CN109134350A - Donepezil-BHT heterozygote, preparation method and its for treating Alzheimer's disease - Google Patents
Donepezil-BHT heterozygote, preparation method and its for treating Alzheimer's disease Download PDFInfo
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- CN109134350A CN109134350A CN201710462013.4A CN201710462013A CN109134350A CN 109134350 A CN109134350 A CN 109134350A CN 201710462013 A CN201710462013 A CN 201710462013A CN 109134350 A CN109134350 A CN 109134350A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Abstract
The present invention relates to field of medicinal chemistry, more particularly to a kind of donepezil-BHT heterozygote, this kind of compound is as multi-functional acetylcholinesterase (AChE) inhibitor processed and monoamine oxidase B (MAO-B) inhibitor, and there is preferable Antioxidation in vitro, for hydrogen peroxide (H2O2) PC12 nerve cell oxidative damage and bacteria lipopolysaccharide (LPS) is induced to stimulate BV-2 inflammation damnification; there is preferable neuroprotection; and prove play the role of preferably improving cognitive function in zoopery, it is contemplated that the drug candidate as treatment Alzheimer's disease.Most preferred compound structure is as follows:
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of donepezil-BHT heterozygote, this kind of compound conduct
Multi-functional acetylcholinesterase processed (AChE) inhibitor and monoamine oxidase B (MAO-B) inhibitor, and have preferable external anti-
Oxidation, for hydrogen peroxide (H2O2) induce PC12 nerve cell oxidative damage and bacteria lipopolysaccharide (LPS) stimulation BV-2 scorching
Disease damage, there is preferable neuroprotection, and proves there is the preferable work for improving cognitive function in zoopery
With, it is contemplated that the drug candidate as treatment Alzheimer's disease.
Background technique
Alzheimer disease (Alzheimer ' s disease, AD) is also known as senile dementia, is one kind in the elderly
Common neurodegenerative disease.AD pathogenesis is complicated, still endless to the pathology of Alzheimer's disease so far
All clear Chu, the origin cause of formation in addition to intracerebral choline levels reduction mutually outside the Pass, also with oxidative stress, the generation of neuroinflamation, starch
The factors such as aggregation, the disorder that metal ion is metabolized and the imbalance of calcium balance of sample albumen (A β) are closely related.Wherein, cholinergic
Hypothesis (cholinergic hypothesis), the i.e. damage of the cognitive function of the change and Alzheimer's disease of cholinergic system
Degree is closely related.Based on the theory, agonist and acetylcholinesterase of the people to acetylcholinergic receptor
The inhibitor of (acetylcholinesterase, AChE) expands numerous studies.In addition, for intracerebral oxidation stress ask
Topic, main solution is exploitation antioxidant, and reduces oxidative stress to nerve cell by inhibiting monoamine oxidase
Damage and play neuroprotection.
With constantly illustrating for Alzheimer's disease pathogenesis, it has been found that the occurrence and development of Alzheimer's disease are
The multiple action of complicated regulated and control network and regulatory factor as a result, being related to the association between polygenes in organism.For list
The drug of one target spot can only often regulate and control some physiological pathway therein, and cannot fundamentally inhibit Alzheimer's disease
Pathogenesis.Therefore, it finds for multiple targets or the drug with many-sided therapeutic effect into Alzheimer's disease treatment
The new trend of medicament research and development.
Acetylcholinesterase of the donepezil as the treatment moderate Alzheimer Disease patient for being approved listing by FDA
Inhibitor, apparent cholinesterase inhibition and the advantage without obvious toxic-side effects obtain the concern of numerous researchers,
With good development and application prospects.2,6- di-tert-butyl-4-methy phenols (BHT) are as a kind of American-European common food addition
Agent obtains common concern due to its is nontoxic and has preferable antioxidant activity, and finds in recent years, and derivative has good
Anti-inflammatory isoreactivity.Therefore, the present invention has designed and synthesized a series of donepezil-BHT heterozygotes, as multi-functional anti-
Alzheimer's disease preparation.This kind of compound is as multi-functional acetylcholinesterase inhibitor processed and monoamine oxidase B (MAO-B)
Inhibitor, and there is preferable Antioxidation in vitro, for hydrogen peroxide (H2O2) induction PC12 nerve cell oxidative damage and
Bacteria lipopolysaccharide (LPS) stimulates BV-2 inflammation damnification, there is preferable neuroprotection, and has preferably in zoopery
Improvement cognitive function effect, therefore develop it is such with donepezil-BHT a pair of horses going side by side close novel and multifunctional preparation not only conform with
The requirement of anti-Alzheimer disease, and there are good market prospects.
Summary of the invention
The invention discloses a kind of donepezil-BHT heterozygotes.Pharmacodynamic experiment proves that the compound of the present invention can be made
For multifunctional preparation, for treating the treatment of Alzheimer's disease.
The compound of the present invention structure is as follows:
Wherein n=0,1,2;R is respectively CH3, OCH3, NO2, CN, halogen atom etc..
Most preferred compound structure is as follows:
The pharmaceutically acceptable salt of the compounds of this invention is hydrochloride, hydrobromate, sulfate, the phosphorus of general formula compound
Hydrochlorate, mesylate, benzene sulfonate, tosilate, naphthalene sulfonate, citrate, tartrate, lactate, pyruvic acid
Salt, acetate, maleate, succinate, fumarate, salicylate, phenyl acetate salt, mandelate, alkalinous metal sun
Ion salt, alkaline earth metal cation salt or ammonium cation salt.Most preferably alkali metal cations salt.
Present example compound the preparation method is as follows:
1) present example compound 3a-i's the preparation method is as follows:
2) present example compound 3j-1's the preparation method is as follows:
3) present example compound 7a-m's the preparation method is as follows:
R is as defined above.
The compounds of this invention can be prepared with above-mentioned or similar above-mentioned preparation method, according to the variation of chain length,
The difference of substituent group or the difference of substituting group position select corresponding raw material.
Reaction basic process: the preparation method of donepezil-BHT heterozygote of the present invention includes acid amide condensation reaction, replaces
Reaction, de- Boc protecting group process and post-processing each unit process.
The synthesis of compound 3a-i is preferred: the acid (1a-c) of the BHT class of different chain length being added in single-necked flask
(1.1eq) is dissolved with appropriate anhydrous methylene chloride, adds condensing agent I-hydroxybenzotriazole (HOBT) (1.1eq), 1- second
Base-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) (1.1eq) is added dropwise triethylamine (3eq), stirs under ice bath
After reaction 1 hour, the dichloromethane solution of amine (1eq) is added dropwise, overnight, monitoring reaction is complete to amine, and saturated sodium bicarbonate is washed for reaction
It washs 3 times, saturated sodium-chloride is washed three times to after HOBT wash clean, and organic phase merging mixes sample and crosses silicagel column, methylene chloride/methanol product body
It is up to target product.
The synthesis of compound 3j-1 is preferred: 2- 4 '-hydroxy acetophenone of bromo- 3 ', 5 '-di-t-butyl-(1d) (2eq) with not
Same amine (2a-c) (1eq) is in potassium carbonate (K2CO3) and the catalyst of potassium iodide (KI) under, with acetonitrile as solvents reaction overnight, monitoring
Reaction, by crossing silicagel column purification of target product.
The synthesis of compound 7a-m is preferred: aminoethyl piperidine Boc makees solvent in ethyl alcohol from different bromobenzyls, and triethylamine ties up acid
Reaction generates t-butoxycarbonylaminoethyl benzyl piepridine under conditions of agent, further sloughs tertiary butyloxycarbonyl under trifluoroacetic acid effect
Base (Boc protecting group), finally carries out acid amide condensation, and method is same as above.
