CN105439876A - 2-hydroxychalcone amine compounds, and preparation method and uses thereof - Google Patents
2-hydroxychalcone amine compounds, and preparation method and uses thereof Download PDFInfo
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- CN105439876A CN105439876A CN201410478475.1A CN201410478475A CN105439876A CN 105439876 A CN105439876 A CN 105439876A CN 201410478475 A CN201410478475 A CN 201410478475A CN 105439876 A CN105439876 A CN 105439876A
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- 0 C*CC(C1[C@@]2C)*1[C@](*)C/C(/N(C1)C1=C)=C\[C@@]2Cl Chemical compound C*CC(C1[C@@]2C)*1[C@](*)C/C(/N(C1)C1=C)=C\[C@@]2Cl 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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-hydroxychalcone amine compounds and pharmaceutically-acceptable salts, preparation method thereof, pharmaceutical composition, and uses for preparing medicines treating and/or preventing neurodegenerative related diseases, the diseases including but not limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntingdon's disease, HIV associated dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma and other neurodegenerative diseases.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to the novel 2-hydroxylated chalcone aminated compounds of a class (
i) and pharmacy acceptable salt, its preparation method, pharmaceutical composition and preparing the purposes that treats and/or prevents in nervus retrogression relative disease medicine, include but not limited to the nerve degenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, huntington disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain, glaucoma.
Background technology
Alzheimer's disease (Alzheimer ' sdisease, AD, senile dementia) be a kind of central nervous system degenerative disease damaged based on Progressive symmetric erythrokeratodermia cognitive disorder and memory, its sickness rate is in ascendant trend year by year, become the frequently-occurring disease being only second to cardiovascular diseases and cancer, rise to the 4th of the cause of death in developed countries such as America and Europes.According to WHO Report, global over-65s old man has 10% dysnoesia, and wherein 1/2nd dementia occur, more than 85 years old sickness rate nearly 50%.In China, AD patient numbers is about 600-700 ten thousand, and sickness rate is more than 5%.Along with the quickening of population in the world aging process, its sickness rate is obvious ascendant trend, point out in " global implication of Alzheimer's disease: the 2013-2050 " report of announcing in December, 2013 according to Alzheimer'sDiseaseInternational, AD will become the coming few decades global maximum Health challenges faced, to the year two thousand thirty, patient numbers by by 2013 4,400 ten thousand rise to 7,600 ten thousand, to the year two thousand fifty, this numerical value will reach surprising 1.35 hundred million.Because AD clinical manifestation is that memory capability, orientation property, thinking and judgement go down, and activity of daily living reduces, and even occurs abnormal Behavioral and psychological symptom etc., makes patient care difficulty comparatively large, brings heavy burden to society and family.The medicine that current approved is used for the treatment of gently/moderate AD has acetylcholinesterase (AChE) inhibitor, and treat for severe AD
n-methyl-
d-aspartic acid (NMDA) receptor antagonist, but Clinical practice shows, these medicines alleviate AD symptom by the exitotoxicity improving levels of acetylcholine or suppression excitatory amino acid in patient body, but can not effectively stop or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, feel sick, the serious toxic side effect such as hepatotoxicity, poor appetite and stool frequency, thus long-term efficacy is not satisfactory.Therefore, there is in the urgent need to research and development the AD medicine of novel mechanism of action clinically.
AD belongs to the disease that causes of many factors, and pathogeny is complicated, does not also illustrate its pathogenesis completely so far, but research shows, in patient's brain levels of acetylcholine decline,
βthe excessive generation of-amyloid and deposition, metal ion metabolism disorder, Ca
2+dysequilibrium,
tauthe neurofibrillary tangles that-protein hyperphosphorylation causes, glutamate receptor activity are too high, oxidative stress produces a large amount of active oxygen (ROS) and the many factors such as free radical and Neuroinflammation is played an important role in the pathogenic process of AD.For above-mentioned pathogenic factors, researchist adopts tradition " medicine one target " drug design strategies, has found a large amount of medicine a certain target spot to high reactivity and highly selective, as: anticholinesterase and
n-methyl-
d-aspartate receptor agonist etc., but these medicines exist that action target spot is single, Clinical practice toxic side effect is more, to the problem such as the long-term efficacy of AD patient is not good enough.
