CN105481796B - One class carbamic acid chalcone ester type compound, preparation method and use - Google Patents
One class carbamic acid chalcone ester type compound, preparation method and use Download PDFInfo
- Publication number
- CN105481796B CN105481796B CN201410478535.XA CN201410478535A CN105481796B CN 105481796 B CN105481796 B CN 105481796B CN 201410478535 A CN201410478535 A CN 201410478535A CN 105481796 B CN105481796 B CN 105481796B
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- ester type
- carbamic acid
- type compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention discloses the new carbamic acid chalcone ester type compound 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 carbamic acid chalcone ester type compound of a class（I）, its preparation
Method, pharmaceutical composition and the purposes in treatment and/or prevention nervus retrogression relevant disease medicine is prepared, including but do not limit
In vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progress
The nerve degenerative diseases such as property 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）, though these compounds have preferable
Acetylcholine ester enzyme level and antioxidation activity, but to Aβ 1-42The suppression of self assemble（Inhibiting rate under 25.0 μM of concentration
Respectively less than 30.0%）, to Cu2+The A of inductionβ 1-42The suppression of aggregation（Inhibiting rate under 25.0 μM of concentration is respectively less than 35.0%）With
And to Cu2+The A of inductionβ 1-42The Disaggregating activity of aggregation（Depolymerization rate under 25.0 μM of concentration is respectively less than 35.0%）It is undesirable,
Cause curative effect of these compounds to AD in animal model not good enough.Therefore, design and find while having anti-acetylcholine ester
Enzyme, anti-oxidation stress, complexing of metal ion, suppressionβThe excessive generation of-amyloid and deposition and activity targets many in a balanced way
Point AD medicines are still research direction important at present.
The content of the invention
Present invention aims at disclose a class carbamic acid chalcone ester type compound（I）And its it is pharmaceutically acceptable
Salt；
Another object of the present invention is to disclose such carbamic acid chalcone ester type compound（I）And its it is pharmaceutically acceptable
Salt preparation method；
A further object of the present invention is open comprising such carbamic acid chalcone ester type compound（I）And its pharmaceutically
The pharmaceutical composition of acceptable salt；
Still a further object of the present invention is to disclose such carbamic acid chalcone ester type compound（I）And its it is pharmaceutically acceptable
Salt there is multiple target effect, available for prepare treatment and/or prevention nervus retrogression relevant disease medicine in purposes, bag
Include but be not limited to vascular dementia, it is Alzheimer's, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple hard
Change the nerve degenerative diseases such as disease, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Carbamic acid chalcone ester type compound provided by the present invention（I）Chemical structure of general formula be：
In formula：R1And R2Expression-OCONR independently of one another5R6Or NR7R8, R1And R2Can be in any possible position of phenyl ring
Put；R3And R4H, OH, C are represented independently of one another1~C12Alkyl, C1~C12Alkoxy, halogen, NR9R10, R3And R4Can be in phenyl ring
Any possible position；R5、R6、R7、R8、R9And R10C is represented independently of one another1~C12Alkyl, C3~C8Cycloalkyl, phenyl, benzyl,
Substituted-phenyl or substituted benzyl, but R5And R6It is asynchronously H, R7And R8It is asynchronously H；NR5R6、NR7R8And NR9R10It may also indicate that
Nafoxidine base, morpholinyl, piperidyl, 4- by C1~C12Piperidyl that alkyl is replaced, piperazinyl, 4- by C1~C12Alkyl
The piperazinyl that is replaced, the 4- piperazinyls that are replaced by benzyl or substituted benzyl；
Above-mentioned term " substituted benzyl " and " substituted-phenyl " refer on phenyl ring to be replaced by the 1-4 groups being selected from the group：
F、Cl、Br、I、C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, amino, dimethylamino, carboxyl, hydroxyl, cyano group,
These substituents can phenyl ring any possible position.
Carbamic acid chalcone ester type compound proposed by the invention（I）It can be prepared by following two methods：
Method one：
In formula：R1、R2、R3And R4Definition and carbamic acid chalcone ester type compound（I）Chemical structure of general formula phase
Together.