Here is the partial pharmacologic experiment and data of the compounds of this invention:
One, cholinesterase activity:
Experimental method:
Acetylcholinesterase (AChE) and butyrylcholine esterase (BuChE) inhibitory activity test method are Ellman method.It will
Compound is dissolved in dimethyl sulfoxide (DMSO), is successively diluted to required concentration with buffer, is controlled in configured solution
DMSO content is lower than 1%.It is sequentially added into 96 blank, 5,5 '-two thiobis (2- nitrobenzoic acid) of the 1.5mM of 160 μ l
(DTNB), the various concentration inhibitor of AChE (0.22U/mL is made with buffer solution B) and 10 μ l of 50 μ l.Hatch 6 points at 37 DEG C
Clock is then quickly added into the acetylcholine iodide (15mM) of 30 μ l.0,60,120 and 180 second absorbance is measured at 405nm
Variation.Acetylcholinesterase used seemingly, is changed to butyryl gallbladder with acetylcholinesterase by the measuring method of butyrylcholine esterase
It is thio iodate BuCh (15mM) that alkali esterase (0.12U/mL) replaces substrate acetylcholine iodide simultaneously.The calculating of inhibiting rate
Are as follows: [1- (experimental group absorbance change/blank group absorbance change)] * 100%.Select five to seven concentration mensurations of compound
The inhibiting rate (0.001-100 μM) of enzyme simultaneously carries out linear regression with the negative logarithm of the compound molar concentration and enzyme inhibition rate, asks
Molar concentration when obtaining 50% inhibition is the IC of the compound50Value.In triplicate, experimental result is expressed as average for each experiment
Value ± SEM.
1 the compounds of this invention cholinesterase inhibition of table
a)IC50: inhibiting rate reaches compound concentration when 50%;
B) selectivity factor=source of people butyrylcholine esterase IC50The acetylcholinesterase IC of/source of people50
As known from Table 1, compound 3a-i has certain activity to acetylcholine on the whole, but poor to BuCh activity,
The inhibitory activity of compound 3i preferably (IC50=0.53 μM).Structure-activity relationship shows that the activity of acetylcholinesterase changes with chain length
The more long acting close relation, chain length the better.It is further transformed on the basis of 3i, is the work of its further modifier below
Property result.The acetylcholine activity of compound 7a-m is suitable with 3i, substantially between 0-1 μM.And compound 7d inhibits source of people second
Phatidylcholine activity is significant, reaches IC50=0.075 μM, poor to the inhibiting effect of butyryl esterase, selectivity is preferably.This result with
The effect of donepezil positive drug is substantially suitable, shows the reasonability being further transformed, also illustrates disclosed in this inventionization
Closing object has good inhibiting effect to acetylcholinesterase.
Two, the dynamics research of acetylcholine ester
Experimental method:
Enzyme dynamics are carried out to compound 3i and 7d with Ellman method.Three various concentrations of compound are made respectively
Dynamics research.It is sequentially added into 96 hollow plates, the DTNB of the 1.5mM of 160 μ l, (0.22U/mL uses buffer to the AChE of 50 μ l
B be made) and 10 μ l various concentration compound.Hatch 6 minutes at 37 DEG C, is then quickly added into the iodine of the various concentration of 30 μ l
Change acetylcholine.0,60,120 and 180 second absorbance change is measured at 405nm.Using the inverse of concentration as X-axis and absorbance
Rate of change is Y-axis mapping, makes first double reciprocal curve.The compound of various concentration is added in method according to this, makes
Two, three, four double reciprocal curve judges binding mode of the compound with enzyme with the intersection point of double reciprocal curve.
The result is shown in Figure 1, Fig. 1 show: increase of the compound disclosed in this invention with concentration, Lineweaver-Burk
Double reciprocal curve slope and intercept be also continuously increased.This mode shows that compound is mixed-type inhibitor, illustrates chemical combination
Object is incorporated into the different loci of enzyme, can simultaneously the periphery anionic sites (PAS) for being incorporated into enzyme and catalytic site (CAS) two
A site is dual site inhibitors, is more advantageous to the treatment of Alzheimer disease.Meanwhile it is also further by its inhibition constant Ki
The activity of compound 7d (Ki=1.4 μM) is demonstrated better than 3i (Ki=3.2 μM)
Three, monoamine oxidase inhibitory activity
Experimental method:
Monoamine oxidase inhibitory activity is tested according to method reported in the literature.Compound is dissolved in DMSO, is successively used
Buffer is diluted to required concentration (the DMSO content in the configured solution of control is lower than 1%).In 96 hole elisa Plates of black according to
80 μ l enzymes (being diluted with buffer) of secondary addition, the various concentration compound of 20 μ l after 37 DEG C are incubated for 15 minutes, are added final concentration of
200 μM of Amplex Red solution, 1U/mL horseradish peroxidase, 1mM tyramine solution.In excitation wavelength 545nm and suction
It receives and measures fluorescent absorption under optical wavelength 590nm.The calculating of inhibiting rate are as follows: [1-FExperimental group/FBlank group] * 100%.Select the five of compound
To seven concentration mensuration enzymes inhibiting rate (0.001-100 μM) and with the negative logarithm of the compound molar concentration and enzyme inhibition rate into
Row linear regression, molar concentration when acquiring 50% inhibition are the IC of the compound50Value.Each experiment in triplicate, is tested
Results expression is average value ± SEM.
2 the compounds of this invention monoamine oxidase inhibitory activity of table
As shown in Table 2, the activity of monoamine oxidase of compound 3a-1 is general, and for anti-AD drug, we pay close attention to list
The activity of amine oxidase B, wherein compound 3h (IC50=8.5 μM) and 3i (IC50=11.7 μM) it is active relatively best and opposite
There is preferable selectivity in monoamine oxidase A.The activity and 3i of the monoamine oxidase of compound 7a-m are substantially suitable.
Four, antioxidation
The antioxidation activity in vitro of compound is embodied by test free radical scavenging ability, and present invention employs ABTS surveys
Examination, DPPH test and ORAC test.Three kinds of method difference are as follows:
1.ABTS test method: 5mM watermiscible vitamin E analog (Trolox) standard items: is configured to dehydrated alcohol
Trolox standard items stock solution, when use is diluted to concentration several different with dehydrated alcohol again, is respectively provided with it
5%~85% free radical scavenging ability, according to preliminary result, suitable Trolox concentration of standard solution are as follows: 0,0.2,
0.4,0.6,0.8,1.0,1.2,1.4,1.6 and 1.8mM.ABTS working solution: by the 140mM's of the ABTS of the 7mM of 5mL and 88 μ l
Potassium persulfate solution mixing, room temperature, be protected from light under conditions of stand overnight, formed ABTS+ stock solution, the stock solution is in room
Temperature is stablized under conditions of being protected from light.It is diluted to working solution with anhydrous methanol using preceding, is incubated for 6 minutes under 30 DEG C of dark surrounds,
The absorption value under 415nm wavelength is measured, experiment is repeatedly for three times.
2.DPPH test method: taking DPPH to be dissolved in methanol in right amount to 400 μM, ultrasound 5 minutes, shake well.Compound
And comparison medicine resveratrol and curcumin are dissolved into different concentration with methanol.Every hole is added 20 μ l's on 96 orifice plates when test
Compound adds the DPPH solution of 180 μ l, room temperature avoid light place 30 minutes, measures the absorption value under 517nm wavelength, real
It tests repeatedly for three times.The calculating of free radical scavenging activity are as follows: 1- [(ADPPH+ACompound)-ADPPH/ACompound)] * 100%.Select compound
Five to seven concentration mensuration inhibiting rates, molar concentration when acquiring 50% inhibition are the IC50 value of the compound.Each experiment
In triplicate, experimental result is expressed as average value ± SEM.
