CN108299365A - A kind of chromocor derivative and its application - Google Patents
A kind of chromocor derivative and its application Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
The invention discloses a kind of chromocor derivative and its applications, the flavone compound of the present invention is the compound of a kind of multiple target point, multiaction anti-Alzheimer disease, the compound and its salt pharmaceutically can be used for preparing corresponding drug, this compound is also applied in antioxidant, a variety of enzyme inhibitors and metal-chelator.
Description
Technical field
The present invention relates to a kind of chromocor derivative and its application, more particularly to a kind of multiple target point, the anti-alzheimer ' of multiaction
The chromocor derivative and its preparation method and application for disease of writing from memory.
Background technology
Alzheimer's disease (AD) is a kind of common neurodegenerative disease of world wide, is twined with nerve fibril
Knot, Tau protein hyperphosphorylations, senile plaque, beta amyloid precipitation etc. are main Histopathological characteristics.AD pathogenesis is multiple
Miscellaneous and be difficult to determine, according to its clinical pathologic characteristic, scientists propose a variety of hypothesis, such as cholinergic hypothesis, amyloid egg
White cascade hypothesis, Tau protein hyperphosphorylations hypothesis, inflammation hypothesis, radical damage hypothesis, calcium ion imbalance hypothesis, gene
It is mutated hypothesis etc..Clinical treatment AD drugs are in addition to nmda receptor antagonist Memantine hydrochloride at present, mainly some acetylcholines
Esterase inhibitor, such as donepezil, Rivastigmine, galanthamine, Huperzine A-Zhulin Antun.However, these drugs can only be when limited
Between window (1-2) and it is slight in the case of improve cognitive function of patients to a certain extent, the disease process of AD can not be changed.Cause
This, finds and finds that novel AD medicines or lead compound are still the emphasis of anti-AD drug researches.
In many AD hypothesis, amyloid protein cascade hypothesis is with strongest influence power, also accepts extensively the most.The hypothesis thinks
Insoluble aβ protein of the amyloid precusor protein through being generated after the proteolysis of β-and gamma-secretase is to lead to AD occurrence and development most
Principal element.Thus, generating closely related BACE1 albumen with aβ protein becomes the popular target spot of exploitation AD medicines.Though
So in recent years surround BACE1 exploitation AD medicines end in failure, but inhibit BACE1 activity, prevent A β formation and
Aggregation is still the treatment potential available strategies of AD.
According to classical " cholinergic hypothesis ", cholinergic nerve caused by being lacked by a large amount of acetylcholines (ACh) transmits damage
Wound is the main reason for leading to AD Patients ' Cognitive obstacles.With Ach hydrolases --- acetylcholinesterase (AChE) is the suppression of target spot
Preparation such as donepezil, profit cut down the bright of this, and galanthamine and huperzine are treated by FDA approvals for AD.In addition, AChE is also
AD progression of disease can be participated in by influencing A β depositions.Research points out that AChE can be used as molecular chaperones, pass through periphery anion position
Point (PAS) accelerates the formation and aggregation of A β fibrinogens, and further increases its neurotoxicity.In addition, BuCh is thought in research
What esterase (BuChE) may hydrolyze Ach has compensating action.Therefore, inhibit cholinesterase, repairing cholinergic nerve function is
One of the effective way of AD treatments.
In addition, research finds metal ion (such as Cu in AD patient's brain2+, Fe2+, Zn2+And Al3+) horizontal significantly high
It is 3-7 times of healthy population in healthy population.The metal ion of high concentration can promote the aggregation of A β, and lead to active oxygen (ROS)
It is increased with oxidative stress." oxidative stress hypothesis " is pointed out, the increase of ROS and free radical can lead to cell biological macromolecular
Damage, causes serious injury of mitochondria, eventually leads to cell death.Research thinks that A β precipitations generate the main way of neurotoxicity
Diameter is the H generated2O2Cause the oxidative stress of intracerebral, and oxidative stress can promote the aggregation of A β in turn, to shape
At vicious circle.Therefore, it is most important to AD treatments to reduce the gentle effective anti-oxidation protection of metal ion water in brain.
Recently, monoamine oxidase (MAO) is because the height in AD patient's brain is expressed and free radical nucleus formation is promoted to draw
Play more and more concerns.MAO is and neuron, the mitochondrial outer membrane combination of spongiocyte and other cells contain flavine gland
The enzyme of glycosides dinucleotides is responsible for being catalyzed the oxidative deamination of neurotransmitter.Particularly, MAO isodynamic enzymes B (MAO-B) is because of catalysis
Hydrogen peroxide is generated while β-phenyl ethylamine oxygenolysis, is considered closely related with the progress of AD[13].On the other hand, MAO-B
Inhibitor such as selegiline and Rasagiline have been demonstrated to the learning and memory defect for being effectively improved AD animal models, and slow down
The progress of the AD state of an illness.Therefore, MAO-B inhibitory activity should be that anti-AD drugs rationally design an important factor for considering.
In conclusion more and more evidences show signal path and cell factor of the occurrence and development by Various Complex of AD
Influence.In view of the complexity of AD inducements, traditional " unimolecule, single target spot " the effect is unsatisfactory for drug design strategies, based on " fixed
To more target ligands " (MTDLs) strategy find and find with AD target enzymes inhibitory activity, metal-chelating, it is anti-oxidant etc. two kinds or
The multiple target point drug or lead compound of a variety of complementary bioactives may be the ideal of AD medicines design and discovery
Approach.
