CN110003033A - Flurbiprofen chalcone Mannich alkaloid compound, preparation method and use - Google Patents
Flurbiprofen chalcone Mannich alkaloid compound, preparation method and use Download PDFInfo
- Publication number
- CN110003033A CN110003033A CN201810011184.XA CN201810011184A CN110003033A CN 110003033 A CN110003033 A CN 110003033A CN 201810011184 A CN201810011184 A CN 201810011184A CN 110003033 A CN110003033 A CN 110003033A
- Authority
- CN
- China
- Prior art keywords
- acid
- flurbiprofen
- chalcone
- compound
- pharmaceutically acceptable
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of novel Flurbiprofen chalcone Mannich alkaloid compound (I) and its pharmaceutically acceptable salt, preparation method, pharmaceutical composition and the purposes in preparation treatment and/or prevention nervus retrogression related disease drug, the including but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma;
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to a kind of novel Flurbiprofen chalcone Mannich alkaloid compound (I)
And its pharmaceutically acceptable salt, preparation method, pharmaceutical composition are related in preparation treatment and/or prevention nervus retrogression
Purposes in disease medicament, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV
The nervus retrogressions diseases such as related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma
Disease.
Background technique
Alzheimer's disease (Alzheimer ' s disease, AD, senile dementia) is one kind with progressive cognitive disorder
With the central nervous system degenerative disease based on memory damage, disease incidence becomes in trend is risen year by year and is only second to the heart
The high incidence disease of angiosis and cancer, having gone up in developed countries such as America and Europes is the 4th of the cause of death.According to world health
Organisation Report, global over-65s old man have 10% dysnoesia, and wherein half occurs dull-witted, fall ill within 85 years old or more
Rate nearly 50%.The AD patient numbers about 600-700 ten thousand in China, disease incidence are more than 5%.With adding for population in the world aging process
Fastly, disease incidence is in obvious ascendant trend, is announced according to Alzheimer's Disease International in December, 2013
" global implication of Alzheimer's disease: 2013-2050 " report in point out, AD will become the coming few decades whole world face most
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.Due to AD clinical manifestation be memory capability, capacity of orientation, thinking and judgement decline, and
Activity of daily living reduces, or even abnormal Behavioral and psychological symptom occur etc., keep patient care difficulty larger, to society and family's band
Carry out heavy burden.The drug that approved is used to treat light/moderate AD at present has acetylcholinesterase (AChE) inhibitor, Yi Jiyong
In severe AD treatmentNMethyl-DAspartic acid (NMDA) receptor antagonist, but clinical use shows that these drugs can pass through
It improves patient's body levels of acetylcholine or inhibits the exitotoxicity of excitatory amino acid to alleviate AD symptom, but cannot be effective
Prevent or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, nausea, hepatotoxicity, loss of appetite and
The serious toxic side effect such as stool frequency, thus long-term efficacy is not satisfactory.Therefore, clinically there is an urgent need to research and develop with novel work
With the AD therapeutic agent of mechanism.
AD belongs to disease caused by many factors, and pathogenesis is complicated, and pathogenesis does not illustrate also completely so far, but studies
Show patient's intracerebral levels of acetylcholine decline,βThe excessive of amyloid protein generates and the blood platelet in deposition, the cerebrovascular
Aggregation, metal ion metabolic disorder, Ca2+Dysequilibrium,tauNeurofibrillary tangles caused by protein hyperphosphorylation, glutamic acid
Receptor active is excessively high, oxidative stress generates a large amount of active oxygens (ROS) and many factors such as free radical and Neuroinflammation exist
It plays an important role in the pathogenic process of AD.For above-mentioned pathogenic factors, researcher is set using traditional " one target of a medicine " drug
Stratagem omit, it was found that largely to a certain target spot have high activity and highly selective drug, such as: anticholinesterase andNFirst
Base-DAspartate receptor agonist etc..But that there are action target spots is single for these drugs, clinical use toxic side effect is more, right
Not the problems such as long-term efficacy of AD patient is not good enough.
In recent years, with constantly illustrating to AD pathogenesis, it is found that the occurrence and development of AD have multimachine system, multifactor
It is the characteristics of effect, again interrelated between different mechanisms to influence each other, constitute complicated network during AD occurrence and development
Regulator control system.Obviously, it is current inevitable choice that research and development can act on the therapeutic agent of multiple links in AD pathologic process simultaneously.