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 carbamic acid chalcone ester type compound（I）.Wherein, reacting alkali used is：Alkali gold
Belong to hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth gold
Belong to 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,
Potassium carbonate, triethylamine, pyridine or sodium methoxide；Reacting solvent for use is：C1-8Fatty alcohol, C3-8Aliphatic ketone, ether, tetrahydrofuran,
2- methyltetrahydrofurans,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, first
Benzene, acetonitrile or C5-8Alkane, preferred solvent is：Methanol, ethanol, isopropanol,N,N- dimethylformamide, acetone, acetonitrile, tetrahydrochysene
Furans, dichloromethane or toluene；Compound of benzaldehyde category（1）：2- hydroxy acetophenone class compounds（2）：The molar feed ratio of alkali
For 1.0 ~ 10.0：1.0：1.0 ~ 10.0, preferably molar feed ratio is 1.0 ~ 5.0：1.0：1.0~5.0；Reaction temperature is 0 ~ 150
DEG C, preferable reaction temperature is room temperature ~ 120 DEG C；Reaction time is 1 ~ 120 hour, and preferred reaction time is 2 ~ 72 hours.
Method two：
（1）Work as R1Represent OCONR5R6, R2Represent NR7R8When
Or
（2）Work as R1Represent NR7R8, R2Represent OCONR5R6When
In above formula：R1、R2、R3、R4、R5And R6Definition and carbamic acid chalcone ester type compound（I）Chemical constitution
Formula is identical.
With corresponding hydroxy benzaldehyde compound（3）With 2- hydroxy acetophenone class compounds（4）For initiation material, molten
Direct polycondensation under agent and alkalescence condition, obtains corresponding Hydroxylated Chalcones and Related compound（7）, gained intermediate（7）Alkaline and molten
Under the conditions of agent respectively with carbamyl chlorine derivative（5）Or isocyanate ester compound（6）Condensation, you can obtain corresponding amino
Formic acid chalcone ester type compound（I）；Can also compound of benzaldehyde category（8）With double hydroxy acetophenone class compounds（9）To rise
Beginning raw material, the direct polycondensation under solvent and alkalescence condition obtains double Hydroxylated Chalcones and Related compounds accordingly（10）, gained intermediate
（10）Alkalescence and solvent condition under respectively with carbamyl chlorine derivative（5）Or isocyanate ester compound（6）Condensation, you can
Obtain corresponding carbamic acid chalcone ester type compound（I）；
Wherein, Hydroxylated Chalcones and Related compound is being prepared（7）With（10）Reaction in, alkali used is：Alkali metal hydroxide
Thing, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline-earth metal bicarbonate
Salt, C1-8Alkali metal salt, trimethylamine class or the quaternary ammonium bases of alcohol（Such as：Triethylamine, tri-n-butylamine, trioctylamine, pyridine,N- methyl
Quinoline,N- methyl piperidine, triethylene diamine, TBAH）, preferably alkali is：Potassium hydroxide, sodium hydroxide, potassium carbonate, three
Ethamine, pyridine or sodium methoxide；Reacting solvent for use is：C1-8Fatty alcohol, C3-8Aliphatic ketone, ether, tetrahydrofuran, 2- methyl tetrahydrochysenes
Furans,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8
Alkane, preferred solvent is：Methanol, ethanol, isopropanol,N,N- dimethylformamide, acetone, acetonitrile, tetrahydrofuran, dichloromethane
Or toluene；Compound of benzaldehyde category（3）Or（8）：2- hydroxy acetophenone class compounds（4）Or double hydroxy acetophenone class compounds
（9）：The molar feed ratio of alkali is 1.0 ~ 10.0：1.0：1.0 ~ 10.0, preferably molar feed ratio is 1.0 ~ 5.0：1.0：1.0~
5.0；Reaction temperature is 0 ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C；Reaction time is 1 ~ 120 hour, when preferably reacting
Between be 2 ~ 72 hours.