Invention content
The present invention is based on multiple target point, multifunctional thinkings, and a large amount of of Alzheimer disease drugs are fought in conjunction with the present inventor
Research experiment devises a series of with multiple target point (choline from the natural flavone compound with anti-Alzheimer disease
Esterase, monoamine oxidase, beta-secretase), the anti-A Er of multiaction pattern (antioxidation, biological metal ion sequestration)
Ci Haimo disease chromocor derivatives, and provide the preparation method of chromocor derivative.
The technical scheme is that providing a kind of chromocor derivative and its salt, hydrate, solvate, the flavones spread out
The structural formula of biology is as shown in Formulas I, II or III：
Wherein, substituent R may replace the hydrogen instead of at least one site in site at four, each to replace on site
R is respectively and independently selected from halogen atom, alkyl, halogenated alkyl, alkoxy, nitro, hydroxyl, substituted or non-substituted aryl, heteroaryl
Base or-Y-M；Wherein Y represents O, S or NH；M is selected from substituted or non-substituted aryl, heteroaryl；
R1、R2、R3It is respectively and independently selected from hydrogen atom, hydroxyl, halogen, alkyl, halogenated alkyl, alkoxy, cyano, nitro, hydroxyl
Base, carboxyl, ester group, amide groups, benzyloxy；
X is selected from O, S or NH.
Above-mentioned substituent R, R1、R2、R3Substitution site on the corresponding ring of gas is unlimited, and substitution quantity is unlimited.
Preferably, the quantity of substituent R hydroxyl and/or methoxyl group, substituent R is 1 or more.
Preferably, in Formulas I, R is respectively and independently selected from substituted or non-substituted aryl, heteroaryl or-Y-M；Wherein Y generations
Table O, S or NH；M is selected from substituted or non-substituted aryl, heteroaryl.
Preferably, the structural formula of the chromocor derivative is as shown in Formulas I -1, I-2, I-3 or I-4：
Preferably, the structural formula of the chromocor derivative such as Formula II -1, II-2 or II-3：
Above-mentioned substituent R4、R5、R6、R7、R8、R9In, di indicates disubstituted, and tri indicates that three substitutions, Me indicate methyl, Bn
It indicates benzyl, is the essential term in organic chemistry.Above-mentioned substituent group is replaced on hexatomic ring, and the hexatomic ring
It is connected with precursor structure by singly-bound, using the substitution site for the singly-bound being wherein connected with precursor structure as No. 1 position, by clockwise
The positions 2-6, the contraposition that No. 4 positions are No. 1 are determined successively.
Preferably, the structural formula of the chromocor derivative is as shown in formula III -1：
Wherein R10Selected from following substituent group：
The present invention also provides the chromocor derivatives and its salt, hydrate, solvate to prepare anti-Alzheimer
Application in medicine.
The present invention also provides the chromocor derivatives and its salt, hydrate, solvate to prepare cholinesterase, monoamine
Application in oxidizing ferment and/or beta-secretase inhibitor.
The present invention also provides the chromocor derivatives and its salt, hydrate, solvate in preparing antioxidant
Using.
The present invention also provides the chromocor derivatives and its salt, hydrate, solvate to prepare metal ion-chelant
Application in agent.
The synthetic route of the subsequent embodiment of synthesized reference of every flavone derivatives of the application, differs only in it
The difference of substituent group, the synthetic route per the chromocor derivative under class general formula is identical.
The invention has the advantages that the flavone compound of the present invention is a kind of multiple target point, the anti-alzheimer ' of multiaction
The compound for disease of writing from memory, the compound and its salt pharmaceutically can be used for preparing corresponding drug, this compound can also be applied
Into antioxidant, a variety of enzyme inhibitors and metal-chelator.
Description of the drawings
Protective effect Fig. 1 shows the present application compound to the induction PC12 cellular damages of A β 42.
Specific implementation mode
Following embodiment further describes the present invention, and still, these embodiments are only for illustrating the present invention, rather than right
The limitation of the scope of the invention.
Embodiment 1：The preparation of compound II-3c
Chemical equation：
The synthesis of intermediate e
It weighs anhydrous zinc chloride powder (10.0g, 73.3mmol) to be added in anhydrous acetonitrile (30g, 0.73mol), be heated to
It 60-70 DEG C, is vigorously stirred to no zinc chloride particle, addition phloroglucin (20g, 0.15mol), after stirring and dissolving, reaction solution
It is cooled to 0-5 DEG C.Anhydrous ether (100mL) is added, is passed through dry hydrogen chloride gas 12h, until no solid generates.It will be anti-
Liquid is answered to be placed in cold in 4 DEG C of refrigerators set overnight.It filters, filter cake is washed with anhydrous ether.Filter cake is transferred in the flask of original place, and water is added
(1L) after boiling 2h, is filtered while hot, filtrate is cold set overnight after, have crystal precipitation, filter, dry product, yield 75%.1H
NMR(500MHz,DMSO-d6):δH=12.24 (s, 2H), 10.38 (s, 1H), 5.80 (s, 2H), 2.55 (s, 3H)13C NMR
(125MHz,DMSO-d6):δC=202.9,165.2,164.7,104.4,94.9,32.9.MS (ESI):m/z[M+H]+
169.11.
