CN110003033A - Flurbiprofen chalcone Mannich alkaloid compound, preparation method and use - Google Patents

Flurbiprofen chalcone Mannich alkaloid compound, preparation method and use Download PDF

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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
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acid
flurbiprofen
chalcone
compound
pharmaceutically acceptable
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CN110003033B (en
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邓勇
强晓明
宋青
田超全
杨子仪
李维
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Sichuan University
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Sichuan University
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    • 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

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  • 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

Flurbiprofen chalcone Mannich alkaloid compound, preparation method and use
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.
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