3.ORAC test method: before test, getting out fluorescein (FL) and free radical releasing agent (APPH) be made into stock solution,
It is ready-to-use before use, the AAPH solution of the FL and 40mM of 110nM are made into PBS, compound and Trolox are made into various concentration.
20 μ l compounds are added in every hole on 96 orifice plate of black when test, add the FL of 120 μ l, and shaking 15 minutes is protected from light at 37 DEG C,
The AAPH for rapidly joining 60 μ l again detects read plate under exciting light 485nm and transmitting light 538nm, reads primary, scanning per minute
120min.Area (AUC) under fluorescence curve is calculated, result is expressed as the equivalent value of trolox, ORAC-FL=(AUCSample-
AUCBlank)/(AUCtrolox-AUCBlank)*(Ctrolox/CSample)
5 the compounds of this invention free radical scavenging activity of table
aIC50: inhibiting rate reaches compound concentration when 50%;
bCompound with oxidation resistance activity indicates (mmol trolox/mmol measures compound) with trolox multiple under same concentration
The results are shown in Table 3 for antioxidation, using BHT and resveratrol as positive control drug, with the compounds of this invention
Its antioxidation is measured to compare.Compound with oxidation resistance activity is indicated in ABTS test with trolox multiple under same concentration
(mmoltrolox/mmol measures compound).Measurement result shows that majority of compounds shows medium preferable anti-oxidant
Effect, oxidation resistance are slightly weaker than trolox.The oxidation resistance of optimal compound 3i and 7d is trolox respectively
0.91 and 0.82 times.Compound with oxidation resistance activity IC in DPPH test50It indicates, the antioxidant activity of majority of compounds is better than
Comparison medicine resveratrol and parent BHT, wherein the oxidation resistance IC of optimal compound 3i and 7d50It is 71.7 μM and 55.9 respectively
μM.ORAC test result indicates (mmol trolox/mmol measures compound) with trolox multiple under same concentration, the results showed that
Most of, the individual compound a little higher than parent suitable with parent BHT of the antioxidant activity of compound, but it is superior to Trolox, this
, can be to anti-oxidation stress a bit the result shows that such compound has preferable antioxidant activity, and then be applied to AD and treat.
Five, PC12 cytotoxicity and to H2O2The protective effect of the PC12 cellular damage of induction
PC12 cell inoculation in fill 1: 1 mixed Dulbecco ' s modified Eagle ' s medium (EMEM) and
In the 25ml culture bottle of ham ' s F-12 culture medium, and be aided with 10% fetal calf serum, 100U/mL penicillin and 100 μ g/mL chains
Mycin is placed at 37 DEG C, cultivates in 5% carbon dioxide incubator.Then cell is planted with the density in 20000 every holes point in 96 holes
It is grown in plate.After cell growth reaches requirement, cell is placed in serum free medium, 200 μM of H is added2O2With it is difference dense
The compound culture of degree 24 hours.After culture, be added at 37 DEG C of MTT of 20 μ l and cultivate 4 hours, after 200 μ l are added
DMSO dissolution first a ceremonial jade-ladle, used in libation crystallization, measure its absorbance under 570nm.
Optimal compound 3i is chosen, 7d evaluates its cytotoxicity to nerve cell with mtt assay.As a result as shown in Fig. 2, changing
Object is closed under 30 μM of concentration by cell exposure in 24 hours, compound 3i, 7d show certain acceptable cell toxicant
Property, but substantially on cell viability without influence under 20 μM.It is further studied to H2O2The effect of the PC12 cellular damage of induction,
Experimental result is as shown in figure 3, and H2O2Cellular damage group is compared, and compound can significantly improve cells survival rate under 5-20 μM.
Compound is to H under 5 μM of concentration2O2The PC12 cellular damage of induction has significant protective effect.These compounds are to H2O2It lures
The protective effect degree for the PC12 cellular damage led is consistent with its antioxidation activity in vitro, illustrates the compound designed by us
Neuroprotection may be related with its effect of scavenging radical.
Six, inhibit the effect of BV-2 cell release inflammatory factor nitric oxide (NO) of LPS induction
BV-2 cell culture processes are similar to PC12 cell, and BV-2 cell inoculation is in filling Dulbecco ' s modified
Eagle ' s medium is aided with the fetal calf serum of 10%Gemini, 100U/mL penicillin and 100 μ g/mL streptomysins, is placed in 37 DEG C
Under, it is cultivated in 5% carbon dioxide incubator.Then cell is planted with the density in 30000 every holes point and grows 18h in 96 orifice plates
Afterwards, the compound culture of various concentration is added, after the LPS that the concentration that 10 μ L are added after 1 hour is 1ng/ml cultivates 18h, takes
Clear 50 μ l measures the inhibiting rate of NO using NO detection kit.Experimental result is as shown in figure 4, with parent drug BHT and Duo Nai piperazine
It compares together, there is preferable NO inhibitory activity.
Seven, acute toxicity testing and behaviouristics cognition improve experiment
According to acute toxicity guideline, 20 KM mouse are randomly divided into 4 groups, and respectively normal group, administration group (677,
1333,2000mg/kg) preceding reaction in four hours after mouse is administered is observed after, being administered in a manner of stomach-filling, no phenomena of mortality continue
Observation is put to death after observation 14 days, 14 days without apparent damage, shows that the safety of compound 7d is higher.
Pharmacodynamic evaluation is carried out after having rated safety, using amnesia model caused by hyoscine, with passively keeping away
The effect that dark laboratory facilities research compound improves its behaviouristics after the completion of Behaviors survey, to it under administration concentration, is tied
It closes pathology section examination and measures the vigor of glutamic-pyruvic transaminase and glutamic-oxalacetic transaminease (ALT/AST), the influence to liver carries out
Assessment, as a result as shown in figure 5, showing that compound plays the role of preferably improving cognition, and at concentration accordance with tolerance.And giving medicament
Without hepatotoxicity wind agitation under amount, as a result can be obtained by Fig. 6 and Fig. 7.
Donepezil-BHT heterozygote of the present invention proves it in combination with acetylcholinesterase and monoamine oxygen by molecular docking
Change enzyme B, to show preferable acetylcholine esterase inhibition activity and inhibit the activity of monoamine oxidase B;In addition, passing through body
Outer blood-brain barrier permeability experiment shows that optimal compound 3i and 7d can penetrate blood-brain barrier.In short, donepezil-
BHT heterozygote shows preferable acetylcholine esterase inhibition activity in vitro experiment, inhibits monoamine oxidase B activity and resists
The effect of oxidation has to hydrogen peroxide (H2O2) induce PC12 nerve cell oxidative damage and bacteria lipopolysaccharide (LPS) stimulation
BV-2 inflammation damnification has preferable neuroprotection, and preferably improves the effect of cognitive function in zoopery,
Therefore they can be used as multifunctional preparation to control the development of the AD course of disease.
Detailed description of the invention
Fig. 1 is the dynamics research of compound 3i and 7d acetylcholine esterase inhibition
Fig. 2 is compound PC12 cytotoxicity
Fig. 3 is that compound 3i and 7d are compound PC12 neuroprotections
Fig. 4 is the effect for the BV-2 cell release inflammatory factor NO that compound 7d inhibits LPS induction
Fig. 5 is that compound 7d behaviouristics improves cognition effect and changes of weight
Fig. 6 is the variation that glutamic-pyruvic transaminase and glutamic-oxalacetic transaminease (ALT/AST) in serum are measured after compound 7d is administered
Fig. 7 is the hepatic pathology section result after compound 7d administration
Fig. 8 is abridgments of specifications attached drawing
Specific synthesis embodiment
Embodiment 1
The preparation of 4- (N-1- benzyl piepridine) amino -2,4- di-t-butyl para hydroxybenzene formamide (3a).