The synthesis of intermediate f
By 2,4,6- trihydroxy-acetophenones (55.8g, 0.3mol), Anhydrous potassium carbonate (104.0g, 0.75mol), acetone
(500mL) is sequentially added in three-necked bottle, and under return stirring, dimethyl suflfate (75.6g, 0.6mol) is slowly added dropwise.Drop finishes, and continues
Reaction 2.5 hours.TLC is monitored, and reaction terminates.It is cooled to room temperature, filters, filtrate concentrates, and residue is even with 5% hydrochloric acid solution
Slurry, filtering, filter cake are washed with water to neutrality.Filter cake recrystallizing methanol is collected, white solid, i.e. product, yield 95% are obtained.1H
NMR(400MHz,DMSO-d6):δH=13.80 (s, 1H), 6.12 (d, J=2.4Hz, 1H), 6.09 (d, J=2.4Hz, 1H),
3.87(s,3H),3.82(s,3H),2.55(s,3H).MS(ESI):m/z[M+H]+197.13.
The synthesis of intermediate g
Take 4-methoxybenzaldehyde (6.8g, 50mmol), iodine (6.3g, 25mmol), sodium metaperiodate (2.7g,
12.5mmol) it is dissolved in acetic acid-water mixture (2:1,500mL) in, after being slowly added to sulfuric acid (10mL), 90 DEG C of reactions are overnight.It is cold
But, reaction solution is poured into 5 times of amount ice water, appropriate sodium hydrogensulfite to purple is added and disappears, has precipitation to generate.It filters, filter cake
It is washed with water, is dried in vacuo, obtains white solid, yield 91%.1H NMR(400MHz,DMSO-d6):δH=9.83 (s, 1H),
8.28 (d, J=2.0Hz, 1H), 7.94 (dd, J=8.5,2.0Hz, 1H), 7.20 (d, J=8.5Hz, 1H), 3.95 (s, 3H)
.13C NMR(100MHz,DMSO-d6):δC=206.4,190.9,162.9,140.7,132.4,131.6,112.1,87.3,
57.5.MS(ESI):m/z[M+H]+263.04.
The synthesis of intermediate h
Take Xanthoxylin (19.6g, 0.1mol), the iodo- 4-methoxybenzaldehydes of 3- (33.8g,
It 0.1mol) is dissolved in ethyl alcohol (350mL) after stirring and dissolving, 30%KOH aqueous solutions (100mL) is slowly added dropwise, finish.It is stirred at room temperature
48 hours.10% hydrochloric acid solution is added, adjusts pH to 5.There is yellow solid precipitation.Filtering, filter cake are washed to neutrality.Recrystallizing methanol
Obtain yellow solid, yield 87%.1H NMR(500MHz,DMSO-d6):δH=13.36 (s, 1H), 8.13 (d, J=2.1Hz,
1H), 7.78 (dd, J=8.6,2.2Hz, 1H), 7.63 (d, J=15.7Hz, 1H), 7.57 (d, J=15.7Hz, 1H), 7.08
(d, J=8.5Hz, 1H), 6.16 (d, J=2.3Hz, 1H), 6.13 (d, J=2.3Hz, 1H), 3.89 (s, 3H), 3.89 (s,
3H),3.82(s,3H).13C NMR(125MHz,DMSO-d6):δC=168.9,165.9,162.2,159.9,141.4,
139.7,130.5,123.0,126.6,112.3,94.3,91.5,87.3,57.1,56.7,56.1.MS(ESI):m/z[M+H]+
441.02.
The synthesis of intermediate i
Intermediate h (10mmol), elemental iodine (2.5g, 1mmol) is taken to be dissolved in dimethyl sulfoxide (DMSO) (25ml), 110 DEG C of reactions
8h stops reaction.After being cooled to room temperature, reaction solution is imported in 5% aqueous solution of sodium bisulfite, there is yellow solid wash-off, taken out
Filter, is dried to obtain faint yellow solid, yield 92%.1H NMR(500MHz,DMSO-d6):δH=8.44 (d, J=2.3Hz, 1H),
8.06 (dd, J=8.7,2.3Hz, 1H), 7.54-7.49 (m, 3H), 7.43 (dd, J=8.3,6.9Hz, 2H), 7.38-7.33
(m, 1H), 7.23 (d, J=8.9Hz, 1H), 6.93 (d, J=2.3Hz, 1H), 6.75 (s, 1H), 6.50 (d, J=2.3Hz,
1H),5.32(s,2H),3.91(s,3H),3.83(s,3H).13C NMR(125MHz,DMSO-d6):δC=176.0,164.2,
160.6,160.6,159.6,158.7,136.6,128.4,125.4,112.1,108.8,107.8,96.8,93.9,87.3,
57.3,56.5,56.5.MS(ESI):m/z[M+H]+454.02.