In Hydroxylated Chalcones and Related compound（7）With（10）With carbamyl chlorine derivative（5）Or isocyanate ester compound
（6）Condensation prepares carbamic acid chalcone ester type compound（I）Reaction in, reaction solvent for use be：Ether, tetrahydrofuran,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, C3~C8Aliphatic ketone, benzene, toluene, acetonitrile, pyridine or C5~C8
Alkane, preferred solvent is：N,N- dimethylformamide, acetone, chloroform, acetonitrile, tetrahydrofuran or pyridine；Reaction alkali used is alkali
Metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, alkali metal or alkali metal bicarbonates, You Jishu
Amine or quaternary ammonium bases（Such as：Triethylamine, tri-n-butylamine, trioctylamine, pyridine,N- methyl morpholine,N- methyl piperidine, triethylene diamine,
TBAH）, preferably alkali is：Sodium acid carbonate, potassium carbonate, triethylamine or pyridine；Hydroxylated Chalcones and Related compound（7）Or
（10）：Carbamyl chlorine derivative（5）Or isocyanate ester compound（6）：The molar feed ratio of alkali is 1.0：1.0~6.0：1.0
~ 6.0, preferably molar feed ratio is 1.0：1.0~4.5：1.0~4.5；Reaction temperature is 0 ~ 130 DEG C, preferably room temperature ~ 80 DEG C；Contracting
It is 1 ~ 96 hour, preferably 2 ~ 24 hours to close the reaction time.
Initiation material --- the compound of benzaldehyde category of the present invention（1）Or 2- hydroxy acetophenone class compounds（2）（Molecule knot
Contain-OCONR in structure5R6Substituent）Can be with the common technology in this area, using the compound of corresponding phenolic hydroxy group as raw material, in alkali
Under property and solvent condition respectively with carbamyl chlorine derivative（5）Or isocyanates（R6During=H）Class compound（6）It is condensed to yield,
Method including but not limited to disclosed in documents below：1、Yong D.,et al. CN 200810045869.2；2、
Yong D., et al. CN 201210329696.3；3、Yong D.,et al. CN 201210329644.6；4、Yong
D., et al. CN 201210033040.7。
The carbamic acid chalcone ester type compound of gained according to the method described above（I）Contain amino in molecule, the amino is in
Alkalescence, can be made its pharmaceutically acceptable salt with any suitable sour salifying method by pharmaceutically routine, described
Acid is：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,
Salicylic 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 carbamic acid chalcone esters 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 animal
The amount of biological or medicine reaction medicine or medicament；" composition " refers to by by more than one materials or component mixing
Into 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.Institute of the present invention
Its preferable ratio of the pharmaceutical composition of offer is, carbamic acid chalcone ester type compound（I）Or its is pharmaceutically acceptable
Salt accounts for gross weight than 2%~99.5% as active component, and remainder is to account for gross weight than less than 98%.
Carbamic acid chalcone ester type compound disclosed in this invention（I）And its pharmaceutically acceptable salt carried out as
Under bioactivity screening.
（1）Carbamic acid chalcone ester type compound（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 2.5 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 amino first disclosed in the embodiment of the present invention
Sour chalcone ester type compound（I）To Aβ 1-42Self assemble is respectively provided with remarkable inhibiting activity, to A under 25.0 μM of concentrationβ 1-42
The inhibiting rate of self assemble is all higher than 65.0%；And inhibiting rate of the curcumin under same concentrations is 43.1%, clinically make extensively
Anti- AD medicines：Donepezil, Rivastigmine, memantine hydrochloride and compound（I）Parent nucleus --- 2- hydroxyls Cha Er
Ketone（R1=R2=R3=R4=H）To A under 25.0 μM of concentrationβ 1-42The inhibiting rate of self assemble is respectively less than 10%.
（2）Carbamic acid chalcone ester type compound（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 carbamic acid chalcone ester type compound（I）Show have strong complexing to metal ion.
（3）Carbamic acid chalcone ester type compound（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（2.5 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 1-42The μ L test compounds of solution+20
Thing 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 holes
In 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 carbamic acid chalcone ester type compound disclosed in the embodiment of the present invention（I）Under 25.0 μM of concentration
To 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%,
Compound（I）Parent nucleus --- 2- hydroxylated chalcones（R1=R2=R3=R4=H）Inhibiting rate under same concentrations is less than 20.0%.