By 100mg (0.39mmol, 1eq) raw material 2,4- di-t-butyl P-hydroxybenzoic acid (1a) the anhydrous dichloromethane of 6ml
Alkane dissolution, is added condensing agent I-hydroxybenzotriazole (HOBT) 49.74mg (0.36mmol, 1.1eq) and 1- ethyl-(3- diformazan
Base aminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) 69.62mg (0.36mmol, 1.1eq), 151 μ l of triethylamine is added dropwise
After being stirred to react 1 hour under ice bath, 4- amino -1- benzyl piepridine (2a) 69.1mg is added dropwise in (1.09mmol, 3eq)
Overnight, monitoring reaction is complete to amine, and saturated sodium bicarbonate washs 3 times, saturation for the dichloromethane solution reaction of (0.36mmol, 1eq)
Sodium chloride is washed three times to after HOBT wash clean, and organic phase merging mixes sample and crosses silicagel column, and methylene chloride/methanol product system is up to target
Product as white solid 3a about 140mg, yield about 80%.m.p.220-222℃.1H NMR (500MHz, DMSO) δ 8.02 (d, J=
7.7Hz, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 7.37-7.31 (m, 4H), 3.78 (d, J=7.2Hz, 1H), 3.49 (s,
2H), 2.84 (d, J=8.2Hz, 2H), 2.03 (s, 2H), 1.77 (d, J=10.9Hz, 1H), 1.62 (d, J=10.3Hz, 2H),
1.41 (s, 18H), 1.25 (s, 1H);13C NMR (126MHz, DMSO) δ 167.13,156.95,138.65,129.29,
128.65,127.44,126.57,124.51,62.47,52.76,34.94,30.69,30.52.ESI-MS m/z:423.3 [M+
H]+;HRMS(ESI)m/z 423.3004[M+H]+(calcd for 423.3006, C27H39N2O2).
Embodiment 2
The preparation of 4- (N-1- benzyl piepridine) aminomethyl -2,4- di-t-butyl para hydroxybenzene formamide (3b)
Raw material 4- amino -1- benzyl piepridine (2a) is changed to 4- aminomethyl -1- benzyl piepridine (2b) with 1 by preparation process, is received
Rate 82%;White solid, m.p.217-218 DEG C,1H NMR (500MHz, DMSO) δ 8.27 (d, J=7.7Hz, 1H), 7.60 (s,
2H), 7.31 (m, 5H), 3.45 (s, 2H), 3.13 (t, J=6.2Hz, 2H), 2.81 (d, J=11.0Hz, 2H), 1.90 (t, J=
11.0Hz, 2H), 1.64 (d, J=12.2Hz, 2H), 1.54 (d, J=6.2Hz, 1H), 1.41 (s, 18H), 1.22-1.11 (m,
2H);13C NMR (126MHz, DMSO) δ 167.51,156.51,139.24,138.64,129.20,128.56,127.24,
126.45,124.43,62.91,53.46,45.20,36.33,35.03,30.71,30.36.ESI-MS m/z:437.3 [M+H
]+;HRMS (ESI) m/z:437.3164 [M+H]+(calcd for 437.3163, C28H41N2O2).
Embodiment 3
The preparation of 4- (N-1- benzyl piepridine) aminoethyl -2,4- di-t-butyl para hydroxybenzene formamide (3c)
Raw material 4- amino -1- benzyl piepridine (2a) is changed to 4- aminoethyl -1- benzyl piepridine (2c) with 1 by preparation process, is received
Rate 75%;White solid, m.p.182-183 DEG C,1H NMR (500MHz, CDCl3) δ 7.61 (s, 2H), 7.42-7.33 (m,
4H), 7.32 (s, 1H), 5.99 (s, 1H), 5.57 (s, 1H), 3.60 (s, 2H), 3.51 (dd, J=14.1,6.4Hz, 2H),
2.98 (d, J=10.3Hz, 2H), 2.06 (s, 2H), 1.78 (d, J=10.3Hz, 2H), 1.61 (d, J=6.4Hz, 2H), 1.50
(s, 18H), 1.43 (s, 2H), 1.32 (d, J=14.1Hz, 1H);13C NMR (126MHz, DMSO) δ 167.95,156.51,
135.96,129.56,128.31,126.04,123.98,53.30,37.76,36.50,34.43,33.62,31.54,
30.20.ESI-MS m/z:451.3 [M+H]+;HRMS (ESI) m/z:451.3317 [M+H]+(calcd for 451.3319,
C29H43N2O2).
Embodiment 4
The preparation of 4- (N-1- benzyl piepridine) amino -2,4- di-t-butyl para hydroxybenzene propionamide (3d)
Preparation process is with 1, and by raw material 2,4- di-t-butyl P-hydroxybenzoic acid (1a) changes 2,4- di-t-butyl into hydroxyl
Benzenpropanoic acid (1b), yield 76%;White solid, m.p.142-144 DEG C,1H NMR (500MHz, DMSO) δ 7.71 (d, J=
7.6Hz, 1H), 7.36-7.22 (m, 5H), 6.69 (s, 1H), 3.54 (m, 1H), 3.45 (s, 2H), 2.71 (dd, J=11.1,
7.7Hz, 4H), 2.30 (t, J=7.7Hz, 2H), 1.99 (t, J=10.4Hz, 2H), 1.68 (d, J=10.4Hz, 2H), 1.42
(s, 1H), 1.37 (s, 18H), 1.33 (d, J=11.1Hz, 2H), 1.25 (m, 1H);13C NMR (126MHz, DMSO) δ
171.37,152.33,139.20,132.67,129.19,128.60,127.30,124.62,62.62,52.40,46.37,
38.01,34.89,32.04,31.67,30.83.ESI-MS m/z:451.3 [M+H]+;HRMS (ESI) m/z:451.3320 [M+
H]+(calcd for 451.3319, C29H43N2O2).
Embodiment 5
The preparation of 4- (N-1- benzyl piepridine) aminomethyl -2,4- di-t-butyl para hydroxybenzene propionamide (3e)
Preparation process is the same as 1, by raw material 2,4- di-t-butyl P-hydroxybenzoic acid (1a) and 4- amino -1- benzyl piepridine (2a)
Change 2,4- di-t-butyl para hydroxybenzene propionic acid (1b) and 4- aminomethyl -1- benzyl piepridine (2b), yield 62% into respectively;Brown oil
Shape object,1H NMR (500MHz, DMSO) δ 7.36-7.21 (m, 5H), 6.91 (s, 2H), 3.45 (s, 2H), 2.94 (t, J=
6.2Hz, 2H), 2.78 (d, J=9.2Hz, 2H), 2.70 (s, 2H), 2.33 (s, 2H), 1.87 (s, 2H), 1.56 (s, 2H),
1.37 (s, 18H), 1.25 (s, 1H), 1.10 (m, 2H);13C NMR (126MHz, DMSO) δ 172.06,152.30,139.42,
132.65,129.28,128.57,127.37,124.60,62.79,53.22,44.54,37.90,35.99,34.89,31.67,
30.77,29.89.ESI-MS m/z:465.3 [M+H]+;HRMS (ESI) m/z:465.3474 [M+H]+(calcd for
465.3476, C30H45N2O2).