The synthesis of II-1c
Take compound i (2.6g, 5mmol), 4- Carboxybenzeneboronic acids (0.9g, 6mmol), Carbon Dioxide caesium (3.9g,
10mmol), tetra-triphenylphosphine palladium (0.55g, 0.5mmol), DMF-H2O(9:1,20mL) it sequentially adds in reaction bulb, nitrogen is protected
It protects, is reacted at 110 DEG C, TLC monitorings, reaction terminates, and stops heating.After being cooled to room temperature, ethyl acetate dilution is added, uses successively
Water, dilute hydrochloric acid, water, saturated common salt water washing.The faint yellow solid of column chromatography after organic phase concentration.Yield 87%.1H NMR
(500MHz,DMSO-d6):δH=7.92 (d, J=8.8Hz, 2H), 7.67 (dd, J=8.6,2.1Hz, 1H), 7.63 (s, 2H),
7.58 (d, J=2.1Hz, 1H), 7.28 (d, J=8.6Hz, 1H), 6.94 (d, J=8.8Hz, 2H), 6.14 (s, 1H), 6.12
(d, J=2.5Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H)13C NMR(125MHz,DMSO-d6):δC=
177.5,167.2,165.9,165.8,162.2,161.8,153.7,142.1,132.0,128.8,128.0,126.6,
125.0,122.4,115.9,114.3,106.8,103.4,94.3,91.5,56.6,56.5,56.1.MS(ESI):m/z[M+H
]+433.13.
The synthesis of II-2c
It takes previous step product II-1c (4.2g, 10mmol) to be dissolved in anhydrous acetonitrile (25mL), aluminum trichloride (anhydrous) is added
(1.3g, 10mmol), under nitrogen protection, back flow reaction is overnight.It cools down, 30% hydrochloric acid of addition (25mL), after back flow reaction 4h, stops
Only react.Reaction solution is poured into ice water, there is solid precipitation, is filtered.Filter cake is washed with water and a small amount of ethyl alcohol successively, and drying obtains
Faint yellow solid, yield 83%.1H NMR(500MHz,DMSO-d6):δH=12.94 (s, 1H), 8.05 (dd, J=8.7,
2.4Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 7.49 (d, J=8.6Hz, 2H), 7.25 (d, J=8.8Hz, 1H), 7.02-
7.00 (m, 3H), 6.82 (d, J=2.2Hz, 1H), 6.36 (d, J=2.2Hz, 1H), 3.86 (s, 3H), 3.86 (s, 3H)13C
NMR(125MHz,DMSO-d6):δC=182.4,167.5,164.1,161.6,159.7,159.1,157.8,142.5,131.1,
129.7,129.2,128.7,127.7,123.3,114.0,112.6,105.2,104.5,98.6,93.2,56.5,56.4.MS
(ESI):m/z[M+H]+419.11.
The synthesis of II-3c
In three-neck flask, compound II-2c (4.2g, 10mmol), phenol (0.4g, 40mmol), ice vinegar are sequentially added
Under nitrogen protection, 47% hydroiodic acid (10mL) is added in sour (20mL).Back flow reaction is stayed overnight, cooling, and reaction solution is poured into 5% Asia
In sodium sulphate ice water solution, there is white solid precipitation, filter, filter cake is washed with water and 95% ethyl alcohol successively, is dried in vacuo, is obtained yellow
Color solid, yield 87%.1H NMR(500MHz,DMSO-d6):δH=12.96 (s, 1H), 10.84 (s, 1H), 10.71 (s,
1H), 8.01 (d, J=8.1Hz, 3H), 7.95 (dd, J=8.5,2.3Hz, 1H), 7.77 (d, J=8.0Hz, 2H), 7.14 (d, J
=8.6Hz, 1H), 6.92 (s, 1H), 6.50 (s, 1H), 6.20 (s, 1H)13C NMR(125MHz,DMSO-d6):δC=
182.2,167.7,164.6,163.9,161.9,158.6,157.8,142.3,129.9,129.7,129.5,129.4,
128.4,127.9,122.4,117.2,104.2,103.9,99.3,94.5.MS(ESI):m/z[M+H]+391.08.
Embodiment 2：The preparation of compound I-2c
The synthesis of intermediate j
Take Xanthoxylin (19.6g, 0.1mol), elemental iodine (11.4g, 0.045mol), ethyl alcohol
(200mL) is sequentially added in reaction bulb, is sufficiently stirred.Separately take HIO3After (2.6g, 0.015mol) is dissolved in water (5mL), it is added anti-
It answers in liquid, is sufficiently stirred reaction about 2.5 hours at room temperature.TLC is stirred, after raw material point disappears.Stop stirring, filters.Filtrate is dense
After being reduced to 1/2 volume, cooling is static, then filters, and merges filter cake, obtains white solid, yield 93%.MS(ESI):m/z[M+H]+
322.98.
The synthesis of intermediate k
Take iodo- 4, the 6- dimethoxy-acetophenones (32.2g, 0.1mol) of 2- hydroxyls -3-, 4- benzoxybenzaldehydes (21.2g,
It 0.1mol) is dissolved in ethyl alcohol (350mL) after stirring and dissolving, 30%KOH aqueous solutions (100mL) is slowly added dropwise, finish.It is stirred at room temperature
48 hours, TLC monitorings.Reaction terminates, and 10% hydrochloric acid solution is added, and adjusts PH to 5, there is yellow solid precipitation.Filtering, filter cake washing
To neutrality, recrystallizing methanol obtains yellow solid, yield 90%.1H NMR(500MHz,DMSO-d6):δH=14.81 (s, 1H),
7.78(s,2H),7.75-7.70(m,2H),7.05-7.01(m,2H),6.39(s,1H),4.04(s,3H),3.98(s,3H),
3.83(s,3H).13C NMR(125MHz,DMSO-d6):δC=192.4,164.7,164.6,163.9,161.9,143.9,
131.1,127.8,124.5,115.1,106.7,89.1,67.4,57.4,57.1,55.9.MS(ESI):m/z[M+H]+
517.05.