（4）Carbamic acid chalcone ester type compound（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 25 μM）, 24h is incubated again at 37 °C, then adds 190 μ L
The glycine-NaOH buffer of 50 mM containing 5 μM of thioflavine Ts（pH=8.5）, existed immediately with multi-function microplate reader 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
Carbamic acid chalcone ester type compound（I）To Cu under 25.0 μM of concentration2+The A of inductionβ 1-42The depolymerization rate of aggregation is all higher than
70.0%, and depolymerization rate of the curcumin under same concentrations is 56.5%, compound（I）Parent nucleus compound --- 2- hydroxyls Cha Er
Ketone（R1=R2=R3=R4=H）Depolymerization rate under same concentrations is less than 20.0%.
（5）Carbamic acid chalcone ester type compound（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）The molten of 250nmol/L is made into pH7.4 PBS
Liquid, 2,2 '-azo diisobutyl amidine dihydrochloride（AAPH）With pH7.4 PBS the molten of 40mmol/L is made into using preceding
Liquid.50-10 μm of ol/L compound solution and luciferin solution, mixing, 37 °C of incubation 15min is added into 96 orifice plates, is added
AAPH solution, it is 200 μ L to make every hole cumulative volume, mixes, is immediately placed on Varioskan Flash Multimode Reader instrument
In, the min of METHOD FOR CONTINUOUS DETERMINATION 90 under 485 nm excitation wavelengths and 535 nm launch wavelengths.Calculate area under fluorescence decay curve
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 knot of compound
Fruit is expressed asTroloxEquivalent, 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 that the carbamic acid disclosed in the embodiment of the present invention is looked into
That ketone ester type compound（I）Antioxidation activity beTrolox1.0-10.0 times, illustrate that such compound has strong anti-oxidation
Activity.
（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
Acetylcholinesterase（Rat brain cortex 5% is homogenized supernatant, and pH7.4 phosphate buffer makees homogenate medium）Or BuCh ester
Enzyme（The supernatant of rat blood serum 25%, pH7.4 phosphate buffers make homogenate medium）Solution, is finished after mixing, 37 DEG C of incubation 15min,
5,5 '-two thio-bis- (the 2- nitrobenzoic acids) of addition 0.2% into each hole（DTNB）The μ L of solution 30 develop the color, and are determined with ELIASA
The optical density in each hole at 405nm（OD values）, compared with the blank well for being not added with testing sample, calculate inhibiting rate of the compound to enzyme
（Enzyme inhibition rate (%)=(1- sample sets OD values/blank group OD values) × 100%）；Five to six concentration of compound are selected, it is determined
Enzyme inhibition rate, and with the inhibiting rate linear regression of the negative logarithm of the compound molar concentration and enzyme, rubbing when trying to achieve 50% inhibiting rate
Your concentration is the IC of the compound50.Measurement result shows, the carbamic acid chalcone esters disclosed in the embodiment of the present invention
Compound（I）The effect of significantly inhibiting is respectively provided with to acetylcholinesterase, its IC50For 0.1 μM ~ 50.0 μM；Measurement result also table
It is bright：4 '-dimethylamino -2- hydroxylated chalcones（R1=NMe2, R2=R3=R4=H）, 4- dimethylamino -2- hydroxylated chalcones（R1=R3=R4
=H, R2=NMe2）, compound（I）Parent nucleus --- 2- hydroxylated chalcones（R1=R2=R3=R4=H）And the like（R1=R3=R4=H,
R2=OCONMe2And positioned at phenyl ring 4-）To the IC of acetylcholine ester enzyme level50It is all higher than 300 μM.