Embodiment 6
The preparation of 4- (N-1- benzyl piepridine) aminoethyl -2,4- di-t-butyl para hydroxybenzene propionamide (3f)
Preparation process is the same as 1, by raw material 2,4- di-t-butyl P-hydroxybenzoic acid (1a) and 4- amino -1- benzyl piepridine (2a)
Change 2,4- di-t-butyl para hydroxybenzene propionic acid (1c) and 4- aminomethyl -1- benzyl piepridine (2c), yield 64% into respectively;Light brown
Grease,1H NMR (500MHz, DMSO) δ 7.75 (t, J=7.6Hz, 1H), 7.35-7.23 (m, 5H), 6.69 (s, 1H),
3.45 (s, 4H), 3.07 (d, J=6.4Hz, 2H), 2.78 (d, J=11.1Hz, 2H), 2.70 (t, J=7.6Hz, 2H), 2.30
(t, J=7.7Hz, 2H), 1.90 (t, J=12.4Hz, 2H), 1.61 (d, J=12.4Hz, 2H), 1.38 (s, 18H), 1.25 (d,
J=6.4Hz, 1H), 1.12 (m, 2H);13C NMR (126MHz, DMSO) δ 171.89,152.35,139.47,132.71,
129.24,128.55,127.26,124.62,62.62,53.64,38.01,36.65,36.45,34.90,33.32,32.24,
31.67,30.93.ESI-MS m/z:479.3 [M+H]+;HRMS (ESI) m/z:479.3635 [M+H]+(calcd for
479.3632, C31H47N2O2).
Embodiment 7
The preparation of 4- (N-1- benzyl piepridine) amino -2,4- di-t-butyl para hydroxybenzene acrylamide (3g)
Preparation process is with 1, and by raw material 2,4- di-t-butyl P-hydroxybenzoic acid (1a) changes 2,4- di-t-butyl into hydroxyl
Cinnamic acid (1c), yield 70%;Brown solid, m.p.214-215 DEG C,1H NMR (500MHz, DMSO) δ 7.91 (d, J=
15.7Hz, 1H), 7.37-7.31 (m, 7H), 6.48 (d, J=15.7Hz, 1H), 3.67 (d, J=6.6Hz, 1H), 3.35 (s,
2H), 2.78 (d, J=11.1Hz, 2H), 2.06 (s, 2H), 1.78 (m, 2H), 1.41 (s, 18H), 1.30 (dd, J=11.1,
6.6Hz, 2H);13C NMR (125MHz, DMSO) δ 165.03,155.74,140.04,139.70,129.25,128.53,
127.24,126.81,124.66,119.56,62.66,52.21,46.65,34.96,32.15,30.60.ESI-MS m/z:
449.3[M+H]+;HRMS (ESI) m/z:449.3165 [M+H]+(calcd for 449.3163, C29H41N2O2).
Embodiment 8
The preparation of 4- (N-1- benzyl piepridine) aminomethyl -2,4- di-t-butyl para hydroxybenzene acrylamide (3h)
Preparation process is the same as 1, by raw material 2,4- di-t-butyl P-hydroxybenzoic acid (1a) and 4- amino -1- benzyl piepridine (2a)
Change 2,4- di-t-butyl para hydroxybenzene propionic acid (1c) and 4- aminomethyl -1- benzyl piepridine (2b), yield 65% into respectively;Brown is solid
Body,1H NMR (500MHz, DMSO) δ 7.96 (d, J=15.7Hz, 1H), 7.35 (d, J=6.8Hz, 1H), 7.32-7.28 (m,
5H), 7.26 (d, J=6.8Hz, 1H), 6.51 (d, J=15.7Hz, 1H), 3.45 (s, 2H), 3.08 (t, J=6.1Hz, 2H),
2.81 (d, J=11.2Hz, 2H), 1.98-1.83 (m, 2H), 1.64 (d, J=11.8Hz, 2H), 1.41 (s, 18H), 1.19 (d,
J=6.1Hz, 2H), 1.06 (s, 1H);13C NMR (126MHz, DMSO) δ 165.90,155.89,139.97,139.69,
129.24,129.24,128.46,128.46,127.27,126.82,124.64,119.53,62.87,53.30,53.30,
44.73,44.73,36.28,36.28,34.91,34.91,30.58,30.58,30.17,30.17.ESI-MS m/z:463.3
[M+H]+;HRMS (ESI) m/z:463.3321 [M+H]+(calcd for 463.3319, C30H43N2O2).
Embodiment 9
The preparation of 4- (N-1- benzyl piepridine) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide (3i)
Preparation process is the same as 1, by raw material 2,4- di-t-butyl P-hydroxybenzoic acid (1a) and 4- amino -1- benzyl piepridine (2a)
Change 2,4- di-t-butyl para hydroxybenzene propionic acid (1c) and 4- aminomethyl -1- benzyl piepridine (2c), yield 70% into respectively;Brown is solid
Body, m.p.126-128 DEG C.1H NMR (500MHz, DMSO) δ 7.93 (d, J=15.7Hz, 1H), 7.33-7.28 (m, 7H),
6.46 (d, J=15.7Hz, 1H), 3.35 (s, 4H), 3.20 (dd, J=12.8,6.6Hz, 2H), 2.81 (d, J=6.6Hz,
2H), 1.93 (s, 2H), 1.66 (d, J=12.9Hz, 2H), 1.42 (s, 18H), 1.32 (s, 1H), 1.20-1.13 (m, 2H);13C
NMR (126MHz, DMSO) δ 165.73,155.49,139.91,139.70,129.49,128.57,127.31,126.81,
124.65,119.48,62.89,53.29,36.68,36.38,34.96,33.23,32.22,30.68.ESI-MS m/z:
477.3[M+H]+;HRMS (ESI) m/z:477.3475 [M+H]+(calcd for 477.3476, C31H45N2O2).
Embodiment 10
The preparation of 4- (N-1- benzyl piepridine) amino -2,4- di-t-butyl Uteramin -2- ketone (3j)
By raw material 2,4- di-t-butyl parahydroxyacet-ophenone (1d) 100mg (0.31mmol, 1.1eq) is dissolved in acetonitrile,
Potassium carbonate (K is added2CO3) 115mg (0.833mmol, 3eq), it adds dropwise 4- amino -1- benzyl piepridine (2a) and is stirred overnight,
Monitoring react to amine, is spin-dried for solvent, obtains brown oil target product with mixing sample after methylene chloride and water extraction and crossing silicagel column, receipts
Rate 32%,1H NMR (500MHz, DMSO) δ 7.34 (t, J=5.3Hz, 5H), 7.14 (d, J=2.3Hz, 1H), 6.79 (d, J=
2.4Hz, 1H), 5.78 (s, 1H), 3.56-3.49 (m, 2H), 2.86 (d, J=10.0Hz, 2H), 2.23 (d, J=6.3Hz,
2H), 1.78-1.63 (m, 4H), 1.26 (m, 18H), 1.19-1.00 (m, 2H), 0.86 (dd, J=10.0,6.1Hz, 1H);13C
NMR (126MHz, DMSO) δ 188.05,157.19,152.34,150.75,138.75,136.37,129.12,128.61,
127.33,124.51,119.03,62.71,51.55,35.83,35.03,33.84,30.71,29.55.ESI-MS m/z:
437.3.[M+H]+;HRMS (ESI) m/z:437.3165 [M+H]+(calcd for 437.3163, C28H41N2O2).