Based on the above results, researcher propose " multiple target point guiding aglucon " (Multitarget-directed Ligands,
MTDLs) strategy researches and develops anti-neurodegenerative disease drug.So-called " multiple target point aglucon " refers to single chemical entities while acting on
Multiple target spots in disease network can produce synergistic effect to the effect of each target spot, so that gross effect is greater than each single-action and the sum of answers,
Such compound is also referred to as " Multifunctional " or " Multipotential " drug.Multiple target point drug is combined with multiple medicine
Using and the main distinction of compound medicine be: dosage can be reduced, therapeutic effect is improved, avoid the phase interaction between drug
With and thus bring toxic side effect, uniform pharmacokinetic properties, be easy to use etc..Therefore, research and development have novel
Chemical structure, novel mechanism of action, and with multiple target effect, less toxic side effect anti-neurodegenerative disease therapeutic agent not
Only meet the urgent need of social senilization's process, and there are good market prospects.It designs and finds that there is antioxygen simultaneously
Change stress, complexing of metal ion, inhibitionβThe excessive more targets generated with deposition and anti-Neuroinflammation of amyloid protein
Point AD therapeutic agent is still research direction important at present.
Summary of the invention
Present invention aims at open a kind of novel Flurbiprofen chalcone Mannich alkaloid compounds (I) and its pharmacy
Upper acceptable salt.
Another object of the present invention is to disclose such Flurbiprofen chalcone Mannich alkaloid compound (I) and its pharmaceutically
Acceptable salt production process.
Another object of the present invention is to open comprising such Flurbiprofen chalcone Mannich alkaloid compound (I) and its
The pharmaceutical composition of pharmaceutically acceptable salt.
Still a further object of the present invention is to disclose such Flurbiprofen chalcone Mannich alkaloid compound (I) and its pharmaceutically
Acceptable salt has multiple target effect, in the drug that can be used for preparing treatment and/or prevention nervus retrogression related disease
It is purposes, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, more
The neurodegenerative diseases such as hair property sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
The general formula of the chemical structure of Flurbiprofen chalcone Mannich alkaloid compound (I) provided by the present invention is as follows:
In formula: R1And R2Each independently represent C1~C12Alkyl, benzyl, substituted benzyl, propargyl;NR1R2Also illustrate that tetrahydro pyrrole
Base, morpholinyl, piperidyl, 4- are coughed up by C1~C12Piperidyl replaced alkyl, 4- replaced benzyl or substituted benzyl
Piperidyl, piperazinyl, 4- by C1~C12Piperazinyl replaced alkyl, the 4- piperazines replaced benzyl or substituted benzyl
Base, X indicate O or NH, R3Indicate H or C1~C12Alkyl;Substituent group CH2NR1R2It can be in the arbitrarily possible position of phenyl ring with OH;It is described
Compound isRConfiguration,SConfiguration orRConfiguration andSThe arbitrary proportion mixture of configuration;Above-mentioned term " substituted benzyl " refers to by benzene
The benzyl replaced 1-4 groups selected from the group below on ring: F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, three
Fluorine methoxyl group, NR4R5, hydroxyl, nitro, cyano, these substituent groups can be in any possible position of phenyl ring;R4And R5It is respectively independent
Ground indicates H, C1~C12Alkyl, NR4R5Also illustrate that nafoxidine base, morpholinyl or piperidyl.
Flurbiprofen chalcone Mannich alkaloid compound (I) proposed by the invention can be prepared by the following method
It arrives, reaction equation is as follows:
In formula: R1、R2、R3Definition with X is identical as general formula of the chemical structure (I).
For said synthesis route, specific preparation method is described as follows:
It is that starting is former with corresponding 4 '-acetyl Flurbiprofen class compound (1) and hydroxy benzaldehyde Mannich alkaloid compound (2)
Material, the direct polycondensation under solvent and alkaline condition obtain corresponding Flurbiprofen chalcone Mannich alkaloid compound (I);Wherein,
React alkali used are as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali gold
Belong to bicarbonate, alkali metal bicarbonates, C1-8Alkali metal salt, trimethylamine class or the quaternary ammonium bases of alcohol are (such as: triethylamine, three
Butylamine, trioctylamine, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene diamine, tetrabutylammonium hydroxide), preferred alkali are as follows: hydrogen
Potassium oxide, sodium hydroxide, potassium carbonate, triethylamine or pyridine;React solvent for use are as follows: C1-8Fatty alcohol, ether, tetrahydrofuran, 2-
Methyltetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, 1,4- dioxane, benzene, toluene or
Acetonitrile, preferred solvent are as follows: methanol, ethyl alcohol, isopropanol,N,NDimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or first
Benzene;Compound (1): hydroxy benzaldehyde Mannich alkaloid compound (2): the molar feed ratio of alkali be 1.0:1.0 ~ 3.0:1.0 ~
20.0, preferably molar feed ratio is 1.0:1.0 ~ 2.0:1.0 ~ 10.0;Reaction temperature is 0 ~ 150 DEG C, and preferable reaction temperature is room
Temperature ~ 100 DEG C;Reaction time is 1 ~ 120 hour, and preferred reaction time is 2 ~ 72 hours.