The synthesis of intermediate l
Intermediate k (10mmol), elemental iodine (2.5g, 1mmol) is taken to be dissolved in dimethyl sulfoxide (DMSO) (25ml), 110 DEG C of reactions
8h stops reaction.After being cooled to room temperature, reaction solution is imported in 5% aqueous solution of sodium bisulfite, there is yellow solid wash-off, taken out
Filter, is dried to obtain faint yellow solid, yield 92%.1H NMR(500MHz,DMSO-d6):δH=7.49-7.47 (m, 3H),
7.44-7.39 (m, 3H), 7.37-7.34 (m, 1H), 7.19 (d, J=9.1Hz, 2H), 6.76 (s, 1H), 6.69 (s, 1H),
5.22(s,2H),4.01(s,4H),3.93(s,3H).13C NMR(125MHz,DMSO-d6):δC=176.0,162.9,
161.5,160.3,159.6,157.2,137.0,1289.0,128.5,128.3,128.2,123.5,115.9,109.3,
106.9,93.7,70.0,69.3,57.6,56.9.MS(ESI):m/z[M+H]+530.06.
The synthesis of compound I-1c
Take compound l (5mmol), 4- Carboxybenzeneboronic acids (0.9g, 6mmol), Carbon Dioxide caesium (3.9g, 10mmol), four
Triphenylphosphine palladium (0.55g, 0.5mmol), DMF-H2O(9:1,20mL) it sequentially adds in reaction bulb, nitrogen protection, at 110 DEG C
Reaction, TLC monitorings, reaction terminate, and stop heating.After being cooled to room temperature, be added ethyl acetate dilution, successively use water, dilute hydrochloric acid,
Water, saturated common salt water washing.The faint yellow solid of column chromatography after organic phase concentration.Yield 87%.1H NMR(500MHz,DMSO-
d6):δH=8.06 (d, J=8.1Hz, 2H), 7.57 (d, J=8.1Hz, 2H), 7.54 (d, J=8.8Hz, 2H), 7.43 (d, J=
7.2Hz, 2H), 7.38 (t, J=7.5Hz, 2H), 7.33 (t, J=7.1Hz, 1H), 7.01 (d, J=8.6Hz, 2H), 6.77 (s,
1H),6.67(s,1H),5.14(s,2H),3.97(s,3H),3.90(s,3H).13C NMR(125MHz,DMSO-d6):δC=
176.3,167.9,161.2,160.8,160.8,160.1,155.4,137.0,131.8,129.3,128.9,128.4,
128.2,127.9,123.7,115.6,110.1,108.3,106.9,93.4,69.9,56.8,56.7.MS(ESI):m/z[M+
H]+509.16.
The synthesis of compound I-2c
Take previous step product I-1c (1mmol) to be dissolved in anhydrous acetonitrile (25mL), be added aluminum trichloride (anhydrous) (0.13g,
1mmol), under nitrogen protection, back flow reaction is overnight.It cools down, 30% hydrochloric acid of addition (25mL), after back flow reaction 4h, stops reaction.
Reaction solution is poured into ice water, there is solid wash-off, is filtered.Filter cake is washed with water and a small amount of ethyl alcohol successively, and drying obtains faint yellow
Solid, yield 89%.1H NMR(500MHz,DMSO-d6):δH=13.37 (s, 1H), 12.97 (s, 1H), 10.35 (s, 1H),
8.05 (d, J=8.2Hz, 2H), 7.59 (d, J=8.2Hz, 2H), 7.56 (d, J=8.8Hz, 2H), 6.86 (s, 1H), 6.79
(d, J=8.8Hz, 2H), 6.67 (s, 1H), 3.84 (s, 3H)13C NMR(125MHz,DMSO-d6):δC=182.8,167.7,
164.6,162.4,162.0,161.7,153.6,136.8,131.8,129.3,128.8,121.5,116.3,108.5,
104.6,103.1,96.0,57.0.MS(ESI):m/z[M+H]+405.10.
Embodiment 3：The preparation of compound I-4a
The synthesis of intermediate n
It weighs intermediate m (0.69g, 1.77mmol) to be dissolved in chloroform (70ml), after being completely dissolved, tetrabutyl tribromo is added
Change ammonium (TBATB, 0.85g, 1.77mmol), is stirred at room temperature, TLC monitorings.After reaction, reaction solution is transferred to separatory funnel
It is interior.Water, saturated common salt water washing, anhydrous sodium sulfate drying, organic phase is used to concentrate successively, column chromatography obtains yellow solid, yield
56%.m.p.230-232℃.1H NMR(500MHz,DMSO-d6):δH=8.07-8.03 (m, 2H), 7.51-7.46 (m, 4H),
7.41 (t, J=7.4Hz, 4H), 7.38-7.33 (m, 2H), 7.22-7.18 (m, 3H), 6.77 (s, 1H), 6.74 (s, 1H),
5.22(s,2H),4.04(s,3H),3.94(s,3H).MS(ESI):m/z[M+H]+467.05.