In recent years, along with constantly illustrating AD pathogenesis, find that the generation of AD and development have the feature of multimachine system, multifactor effect, interrelatedly again between different mechanisms to influence each other, constitute AD and occur and the network regulation system of complexity in evolution.Based on the above results, researchist proposes " Mutiple Targets targeted drug " (Multitarget-directedLigands, MTDLs) strategy is to research and develop anti-nerve degenerative diseases medicine.So-called " Mutiple Targets medicine " refers to that single chemical entities acts on the multiple target spots in disease network simultaneously, synergistic effect can be produced to the effect of each target spot, make total effect be greater than each single-action and answer sum, this type of medicine is also referred to as " Multifunctional " or " Multipotential " medicine.The key distinction of Mutiple Targets medicine and multiple medicines combined utilization and compound medicine is: the toxic side effect that can reduce dosage, improve result for the treatment of, avoid the interaction between medicine and bring thus, and homogeneous pharmacokinetic properties is easy to use etc.Therefore, research and development have novel chemical structure, novel mechanism of action, and there is multiple target effect, active demand that the anti-neurodegenerative disease therapeutic agent of low toxic side effect not only meets social senilization's process, and there are good market outlook.In early-stage Study, we are for the acetylcholinesterase in AD pathogenic process and oxidative stress factor, design and synthesize Scutellarein carbamate derivates (CN101337956A, CN102603698A), toluylene or ethane amino formate compounds (CN102816090A), isoflavones amino formate compounds (CN102827131A), flavones alkyl amine compound (CN103087024A), Genistein alkyl amine compound (CN103113340A), toluylene oxyalkyl amine based compound (CN103073440A), though these compounds have good acetylcholine ester enzyme level and anti-oxidant activity, but to A
β 1-42the suppression (inhibiting rate under 20.0 μMs of concentration is all less than 65.0%) of self assemble, to Cu
2+the A of induction
β 1-42assemble suppression (inhibiting rate under 20.0 μMs of concentration is all less than 65.0%) and to Cu
2+the A of induction
β 1-42the Disaggregating activity (the depolymerization rate under 20.0 μMs of concentration is all less than 60.0%) assembled is all undesirable, causes these compounds not good enough to the curative effect of AD in animal model.Therefore, design and find that there is anti-acetylcholinesterase, anti-oxidation stress, complexing of metal ion, suppression simultaneously
βthe excessive generation of-amyloid is with deposition and active balanced Mutiple Targets AD medicine is still research direction important at present.
Summary of the invention
The object of the invention be to disclose a class 2-hydroxylated chalcone aminated compounds (
i) and pharmacy acceptable salt;
Another object of the present invention be to disclose such 2-hydroxylated chalcone aminated compounds (
i) and the preparation method of pharmacy acceptable salt;
Another object of the present invention be openly to comprise such 2-hydroxylated chalcone aminated compounds (
i) and the pharmaceutical composition of pharmacy acceptable salt;
Still a further object of the present invention be to disclose such 2-hydroxylated chalcone aminated compounds (
i) and pharmacy acceptable salt there is multiple target effect, can be used for preparing the purposes in the medicine treating and/or preventing nervus retrogression relative disease, include but not limited to the nerve degenerative diseases such as vascular dementia, Alzheimer, parkinsonism, huntington disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain, glaucoma.
2-hydroxylated chalcone aminated compounds disclosed in this invention (
i) chemical structure of general formula be:
In formula: R
1represent O (CH
2) nNR
5r
6or R
5r
6n, R
1can in the possible arbitrarily position of phenyl ring; R
2, R
3and R
4represent H or C independently of one another
1~ C
12alkyl; R
5represent H, C
1~ C
12alkyl; R
6represent C
1~ C
12alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydro acridine-9-base, chloro-1,2,3, the 4-tetrahydro acridine-9-base of 6-, chloro-1,2,3, the 4-tetrahydro acridine-9-base of 8-or chloro-1,2,3, the 4-tetrahydro acridine-9-base of 6,8-bis-; R
5r
6n also can represent
n-demethylgalanthamine base, Pyrrolidine base, morpholinyl, piperidyl, 4-position are by C
1~ C
12the piperidyl that alkyl replaces, 4-position by benzyl or substituted benzyl replace piperidyl, piperazinyl, 4-position is by C
1~ C
12the piperazinyl that alkyl replaces, 4-position by benzyl or substituted benzyl the piperazinyl that replaces; O (CH
2) nNR
5r
6also can represent
, m represents 0-10, R
7represent H, C
1~ C
12alkyl, benzyl or substituted benzyl; Above-mentioned term " substituted benzyl " refer to by phenyl ring by 1-4 to be selected from the group of lower group the benzyl that replaces: F, Cl, Br, I, C
1-4alkyl, C
1-4alkoxyl group, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano group, these substituting groups can at any possible position of phenyl ring.