The technology system that starting material of the invention --- 4 '-acetyl Flurbiprofen class compounds (1) can use this field common
It obtains, including but not limited to the method disclosed in following documents: 1, Robert Jameset al. WO
2003003012A1;2,Yao Chen. et al.Bioorganic & Medicinal Chemistry2013, 21,
2462-2470。
Contain amino in Flurbiprofen chalcone Mannich alkaloid compound (I) molecule of gained according to the method described above, it should
In alkalinity its pharmaceutically acceptable salt can be made by pharmaceutically conventional salifying method with any suitable acid in amino,
The acid are as follows: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, amidosulfonic acid, C1-6Aliphatic carboxylic acid is (such as: formic acid, acetic acid, propionic acid
Deng), trifluoroacetic acid, stearic acid, flutter acid, oxalic acid, benzoic acid, phenylacetic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, winestone
Acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, glutamic acid, ascorbic acid, lipoic acid, C1-6Alkyl sulfonic acid
(such as: methane sulfonic acid, ethylsulfonic acid), camphorsulfonic acid, naphthalene sulfonic acids, benzene sulfonic acid, p-methyl benzenesulfonic acid or 1,4- fourth disulfonic acid.
Pharmaceutical composition disclosed in this invention includes one or more Flurbiprofen chalcone Mannies of therapeutically effective amount
Uncommon alkaloid compound (I) or its pharmaceutically acceptable salt, the pharmaceutical composition can further containing it is one or more pharmaceutically
Acceptable carrier or excipient." therapeutically effective amount " refer to cause researcher or the targeted tissue of doctor, system or
The amount of the biology of animal or the drug of medicine reaction or medicament;" composition " refers to by by more than one substances or component
Product made of mixing;" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable substance, composition or carrier,
Such as: liquid or solid filler, diluent, excipient, solvent or packing substance, they carry or transport certain chemical substance.
Its ideal ratio of pharmaceutical composition provided by the present invention is, Flurbiprofen chalcone Mannich alkaloid compound (I) or its
Pharmaceutically acceptable salt accounts for total weight than 5%~99.5% as active constituent, and rest part is to account for total weight than 95% or less.
Flurbiprofen chalcone Mannich alkaloid compound (I) disclosed in this invention and its pharmaceutically acceptable salt into
Following bioactivity screening is gone.
(1) suppression of the Flurbiprofen chalcone Mannich alkaloid compound (I) to acetylcholinesterase and butyrylcholine esterase
System activity
1.0 mmol/L acetylthiocholine iodides or iodine bisulfide are sequentially added into 96 orifice plates for 30 μ L of BuCh, pH7.4
40 μ L of PBS buffer solution, 1%) and 10 μ L acetylcholinesterases or butyryl 20 μ L(DMSO content of testing compound solution is less than
Cholinesterase solution, after finishing mixing, 0.2% 5,5 '-two thio-bis- (2- nitros are added into each hole by 37 DEG C of incubation 15min
Benzoic acid) (DTNB) solution 30 μ L colour developing and be not added to test sample with the optical density (OD value) in each hole at microplate reader measurement 405nm
The blank well of product compares, calculate compound to the inhibiting rate of enzyme (enzyme inhibition rate (%)=(1- sample sets OD value/blank group OD value) ×
100%);Five to six concentration for selecting compound, measure its enzyme inhibition rate, and with the negative logarithm of the compound molar concentration with
The inhibiting rate linear regression of enzyme, molar concentration when acquiring 50% inhibiting rate are the IC of the compound50.Measurement result shows this
Flurbiprofen chalcone Mannich alkaloid compound (I) disclosed in inventive embodiments all has significantly acetylcholinesterase
Inhibiting effect (its IC50It is 0.2 μM ~ 30.0 μM), and such compound is to weaker (eachization of the inhibitory activity of butyrylcholine esterase
Close inhibiting rate of the object under 50.0 μM of concentration < 10%), illustrate that compound disclosed in this invention has acetylcholinesterase
Selective inhibitory.Measurement result is also shown that the parent nucleus of Flurbiprofen chalcone Mannich alkaloid compound (I) --- fluorine ratio
Ibuprofen, 4 '-acetyl Flurbiprofen methyl esters andThe IC that acetylcholinesterase is inhibited50
It is all larger than 200 μM.