Embodiment 11
4- (N-1- benzyl piepridine) aminomethyl -2,4- di-t-butyl Uteramin -2- ketone (3k) preparation
Process changes raw material 4- amino -1- benzyl piepridine (2a) into 4- aminomethyl -1- benzyl piepridine, yield 34% with 10;
Brown oil.1H NMR (500MHz, DMSO) δ 8.06-7.94 (m, 1H), 7.77 (s, 1H), 7.43-7.15 (m, 5H),
5.23-4.82 (m, 1H), 4.74 (s, 1H), 3.47 (s, 2H), 3.18 (d, J=7.4Hz, 2H), 2.82 (d, J=10.2Hz,
2H), 1.91 (d, J=10.2Hz, 2H), 1.64-1.55 (m, 2H), 1.49-1.27 (m, 18H), 1.26 (s, 1H), 1.19-
0.72 (m, 2H);13C NMR (126MHz, DMSO) δ 193.94,163.78,138.80,129.21,128.57,127.29,
125.55,62.78,53.20,49.58,34.99,34.01,31.43,30.47,29.72.ESI-MS m/z:451.3 [M+H
]+;HRMS (ESI) m/z:451.3321 [M+H]+(calcd for 451.3319, C29H43N2O2).
Embodiment 12
The preparation of 4- (N-1- benzyl piepridine aminoethyl) -2,4- di-t-butyl Uteramin -2- ketone (3l)
Preparation process changes raw material 4- amino -1- benzyl piepridine (2a) into 4- aminoethyl -1- benzyl piepridine, yield with 10
30%;Brown oil.1H NMR (500MHz, DMSO) δ 7.99 (s, 1H), 7.53 (s, 1H), 7.32 (m, 6H), 3.49 (s,
2H), 3.10 (m, 2H), 2.83 (s, 3H), 2.11 (s, 1H), 1.90 (d, J=9.8Hz, 2H), 1.56 (m, 3H), 1.46-1.18
(m, 18H), 1.16-0.92 (m, 3H), 0.87 (d, J=9.2Hz, 2H);13C NMR (126MHz, DMSO) δ 193.94,
163.78,138.80,129.21,128.57,127.29,125.55,62.89,53.29,36.68,36.38,34.96,
33.23,32.22,30.68.ESI-MS m/z:465.3 [M+H]+;HRMS (ESI) m/z:465.3479 [M+H]+(calcd for
465.3476, C30H45N2O2).
Embodiment 13
The system of 4- (N-1- (4- methyoxy-benzyl piperidines)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7a
It is standby
The 4- methoxyl group bromobenzyl of raw material 100mg aminoethyl piperidine Boc (0.5mmol, 1.1eq) and 104.24mg
(0.45mmol, 1eq) makees solvent in ethyl alcohol, and reaction generates tertiary fourth oxygen under conditions of triethylamine (1.36mmol, 3eq) does acid binding agent
Carbonyl aminoethyl benzyl piepridine further sloughs tertbutyloxycarbonyl (Boc protecting group) under trifluoroacetic acid effect, finally carries out acid
Amine method of condensing is same as above 1.
Obtain white solid, yield 58%;M.p.197-198 DEG C,1H NMR (500MHz, DMSO) δ 7.99 (s, 1H), 7.53
(s, 1H), 7.32 (m, 6H), 3.89 (s, 3H), 3.10 (m, 2H), 2.83 (s, 3H), 2.11 (s, 1H), 1.90 (d, J=
9.2Hz, 2H), 1.56 (m, 3H), 1.46-1.18 (m, 18H), 1.16-0.92 (m, 3H), 0.87 (d, J=9.2Hz, 2H);13C
NMR (126MHz, DMSO) δ 165.65,158.61,155.95,139.88,139.64,130.90,130.41,126.70,
124.67,119.41,113.92,62.39,55.43,53.60,36.62,36.42,34.97,33.30,32.31,
30.64.ESI-MS m/z:507.3 [M+H]+;HRMS (ESI) m/z:507.3581 [M+H]+(calcd for 507.3579,
C32H47N2O3).
Embodiment 14
The preparation of 4- (N-1- (2- Methyl-benzvl piperidines)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7b
Raw material 4- methoxyl group bromobenzyl is changed to 2- methyl bromobenzyl, yield 48% with 13 by preparation process;Brown solid,
M.p.182-184 DEG C,1H NMR (500MHz, DMSO) δ 7.95 (d, J=15.7Hz, 1H), 7.32 (s, 3H), 7.19 (m, 4H),
6.47 (d, J=15.7Hz, 1H), 3.39 (s, 2H), 3.19 (s, 2H), 2.78 (d, J=11.1Hz, 2H), 2.32 (s, 3H),
1.91 (t, J=7.1Hz, 2H), 1.65 (d, J=11.1Hz, 2H), 1.40 (s, 18H), 1.32 (d, J=7.2Hz, 1H), 1.11
(s, 2H), 0.99 (s, 2H)13C NMR (151MHz, DMSO) δ 165.66,155.92,139.87,139.65,137.40,
137.24,130.46,129.88,127.21,126.73,125.79,124.67,119.43,61.02,53.96,46.16,
36.64,36.34,34.97,32.40,30.64,28.75,19.28.ESI-MS m/z:491.3 [M+H]+;HRMS(ESI)m/
Z:491.3632 [M+H]+(calcd for 491.3629, C32H47N2O2).
Embodiment 15
The preparation of 4- (N-1- (4- Methyl-benzvl piperidines)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7c
Raw material 4- methoxyl group bromobenzyl is changed to 4- methyl bromobenzyl, yield 44% with 13 by preparation process;Brown solid,
M.p.190-191 DEG C, 1H NMR (500MHz, DMSO) δ 7.95 (d, J=15.7Hz, 1H), 7.32 (s, 3H), 7.19 (m, 4H),
6.47 (d, J=15.7Hz, 1H), 3.39 (s, 2H), 3.19 (s, 2H), 2.78 (d, J=11.1Hz, 2H), 2.32 (s, 3H),
1.93 (t, J=7.1Hz, 2H), 1.65 (d, J=11.1Hz, 2H), 1.40 (s, 18H), 1.32 (d, J=7.2Hz, 1H), 1.11
(s, 2H), 0.99 (s, 2H)13C NMR (151MHz, DMSO) δ 165.66,155.92,139.87,139.65,137.40,
137.24,130.46,129.88,127.21,126.73,125.79,124.67,119.43,61.02,53.96,46.16,
36.64,36.34,34.97,32.40,30.64,28.75,19.28.ESI-MS m/z:491.3 [M+H]+;HRMS(ESI)m/
Z:491.3632 [M+H]+(calcd for 491.3629, C32H47N2O2).
Embodiment 16
The preparation of 4- (N-1- (the fluoro- benzyl piepridine of 2-)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7d
Raw material 4- methoxyl group bromobenzyl is changed to 2- fluorine bromobenzyl, yield 62% with 13 by preparation process;Brown solid, mp 177-
178℃。1H NMR (500MHz, DMSO) δ 7.97 (d, J=15.7Hz, 1H), 7.38-7.30 (m, 6H), 7.14 (t, J=
8.8Hz, 2H), 6.46 (d, J=15.7Hz, 1H), 3.52 (s, 2H), 3.22 (d, J=6.7Hz, 2H), 2.78 (d, J=
11.3Hz, 2H), 2.11 (dd, J=10.8,6.7Hz, 1H), 1.89 (t, J=10.8Hz, 2H), 1.65 (d, J=11.3Hz,
2H), 1.41 (s, 18H), 1.34-1.26 (m, 4H)13C NMR (126MHz, DMSO) δ 165.69,155.91,139.91,
139.66,132.01,129.36,126.74,124.63,119.43,115.54,55.34,53.53,36.61,36.36,
34.97,33.09,32.23,30.65.ESI-MS m/z:495.3 [M+H]+;HRMS (ESI) m/z:495.3381 [M+H]+
(calcd for 491.3382, C31H44FN2O2).