The synthesis of intermediate compound I -3a
Take compound n (5mmol), 4- Carboxybenzeneboronic acids (0.9g, 6mmol), Carbon Dioxide caesium (3.9g, 10mmol), four
Triphenylphosphine palladium (0.55g, 0.5mmol), DMF-H2O(9:1,20mL) it sequentially adds in reaction bulb, nitrogen protection, at 110 DEG C
Reaction, TLC monitorings, reaction terminate, and stop heating.After being cooled to room temperature, be added ethyl acetate dilution, successively use water, dilute hydrochloric acid,
Water, saturated common salt water washing.The faint yellow solid of column chromatography, yield 87% after organic phase concentration.1H NMR(500MHz,DMSO-
d6):δH=10.11 (s, 1H), 8.04 (d, J=8.2Hz, 2H), 7.69 (d, J=7.9Hz, 2H), 7.54 (d, J=8.7Hz,
2H), 7.44-7.41 (m, 3H), 7.41-7.37 (m, 3H), 7.35-7.30 (m, 1H), 7.02 (d, J=8.8Hz, 2H), 6.78
(s, 1H), 6.69 (d, J=1.1Hz, 1H), 5.14 (s, 3H), 3.98 (s, 3H), 3.91 (s, 3H)13C NMR(125MHz,
DMSO-d6):δC=191.8,181.7,164.0,161.8,161.0,159.7,157.9,137.9,137.0,13 5.6,
132.5,129.5,128.9,128.4,128.1,127.9,121.7,115.7,105.0,103.9,94.5,70.5,61.3,
56.2.MS(ESI):m/z[M+H]+493.17.
The synthesis of compound I-4a
It takes intermediate n (1mmol) to be dissolved in anhydrous acetonitrile (25mL), aluminum trichloride (anhydrous) (0.13g, 1mmol), nitrogen is added
Under protection, back flow reaction is overnight.It cools down, 30% hydrochloric acid of addition (25mL), after back flow reaction 4h, stops reaction.Reaction solution is fallen
Enter in ice water, there is solid wash-off, filters.Filter cake is washed with water and a small amount of ethyl alcohol successively, and drying obtains faint yellow solid, yield
89%.1H NMR(500MHz,DMSO-d6):δH=13.42 (s, 1H), 10.44 (s, 1H), 10.04 (s, 1H), 8.09 (d, J=
8.9Hz, 2H), 7.93 (d, J=7.9Hz, 2H), 7.60 (d, J=8.0Hz, 2H), 7.11 (d, J=9.0Hz, 2H), 7.04 (s,
1H),6.97(s,1H),3.77(s,3H).13C NMR(125MHz,DMSO-d6):δC=193.2,182.5,164.1,161.3,
160.9,158.5,157.4,139.3,135.1,132.2,129.1,129.0,122.7,116.3,108.1,104.9,
104.1,92.9,56.4.MS(ESI):m/z[M+H]+389.11.
Embodiment 4：The synthesis of III-1c
3.4.1 the synthesis of compound o
With 2,4- dimethoxy -6- hydroxy acetophenones and 3- hydroxyls -4-methoxybenzaldehyde for raw material, synthesizing chalcone
Afterwards, without further purification, next step reaction is directly carried out, compound II, faint yellow solid, yield 83% is made.1H NMR
(500MHz,DMSO-d6):δH=9.38 (s, 1H), 7.49 (dd, J=8.5,2.3Hz, 1H), 7.41 (d, J=2.3Hz, 1H),
7.07 (d, J=8.6Hz, 1H), 6.81 (d, J=2.3Hz, 1H), 6.55 (s, 1H), 6.50 (d, J=2.3Hz, 1H), 3.90
(s,3H),3.86(s,3H),3.83(s,3H).13C NMR(125MHz,DMSO-d6):δC=176.0,164.1,160.7,
160.3,159.6,151.0,147.2,123.7,118.4,113.1,112.5,108.7,107.2,96.7,93.7,56.5,
56.4,56.2.MS(ESI):m/z[M+H]+344.13.
3.4.2 the synthesis of compound p
Weigh Compound o (3.4g, 10mmol), bromobenzene derivative (10mmol), Carbon Dioxide caesium (6.5g, 20mmol),
Cesium fluoride (1.5g, 10mmol), cuprous oxide (0.14g, 1mmol) are added in three-neck flask, and under nitrogen protection, drying is added
DMF (20mL), overnight, TLC monitorings, reaction terminates for 130 DEG C of reactions.It filters while hot, after filtrate cooling, pours into 5% hydrochloric acid ice water
It in solution, is vigorously stirred down, there is solid wash-off, filter.Filter cake acetate-methanol (1:1) mixed liquor thermosol, while hot mistake
Filter, filtrate cooling, there is solid precipitation, collects solid.This step product solubility is very poor, is not easy analysis purifying, therefore directly carries out down
Step reaction.
3.4.3 the synthesis of compound III-1c
The crude product (4.3g) of previous step compound p is taken to be added in acetonitrile (50mL), addition aluminum trichloride (anhydrous) (1.3g,
10mmol), after back flow reaction is stayed overnight, 30% hydrochloric acid (25mL) back flow reaction 6h is added, methanol (50mL), filtering, filter cake is added
It is washed with a small amount of methanol.After filter cake vacuum drying, after a small amount of DMF and ethyl alcohol dissolving, is prepared, obtained with preparative liquid chromatography
White solid, yield 7%.1H NMR(500MHz,DMSO-d6):δH=12.96 (s, 1H), 12.80 (s, 1H), 8.08 (dd, J
=8.5,2.0Hz, 1H), 7.92 (d, J=8.8Hz, 2H), 7.63 (d, J=2.0Hz, 1H), 7.44 (d, J=8.5Hz, 1H),
6.96 (d, J=8.8Hz, 2H), 6.79 (s, 1H), 6.48 (d, J=2.4Hz, 1H), 6.19 (d, J=2.4Hz, 1H), 3.89
(s,3H),3.88(s,3H).13C NMR(125MHz,DMSO-d6):δC=182.3,170.1,166.6,164.1,162.8,
160.7,158.6,156.0,144.7,129.2,123.9,122.1,121.1,116.8,114.6,112.8,105.8,
104.7,96.7,93.9,56.5,56.5.MS(ESI):m/z[M+H]+435.11.