(2) inhibitory activity of the Flurbiprofen chalcone Mannich alkaloid compound (I) to monoamine oxidase B
Recombined human MAO-B is made into 75 μ g/mL sample liquids with 7.4 kaliumphosphate buffer of pH of 100 mM.To 96 orifice plate of black
Middle 20 μ L of addition testing compound solution, 80 μ L of monoamine oxidase are mixed, and 37 DEG C are incubated for 15 min in the place of being protected from light, and are added 200
μM Amplex Red reagent, 2U/mL horseradish peroxidase, 2 mM benzene methanamine initiation reactions, 37 DEG C of 20 min of incubation, more
In function microplate reader, to fix 545 nm of excitation wavelength, fluorescent emission intensity at 590 nm is surveyed, is replaced with kaliumphosphate buffer
MAO-B is blank;The inhibiting rate calculation formula of compound inhibition monoamine oxidase are as follows: 100- (IFi)/(IFc) * 100, in formula,
IFiAnd IFcRespectively there is the difference of the fluorescence intensity and blank fluorescence intensity under inhibitor and no inhibitor.Each compound is every
3 multiple holes of secondary measurement, every group of experiment are independent in triplicate.Five to six concentration for selecting compound, measure its enzyme inhibition rate, and
With the inhibiting rate linear regression of the negative logarithm of the compound molar concentration and enzyme, molar concentration when acquiring 50% inhibiting rate is
The IC of the compound50.Measurement result shows the Flurbiprofen chalcone Mannich bases chemical combination disclosed in the embodiment of the present invention
Object (I) all has the effect of significantly inhibiting, IC to MAO-B50It is 0.1 μM ~ 30.0 μM;And Flurbiprofen chalcone Mannich base
The parent nucleus of class compound (I) --- Flurbiprofen, 4 '-acetyl Flurbiprofen methyl esters and
The IC that MAO-B is inhibited50>100 µM。
(3) antioxidant activity (ORAC-FL method) of Flurbiprofen chalcone Mannich alkaloid compound (I)
Reference literature (Qiang, X.M.et al.Eur. J Med. Chem.Side 2014,76,314-331) reported
Method is measured, it may be assumed that 6- hydroxyl -2,5,7,8- tetramethyl primary colours alkane -2- carboxylic acids (Trolox) be made into the PBS buffer solution of pH7.4
The solution of 10-80 μm of ol/L, fluorescein (fluorescein) are made into the solution of 250 nmol/L with the PBS buffer solution of pH7.4,
2,2 '-azo diisobutyl amidine dihydrochlorides (AAPH) use the preceding solution that 40 mmol/L are made into the PBS buffer solution of pH7.4.
The compound solution and luciferin solution of 50-10 μm of ol/L are added into 96 orifice plates, mixes, 37 DEG C of incubation 15min, is added
AAPH solution makes every 200 μ L of hole total volume, mixes, is immediately placed on Varioskan Flash Multimode Reader instrument
In, 90 min of METHOD FOR CONTINUOUS DETERMINATION 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'sTroloxAs standard, sample to be tested is not added as blank, the antioxidant 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 are independent in triplicate.Measurement result shows that the Flurbiprofen disclosed in the embodiment of the present invention is looked into
You are at the antioxidant activity of ketone Mannich alkaloid compound (I)Trolox0.8-4.5 times, and compare drug Flurbiprofen and
The antioxidant activity of 4 '-acetyl Flurbiprofen methyl esters is respectively less thanTrolox0.2 times, illustrate such compound have stronger antioxygen
Change activity;Experimental study is further discovered that the chiral centre of Flurbiprofen chalcone Mannich alkaloid compound (I) to compound
Antioxidant activity substantially without influence.
(4) measurement of Flurbiprofen chalcone Mannich alkaloid compound (I) and complexing of metal ion effect
CuCl is dissolved with methanol2·2H2O、ZnCl2、FeSO4·7H2O、AlCl3And untested compound, it is made into the molten of 75 μm of ol/L
100 μ L testing compound solutions and 100 μ L metal ion solutions are added into 96 orifice plates for liquid, mix, are stored at room temperature 30 min,
UV absorption of the mixture within the scope of 200-600 nm is recorded on Varioskan Flash Multimode Reader instrument
Curve, and be control with 100 μ L testing compound solutions and 100 μ L methyl alcohol mixed liquors, observe metal ion and untested compound
The Red Shift Phenomena of the maximum absorption band of mixed liquor and the intensity of maximum absorption band.Measurement result shows institute in the embodiment of the present invention
Disclosed Flurbiprofen chalcone Mannich alkaloid compound (I) shows complexing selective to copper ion and aluminium ion and makees
With.