Embodiment 17
The preparation of 4- (N-1- (the fluoro- benzyl piepridine of 3-)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7e
Raw material 4- methoxyl group bromobenzyl is changed to 3- fluorine bromobenzyl, yield 51% with 13 by preparation process;Brown solid,
M.p.167-169 DEG C,1H NMR (500MHz, DMSO) δ 7.93 (d, J=15.7Hz, 1H), 7.38-7.30 (m, 6H), 7.14
(t, J=8.8Hz, 2H), 6.46 (d, J=15.7Hz, 1H), 3.42 (s, 2H), 3.20 (d, J=6.7Hz, 2H), 2.77 (d, J
=11.3Hz, 2H), 2.13 (dd, J=10.8,6.7Hz, 1H), 1.89 (t, J=10.8Hz, 2H), 1.65 (d, J=11.2Hz,
2H), 1.41 (s, 18H), 1.34-1.26 (m, 4H)13C NMR (126MHz, DMSO) δ 165.69,155.91,139.91,
139.66,132.01,129.36,126.74,124.63,119.43,115.54,55.34,53.53,36.61,36.36,
34.97,33.09,32.23,30.65.ESI-MS m/z:495.3 [M+H]+;HRMS (ESI) m/z:495.3381 [M+H]+
(calcd for 491.3382, C31H44FN2O2).
Embodiment 18
The preparation of 4- (N-1- (the fluoro- benzyl piepridine of 4-)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7f
Raw material 4- methoxyl group bromobenzyl is changed to 4- fluorine bromobenzyl, yield 54% with 13 by preparation process;Brown solid,
m.p.181-183℃。1H NMR (500MHz.DMSO) δ 7.93 (d, J=15.7Hz, 1H), 7.38-7.30 (m, 6H), 7.14
(t, J=8.8Hz, 2H), 6.46 (d, J=15.7Hz, 1H), 3.42 (s, 2H), 3.20 (d, J=6.7Hz, 2H), 2.77 (d, J
=11.3Hz, 2H), 2.13 (dd, J=10.8,6.7Hz, 1H), 1.89 (t, J=10.8Hz, 2H), 1.65 (d, J=11.0Hz,
2H), 1.41 (s, 18H), 1.34-1.26 (m, 4H)13C NMR (126MHz, DMSO) δ 165.69,155.91,139.91,
139.66,132.01,129.36,126.74,124.63,119.43,115.54,55.34,53.53,36.61,36.36,
34.97,33.09,32.23,30.65.ESI-MS m/z:495.3 [M+H]+;HRMS (ESI) m/z:495.3381 [M+H]+
(calcd for 491.3382, C31H44FN2O2).
Embodiment 19
The system of 4- (N-1- (2,4- diiluoro-benzyl piperidines)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7g
It is standby
Raw material 4- methoxyl group bromobenzyl is changed to 2,4- difluorobenzyl bromide, yield 44% with 13 by preparation process;Brown solid,
m.p.217-218℃。1H NMR (500MHz, DMSO) δ 7.93 (t, J=10.1Hz, 1H), 7.44 (dd, J=15.7,8.5Hz,
1H), 7.33 (m, 4H), 7.19 (td, J=10.1,2.5Hz, 1H), 7.06 (td, J=8.5,2.3Hz, 1H), 6.46 (d, J=
15.7Hz, 1H), 3.47 (s, 2H), 3.19 (d, J=6.1Hz, 2H), 2.79 (d, J=11.2Hz, 2H), 1.94 (t, J=
10.7Hz, 2H), 1.65 (d, J=10.7Hz, 2H), 1.47-1.37 (m, 18H), 1.34-1.23 (m, 3H), 1.10 (dd, J=
11.2,6.4Hz, 2H)13C NMR (151MHz, DMSO) δ 165.66,155.90,139.89,139.64,133.06,126.70,
124.66,119.39,111.66,103.82,54.83,53.39,46.13,36.62,36.33,35.03,33.04,32.19,
30.50.ESI-MS m/z:513.3 [M+H]+;HRMS (ESI) m/z:513.3287 [M+H]+(calcd for 513.3290,
C31H43F2N2O2).
Embodiment 20
The system of 4- (N-1- (3,4- diiluoro-benzyl piperidines)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7h
It is standby
Raw material 4- methoxyl group bromobenzyl is changed to 3- fluorine bromobenzyl, yield 46% with 13 by preparation process;Brown solid, mp 224-
226 DEG C,1H NMR (500MHz, DMSO) δ 7.93 (t, J=10.1Hz, 1H), 7.44 (dd, J=15.7,8.5Hz, 1H), 7.33
(m, 4H), 7.19 (td, J=10.1,2.5Hz, 1H), 7.06 (td, J=8.5,2.5Hz, 1H), 6.46 (d, J=15.7Hz,
1H), 3.47 (s, 2H), 3.19 (d, J=6.1Hz, 2H), 2.79 (d, J=11.2Hz, 2H), 1.94 (t, J=10.7Hz, 2H),
1.65 (d, J=10.7Hz, 2H), 1.47-1.37 (m, 18H), 1.34-1.23 (m, 3H), 1.10 (dd, J=11.8,6.1Hz,
2H).13C NMR (151MHz, DMSO) δ 165.66,155.90,139.89,139.64,133.06,126.70,124.66,
119.39,111.66,103.82,54.83,53.39,46.13,36.62,36.33,35.03,33.04,32.19,
30.50.ESI-MS m/z:513.3 [M+H]+;HRMS (ESI) m/z:513.3287 [M+H]+(calcd for 513.3290,
C31H43F2N2O2).
Embodiment 21
The preparation of 4- (N-1- (the chloro- benzyl piepridine of 2-)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7i
Raw material 4- methoxyl group bromobenzyl is changed to 2- chlorine bromobenzyl, yield 48% with 13 by preparation process;Brown solid, mp 203-
205 DEG C,1H NMR (500MHz, DMSO) δ 7.93 (d, J=15.7Hz, 1H), 7.40-7.25 (m, 7H), 6.45 (d, J=
15.7Hz, 1H), 3.45 (s, 2H), 3.35 (s, 5H), 2.78 (d, J=11.3Hz, 2H), 1.92 (t, J=10.6Hz, 2H),
1.66 (d, J=11.0Hz, 2H), 1.41 (s, 18H), 1.16 (dd, J=11.8,10.6Hz, 2H)13C NMR (126MHz,
DMSO) 165.69,155.91,139.91,139.66,132.01,129.36,126.74,124.63,119.43,115.54 δ),
55.34,53.53,36.61,36.36,34.97,33.09,32.23,30.65.ESI-MS m/z:511.3 [M+H]+;HRMS
(ESI) m/z:511.3086 [M+H]+(calcd for 511.3088, C31H43ClN2O2).
Embodiment 22
The preparation of 4- (N-1- (3- chloro piperidines)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7j
Raw material 4- methoxyl group bromobenzyl is changed to 3- chlorine bromobenzyl, yield 64% with 13 by preparation process;Brown solid,
M.p.194-196 DEG C,1H NMR (500MHz, DMSO) δ 7.93 (d, J=15.7Hz, 1H), 7.40-7.25 (m, 7H), 6.45
(d, J=15.7Hz, 1H), 3.45 (s, 2H), 3.35 (s, 5H), 2.78 (d, J=11.3Hz, 2H), 1.92 (t, J=10.6Hz,
2H), 1.66 (d, J=11.0Hz, 2H), 1.41 (s, 18H), 1.16 (dd, J=11.8,10.6Hz, 2H)13C NMR
(126MHz, DMSO) δ 165.69,155.91,139.91,139.66,132.01,129.36,126.74,124.63,119.43,
115.54,55.34,53.53,36.61,36.36,34.97,33.09,32.23,30.65.ESI-MS m/z:511.3 [M+H]
+;HRMS (ESI) m/z:511.3086 [M+H]+(calcd for 511.3088, C31H43ClN2O2).