2-hydroxylated chalcone aminated compounds disclosed in this invention (
i) prepare by following methods:
In formula: R
1, R
2, R
3and R
4definition and 2-hydroxylated chalcone aminated compounds (
i) chemical structure of general formula identical.
With corresponding compound of benzaldehyde category (
1) and 2-hydroxy acetophenone compounds (
2) be starting raw material, direct polycondensation under solvent and alkaline condition, obtain corresponding 2-hydroxylated chalcone aminated compounds (
i).Wherein, reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, C
1-8an alkali metal salt of alcohol, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine,
n-methylmorpholine,
n-methyl piperidine, triethylene diamine, TBAH), preferred bases is: potassium hydroxide, sodium hydroxide, salt of wormwood, triethylamine, pyridine or sodium methylate; Reaction solvent for use is: C
1-8fatty alcohol, C
3-8aliphatic ketone, ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran,
n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, Isosorbide-5-Nitrae-dioxane, benzene, toluene, acetonitrile or C
5-8alkane, preferred solvent is: methyl alcohol, ethanol, Virahol,
n,N-dimethyl formamide, acetone, acetonitrile, tetrahydrofuran (THF), methylene dichloride or toluene; Compound of benzaldehyde category (
1): 2-hydroxy acetophenone compounds (
2): the molar feed ratio of alkali is 1.0 ~ 10.0:1.0:1.0 ~ 10.0, and preferred molar feed ratio is 1.0 ~ 4.0:1.0:1.2 ~ 6.0; Temperature of reaction is 0 ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 100 DEG C; Reaction times is 1 ~ 120 hour, and the preferred reaction time is 2 ~ 72 hours.
Starting raw material of the present invention---R
1represent O (CH
2) nNR
5r
6time compound of benzaldehyde category (
1) can according to document (YongD.,
etal.
cN201310054592.0) institute's report method, first reacts with corresponding dibromide with hydroxy benzaldehyde compound, gained list bromide again with HNR
5r
6through alkylated reaction and get final product.
According to the method described above gained 2-hydroxylated chalcone aminated compounds (
i) in molecule containing amino, this amino is in alkalescence, and can obtain acceptable salt on its pharmacology with any suitable acid by the salifying method of pharmaceutically routine, described acid is: hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, C
1-6aliphatic carboxylic acid (as: formic acid, acetic acid, propionic acid etc.), oxalic acid, phenylformic acid, Whitfield's ointment, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid, oxysuccinic acid, Thioctic Acid, C
1-6alkylsulphonic acid (as: methylsulphonic acid, ethylsulfonic acid etc.), camphorsulfonic acid, Phenylsulfonic acid or tosic acid.
Pharmaceutical composition disclosed in this invention comprise treatment significant quantity one or more 2-hydroxylated chalcone aminated compoundss (
i) or its pharmacy acceptable salt, this pharmaceutical composition can contain one or more pharmaceutically acceptable carrier or vehicle further.Described " treatment significant quantity " refer to cause investigator or doctor for tissue, the biology of system or animal or the medicine of medicine reaction or the amount of medicament; Described " composition " refers to the product by more than one materials or component being mixed; Described " pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, composition or carrier, as: liquid or solid weighting agent, thinner, vehicle, solvent or packing material, they carry or transport certain chemical substance.Its desirable ratio of pharmaceutical composition provided by the present invention is, 2-hydroxylated chalcone aminated compounds (
i) or its pharmacy acceptable salt account for gross weight than 2% ~ 99.5% as activeconstituents, rest part is for accounting for gross weight than less than 98%.
2-hydroxylated chalcone aminated compounds disclosed in this invention (
i) and pharmacy acceptable salt carried out following bioactivity screening.