（7）To AβCause the influence of cognition dysfunction in Model of Dementia in Rats（Illustrated by taking compound 1-1-2 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（8mg/kg）, in（4mg/kg）, it is low（2mg/kg）Dosage group and positive control donepezil
（5mg/kg）Group, every group 8, gastric infusion（Control group and model group give isometric solvent）, 1 day 1 time, continuous 4 weeks；To
Medicine determines the ability of learning and memory of rat on the 3rd week with Morris water mazes.Measurement result shows, compared with control group, dull-witted
The incubation period of model group Morris water mazes test is obviously prolonged（P<0.01）；Medicine is high, the incubation period of middle dose group is more dull-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 necessarily
Shortening 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 carbamic acid chalcone ester type compound 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）, 8.0 mmol Anhydrous potassium carbonates and 50 ml acetonitriles, after stirring, temperature rising reflux stirring reaction 2.0
~72.0 hours（Reaction process is tracked with TLC）；After reaction terminates, room temperature is cooled to, reaction solution is adjusted with 10% aqueous hydrochloric acid solution
PH adjusts reaction solution pH to alkalescent to highly acid, then with saturated sodium bicarbonate aqueous solution, removes under reduced pressure in acetonitrile, residual solution and adds
Enter 80 mL deionized waters, extracted in three times with 300 mL dichloromethane, organic layer is washed after merging with saturated sodium-chloride water solution
Wash, filtered after anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is purified through column chromatography（Eluent：Ethyl acetate:Third
Ketone=5:1 v/v）, obtain corresponding carbamic acid chalcone ester type compound（I）, yield 38.0%-90.0%, its chemical constitution is equal
Through1H-NMR、13C-NMR and ESI-MS confirmations；The purity of gained object determines through HPLC and is all higher than 97.0%.Using above-mentioned logical
The object structure that method is prepared is as follows：
（1）R1Represent R7R8N, R3=R4=H, R2Represent OCONR5R6Compound（I）：
。
（2）R1Represent R7R8N, R3=OH, R4=H, R2Represent OCONR5R6Compound（I）：
。
The carbamic acid chalcone ester type compound of embodiment 2（I）Preparation lead to method
The corresponding 2- hydroxy acetophenones class compounds of 2.0 mmol are added in reaction bulb（4）Or double hydroxy acetophenone classes
Compound（9）, the corresponding hydroxy benzaldehyde compounds of 3.0 mmol（3）Or compound of benzaldehyde category（8）And 40 ml ethanol,
After stirring, the mmol of the 30% KOH aqueous solution 8.0 is added dropwise to, reaction is stirred at room temperature 2.0~72.0 hours（Reaction process is used
TLC is tracked）；After reaction terminates, reaction solution pH is adjusted with 10% aqueous hydrochloric acid solution molten to highly acid, then with saturated sodium bicarbonate water
Liquid adjusts reaction solution pH to alkalescent, removes under reduced pressure and 80 mL deionized waters are added in ethanol, residual solution, with 300 mL dichloromethanes
Alkane is extracted in three times, and organic layer is washed after merging with saturated sodium-chloride water solution, is filtered after anhydrous sodium sulfate drying, and decompression is steamed
Except solvent, residue is purified through column chromatography（Eluent：Dichloromethane:Acetone=10:1 v/v）, obtain corresponding Hydroxylated Chalcones and Related
Compound（7）Or double Hydroxylated Chalcones and Related compounds（10）, yield 45.0%-90.0%；
The corresponding Hydroxylated Chalcones and Related compounds of 2.0 mmol are added in reaction bulb（7）Or double Hydroxylated Chalcones and Related chemical combination
Thing（10）, 8.0 mmol Anhydrous potassium carbonates and 50 ml acetonitriles, after stirring, add 3.0 mmol carbamyl chlorine derivatives
（5）Or isocyanates（R6During=H）Class compound（6）, reaction 2-24 hours is stirred at room temperature（Reaction process is tracked with TLC）；Reaction
After end, solid is filtered out, solvent is evaporated off in filtrate decompression, and residue is purified through silica gel column chromatography（Eluent：Ethyl acetate:Acetone=
5:1 v/v）, obtain corresponding carbamic acid chalcone ester type compound（I）, yield 51.0%-95.6%, its chemical constitution passes through1H-NMR、13C-NMR and ESI-MS confirmations；The purity of gained object determines through HPLC and is all higher than 97.0%.Using above-mentioned logical method
The object structure prepared is as follows：
（1）R1Represent OCONR5R6, R3=R4=H, R2Represent R7R8N compound（I）：
。
（2）R1Represent OCONR5R6, R3=H, R4=OH, R2Represent R7R8N compound（I）：
。
The carbamic acid chalcone ester type compound of embodiment 3（I）With acid logical method is prepared into salt
The carbamic acid chalcone ester type compound according to the gained of above-described embodiment 1 or 2 is added in reaction bulb（I）2.0
The mmol and 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, reaction knot
Room temperature is cooled to after beam, solvent is removed under reduced pressure, residue acetone recrystallization filters the solid separated out, produces carbamic acid and look into
That ketone ester type compound（I）Salt, its chemical constitution warp1H NMR and ESI-MS are confirmed.