Embodiment 23
The preparation of 4- (N-1- (the bromo- benzyl piepridine of 4-)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7k
Raw material 4- methoxyl group bromobenzyl is changed to 4- bromine bromobenzyl, yield 64% with 13 by preparation process;Brown solid,
M.p.154-155 DEG C,1H NMR (500MHz, DMSO) δ 7.94 (d, J=15.7Hz, 1H), 7.49 (s, 1H), 7.47-7.44
(m, 1H), 7.35-7.29 (m, 5H), 6.45 (d, J=15.7Hz, 1H), 4.13 (s, 2H), 3.45 (s, 2H), 2.77 (d, J=
11.3Hz, 2H), 1.92 (t, J=10.6Hz, 2H), 1.66 (d, J=10.8Hz, 2H), 1.41 (m, 20H), 1.22-1.10 (m,
3H).13C NMR (126MHz, DMSO) δ 165.73,155.49,139.91,139.70,129.49,128.57,127.31,
126.81,124.65,119.48,62.89,53.29,36.68,36.38,34.96,33.23,32.22,30.68.ESI-MS
M/z:555.2 [M+H]+;HRMS (ESI) m/z:555.2509 [M+H]+(cal cd for 555.2508, C31H43BrN2O2).
Embodiment 24
The preparation of 4- (N-1- (4- Nitro-benzyl piperidines)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 71
Raw material 4- methoxyl group bromobenzyl is changed to 4- nitro bromobenzyl, yield 64% with 13 by preparation process;Brown solid,
M.p.127-128 DEG C,1H NMR (500MHz, DMSO) δ 8.18-8.10 (m, 2H), 7.94 (d, J=15.7Hz, 1H), 7.77
(d, J=7.6Hz, 1H), 7.64 (t, J=7.9Hz, 1H), 7.36-7.30 (m, 4H), 6.46 (d, J=15.7Hz, 1H), 3.60
(s, 2H), 3.21 (dd, J=12.8,6.7Hz, 2H), 2.80 (d, J=12.8Hz, 2H), 1.97 (t, J=11.3Hz, 2H),
1.67 (d, J=11.3Hz, 2H), 1.41 (m, 20H), 1.34 (s, 3H)13C NMR (151MHz, DMSO) δ 165.69,
155.91,148.26,141.77,139.91,139.64,135.81,130.12,126.70,124.66,123.38,122.33,
119.37,61.66,53.64,36.62,36.33,34.95,33.11,32.25,31.64,30.63..ESI-MS m/z:
522.3[M+H]+;HRMS (ESI) m/z:522.3326 [M+H]+(calcd for 522.3325, C31H44N3O4).
Embodiment 25
The preparation of 4- (N-1- (4- Cyano-benzyl piperidines)) aminoethyl -2,4- di-t-butyl para hydroxybenzene acrylamide 7m
Raw material 4- methoxyl group bromobenzyl is changed to 4- cyano-benzyl bromide, yield 64% with 13 by preparation process;Brown solid,
m.p.215-217℃。1H NMR (500MHz, DMSO) δ 8.18-8.10 (m, 2H), 7.94 (t, J=7.9Hz, 1H), 7.77 (d,
J=15.6Hz, 1H), 7.64 (t, J=7.9Hz, 1H), 7.36-7.30 (m, 4H), 6.46 (d, J=15.7Hz, 1H), 3.60
(s, 2H), 3.21 (dd, J=12.8,6.7Hz, 2H), 2.80 (d, J=12.8Hz, 2H), 1.97 (t, J=11.0Hz, 2H),
1.67 (d, J=11.3Hz, 2H), 1.41 (m, 20H), 1.34 (s, 3H)13C NMR (151MHz, DMSO) δ 165.69,
155.91,148.26,141.77,139.91,139.64,135.81,130.12,126.70,124.66,123.38,122.33,
119.37,61.66,53.64,36.62,36.33,34.95,33.11,32.25,31.64,30.63.ESI-MS m/z:502.3
[M+H]+;HRMS (ESI) m/z:502.3357 [M+H]+(calcd for 522.3355, C32H43N3O2)
Claims (7)
1. a kind of donepezil-BHT heterocomplex or its pharmaceutically acceptable salt that general formula is following:
Wherein n=0,1,2, R is respectively CH3, OCH3, NO2, CN, halogen atom etc..
2. the compound of claim 1 or its pharmaceutically acceptable salt, wherein optimal compound is:
3. the compound of claim 1 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt is general formula compound
Hydrochloride, hydrobromate, sulfate, phosphate, mesylate, benzene sulfonate, tosilate, naphthalene sulfonate, lemon
Hydrochlorate, tartrate, lactate, acetonate, acetate, maleate, succinate, fumarate, salicylate, phenyl
Acetate, mandelate, alkali metal cations salt, alkaline earth metal cation salt or ammonium cation salt.
4. a kind of pharmaceutical composition, the compound of the general formula containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically
Acceptable carrier.
5. preparing claim
A kind of preparation method of claim formula (1) compound, this method comprises:
1) acid with the benzyl piepridine amine of different chain length of the BHT class of different chain length in condensing agent I-hydroxybenzotriazole (HOBT) and
Target product 3a-i is generated under 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI);
2) bromo- 3 ', 5 '-di-t-butyl-the 4 '-hydroxy acetophenone of 2- and the amine of different chain length are in K2CO3With acetonitrile as solvents under effect
Generate target product 3j-1;
3) the different bromobenzyls replaced and t-butoxycarbonylaminoethyl piperidines are in ethanol as solvent, and triethylamine is under conditions of acid binding agent
Then the t-butoxycarbonylaminoethyl benzyl piepridine of generation takes off tertbutyloxycarbonyl (Boc protection under the action of trifluoroacetic acid
Base), then reacted with 2,5- di-t-butyl -4- hydroxy-cinnamic acid and generate target product 7a-m.
6. the compound of the general formula of claim 1 or its pharmaceutically acceptable salt are used to be used as acetylcholinesterase inhibitor,
With preferable Antioxidation in vitro, apparent neuroprotection is shown on cell, anti-inflammatory effect and in animal row
Prove to have the preferable purposes for improving related disease drug to learn.
7. the purposes of claim 6, wherein disease relevant to such activity is Alzheimer disease.
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Cited By (3)
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CN110669044A (en) * | 2019-09-09 | 2020-01-10 | 中国药科大学 | Donepezil-oxadiazole fusion compound and preparation method and application thereof |
CN113603684A (en) * | 2021-07-14 | 2021-11-05 | 中国药科大学 | 1,2, 4-oxadiazole Nrf2 activator-tacrine split product and preparation method and application thereof |
CN115160300A (en) * | 2022-07-21 | 2022-10-11 | 中国人民解放军北部战区总医院 | Coumarin compound, preparation method thereof and application of coumarin compound in resisting Alzheimer disease |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110669044A (en) * | 2019-09-09 | 2020-01-10 | 中国药科大学 | Donepezil-oxadiazole fusion compound and preparation method and application thereof |
CN110669044B (en) * | 2019-09-09 | 2022-12-06 | 中国药科大学 | Donepezil-oxadiazole fusion compound and preparation method and application thereof |
CN113603684A (en) * | 2021-07-14 | 2021-11-05 | 中国药科大学 | 1,2, 4-oxadiazole Nrf2 activator-tacrine split product and preparation method and application thereof |
CN113603684B (en) * | 2021-07-14 | 2023-12-19 | 中国药科大学 | 1,2, 4-oxadiazole Nrf2 activator-tac Lin Pinge product and preparation method and application thereof |
CN115160300A (en) * | 2022-07-21 | 2022-10-11 | 中国人民解放军北部战区总医院 | Coumarin compound, preparation method thereof and application of coumarin compound in resisting Alzheimer disease |
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