(1) 2-hydroxylated chalcone aminated compounds (I) is to A
β
1-42
the inhibit activities of self assemble
Reference literature (Qiang, X.M.
etal.Eur.JMed.Chem. 2014, 76,314-331) and the method reported measures, that is: pretreated A
β 1-42be made into storing solution with DMSO, use the PBS damping fluid of front pH7.4 to be diluted to 50 μMs; Testing compound DMSO is made into 2.0mM storing solution, uses the PBS damping fluid of front pH7.4 to be diluted to respective concentration, gets the A of 20 μ L
β 1-42the testing compound solution of solution+20 μ L, the A of 20 μ L
β 1-42the PBS damping fluid (containing 2%DMSO) of solution+20 μ L is in 96 orifice plates, 37 ° of C hatch 24h, then add the glycine-NaOH buffer (pH=8.5) that 160 μ L contain the 50mM of 5 μMs of thioflavine Ts, after jolting 5s, under 446nm excitation wavelength and 490nm emission wavelength, measure fluorescent value by multi-functional microplate reader immediately; A
β 1-42the fluorescent value of+testing compound is designated as IF
i, A
β 1-42the fluorescent value of+PBS damping fluid is designated as IF
c, the fluorescent value only containing PBS damping fluid is designated as IF
0, compound suppresses A
β 1-42the inhibiting rate of self assemble is: 100-(IF
i-IF
0)/(IF
c-IF
0) * 100; Select five to six concentration of compound, measure its inhibiting rate, and with the negative logarithm of this compound volumetric molar concentration and corresponding inhibiting rate linear regression, volumetric molar concentration when trying to achieve 50% inhibiting rate is the IC of this compound
50value.The each concentration repetition measurement of each compound three times take curcumine as positive control.Measurement result shows, 2-hydroxylated chalcone aminated compounds disclosed in the embodiment of the present invention (
i) to A
β 1-42self assemble all has remarkable inhibiting activity, to A under 20.0 μMs of concentration
β 1-42the inhibiting rate of self assemble is all greater than 65.0%, and the inhibiting rate of curcumine under same concentrations is 43.1%; And clinical widely used anti-AD medicine: E2020, rivastigmine, memantineHCl and compound (
i) parent nucleus---2-hydroxylated chalcone compounds [(1) R
1=R
2=R
3=R
4compound represented by=H; (2) R
1=R
3=H, R
2=R
4=CH
3represented compound; (3) R
1=H, R
2=R
3=R
4=CH
3represented compound] under 20.0 μMs of concentration to A
β 1-42the inhibiting rate of self assemble is all less than 20%.
(2) mensuration of 2-hydroxylated chalcone aminated compounds (I) and complexing of metal ion effect
Use dissolve with methanol CuCl
22H
2o, ZnCl
2, FeSO
47H
2o, AlCl
3and testing compound, be made into the solution of 75 μm of ol/L, 100 μ L testing compound solutions and 100 μ L metal ion solutions are added in 96 orifice plates, mixing, room temperature leaves standstill 30min, VarioskanFlashMultimodeReader instrument records the ultraviolet absorption curve of mixture within the scope of 200-600nm, and with 100 μ L testing compound solutions and 100 μ L methyl alcohol mixed liquors for contrast, observe the Red Shift Phenomena of maximum absorption band and the intensity of maximum absorption band of metal ion and testing compound mixed solution.Measurement result shows, 2-hydroxylated chalcone aminated compounds disclosed in the embodiment of the present invention (
i) all show and have strong complexing action to metal ion.
(3) 2-hydroxylated chalcone aminated compounds (I) is to Cu
2+
the A of induction
β
1-42
the inhibit activities assembled
By CuCl
275 μMs of solution are made into, with the A of HEPES damping fluid by compound stock solution (2.0mM) and 200 μMs with HEPES damping fluid
β 1-42storing solution is diluted to 75 μMs, gets 20 μ LCu respectively
2+solution+20 μ LA
β 1-42solution+20 μ L testing compound solution, 20 μ LCu
2+solution+20 μ LA
β 1-42solution+20 μ LHEPES damping fluid and 60 μ LHEPES damping fluids are in 96 orifice plates, mixing, 37 ° of C hatch 24h, then add the glycine-NaOH buffer (pH=8.5) that 190 μ L contain the 50mM of 5 μMs of thioflavine Ts, after jolting 5s, under 446nm excitation wavelength and 490nm emission wavelength, measure fluorescent value by multi-functional microplate reader immediately; Cu
2++ A
β 1-42the fluorescent value of+testing compound is recorded as IF
i, Cu
2++ A
β 1-42the fluorescent value of+HEPES damping fluid is recorded as IF
c, the fluorescent value only containing HEPES damping fluid is recorded as IF
0, compound is to Cu
2+the A of induction
β 1-42the inhibiting rate assembled is: 100-(IF
i-IF
0)/(IF
c-IF
0) * 100.The multiple hole of each concentration determination of each compound three take curcumine as positive control.Measurement result shows, 2-hydroxylated chalcone aminated compounds disclosed in the embodiment of the present invention (
i) under 20.0 μMs of concentration to Cu
2+the A of induction
β 1-42the inhibiting rate assembled all is greater than 80.0%, and the inhibiting rate of curcumine under same concentrations is 54.0%; And compound (
i) parent nucleus---2-hydroxylated chalcone compounds [(1) R
1=R
2=R
3=R
4compound represented by=H; (2) R
1=R
3=H, R
2=R
4=CH
3represented compound; (3) R
1=H, R
2=R
3=R
4=CH
3represented compound] inhibiting rate under same concentrations is less than 20.0%.
