incubation period of slow-witted model group Morris water mazes test is obviously prolonged（P<0.01）；Medicine is high, the incubation period of middle dose group is relatively crazy about
Slow-witted model group significantly shortens（P<0.01）, and medicine low dose group and donepezil the group incubation period compared with Model of Dementia group have one
Reduced short trend but there was no significant difference（P>0.05）.
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 on the premise of without departing substantially from the spirit and scope of the present invention
The present invention carries out various change and modification.
The 2- hydroxylated chalcone aminated compounds of embodiment 1（I）Preparation lead to method
The corresponding 2- hydroxy acetophenones class compounds of 2.0 mmol are added in reaction bulb（2）, the corresponding benzene of 3.0 mmol
Benzaldehyde compound（1）With 30 ml ethanol, after stirring, the mmol of the 30% KOH aqueous solution 12.0 is added dropwise to, 40-50 DEG C is stirred
Mix reaction 2.0~72.0 hours（Reaction process is tracked with TLC）；After reaction terminates, room temperature is cooled to, 10% aqueous hydrochloric acid solution is used
Reaction solution pH is adjusted to highly acid, then reaction solution pH is adjusted to alkalescent with saturated sodium bicarbonate aqueous solution, ethanol is removed under reduced pressure,
100 mL deionized waters are added in residual solution, are extracted in three times with 300 mL dichloromethane, organic layer uses saturation chlorination after merging
Sodium water solution is washed, and is filtered after anhydrous sodium sulfate drying, is removed solvent under reduced pressure, residue is purified through column chromatography（Eluent：Two
Chloromethanes:Methanol=100:1 v/v）, obtain corresponding 2- hydroxylated chalcones aminated compounds（I）, yield 30.0%-92.0%, it is changed
Structure is learned to pass through1H-NMR、13C-NMR and ESI-MS confirmations；The purity of gained object determines through HPLC and is all higher than 97.0%.Adopt
The object structure prepared with above-mentioned logical method is as follows：
（1）R1Represent O (CH2)nNR5R6：
Note：R in table5And R6When sharing a cell, substituent " NR is represented5R6”。
（2）R1Represent R5R6During N：
。
（3）Work as R1RepresentWhen：
。
The 2- hydroxylated chalcone aminated compounds of embodiment 2（I）With acid logical method is prepared into salt
The 2- hydroxylated chalcone aminated compounds according to the gained of above-described embodiment 1 is added in reaction bulb（I）2.0 mmol
With the ml of acetone 50, it is sour accordingly to be stirring evenly and then adding into 8.0 mmol, temperature rising reflux stirring reaction 20 minutes, after reaction terminates
Room temperature is cooled to, solvent is removed under reduced pressure, residue acetone recrystallization filters the solid separated out, produces 2- hydroxylated chalcone amine
Class compound（I）Salt, its chemical constitution warp1H NMR and ESI-MS are confirmed.
The part 2- hydroxylated chalcone aminated compounds of embodiment 3（I）Bioactivity screening result
。
Claims (7)
1. a class 2- hydroxylated chalcones aminated compounds or its pharmaceutically acceptable salt, it is characterised in that the change of such compound
Learn general structure such as（I）It is shown：
In formula：R1Represent O (CH2)nNR5R6Or R5R6N, R1In any possible position of phenyl ring；R2、R3And R4Represent independently of one another
H or C1~C12Alkyl；R5Represent H, C1~C12Alkyl；R6Represent C1~C12Alkyl, benzyl, substituted benzyl, 1,2,3,4- tetrahydro acridines-
The chloro- 1,2,3,4- tetrahydro acridines -9- bases of 9- bases, 6-, the chloro- 1,2,3,4- tetrahydro acridines -9- bases of 8- or the chloro- 1,2,3,4- of 6,8- bis-
Tetrahydro acridine -9- bases；Above-mentioned term " substituted benzyl " refers to the benzyl replaced on phenyl ring by the 1-4 groups being selected from the group：
F、Cl、Br、I、C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano group, these substituents
Can phenyl ring any possible position；Particular compound represented by above-mentioned 2- hydroxylated chalcones aminated compounds is as follows：
。
2. 2- hydroxylated chalcones aminated compounds as claimed in claim 1 or its pharmaceutically acceptable salt, it is characterised in that
Described pharmaceutically acceptable salt is such 2- hydroxylated chalcones aminated compounds 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, butanedioic acid, tartaric acid, citric acid, malic acid,
Lipoic acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, the salt of benzene sulfonic acid or p-methyl benzenesulfonic acid.