(5) inhibitory activity of the Flurbiprofen chalcone Mannich alkaloid compound (I) to neuroinflamation
(a) influence of compound and lipopolysaccharides (LPS) to BV-2 cell activity
The BV-2 cell of logarithmic growth phase is made into cell suspension inoculation in 96 orifice plates, sets 37 DEG C, 5%CO2Training in cell incubator
The 90 μ L of fresh medium that 24 h are changed to serum-free after cell is adherent is supported, it is pre- to be separately added into each 10 μ L of concentration untested compound
30 min, 3 parallel holes of each concentration are incubated for, while setting blank control group;Then plus or LPS is not added, set 37 DEG C, 5%CO2Carefully
Continue to cultivate 24 h in born of the same parents' incubator, MTT solution is added, 37 DEG C of 4 h of incubation discard supernatant liquid, and 200 μ LDMSO are added in every hole
Solution after 10 min of slight oscillatory, measures OD value with microplate reader at 490 nm, calculates measured by each given the test agent various concentration
The mean value of OD value, and cell survival rate is calculated by following company: cell survival rate (%)=administration group OD mean value/control group OD is equal
Value × 100%.Test result shows the Flurbiprofen chalcone Mannich alkaloid compound (I) disclosed in the embodiment of the present invention
Cytotoxicity is not shown in the case where being no more than 25 μM of concentration with LPS (inhibiting rate is less than < 5%).
(b) influence of the Flurbiprofen chalcone Mannich alkaloid compound (I) to the LPS BV-2 cell release NO induced
The BV-2 cell of logarithmic growth phase is made into cell suspension inoculation in 96 orifice plates, sets 37 DEG C, 5%CO2Training in cell incubator
The 90 μ L of fresh medium that 24 h are changed to serum-free after cell is adherent is supported, it is pre- to be separately added into each 10 μ L of concentration untested compound
30 min, 3 parallel holes of each concentration are incubated for, while setting blank control group;Then LPS stimulation is added, sets 37 DEG C, 5%CO2Carefully
Continue to cultivate 24 h in born of the same parents' incubator, takes different disposal group cell culture supernatant, isometric Griess reagent I is added and waits
The Griess reagent II of volume, room temperature are protected from light 10 min, measure absorbance at 540 nm to detect in cell supernatant
NO horizontal (concrete operations are carried out according to NO detection kit specification).Test result shows disclosed in the embodiment of the present invention
All Flurbiprofen chalcone Mannich alkaloid compounds (I) all shown in 0.5 μM to 25 μM concentration range it is relatively strong
Inhibition LPS induction BV-2 cell NO nucleus formation (inhibiting rate under 2.5 μM of concentration is more than 20.0%), and have it is bright
Aobvious dose-effect relationship;And their inhibitory activity significantly increase compared with the Flurbiprofen under same concentrations (n=3,P< 0.05), show
Flurbiprofen chalcone Mannich alkaloid compound (I) disclosed in the embodiment of the present invention has significant anti-neuroinflamation living
Property.Test is not it has further been found that the chiral centre of compound (I) makes significant difference to the anti-neuroinflamation activity of compound.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention is not limited to
Following embodiments.One of skill in the art, can be right it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
The present invention carries out various change and modification.
Method is led in the preparation of 1 Flurbiprofen chalcone Mannich alkaloid compound (I) of embodiment
The corresponding 4 '-acetyl Flurbiprofen class compound (1) of 2.0 mmol, the corresponding hydroxyl of 3.0 mmol are added in reaction flask
Benzaldehyde Mannich alkaloid compound (2), 8.0 mmol Anhydrous potassium carbonates and 50 ml acetonitriles, after mixing evenly, temperature rising reflux stirs
It mixes reaction 2.0~72.0 hours (reaction process is tracked with TLC);After reaction, it is cooled to room temperature, with 10% aqueous hydrochloric acid solution
Reaction solution pH is adjusted to highly acid, then adjusts reaction solution pH to alkalescent with saturated sodium bicarbonate aqueous solution, removes acetonitrile under reduced pressure,
50 mL deionized waters are added in residual solution, are extracted in three times with 150 mL methylene chloride, organic layer uses saturated sodium-chloride after merging
Aqueous solution washing, is filtered, evaporating solvent under reduced pressure, residue is purified by silica gel column chromatography, and is obtained accordingly after being dried over anhydrous sodium sulfate