Pharmacological activity is tested：
Pharmacological evaluation proves that the compound of the present invention all has preferable multiple target point, multiaction anti-Alzheimer disease is lived
Property.Therefore, the compounds of this invention can be used for preparing the drug of Alzheimer disease.Here is the drug effect of part of compounds of the present invention
Learn experiment and result.The structure of compound is shown in embodiment.
One, inhibitory activity of the Ellman spectrophotometry evaluation compound to acetylcholinesterase and butyrylcholine esterase
The experiment is tested using 96 orifice plates.Experimental setup blank control group (not enzyme and compound), negative control
Group (being not added with compound), positive controls (donepezil group) and sample to be tested group, every group of 3 multiple holes.Test method is as follows：
A) following table is referred in designed 96 orifice plate, and enzyme, substrate, color developing agent and the compound that phase application amount is added are molten
Liquid.
1 each reaction solution of table forms
B) after being incubated 15 minutes at 37 DEG C, OD values of each hole at 405nm is measured using microplate reader.
C) calculating of enzyme inhibition rate：Inhibiting rate %=100% × [(ODIt is negative-ODSample)/(ODIt is negative-ODBlank)]
As a result：Compound has certain inhibiting effect, wherein compound to acetylcholinesterase and butyrylcholine esterase
With significant inhibitory activity.Using 7.0 softwares of Graphpad Prism calculate separately this compound to acetylcholinesterase and
The IC50 values (being shown in Table) of butyrylcholine esterase.
The external AChE half-inhibition concentrations of 2 chromocor derivative of table
The external BuChE half-inhibition concentrations of 3 chromocor derivative of table
Two, recombined human monoamine oxidase B inhibitory activity research
The experiment of Compound ira vitro monoamine oxidase B inhibitory activity uses the Monoamine of BioVision Inc. companies
Oxidase B (MAO-B) Inhibitor Screening Kit (Fluorometric) kits and 96 hole of black non transparent
Plate is tested according to kit operation instruction.Experimental setup blank control group (not enzyme and compound), negative control group
(being not added with compound) and experimental group, 3 multiple holes of every group of setting.This chemical combination is calculated separately using 7.0 softwares of Graphpad Prism
IC of the object to acetylcholinesterase and butyrylcholine esterase50Value (is shown in Table).
As a result：So in test compound, there is preferable inhibitory activity, part chemical combination to recombined human monoamine oxidase B
The IC of object50It is as shown in the table for value.
The external MAOs half-inhibition concentrations (IC of 4 chromocor derivative of table50,μM)
Three, human beta-secretase enzyme inhibitory activity research is recombinated
Method：Using 384 orifice plate of BACE1FRET Assay Kit kits and black non transparent of Thermo companies, press
It is tested according to kit operation instruction.Experimental setup blank control group (not enzyme and compound), negative control group (being not added with
Close object) and experimental group, 3 multiple holes of every group of setting.This compound is calculated separately to β points using 7.0 softwares of Graphpad Prism
Secrete the IC50 values (being shown in Table) of enzyme.
As a result：So in test compound, there is preferable inhibitory activity, IC50 values to be less than 10 μ recombination human beta-secretase enzyme
The compound of M is.
The external BACE1 half-inhibition concentrations of 5 chromocor derivative of table
Four, antioxidation activity in vitro measures
Method：Precision weighs DPPH 8.0mg, is dissolved in absolute ethyl alcohol, and is settled in 200ml brown volumetric flasks, obtains end
The DPPH solution of a concentration of 0.08mM.It is protected from light, it is now with the current.Using absolute ethyl alcohol as solvent, the sample solution of various concentration is prepared；
Various concentration sample solution 1.0ml, DPPH solution 3.0ml is taken to be added in 10ml centrifuge tubes respectively, room temperature is protected from light 30min.
Using absolute ethyl alcohol as blank, DPPH solution and alcohol mixeding liquid (3:1) it is negative control, measures the light absorption value at 517nm.Freely
The calculating of base clearance rate, calculation formula are as follows：DPPH free radical scavenging activities (%)=[(ODIt is negative-ODSample)/(ODIt is negative-ODBlank)]×
100%.
As a result：
The free clearance rates of DPPH of 6 various concentration chromocor derivative of table
Five, chelation of metal ion
Its metal ion chelant ability is determined using UV differential spectra technology.Using methanol as solvent, by chemical combination
After object is mixed with metal ion, the ultimate density for obtaining test compound and metal ion is the reaction solution of 37.5 μ Μ, room temperature
Stand 30 minutes.Using ultraviolet specrophotometer respectively record test compound individually or and CuCl2, ZnCl2And FeSO4Mixing
Ultra-violet absorption spectrum afterwards, wave-length coverage 200-600nm.By subtracted from the spectrum of mixture individual metal and individually
Compound spectrum numerical value, obtain due to compound formed obtained from ultraviolet-visible spectrum.