3. the preparation of 2- hydroxylated chalcones aminated compounds 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 the following method and obtain：
In formula：R1、R2、R3And R4Definition and 2- hydroxylated chalcone aminated compounds（I）Chemical structure of general formula it is identical；
With corresponding compound of benzaldehyde category（1）With 2- hydroxy acetophenone class compounds（2）For initiation material, in solvent and alkalescence
Under the conditions of direct polycondensation, obtain corresponding 2- hydroxylated chalcones aminated compounds（I）；Utilize the 2- hydroxyls Cha Er of above method gained
Ketone aminated compounds（I）Contain amino in molecule, the amino in alkalescence, can with any suitable acid by pharmaceutically it is conventional into
Its pharmaceutically acceptable salt is made in salt method.
4. the preparation method of 2- hydroxylated chalcones aminated compounds as claimed in claim 3 or its pharmaceutically acceptable salt, its
It is characterised by that reacting alkali used is：Alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline-earth metal carbon
Hydrochlorate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8Alkali metal salt, triethylamine, tri-n-butylamine, trioctylamine, the pyrrole of alcohol
Pyridine,N- methyl morpholine,N- methyl piperidine, triethylene diamine or TBAH；Reacting solvent for use is：C1-8Fat
Alcohol, C3-8Aliphatic ketone, ether, tetrahydrofuran, 2- methyltetrahydrofurans,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane
Alkane, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane.
5. the preparation method of 2- hydroxylated chalcones aminated compounds as claimed in claim 3 or its pharmaceutically acceptable salt, its
It is characterised by compound of benzaldehyde category（1）：2- hydroxy acetophenone class compounds（2）：The molar feed ratio of alkali is 1.0 ~ 10.0：
1.0：1.0~10.0；Reaction temperature is 0 ~ 150 DEG C；Reaction time is 1 ~ 120 hour.
6. a class pharmaceutical composition, it is characterised in that include the 2- hydroxylated chalcone amines as described in claim any one of 1-2
Compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipient.
7. the 2- hydroxylated chalcones aminated compounds or its pharmaceutically acceptable salt as described in claim any one of 1-2 are in system
Standby to treat and/or prevent the purposes in nervus retrogression relevant disease medicine, this kind of nervus retrogression relevant disease is：Vascular
Dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive spinal cord side
Rope sclerosis, neuropathic pain or glaucoma.
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| CN105968031A (en) * | 2016-05-15 | 2016-09-28 | 华南理工大学 | Carbamate-chalcones cholinesterase inhibitors as well as preparation method and application thereof |
| CN110003034B (en) * | 2018-01-05 | 2021-06-18 | 四川大学 | Hydroxyflurbiprofen Mannich base compounds, and preparation method and application thereof |
| CN108101780B (en) * | 2018-01-05 | 2020-04-10 | 四川大学 | Flurbiprofen chalcone compounds, preparation method and application thereof |
| CN110003033B (en) * | 2018-01-05 | 2021-06-18 | 四川大学 | Flurbiprofen chalcone Mannich base compound, and preparation method and application thereof |
| RU2770763C1 (en) * | 2018-11-19 | 2022-04-21 | Вайсориг Текнолоджиз Пте. Лимитед | Methods for using a diphenylpropenone compound in the preparation of an animal feed additive or animal feed and a feed composition containing said compound |
| CN109608346B (en) * | 2019-01-11 | 2022-04-22 | 四川大学 | Chalcone bis-Mannich base compound, and preparation method and application thereof |
| CN109665969B (en) * | 2019-01-11 | 2022-04-22 | 四川大学 | 3-methoxy-4-hydroxychalcone bis-Mannich base compound, and preparation method and application thereof |
| CN109912443B (en) * | 2019-04-03 | 2021-06-18 | 四川大学 | Benzylamine flurbiprofen compound, preparation method and application thereof |
| CN111792990A (en) * | 2019-04-09 | 2020-10-20 | 中国科学院上海药物研究所 | Unsaturated ketone compound, preparation method and application thereof |
| CN110240549B (en) * | 2019-07-10 | 2022-01-07 | 南阳师范学院 | Amine alkoxy chalcone compound and preparation method and application thereof |
| CN110272349B (en) * | 2019-07-10 | 2022-01-07 | 南阳师范学院 | 2' -hydroxy-3-phenyl propiophenone compound and preparation method and application thereof |
| CN114315689B (en) * | 2020-10-09 | 2023-04-07 | 四川大学 | Disulfanylphthalimide compound, preparation method and application thereof |
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