Claims (10)
1. a class carbamic acid chalcone ester type compound or its pharmaceutically acceptable salt, it is characterised in that such compound
Chemical structure of general formula is such as（I）It is shown：
In formula：R1And R2Expression-OCONR independently of one another5R6Or NR7R8, but R1And R2Asynchronously represent NR7R8, R1And R2Can be with
In any possible position of phenyl ring；R3And R4H, OH, C are represented independently of one another1~C12Alkyl, C1~C12Alkoxy, halogen,
NR9R10；R3And R4Can be in any possible position of phenyl ring；R5、R6、R7And R8C is represented independently of one another1~C12Alkyl, benzyl or
Substituted benzyl；R9And R10C is represented independently of one another1~C12Alkyl；NR5R6、NR7R8And NR9R10Also illustrate that nafoxidine base, morpholine
Base, piperidyl, 4- by C1~C12Piperidyl that alkyl is replaced, piperazinyl, 4- by C1~C12Piperazinyl that alkyl is replaced,
The 4- piperazinyls that are replaced by benzyl or substituted benzyl；Above-mentioned term " substituted benzyl " refers on phenyl ring to be selected from down by 1-4
The group of group is replaced：F、Cl、Br、I、C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, dimethylamino, hydroxyl, cyano group, these take
Any possible positions of the Dai Jike in phenyl ring.
2. carbamic acid chalcone ester type compound as claimed in claim 1 or its pharmaceutically acceptable salt, its feature exist
In described pharmaceutically acceptable salt be such carbamic acid chalcone ester type compound and hydrochloric acid, hydrobromic acid, nitric acid, sulphur
Acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, butanedioic acid, tartaric acid, citric acid, apple
Tartaric acid, lipoic acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, the salt of benzene sulfonic acid or p-methyl benzenesulfonic acid.
3. the system of carbamic acid chalcone ester type compound or its pharmaceutically acceptable salt as described in claim any one of 1-2
Preparation Method, it is characterised in that the compound can be prepared by the following method and obtain：
Method one：
In formula：R1、R2、R3And R4Definition and carbamic acid chalcone ester type compound（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 carbamic acid chalcone ester type compound（I）；
Method two：
（1）Work as R1Represent OCONR5R6, R2Represent NR7R8When：
Or
（2）Work as R1Represent NR7R8, R2Represent OCONR5R6When：
In above formula：R1、R2、R3、R4、R5And R6Definition and carbamic acid chalcone ester type compound（I）Chemical structure of general formula
It is identical；
With corresponding hydroxy benzaldehyde compound（3）With 2- hydroxy acetophenone class compounds（4）For initiation material, in solvent and
Direct polycondensation under alkalescence condition, obtains corresponding Hydroxylated Chalcones and Related compound（7）, gained intermediate（7）In alkalescence and solvent bar
Under part respectively with carbamyl chlorine derivative（5）Or isocyanate ester compound（6）Condensation, you can obtain corresponding carbamic acid
Chalcone ester type compound（I）；Can also compound of benzaldehyde category（8）With double hydroxy acetophenone class compounds（9）It is former for starting
Material, the direct polycondensation under solvent and alkalescence condition obtains double Hydroxylated Chalcones and Related compounds accordingly（10）, gained intermediate（10）
Alkalescence and solvent condition under respectively with carbamyl chlorine derivative（5）Or isocyanate ester compound（6）Condensation, you can obtain
Corresponding carbamic acid chalcone ester type compound（I）；
Utilize the carbamic acid chalcone ester type compound of above method gained（I）Contain amino in molecule, the amino is in alkalescence,
Its pharmaceutically acceptable salt can be made with any suitable sour salifying method by pharmaceutically routine.
4. the preparation method of carbamic acid chalcone ester type compound as claimed in claim 3 or its pharmaceutically acceptable salt,
It is characterized in that alkali used in being reacted in method one is：Alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate,
Alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, triethylamine, tri-n-butylamine,
Trioctylamine, pyridine,N- methyl morpholine,N- methyl piperidine, triethylene diamine or TBAH；Reacting solvent for use is：
C1-8Fatty alcohol, C3-8Aliphatic ketone, ether, tetrahydrofuran, 2- methyltetrahydrofurans,N,N- dimethylformamide, dimethyl sulfoxide (DMSO),
Dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane.