According to ultra-violet absorption spectrum, we are had studied by ultraviolet-visible (UV-Vis) spectroscopic methodology inhibits to live with preferable enzyme
The different type chromocor derivative of property is to metal ion such as Cu2+, Zn2+And Fe2+There is different degrees of chelation.With
III-1c is representative compound, is studied the potential chelation of metal ion of such compound.As addition CuCl2
When, blue shift occurs for absorption peaks of the compound III-1c at 328nm and 286nm.It is interesting that the absorption maximum at 328nm is aobvious
Show and be blue shifted to 265nm, and absorbance increases.These are the result shows that form III-1c-Cu2+Complex compound.As addition FeSO4With
ZnCl2When, spectrum change is apparent, and absorbance obviously increases, and shows III-1c and Fe2+、Zn2+Between there are certain chelations.
Six, the protective effect that compound induces A β 42 PC12 cellular damages is evaluated using MTS methods
1. it is 12h that method, which induces a concentration of 25 μM of PC12 cellular damages, modeling time with A β 42,.Experiment is divided into experimental group
(various concentration compound solution+PC12 cell+A β 42), model group (PC12 cell+A β 42), negative control group (PC12 cells+
Culture medium), totally four groups of blank control group (culture medium).
The DMEM culture mediums containing the 10% new inactivated serum that calves are added in the PC12 cells of logarithmic growth phase, with 4 ×
104The density of a cell/mL is inoculated into 96 orifice plates.5%CO2, after 37 DEG C of cultures for 24 hours, original culture is replaced with fresh DMEM
Base.10 μ l of compound solution are added per hole into experimental group, continue after being incubated 1h, 20 μM of A β are respectively added in experimental group and model group
10 μ l culture mediums are respectively added in 42 10 μ l, negative control group and blank group.In 5%CO2, under the conditions of 37 DEG C, continue to cultivate 12h.It is small
The heart removes culture medium, and MTS detection liquid is added and measures its absorbance at 490nm using microplate reader after 37 DEG C are incubated 1 hour.
Cell viability (%)=[(ODSample-ODBlank)/(ODIt is negative-ODBlank)] × 100%.
2. result the present application compound induces the protective effect test result of PC12 cellular damages to see Fig. 1 A β 42.
Compared with model group, the PC12 cell viabilities of 11.1 μM of compound groups have apparent increase, 11.1 μM of compound II-2c of this explanation
The PC12 cellular damage beta induced to A with III-1c has protective effect.As compound concentration increases, PC12 cell viabilities increase
By force, but when the concentration of compound II-2c increases to 100 μM, PC12 cell activity does not rise anti-drop, and compound III-1c groups are supreme
State effect.To sum up all compound III-1c have safe range more wider array of than compound II-2c.
Claims (10)
1. a kind of chromocor derivative and its salt, hydrate, solvate, which is characterized in that the structural formula of the chromocor derivative is such as
Shown in Formulas I, II or III：
Wherein, substituent R may replace the hydrogen instead of at least one site in site at four, each the R replaced on site points
Be not independently selected from halogen atom, alkyl, halogenated alkyl, alkoxy, nitro, hydroxyl, substituted or non-substituted aryl, heteroaryl,
Or-Y-M；Wherein Y represents O, S or NH, and M is selected from substituted or non-substituted aryl, heteroaryl；
R1、R2、R3Be respectively and independently selected from hydrogen atom, hydroxyl, halogen, alkyl, halogenated alkyl, alkoxy, cyano, nitro, hydroxyl,
Carboxyl, ester group, amide groups, benzyloxy；
X is selected from O, S or NH.
2. chromocor derivative as described in claim 1 and its salt, hydrate, solvate, which is characterized in that substituent R hydroxyl
The quantity of base and/or methoxyl group, substituent R is 1 or more.
3. chromocor derivative as described in claim 1 and its salt, hydrate, solvate, which is characterized in that in Formulas I, R
It is respectively and independently selected from substituted or non-substituted aryl, heteroaryl or-Y-M；Wherein Y represents O, S or NH；M is selected from substitution or non-takes
Aryl, the heteroaryl in generation.
4. chromocor derivative as described in claim 1 and its salt, hydrate, solvate, which is characterized in that the flavones spreads out
The structural formula of biology is as shown in Formulas I -1, I-2, I-3 or I-4：
5. chromocor derivative as described in claim 1 and its salt, hydrate, solvate, which is characterized in that the flavones spreads out
Structural formula such as Formula II -1, II-2 or the II-3 of biology：
6. chromocor derivative as described in claim 1 and its salt, hydrate, solvate, which is characterized in that the flavones spreads out
The structural formula of biology is as shown in formula III -1：
Wherein R10Selected from following substituent group：
。
7. claim 1-6 any one of them chromocor derivative and its salt, hydrate, solvate are preparing anti-alzheimer '
Application in silent medicine.
8. claim 1-6 any one of them chromocor derivative and its salt, hydrate, solvate prepare cholinesterase,
Application in monoamine oxidase and/or beta-secretase inhibitor.
9. claim 1-6 any one of them chromocor derivative and its salt, hydrate, solvate are in preparing antioxidant
Application.
10. claim 1-6 any one of them chromocor derivative and its salt, hydrate, solvate are preparing metal ion
Application in chelating agent.
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| CN110483541A (en) * | 2019-09-03 | 2019-11-22 | 河南中医药大学 | A kind of isopentene group flavone compound and its preparation method and application |
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