Flurbiprofen chalcone Mannich alkaloid compound (I), yield 20.0%-70.0%, chemical structure passes through1H-NMR、13C-
NMR and ESI-MS confirmation;The purity of gained object is all larger than 97.0% through HPLC measurement.It is prepared using above-mentioned logical method
Object structure is as follows:
;
;
Part of compounds1H-NMR data are as follows:
1H NMR (CDCl3): 8.09 (d, 2H, J = 8.0 Hz), 7.78 (d, 1H, J = 16.0 Hz), 7.68
(d, 2H, J = 8.0 Hz), 7.54 (d, 1H, J= 16.0 Hz), 7.45 (t, 1H, J = 8.0 Hz, 1H),
7.20-7.14 (m, 3H), 7.07 (d, 1H, J = 7.6 Hz), 7.02 (d, 1H, J = 7.6 Hz), 3.78
(q, 1H, J = 7.2 Hz), 3.71 (s, 3H), 3.70 (s, 2H), 2.37 (s, 6H), 1.55 (d, 3H, J
= 7.2 Hz);
1H NMR (CDCl3): 8.08 (d, 2H, J = 8.0 Hz), 7.77 (d, 1H, J = 16.0 Hz), 7.67
(d, 2H, J = 8.0 Hz), 7.52 (d, 1H, J= 16.0 Hz), 7.44 (t, 1H, J = 8.0 Hz),
7.19-7.13 (m, 3H), 7.05 (d, 1H, J = 8.0 Hz), 7.02 (d, 1H, J = 8.0 Hz), 3.86
(s, 2H), 3.77 (q, 1H, J = 6.8 Hz), 3.70 (s, 3H), 2.65-2.60 (m, 4H), 1.87-1.81
(m, 4H), 1.54 (d, 3H, J = 6.8 Hz);
1H NMR (CDCl3): 8.09 (d, 2H, J = 7.8 Hz), 7.78 (d, 1H, J = 15.6 Hz), 7.68
(d, 2H, J = 7.8 Hz), 7.53 (d, 1H, J= 15.6 Hz), 7.45 (t, 1H, J = 7.8 Hz),
7.19-7.12 (m, 3H), 7.05 (d, 1H, J = 7.8 Hz), 7.01 (d, 1H, J = 7.8 Hz), 3.78
(q, 1H, J = 7.8 Hz), 3.76 (s, 3H), 3.75 (s, 2H), 2.63-2.32 (m, 4H), 1.62-1.66
(m, 4H), 1.51-1.58 (m, 5H);
1H NMR (CDCl3): 8.09 (d, 2H, J = 7.8 Hz), 7.77 (d, 1H, J = 15.6 Hz), 7.68
(d, 2H, J = 7.8 Hz), 7.53 (d, 1H, J= 15.6 Hz), 7.45 (t, 1H, J = 7.8 Hz),
7.20-7.14 (m, 3H), 7.08 (d, 1H, J = 7.8 Hz), 7.04 (d, 1H, J = 7.8 Hz), 3.80
(q, 1H, J = 7.2 Hz), 3.78 (s, 2H), 3.71 (s, 3H), 2.80-2.46 (m, 8H), 2.35 (s,
3H);1.55 (d, 3H, J = 6.6 Hz)。
2 Flurbiprofen chalcone Mannich alkaloid compound (I) of embodiment and acid are prepared at salt leads to method
The Flurbiprofen chalcone Mannich alkaloid compound (I) 2.0 of gained in accordance with the above-mentioned embodiment 1 is added in reaction flask
50 ml of mmol and acetone, is stirring evenly and then adding into that 5.0 mmol are sour accordingly, and temperature rising reflux is stirred to react 20 minutes, reaction knot
It is cooled to room temperature after beam, evaporating solvent under reduced pressure, residue is recrystallized with conventional method, is filtered the solid of precipitation to get fluorine and is compared Lip river
The salt of fragrant chalcone Mannich alkaloid compound (I), chemical structure warp1H NMR and ESI-MS confirmation.
Claims (7)
1. a kind of Flurbiprofen chalcone Mannich alkaloid compound or its pharmaceutically acceptable salt, it is characterised in that such change
The general formula of the chemical structure such as (I) for closing object is shown:
In formula: R1And R2Each independently represent C1~C12Alkyl, benzyl, substituted benzyl, propargyl;NR1R2Also illustrate that nafoxidine
Base, morpholinyl, piperidyl, 4- by C1~C12Piperidyl replaced alkyl, the 4- piperazines replaced benzyl or substituted benzyl
Piperidinyl, piperazinyl, 4- by C1~C12Piperazinyl replaced alkyl, the 4- piperazinyls replaced benzyl or substituted benzyl,
X indicates O or NH, R3Indicate H or C1~C12Alkyl;Substituent group CH2NR1R2It can be in the arbitrarily possible position of phenyl ring with OH;Describedization
Closing object isRConfiguration,SConfiguration orRConfiguration andSThe arbitrary proportion mixture of configuration;Above-mentioned term " substituted benzyl " refers to by phenyl ring
On the benzyl replaced 1-4 groups selected from the group below: F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoro
Methoxyl group, NR4R5, hydroxyl, nitro, cyano, these substituent groups can be in any possible position of phenyl ring;R4And R5Each independently
Indicate H, C1~C12Alkyl, NR4R5Also illustrate that nafoxidine base, morpholinyl or piperidyl.
2. Flurbiprofen chalcone Mannich alkaloid compound as described in claim 1 or its pharmaceutically acceptable salt,
It is characterized in that the pharmaceutically acceptable salt is such Flurbiprofen chalcone Mannich alkaloid compound and hydrochloric acid, hydrogen bromine
Acid, nitric acid, sulfuric acid, phosphoric acid, amidosulfonic acid, C1-6Aliphatic carboxylic acid, stearic acid, flutters acid, oxalic acid, benzoic acid, benzene second at trifluoroacetic acid
Acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lactic acid, hydroxymaleic acid, pyruvic acid, paddy
Propylhomoserin, ascorbic acid, lipoic acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, naphthalene sulfonic acids, benzene sulfonic acid, p-methyl benzenesulfonic acid or 1,4- fourth two
The salt of sulfonic acid.