5. the preparation method of carbamic acid chalcone ester type compound as claimed in claim 3 or its pharmaceutically acceptable salt,
It is characterized in that compound of benzaldehyde category in method one（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. the preparation method of carbamic acid chalcone ester type compound as claimed in claim 3 or its pharmaceutically acceptable salt,
It is characterized in that preparing Hydroxylated Chalcones and Related compound in method two（7）Or（10）Reaction in, alkali used is：Alkali metal hydrogen
Oxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline-earth metal carbon
Sour hydrogen salt, C1-8The alkali metal salt of alcohol, triethylamine, tri-n-butylamine, trioctylamine, pyridine,N- methyl morpholine,N- methyl piperidine, triethylene
Diamines or TBAH；Reacting solvent for use is：C1-8Fatty alcohol, C3-8Aliphatic ketone, ether, tetrahydrofuran, 2- methyl
Tetrahydrofuran,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile
Or C5-8Alkane.
7. the preparation method of carbamic acid chalcone ester type compound as claimed in claim 3 or its pharmaceutically acceptable salt,
It is characterized in that preparing Hydroxylated Chalcones and Related compound in method two（7）Or（10）Reaction in, compound of benzaldehyde category（3）
Or（8）：2- hydroxy acetophenone class compounds（4）Or double hydroxy acetophenone class compounds（9）：The molar feed ratio of alkali be 1.0 ~
10.0：1.0：1.0~10.0；Reaction temperature is 0 ~ 150 DEG C；Reaction time is 1 ~ 120 hour.
8. the preparation method of carbamic acid chalcone ester type compound as claimed in claim 3 or its pharmaceutically acceptable salt,
It is characterized in that by Hydroxylated Chalcones and Related compound in method two（7）Or（10）With carbamyl chlorine derivative（5）Or isocyanic acid
Ester type compound（6）Condensation prepares carbamic acid chalcone ester type compound（I）Reaction in, reaction solvent for use be：Ether,
Tetrahydrofuran,N,N- dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, C3~C8Aliphatic ketone, benzene, toluene, acetonitrile, pyrrole
Pyridine or C5~C8Alkane；Reacting alkali used is：Alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth gold
Belong to carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, triethylamine, tri-n-butylamine, trioctylamine, pyridine,N- methyl
Quinoline,N- methyl piperidine, triethylene diamine or TBAH；Hydroxylated Chalcones and Related compound（7）Or（10）：Carbamyl
Chlorine derivative（5）Or isocyanate ester compound（6）：The molar feed ratio of alkali is 1.0：1.0~6.0：1.0~6.0；Reaction temperature
For 0 ~ 130 DEG C；Condensation reaction time is 1 ~ 96 hour.
9. a class pharmaceutical composition, it is characterised in that include the carbamic acid chalcone ester as described in claim any one of 1-2
Class compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipient.
10. carbamic acid chalcone ester type compound or its pharmaceutically acceptable salt as described in claim any one of 1-2
The purposes in treating and/or preventing nervus retrogression relevant disease medicine is being prepared, this kind of nervus retrogression relevant disease is：Blood
Pipe dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive ridge
Marrow lateral schlerosis, neuropathic pain or glaucoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410478535.XA CN105481796B (en) | 2014-09-19 | 2014-09-19 | One class carbamic acid chalcone ester type compound, preparation method and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410478535.XA CN105481796B (en) | 2014-09-19 | 2014-09-19 | One class carbamic acid chalcone ester type compound, preparation method and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105481796A CN105481796A (en) | 2016-04-13 |
| CN105481796B true CN105481796B (en) | 2017-11-07 |
Family
ID=55669116
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410478535.XA Expired - Fee Related CN105481796B (en) | 2014-09-19 | 2014-09-19 | One class carbamic acid chalcone ester type compound, preparation method and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105481796B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN108727350B (en) * | 2017-04-14 | 2021-04-27 | 四川大学 | Piperidine alkyl phthalide compounds, preparation method and application thereof |
| US20200190024A1 (en) * | 2017-05-16 | 2020-06-18 | Industry-Academic Cooperation Foundation, Yonsei University | Novel compound and pharmaceutical composition comprising same as active ingredient |
| 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 |
| CN111039807A (en) * | 2018-10-12 | 2020-04-21 | 南京大学 | Synthesis of novel fluorescent mother nucleus containing chalcone structure |
| CN109734614B (en) * | 2019-01-11 | 2022-04-22 | 四川大学 | 3-hydroxy chalcone Mannich base compound, preparation method and application thereof |
| CN109678736B (en) * | 2019-01-11 | 2022-04-22 | 四川大学 | Chalcone Mannich base compound, preparation method and application thereof |
| CN113105409B (en) * | 2021-04-06 | 2023-06-02 | 四川大学 | 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound, preparation method and application thereof |
| CN115215769B (en) * | 2022-06-28 | 2024-01-30 | 黄淮学院 | Fluorescent probe for detecting acetylcholinesterase as well as preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2014
- 2014-09-19 CN CN201410478535.XA patent/CN105481796B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (2)
| Title |
|---|
| Tuning Excited-State Charge/Proton Transfer Coupled Reaction via the Dipolar Functionality;Pi-Tai Chou et al.;《Journal of Physical Chemistry A》;20040710;第108卷(第31期);第6452-6454页 * |
| 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;于晓宇;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20111215(第S2期);E057-82 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105481796A (en) | 2016-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105481796B (en) | One class carbamic acid chalcone ester type compound, preparation method and use | |
| CN105481706B (en) | The Hydroxylated Chalcones and Related compound of one class 2, preparation method and use | |
| CN105439876B (en) | 2 hydroxylated chalcone aminated compounds, preparation method and use | |
| CN106632181B (en) | Aurone Mannich alkaloid compound, preparation method and use | |
| CN105646417B (en) | A kind of 4 hydroxyl aurone class compounds, preparation method and use | |
| CN106831799B (en) | Hydroxy styrenes pyridine Mannich alkaloid compound, preparation method and use | |
| CN108101780A (en) | A kind of Flurbiprofen chalcone compounds, preparation method and use | |
| CN108218744A (en) | A kind of coffee DOPA amide carbamate compound, preparation method and application | |
| CN111170884B (en) | Salicylamide compound, preparation method and application thereof | |
| CN109734614A (en) | 3- hydroxylated chalcone Mannich alkaloid compound, preparation method and use | |
| CN108586411A (en) | A kind of naringenin carbamate compound, preparation method and application | |
| CN109824637A (en) | A kind of indone chalcone carbamate compound and its preparation method and application | |
| CN110698445B (en) | 3-amine alkyl phthalide compound, preparation method and application thereof | |
| CN114805263B (en) | 3- (hydroxybenzyl) phthalide compound, preparation method and application thereof | |
| CN106632191B (en) | Homoisoflavone Mannich alkaloid compound, preparation method and use | |
| CN109761945A (en) | A kind of naringenin-O- alkyl amine compound, preparation method and application | |
| CN108727352A (en) | A kind of piperidines alkane carbamyl phthalide analog compound, preparation method and use | |
| CN113185447B (en) | Phthaloyl cysteamine compound, preparation method and application thereof | |
| CN108586335A (en) | 2-Hydroxylbenzamide -1,2,3,4- tetrahydroisoquinoline-O- carbamate compounds and preparation method thereof | |
| CN106810532B (en) | A kind of amine alkoxy thioxanthene ketone class compound, preparation method and use | |
| CN110240549B (en) | Amine alkoxy chalcone compound and preparation method and application thereof | |
| CN110272349B (en) | 2' -hydroxy-3-phenyl propiophenone compound and preparation method and application thereof | |
| CN109761883A (en) | A kind of 4- carbamate-cinnamamide -4- benzyl piperidine coumpound and its preparation method and application | |
| CN109665969A (en) | The double Mannich alkaloid compounds of 3- methoxyl group -4-HC, preparation method and use | |
| CN109678795A (en) | 4- carbamate-asafoetide amide -1,2,3,4- tetrahydroisoquinolicompounds compounds and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171107 Termination date: 20190919 |