(4) 2-hydroxylated chalcone aminated compounds (I) is to Cu
2+
the A of induction
β
1-42
the Disaggregating activity assembled
Get 20 μ LCu
2+solution+20 μ LA
β 1-42solution is in 96 orifice plates, and 37 ° of C hatch 24h, adds 20 μ L testing compound solution (Cu
2+, A
β 1-4220 μMs are) with the ultimate density of testing compound, 24h is hatched again at 37 ° of C, then add the glycine-NaOH buffer (pH=8.5) that 190 μ L contain the 50mM of 5 μMs of thioflavine Ts, after jolting 5s, under 446nm excitation wavelength and 490nm emission wavelength, measure fluorescent value by multi-functional microplate reader immediately; With the HEPES damping fluid (20mM) of pH=6.6 for reference, Cu
2++ A
β 1-42the fluorescent value of+testing compound is recorded as IF
i, Cu
2++ A
β 1-42the fluorescent value of+HEPES damping fluid is recorded as IF
c, compound is to Cu
2+the A of induction
β 1-42the calculation formula of the depolymerization rate of assembling is: 100-(IF
i)/(IF
c) * 100.The multiple hole of each concentration determination of each compound three take curcumine as positive control.Measurement result shows, 2-hydroxylated chalcone aminated compounds disclosed in the embodiment of the present invention (
i) under 20.0 μMs of concentration to Cu
2+the A of induction
β 1-42the depolymerization rate of assembling all is greater than 70.0%, and the depolymerization rate of curcumine under same concentrations is 56.5%, and compound (
i) parent nucleus compound---2-hydroxylated chalcone compounds [(1) R
1=R
2=R
3=R
4compound represented by=H; (2) R
1=R
3=H, R
2=R
4=CH
3represented compound; (3) R
1=H, R
2=R
3=R
4=CH
3represented compound] depolymerization rate under same concentrations is all less than 20.0%.
(5) anti-oxidant activity (ORAC-FL method) of 2-hydroxylated chalcone aminated compounds (I)
Reference literature (Qiang, X.M.
etal.Eur.JMed.Chem. 2014, 76,314-331) and the method reported measures, that is: 6-hydroxyl-2,5,7,8-tetramethyl primary colours alkane-2-carboxylic acid (
trolox) solution of 10-80 μm of ol/L is made into the PBS damping fluid of pH7.4, fluorescein (fluorescein) the PBS damping fluid of pH7.4 is made into the solution of 250nmol/L, 2,2 '-azo diisobutyl amidine dihydrochloride (AAPH) uses the PBS damping fluid of front pH7.4 to be made into the solution of 40mmol/L.Compound solution and the luciferin solution of 50-10 μm of ol/L is added in 96 orifice plates, mixing, 37 ° of C hatch 15min, add AAPH solution, every hole cumulative volume is made to be 200 μ L, mixing, is placed in VarioskanFlashMultimodeReader instrument, METHOD FOR CONTINUOUS DETERMINATION 90min under 485nm excitation wavelength and 535nm emission wavelength immediately.Calculate area AUC under fluorescence decay curve, wherein with 1-8 μm of ol/L's
troloxas standard, not add testing sample for blank, the anti-oxidant activity results expression of compound is
troloxequivalent, its calculation formula is: [(AUCSample-AUCblank)/(AUC
trolox-AUCblank)] ' [(concentrationof
trolox/ concentrationofsample)], each compound measures 3 multiple holes at every turn, and often group experiment is independent in triplicate.Measurement result shows, 2-hydroxylated chalcone aminated compounds disclosed in the embodiment of the present invention (
i) anti-oxidant activity be
trolox1.0-15.0 doubly, illustrate that this compounds has strong anti-oxidative activity.