3. the Flurbiprofen chalcone Mannich alkaloid compound or its is pharmaceutically acceptable as described in claim any one of 1-2
The preparation method of salt, it is characterised in that the compound can be prepared by the following method to obtain:
In formula: R1、R2、R3Definition with X is identical as general formula of the chemical structure (I);
It is that starting is former with corresponding 4 '-acetyl Flurbiprofen class compound (1) and hydroxy benzaldehyde Mannich alkaloid compound (2)
Material, the direct polycondensation under solvent and alkaline condition obtain corresponding Flurbiprofen chalcone Mannich alkaloid compound (I);It utilizes
Contain amino in the Flurbiprofen chalcone Mannich bases compound molecule of above method gained, which, can be in alkalinity
Its pharmaceutically acceptable salt is made by pharmaceutically conventional salifying method in any suitable acid.
4. the preparation of Flurbiprofen chalcone Mannich alkaloid compound as claimed in claim 3 or its pharmaceutically acceptable salt
Method, it is characterised in that react alkali used are as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth
Metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8It is the alkali metal salt of alcohol, triethylamine, tri-n-butylamine, three pungent
Amine, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene diamine or tetrabutylammonium hydroxide;React solvent for use are as follows: C1-8
Fatty alcohol, ether, tetrahydrofuran, 2- methyltetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, methylene chloride, chlorine
Imitative, 1,4- dioxane, benzene, toluene or acetonitrile.
5. the preparation of Flurbiprofen chalcone Mannich alkaloid compound as claimed in claim 3 or its pharmaceutically acceptable salt
Method, it is characterised in that 4 '-acetyl Flurbiprofen class compounds (1): hydroxy benzaldehyde Mannich alkaloid compound (2): alkali
Molar feed ratio is 1.0:1.0 ~ 3.0:1.0 ~ 20.0;Reaction temperature is 0 ~ 150 DEG C;Reaction time is 1 ~ 120 hour.
6. a kind of pharmaceutical composition, it is characterised in that graceful comprising such as described in any item Flurbiprofen chalcones of claim 1-2
Buddhist nun wishes alkaloid compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipient.
7. such as described in any item Flurbiprofen chalcone Mannich alkaloid compounds of claim 1-2 or its is pharmaceutically acceptable
Salt preparation treatment and/or prevention nervus retrogression related disease drug in purposes, this kind of nervus retrogression related disease
Are as follows: vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, into
Row lateral sclerosis of spinal cord, neuropathic pain or glaucoma.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810011184.XA CN110003033B (en) | 2018-01-05 | 2018-01-05 | Flurbiprofen chalcone Mannich base compound, and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810011184.XA CN110003033B (en) | 2018-01-05 | 2018-01-05 | Flurbiprofen chalcone Mannich base compound, and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110003033A true CN110003033A (en) | 2019-07-12 |
CN110003033B CN110003033B (en) | 2021-06-18 |
Family
ID=67164565
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810011184.XA Active CN110003033B (en) | 2018-01-05 | 2018-01-05 | Flurbiprofen chalcone Mannich base compound, and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110003033B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115160843A (en) * | 2022-07-05 | 2022-10-11 | 中国石油大学(北京) | Anticorrosive coating and preparation method thereof |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105439876A (en) * | 2014-09-19 | 2016-03-30 | 四川大学 | 2-hydroxychalcone amine compounds, and preparation method and uses thereof |
CN105481706A (en) * | 2014-09-19 | 2016-04-13 | 四川大学 | 2-hydroxyl chalcone compound as well as preparation method and purpose thereof |
CN105481796A (en) * | 2014-09-19 | 2016-04-13 | 四川大学 | Carbamate chalcone compound, preparation method therefor and use of carbamate chalcone compound |
CN105646417A (en) * | 2016-03-31 | 2016-06-08 | 四川大学 | 4-Hydroxylaurone compound and preparation method and application thereof |
CN105732479A (en) * | 2016-04-01 | 2016-07-06 | 南阳师范学院 | 4-cyclamine alkoxy-3-methoxyl cinnamic acid benzamide compound, preparation method and application of compound |
CN105732405A (en) * | 2016-04-01 | 2016-07-06 | 南阳师范学院 | 4-amine alkoxy-3-methoxyl cinnamic acid ester compound, preparation method and application of compound |
CN105777614A (en) * | 2016-04-01 | 2016-07-20 | 南阳师范学院 | Cyclamine alkylamide ferulate compound as well as preparation method and application thereof |