(6) acetylcholinesterase and butyrylcholine esterase inhibit activities
1.0mmol/L acetylthiocholine iodide or sulfur iodide is added successively for BuCh (equal available from Sigma) 30 μ L in 96 orifice plates, the PBS damping fluid 40 μ L of pH7.4, testing compound solution 20 μ L(DMSO content is less than 1%) and 10 μ L acetylcholinesterases (rat brain cortex 5% homogenate supernatant liquor, the phosphoric acid buffer of pH7.4 makes homogenate medium) or butyrylcholine esterase (rat blood serum 25% supernatant liquor, pH7.4 phosphoric acid buffer makes homogenate medium) solution, after finishing mixing, hatch 15min for 37 DEG C, 0.2% 5 are added in each hole, 5 '-dithio-bis-(2-nitrobenzoic acid) (DTNB, available from Sigma) solution 30 μ L develops the color, the optical density(OD) (OD value) in each hole, 405nm place is measured by microplate reader, compare with the blank well not adding testing sample, computerized compound is to the inhibiting rate (enzyme inhibition rate (%)=(1-sample sets OD value/blank group OD value) × 100%) of enzyme, select five to six concentration of compound, measure its enzyme inhibition rate, and with the inhibiting rate linear regression of the negative logarithm of this compound volumetric molar concentration and enzyme, volumetric molar concentration when trying to achieve 50% inhibiting rate is the IC of this compound
50.Measurement result shows, 2-hydroxylated chalcone aminated compounds disclosed in the embodiment of the present invention (
i) to acetylcholinesterase, all there is remarkable restraining effect, its IC
50it is 0.01 μM ~ 50.0 μMs; And compound (
i) inhibit activities to butyrylcholine esterase is significantly higher than to the inhibit activities of acetylcholinesterase, illustrate that compound disclosed in this invention has selective inhibitory to acetylcholinesterase.Measurement result also shows, compound (
i) parent nucleus---2-hydroxylated chalcone compounds [(1) R
1=R
2=R
3=R
4compound represented by=H; (2) R
1=R
3=H, R
2=R
4=CH
3represented compound; (3) R
1=H, R
2=R
3=R
4=CH
3represented compound] IC to acetylcholine ester enzyme level
50all be greater than 500 μMs.
(7) to A
βcause the impact (being described for compound 2-1) of cognition dysfunction in Model of Dementia in Rats
Wistar rat (10 week age) body weight about 280 grams, is divided at random: control group and dull-witted moulding group, dull-witted moulding treated animal vetanarcol anesthesia (40mg/kg,
i.p.) after be fixed on the I-C type rat stereotaxic instrument of gulf, river, cut skin after routine disinfection, expose bregma, slowly inject state of aggregation A with microsyringe to rats with left hippocampus
β 1-42(A
β 1-42storing solution normal saline dilution to 2.0 μ g/ μ L, 37 ° of C hatch 24h) 5.0 μ L, let the acupuncture needle remain at a certain point 5 minutes to make A
βabundant disperse, then slowly removes pin and sews up a wound.Control group gives equal-volume physiological saline.At injection A
βnext day, dull-witted moulding group rat is divided into 5 groups at random: model group, by reagent high (9.9mg/kg), in (3.3mg/kg), low (1.0mg/kg) dosage group and positive control E2020 (5mg/kg) group, often organize 8, gastric infusion (control group and model group give equal-volume solvent), 1 day 1 time, continuous 4 weeks; Within 3rd week, measure the ability of learning and memory of rat with Morris water maze in administration.Measurement result shows, compared with control group, the latent period that Model of Dementia group Morris water maze is tested obviously extends (
p<0.01); Latent period of high, the middle dosage group of medicine comparatively Model of Dementia group significantly shorten (
p<0.01), and medicine low dose group and E2020 group have certain shortening trend a latent period compared with Model of Dementia group but there was no significant difference (
p>0.05).
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.
method is led in the preparation of embodiment 12-hydroxylated chalcone aminated compounds (I)
Add in reaction flask 2.0mmol corresponding 2-hydroxy acetophenone compounds (
2), the corresponding compound of benzaldehyde category of 3.0mmol (
1) and 30ml ethanol, after stirring, be added dropwise to 30%KOH aqueous solution 12.0mmol, 40-50 DEG C of stirring reaction 2.0 ~ 72.0 hours (reaction process TLC follows the tracks of); After reaction terminates, be cooled to room temperature, regulate reaction solution pH to strongly-acid with 10% aqueous hydrochloric acid, regulate reaction solution pH to weakly alkaline with saturated sodium bicarbonate aqueous solution again, remove ethanol under reduced pressure, 100mL deionized water is added in residual solution, three extractions are divided with 300mL methylene dichloride, organic layer washs with saturated sodium-chloride water solution after merging, filter after anhydrous sodium sulfate drying, remove solvent under reduced pressure, resistates through column chromatography purification (elutriant: methylene dichloride: methyl alcohol=100:1v/v), obtain corresponding 2-hydroxylated chalcone aminated compounds (
i), yield 30.0%-92.0%, the equal warp of its chemical structure
1h-NMR,
13c-NMR and ESI-MS confirms; The purity of gained target compound measures through HPLC and is all greater than 97.0%.The target compound structure adopting above-mentioned logical method to prepare is as follows:
(1) R
1
represent O (CH
2
)
n
nR
5
r
6
:
Note: R in table
5and R
6when sharing a cell, represent substituting group " NR
5r
6".
(2) R
1
represent R
5
r
6
during N:
。
(3) R is worked as
1
represent
time:
。
logical method prepared by embodiment 22-hydroxylated chalcone aminated compounds (I) and sour salify
Add in reaction flask according to above-described embodiment 1 gained 2-hydroxylated chalcone aminated compounds (
i) 2.0mmol and acetone 50ml, it is sour accordingly to add 8.0mmol after stirring, temperature rising reflux stirring reaction 20 minutes, be cooled to room temperature after reaction terminates, remove solvent under reduced pressure, resistates acetone recrystallization, filter separate out solid, obtain 2-hydroxylated chalcone aminated compounds (
i) salt, its chemical structure warp
1hNMR and ESI-MS confirms.
the bioactivity screening result of embodiment 3 part 2-hydroxylated chalcone aminated compounds (I)
。
Claims (7)
1. a class 2-hydroxylated chalcone aminated compounds or its pharmacy acceptable salt, it is characterized in that the chemical structure of general formula of this compounds as (
i) shown in:
In formula: R
1represent O (CH
2) nNR
5r
6or R
5r
6n, R
1can in the possible arbitrarily position of phenyl ring; R
2, R
3and R
4represent H or C independently of one another
1~ C
12alkyl; R
5represent H, C
1~ C
12alkyl; R
6represent C
1~ C
12alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydro acridine-9-base, chloro-1,2,3, the 4-tetrahydro acridine-9-base of 6-, chloro-1,2,3, the 4-tetrahydro acridine-9-base of 8-or chloro-1,2,3, the 4-tetrahydro acridine-9-base of 6,8-bis-; R
5r
6n also can represent
n-demethylgalanthamine base, Pyrrolidine base, morpholinyl, piperidyl, 4-position are by C
1~ C
12the piperidyl that alkyl replaces, 4-position by benzyl or substituted benzyl replace piperidyl, piperazinyl, 4-position is by C
1~ C
12the piperazinyl that alkyl replaces, 4-position by benzyl or substituted benzyl the piperazinyl that replaces; O (CH
2) nNR
5r
6also can represent
, m represents 0-10, R
7represent H, C
1~ C
12alkyl, benzyl or substituted benzyl; Above-mentioned term " substituted benzyl " refer to by phenyl ring by 1-4 to be selected from the group of lower group the benzyl that replaces: F, Cl, Br, I, C
1-4alkyl, C
1-4alkoxyl group, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano group, these substituting groups can at any possible position of phenyl ring.
2. 2-hydroxylated chalcone aminated compounds as claimed in claim 1 or its pharmacy acceptable salt, is characterized in that described pharmacy acceptable salt is this type of carboxylamine cinnamophenone ester compound and hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, C
1-6aliphatic carboxylic acid, oxalic acid, phenylformic acid, Whitfield's ointment, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid, oxysuccinic acid, Thioctic Acid, C
1-6the salt of alkylsulphonic acid, camphorsulfonic acid, Phenylsulfonic acid or tosic acid.
3. the preparation method of 2-hydroxylated chalcone aminated compounds or its pharmacy acceptable salt as described in any one of claim 1-2, is characterized in that described compound prepares by following methods:
In formula: R
1, R
2, R
3and R
4definition and 2-hydroxylated chalcone aminated compounds (
i) chemical structure of general formula identical;
With corresponding compound of benzaldehyde category (
1) and 2-hydroxy acetophenone compounds (
2) be starting raw material, direct polycondensation under solvent and alkaline condition, obtain corresponding 2-hydroxylated chalcone aminated compounds (
i); Utilize aforesaid method gained 2-hydroxylated chalcone aminated compounds (
i) in molecule containing amino, this amino, in alkalescence, can obtain acceptable salt on its pharmacology with any suitable acid by the salifying method of pharmaceutically routine.
4. the preparation method of 2-hydroxylated chalcone aminated compounds or its pharmacy acceptable salt as claimed in claim 3, is characterized in that reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, C
1-8an alkali metal salt of alcohol, triethylamine, Tributylamine, trioctylamine, pyridine,
n-methylmorpholine,
n-methyl piperidine, triethylene diamine or TBAH; Reaction solvent for use is: C
1-8fatty alcohol, C
3-8aliphatic ketone, ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran,
n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, Isosorbide-5-Nitrae-dioxane, benzene, toluene, acetonitrile or C
5-8alkane.
5. the preparation method of 2-hydroxylated chalcone aminated compounds or its pharmacy acceptable salt as claimed in claim 3, it is characterized in that compound of benzaldehyde category (
1): 2-hydroxy acetophenone compounds (
2): the molar feed ratio of alkali is 1.0 ~ 10.0:1.0:1.0 ~ 10.0; Temperature of reaction is 0 ~ 150 DEG C; Reaction times is 1 ~ 120 hour.
6. a class pharmaceutical composition, is characterized in that comprising 2-hydroxylated chalcone aminated compounds as described in any one of claim 1-2 or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier or vehicle.
7. the 2-hydroxylated chalcone aminated compounds as described in any one of claim 1-2 or its pharmacy acceptable salt are preparing the purposes treated and/or prevented in nervus retrogression relative disease medicine, and this kind of nervus retrogression relative disease is: vascular dementia, Alzheimer's disease, parkinsonism, huntington disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain or glaucoma.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1705473A (en) * | 2002-10-22 | 2005-12-07 | 詹肯生物科学公司 | Chromones and chromone derivatives and uses thereof |
| CN101684112A (en) * | 2008-09-27 | 2010-03-31 | 昆明制药集团股份有限公司 | Preparation method of 5,6,7,4'-tetramethoxy flavones of scutellarin and aglucone key intermediate thereof |
| KR20110115330A (en) * | 2010-04-15 | 2011-10-21 | 일동제약주식회사 | A novel chromene derivative compounds, a method of preparing the same and a composition including the same |
| CN102267888A (en) * | 2011-06-14 | 2011-12-07 | 黑龙江大学 | Chalcone derivative as well as preparation method and application thereof used as inducer in inducing apoptosis of tumor cells |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073440B (en) * | 2013-02-21 | 2015-06-03 | 四川大学 | Diphenylvinyloxy alkylamine compound and preparation method as well as application thereof |
-
2014
- 2014-09-19 CN CN201410478475.1A patent/CN105439876B/en not_active Expired - Fee Related
- 2014-09-19 CN CN201710856896.7A patent/CN107698492B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1705473A (en) * | 2002-10-22 | 2005-12-07 | 詹肯生物科学公司 | Chromones and chromone derivatives and uses thereof |
| CN101684112A (en) * | 2008-09-27 | 2010-03-31 | 昆明制药集团股份有限公司 | Preparation method of 5,6,7,4'-tetramethoxy flavones of scutellarin and aglucone key intermediate thereof |
| KR20110115330A (en) * | 2010-04-15 | 2011-10-21 | 일동제약주식회사 | A novel chromene derivative compounds, a method of preparing the same and a composition including the same |
| CN102267888A (en) * | 2011-06-14 | 2011-12-07 | 黑龙江大学 | Chalcone derivative as well as preparation method and application thereof used as inducer in inducing apoptosis of tumor cells |
Non-Patent Citations (4)
| Title |
|---|
| WEN YUAN等: "Synthesis of pterostilbene and resveratrol carbamate derivatives as potential dual cholinesterase inhibitors and neuroprotective agents", 《RES CHEM INTERMED》 * |
| XIAOMING QIANG等: "Design, synthesis and evaluation of genistein-O- alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer’s disease", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 于晓宇: "羟基查尔酮类似物的合成及其体内体外抗自由基活性研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 强晓明 等: "染料木素氨基甲酸酯类衍生物的合成及生物活性研究", 《有机化学》 * |
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Also Published As
| Publication number | Publication date |
|---|---|
| CN105439876B (en) | 2017-11-07 |
| CN107698492A (en) | 2018-02-16 |
| CN107698492B (en) | 2020-07-03 |
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