CN106632181A (en) * | 2016-09-30 | 2017-05-10 | 四川大学 | Aurone mannich base compound and preparation method and application thereof |
CN106831799A (en) * | 2016-12-20 | 2017-06-13 | 四川大学 | Hydroxy styrenes pyridine Mannich alkaloid compound, Preparation Method And The Use |
-
2018
- 2018-01-05 CN CN201810011184.XA patent/CN110003033B/en active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105439876A (en) * | 2014-09-19 | 2016-03-30 | 四川大学 | 2-hydroxychalcone amine compounds, and preparation method and uses thereof |
CN105481706A (en) * | 2014-09-19 | 2016-04-13 | 四川大学 | 2-hydroxyl chalcone compound as well as preparation method and purpose thereof |
CN105481796A (en) * | 2014-09-19 | 2016-04-13 | 四川大学 | Carbamate chalcone compound, preparation method therefor and use of carbamate chalcone compound |
CN105646417A (en) * | 2016-03-31 | 2016-06-08 | 四川大学 | 4-Hydroxylaurone compound and preparation method and application thereof |
CN105732479A (en) * | 2016-04-01 | 2016-07-06 | 南阳师范学院 | 4-cyclamine alkoxy-3-methoxyl cinnamic acid benzamide compound, preparation method and application of compound |
CN105732405A (en) * | 2016-04-01 | 2016-07-06 | 南阳师范学院 | 4-amine alkoxy-3-methoxyl cinnamic acid ester compound, preparation method and application of compound |
CN105777614A (en) * | 2016-04-01 | 2016-07-20 | 南阳师范学院 | Cyclamine alkylamide ferulate compound as well as preparation method and application thereof |
CN106632181A (en) * | 2016-09-30 | 2017-05-10 | 四川大学 | Aurone mannich base compound and preparation method and application thereof |
CN106831799A (en) * | 2016-12-20 | 2017-06-13 | 四川大学 | Hydroxy styrenes pyridine Mannich alkaloid compound, Preparation Method And The Use |
Non-Patent Citations (1)
Title |
---|
毕凤云: "氟比洛芬的合成工艺研究", 《中国优秀硕士学位论文全文数据库(电子期刊)》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115160843A (en) * | 2022-07-05 | 2022-10-11 | 中国石油大学(北京) | Anticorrosive coating and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CN110003033B (en) | 2021-06-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106632181B (en) | Aurone Mannich alkaloid compound, preparation method and use | |
CN105481706B (en) | The Hydroxylated Chalcones and Related compound of one class 2, preparation method and use | |
CN105481796B (en) | One class carbamic acid chalcone ester type compound, preparation method and use | |
CN105439876B (en) | 2 hydroxylated chalcone aminated compounds, preparation method and use | |
CN105646417B (en) | A kind of 4 hydroxyl aurone class compounds, preparation method and use | |
JP7170289B2 (en) | Therapeutic agent for lipid peroxidation-induced disease and screening method thereof | |
CN108101780A (en) | A kind of Flurbiprofen chalcone compounds, preparation method and use | |
CN106831799B (en) | Hydroxy styrenes pyridine Mannich alkaloid compound, preparation method and use | |
CN109651321A (en) | A kind of apiolin-O- alkyl amine 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 | |
CN109265362A (en) | A kind of 2,5- dihydroxy paraphenylene terephthalamide's amine compound, preparation method and use | |
CN108218744A (en) | A kind of coffee DOPA amide carbamate compound, preparation method and application | |
CN109761945A (en) | A kind of naringenin-O- alkyl amine compound, preparation method and application | |
CN106831574B (en) | N- (1,2,3,4- tetrahydro isoquinolyl)-asafoetide amide-O- alkyl amine compound and application | |
CN108069942A (en) | Phthalide pyrazolone conjugate, preparation method and use | |
CN108586411A (en) | A kind of naringenin carbamate compound, preparation method and application | |
CN110003033A (en) | Flurbiprofen chalcone Mannich alkaloid compound, preparation method and use | |
CN114478451B (en) | 6- (hydroxybenzyloxy) phthalein mannich base compound, preparation method and application thereof | |
CN106632191B (en) | Homoisoflavone Mannich alkaloid compound, preparation method and use | |
CN110003034A (en) | A kind of hydroxyl Flurbiprofen Mannich alkaloid compound, preparation method and use | |
CN106810532B (en) | A kind of amine alkoxy thioxanthene ketone class compound, preparation method and use | |
CN109665969A (en) | The double Mannich alkaloid compounds of 3- methoxyl group -4-HC, preparation method and use | |
CN108727352A (en) | A kind of piperidines alkane carbamyl phthalide analog compound, preparation method and use | |
CN109912443A (en) | A kind of benzamido group Flurbiprofen class compound, preparation method and use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |