CN108727350A - A kind of piperidines alkylbenzene phthalein compounds, preparation method and use - Google Patents
A kind of piperidines alkylbenzene phthalein compounds, preparation method and use Download PDFInfo
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Abstract
The invention discloses a kind of novel piperidines alkylbenzene phthalein compounds（I）And its pharmaceutically acceptable salt, preparation method, pharmaceutical composition and the purposes in preparing treatment and/or preventing nervus retrogression relevant disease drug, including but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma；
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of novel piperidines alkylbenzene phthalein compounds（I）, its preparation side
Method, pharmaceutical composition and the purposes in preparing treatment and/or preventing nervus retrogression relevant disease drug, including but not limited to
Vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive
The neurodegenerative diseases such as lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Background technology
Alzheimer's disease（Alzheimer ' s disease, AD, senile dementia）Be one kind with progressive cognitive disorder
With the central nervous system degenerative disease based on memory damage, incidence becomes in ascendant trend year by year and is only second to the heart
The frequently-occurring disease of angiosis and cancer, it is the 4th of the cause of death to be had gone up in developed countries such as America and Europes.According to world health
Organisation Report, global over-65s old man have 10% dysnoesia, wherein half to occur dull-witted, fall ill within 85 years old or more
Rate nearly 50%.The AD patient numbers about 600-700 ten thousand in China, incidence are more than 5%.With adding for population in the world aging process
Soon, incidence is in apparent ascendant trend, is announced in December, 2013 according to Alzheimer's Disease International
's《The global implication of Alzheimer's disease：2013-2050》It is pointed out in report, AD will face most as the coming few decades whole world
Big Health challenges, to the year two thousand thirty, patient numbers will rise to 76,000,000 by 44,000,000 in 2013, to the year two thousand fifty, this numerical value
It is up to surprising 1.35 hundred million.Due to AD clinical manifestations be memory capability, capacity of orientation, thinking and judgement decline, and
Activity of daily living reduces, or even abnormal Behavioral and psychological symptom occur etc., keep patient care difficulty larger, to society and family's band
Carry out heavy burden.The drug that approved is used to treat light/moderate AD at present has acetylcholinesterase（AChE）Inhibitor, Yi Jiyong
In severe AD treatmentsNMethyl-DAspartic acid（NMDA）Receptor antagonist.But Clinical practice shows that these drugs can pass through
It improves patient's body levels of acetylcholine or inhibits the exitotoxicity of excitatory amino acid to alleviate AD symptoms, but cannot be effective
Prevent or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, nausea, hepatotoxicity, loss of appetite and
The serious toxic side effect such as stool frequency, thus long-term efficacy is not satisfactory.Therefore, clinically there is an urgent need to research and develop with novel work
With the AD medicines of mechanism.
AD belongs to disease caused by many factors, and pathogenesis is complicated, and pathogenesis does not illustrate also completely so far, but studies
Show patient's intracerebral levels of acetylcholine decline,βThe excessive of amyloid protein generates and the blood platelet in deposition, the cerebrovascular
Aggregation, metal ion metabolic disorder, Ca2+Dysequilibrium,tauNeurofibrillary tangles caused by protein hyperphosphorylation, glutamic acid
Receptor active is excessively high, oxidative stress generates a large amount of active oxygens（ROS）Exist with many factors such as free radical and Neuroinflammations
It plays an important role in the pathogenic process of AD.For above-mentioned pathogenic factors, researcher is set using traditional " one target of a medicine " drug
Stratagem is omited, it was found that largely has high activity and highly selective drug to a certain target spot, such as：Anticholinesterase andNFirst
Base-DAspartate receptor agonist etc..But that there are action target spots is single for these drugs, Clinical practice toxic side effect is more, right
Not the problems such as long-term efficacy of AD patient is not good enough.
In recent years, with constantly illustrating to AD pathogenesis, it is found that the occurrence and development of AD have multimachine system, multifactor
It is the characteristics of effect, again interrelated between different mechanisms to influence each other, constitute complicated network during AD occurrence and development
Regulator control system.Obviously, the medicine that research and development can act on multiple links in AD pathologic processes simultaneously is current inevitable choice.
Based on the above results, researcher proposes " multiple target point targeted drug "（Multitarget-directed Ligands,
MTDLs）Strategy researches and develops anti-neurodegenerative disease drug.So-called " multiple target point drug " refers to single chemical entities while acting on
Multiple target spots in disease network can generate synergistic effect to the effect of each target spot, and gross effect is made the sum of to be answered more than each single-action,
Such medicine is also referred to as " Multifunctional " or " Multipotential " drug.Multiple target point drug and multiple medicine use in conjunction
And the main distinction of compound medicine is：Can reduce dosage, improve therapeutic effect, avoid interaction between drug and
Thus the toxic side effect brought, uniform pharmacokinetic properties, be easy to use etc..Therefore, research and development have new chemical
Structure, novel mechanism of action, and the anti-neurodegenerative disease therapeutic agent with multiple target effect, less toxic side effect not only accords with
The active demand of social senilization's process is closed, and there are good market prospects.It designs and finds that there is inhibition acetyl simultaneously
Cholinesterase, inhibitionβExcessive generation and deposition, anti-oxidation stress, anti-platelet aggregation and the anti-nerve of amyloid protein
The multiple target point AD medicines of inflammatory reaction are still current important research direction.
Invention content
Present invention aims at open a kind of piperidines alkylbenzene phthalein compounds（I）And its pharmaceutically acceptable salt.
Another object of the present invention is to disclose such piperidines alkylbenzene phthalein compounds（I）And its pharmaceutically acceptable salt
Preparation method.
Another object of the present invention is to open comprising such piperidines alkylbenzene phthalein compounds（I）And its it can pharmaceutically connect
The pharmaceutical composition for the salt received.
Still a further object of the present invention is to disclose such piperidines alkylbenzene phthalein compounds（I）And its pharmaceutically acceptable salt
With multiple target effect, the purposes that can be used in the drug of preparation treatment and/or prevention nervus retrogression relevant disease, including but
Be not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis,
The neurodegenerative diseases such as progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Piperidines alkylbenzene phthalein compounds provided by the present invention（I）Chemical structure of general formula be：
In formula：X indicates O, NR6Or S；A1-A2Indicate CH-CH2Or C=CH；Work as A1-A2When indicating C=CH, the compound isZFormula
Configuration,EFormula configuration orZFormula andEThe arbitrary proportion mixture of formula configuration；Work as A1-A2Indicate CH-CH2When, the compound
ForRConfiguration,SConfiguration or raceme；R2And R3Each independently represent H, OH, SH, C1~C12Alkyl, C1~C12Alkoxy, CN, halogen
Element, NR4R5Or C1~C12Alkylthio group；R4And R5Each independently represent H, C1~C12Alkyl；NR4R5Also illustrate that nafoxidine base,
Quinoline base or piperidyl；R2And R3It can be in the arbitrarily possible position of phenyl ring；R1Indicate H, C1~C12Alkyl, benzyl or substituted benzyl；R6
Indicate H, C1~C12Alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl；N indicates 0-12；
Above-mentioned term " halogen " refers to F, Cl, Br or I；" substituted-phenyl " or " substituted benzyl " refers to being selected by 1-4 on phenyl ring
The phenyl or benzyl replaced from the group of the following group：F,Cl,Br,I,C1-4Alkyl, C1-4Alkoxy, NR7R8, trifluoromethyl, trifluoro
Methoxyl group, nitro, amino, carboxyl, hydroxyl, cyano, R7And R8Each independently represent C1~C12Alkyl, NR7R8Also illustrate that tetrahydrochysene
Pyrrole radicals, morpholinyl or piperidyl；These substituent groups can be in the arbitrary possible position of phenyl ring.
Piperidines alkylbenzene phthalein compounds proposed by the invention（I）It can be prepared by the following method to obtain：
With corresponding 3- bromides（1）For starting material, is reacted with triphenylphosphine in appropriate solvent, obtain corresponding 3- triphenyls
Phosphine salt compounds（2）；Gained compound 2 and piperidines -4- alkyl aldehyde compounds（3）It is passed through under appropriate solvent and alkaline condition
Wittig reacts to obtain respective compound（4）'sE/ZConfiguration mixture（NamelyE/ZThe compound I mixtures of configuration）；Compound
（4）Mixture can use conventional method, through silica gel column chromatography separating purification, respectively obtain correspondingEFormula orZFormula configuration chemical combination
Object；Gained compound（4）Mixture can also purify without isolation, directly in appropriate solvent through catalytic hydrogenation by double bond also
Original obtains corresponding piperidines alkylbenzene phthalein compounds（I）Raceme；Using conventional chiral HPLC chromatogram method by corresponding piperidines alkane
Base phthalide analog compound（I）Raceme is detached, you can obtains corresponding optical isomer；Its reaction equation is as follows：
In formula：X,R1、R2、R3Definition with n and piperidines alkylbenzene phthalein compounds（I）Chemical structure of general formula it is identical.
For said synthesis route, specific preparation method is described as follows：
Step A)：3- bromides（1）It is reacted in appropriate solvent with triphenylphosphine, obtains corresponding 3- triphenylphosphines salt compound
（2）；Wherein, reaction solvent for use is：C3-8Aliphatic ketone,N,NDimethylformamide, tetrahydrofuran, 2- methyltetrahydrofurans, second
Acetoacetic ester, ether, benzene, toluene, acetonitrile, 1,4- dioxane, glycol dimethyl ether or C5-8Alkane, preferred solvent are 2- methyl
Tetrahydrofuran, ethyl acetate, acetonitrile, toluene or 1,4- dioxane；3- bromides（1）：The molar feed ratio of triphenylphosphine is
1.0：1.0 ~ 10.0, preferably molar feed ratio is 1.0：1.0~5.0；Reaction temperature be 40 ~ 150 DEG C, preferable reaction temperature be 60 ~
120℃；Reaction time is 1 ~ 120 hour, and preferred reaction time is 2 ~ 72 hours.
Step B)：By step A) obtained 3- triphenylphosphine salt compounds（2）With piperidines -4- alkyl aldehyde compounds
（3）Under appropriate solvent and alkaline condition respective compound is reacted to obtain through Wittig（4）'sE/ZConfiguration mixture；Wherein, it reacts
Solvent for use is：C1-8Fatty alcohol, C3-8Aliphatic ketone, ether, tetrahydrofuran, 2- methyltetrahydrofurans,N,NDimethylformamide,
Dimethyl sulfoxide (DMSO), dichloromethane, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane, preferred solvent are：Chloroform, dichloro
Methane, acetone, acetonitrile, tetrahydrofuran or toluene；Alkali is used in reaction：Alkali metal hydroxide, alkaline earth metal hydroxide, alkali
Metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol has
Machine tertiary amines or quaternary ammonium bases（Such as：Triethylamine, tri-n-butylamine, trioctylamine, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene
Diamines, tetrabutylammonium hydroxide）, preferably alkali is：Potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide；3-
Triphenylphosphine salt compound（2）：Piperidines -4- alkyl aldehyde compounds（3）：The molar feed ratio of alkali is 1.0：1.0~10.0：
1.0 ~ 10.0, preferably molar feed ratio is 1.0：1.0~3.0：1.0~5.0；Reaction temperature is 0 ~ 120 DEG C, and preferable reaction temperature is
Room temperature ~ 100 DEG C；Reaction time is 20 minutes ~ 48 hours, and preferred reaction time is 1 ~ 24 hour.
Step C)：By step B) obtained compound（4）Mixture purifies without isolation, directly through urging in appropriate solvent
Change hydrogenation to restore double bond, obtains corresponding piperidines alkylbenzene phthalein compounds（I）Raceme；Wherein, reaction solvent for use is：
C1-6Fatty alcohol, C3-8Aliphatic ketone, C1-6Aliphatic acid, C1-6Aliphatic acid and C1-6The formed ester of fatty alcohol, ethers（Such as ether, isopropyl
Ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, glycol dimethyl ether etc.）, benzene, toluene or dimethylbenzene, fat
Hydrocarbon（Such as：Hexane, heptane, octane etc.）, preferred solvent is：Tetrahydrofuran, methanol, ethyl alcohol or isopropanol；It is urged used in catalytic hydrogenation
Agent is：Raney Ni,PtO2、1%~30%Pd-C、1%~30% Pd(OH)2- C, preferred catalyst are：Raney Ni,PtO2、5%
~20%Pd-C；Compound（4）Mass ratio with catalyst is 1.0：0.01~1.0；Reaction pressure is the MPa of normal pressure ~ 10.0, preferably
For the MPa of normal pressure ~ 2.0；Reaction temperature is room temperature ~ 150 DEG C, preferably room temperature ~ 80 DEG C；Reaction time is 1 ~ 96 hour, preferably
2 ~ 50 hours.
The piperidines alkylbenzene phthalein compounds of gained according to the method described above（I）Contain amino in molecule, which is in alkalinity,
Its pharmaceutically acceptable salt can be made by pharmaceutically conventional salifying method with any suitable acid, the acid is：
Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid（Such as：Formic acid, acetic acid, propionic acid etc.）, oxalic acid, benzoic acid, bigcatkin willow
Acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Alkyl sulfonic acid（Such as：Pyrovinic acid,
Ethylsulfonic acid etc.）, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
The starting material of the present invention --- 3- bromines close object（1）With piperidines -4- alkyl aldehyde compounds（3）It can be normal with this field
The technology seen is made, including but not limited to the method disclosed in following documents：1,Guidong Z.et al. WO
2011130478A1；2,Sakamoto F. et al.Chem. Pharm. Bull.1983, 31(8), 2698-2707；3,
Chunzhi Z. et al.Chinese Journal of Organic Chemistry2014, 34, 1881-1888；4,
Sugimoto H. et al.US 5100901；5,Mingyu W. et al.European Journal of Medicinal Chemistry2016, 121, 864-879。
Pharmaceutical composition disclosed in this invention includes one or more piperidines alkylbenzene phthaleins chemical combination of therapeutically effective amount
Object（I）Or its pharmaceutically acceptable salt, the pharmaceutical composition can further contain one or more pharmaceutically acceptable loads
Body or excipient." therapeutically effective amount " refers to causing researcher or targeted tissue, system or the biology of animal of doctor
Or the amount of the medical drug reacted or medicament；" composition " refers to by will be made of more than one substances or component mix
Product；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable substance, composition or carrier, such as：Liquid is solid
Body filler, diluent, excipient, solvent or packing substance, they carry or transport certain chemical substance.It is provided by the present invention
Pharmaceutical composition its ideal ratio be piperidines alkylbenzene phthalein compounds（I）Or its pharmaceutically acceptable salt is as work
Property ingredient accounts for total weight than 2%~99.5%.
Piperidines alkylbenzene phthalein compounds disclosed in this invention（I）And its pharmaceutically acceptable salt has carried out as follows
Bioactivity screening.
（1）Piperidines alkylbenzene phthalein compounds（I）To the inhibitory activity of acetylcholinesterase and butyrylcholine esterase
1.0 mmol/L acetylthiocholine iodides or iodine bisulfide are sequentially added into 96 orifice plates for BuCh（It is purchased from
Sigma companies）30 μ L, 40 μ L of PBS buffer solution of pH7.4,20 μ L of testing compound solution（DMSO contents are less than 1%）With 10
μ L acetylcholinesterases（Rat brain cortex 5% is homogenized supernatant, and the phosphate buffer of pH7.4 makees homogenate medium）Or BuCh
Esterase（25% supernatant of rat blood serum, pH7.4 phosphate buffers make homogenate medium）Solution, after finishing mixing, 37 DEG C of incubations
15min is added 0.2% 5,5 '-two thio-bis- (2- nitrobenzoic acids) into each hole（DTNB is purchased from Sigma companies）Solution
30 μ L colour developings, the optical density in each hole at 405nm is measured with microplate reader（OD values）, compared with the blank well for being not added with sample to be tested, meter
Calculate inhibiting rate of the compound to enzyme（Enzyme inhibition rate (%)=(1- sample sets OD values/blank group OD values) × 100%）；Select compound
Five to six concentration, measure its enzyme inhibition rate, and linearly return with the inhibiting rate of the negative logarithm of the compound molar concentration and enzyme
Return, molar concentration when acquiring 50% inhibiting rate is the IC of the compound50.Measurement result shows that institute is public in the embodiment of the present invention
The piperidines alkylbenzene phthalein compounds opened（I）The effect of significantly inhibiting, IC are all had to acetylcholinesterase50It is 1.66 × 10-7
NM ~ 10.0 μM, wherein most strong, the IC of activity for the compound acetylcholine esterase inhibition that number is 1-3-3 in embodiment50For
1.66×10-7nM；Number is 1-4-3 and the IC of the compound acetylcholine esterase inhibition of 4-4-3 in embodiment50Respectively
4.50×10-3NM and 1.46 nM；Further Structure-activity analysis is found, works as A1-A2When indicating C=CH,ZFormula isomers activity
It is better thanEFormula isomers；Work as A1-A2Indicate CH-CH2When, chiral configuration is not notable to the activity influence of acetylcholine esterase inhibition；
Measurement result also shows, piperidines alkylbenzene phthalein compounds（I）The inhibitory activity of acetylcholinesterase is significantly higher than to butyryl
The inhibitory activity of cholinesterase（Selectivity is more than 100 times or more）, illustrate compound disclosed in this invention to acetylcholine ester
Enzyme has selective inhibitory, shows that such compound is smaller to the toxicity of peripheral-system.In addition, measurement result is also shown,
The IC that the Rivastigmine clinically used inhibits AChE50It is 10.5 μM, the IC that butyrylcholine esterase is inhibited50It is 2.6
µM；And control compound as follows（II）（Y in its chemical structural formula indicates O, NH or S respectively）And control compound
（III）The IC that acetylcholinesterase is inhibited50It is all higher than 150 μM；
。
（2）Piperidines alkylbenzene phthalein compounds（I）Antioxidant activity（ORAC-FL methods）
Reference literature（Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331）The side reported
Method is measured, i.e.,：6- hydroxyl -2,5,7,8- tetramethyl primary colours alkane -2- carboxylic acids（Trolox）It is made into the PBS buffer solution of pH7.4
The solution of 10-80 μm of ol/L, fluorescein（fluorescein）The solution of 250 nmol/L is made into the PBS buffer solution of pH7.4,
2,2 '-azo diisobutyl amidine dihydrochlorides（AAPH）Use the preceding solution that 40 mmol/L are made into the PBS buffer solution of pH7.4.
The compound solution and luciferin solution of 50-10 μm of ol/L, mixing are added into 96 orifice plates, 37 °C of incubation 15min are added
AAPH solution, it is 200 μ L to make every hole total volume, and mixing is immediately placed on Varioskan Flash Multimode Reader
In (Thermo Scientific) instrument, 90 min of METHOD FOR CONTINUOUS DETERMINATION under 485 nm excitation wavelengths and 535 nm launch wavelengths.It calculates
Go out area AUC under fluorescence decay curve, wherein with 1-8 μm of ol/L'sTroloxAs standard, to be not added with sample to be tested as blank,
The antioxidant activity results expression of compound isTroloxEquivalent, calculation formula is：[(AUC Sample-AUC
blank)/(AUC Trolox-AUC blank)] ×[(concentration of Trolox/concentration of
Sample)], each compound measures 3 multiple holes every time, and every group of experiment is independent in triplicate.Measurement result shows present invention reality
Apply the piperidines alkylbenzene phthalein compounds disclosed in example（I）Antioxidant activity beTrolox0.2~2.0 times, illustrate this
Class compound has compared with strong anti-oxidative activity.
（3）Piperidines alkylbenzene phthalein compounds（I）To Aβ 1-42The inhibitory activity of self assemble
Reference literature（Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331）The side reported
Method is measured, i.e.,：Pretreated Aβ 1-42It is made into storing solution with DMSO, is diluted to the PBS buffer solution of pH7.4 using preceding
50µM；Untested compound is made into 2.5 mM storing solutions with DMSO, and respective concentration is diluted to the PBS buffer solution of pH7.4 using preceding,
Take the A of 20 μ Lβ 1-42The testing compound solution of+20 μ L of solution, the A of 20 μ Lβ 1-42The PBS buffer solution of+20 μ L of solution（Containing 2%
DMSO）In 96 orifice plates, for 24 hours, the glycine-NaOH that the 50mM that 160 μ L contain 5 μM of thioflavine Ts is then added is slow for 37 °C of incubations
Fliud flushing（pH=8.5）, measured under 446 nm excitation wavelengths and 490 nm launch wavelengths with multi-function microplate reader immediately after shaking 5s
Fluorescent value；Aβ 1-42The fluorescent value of+untested compound is denoted as IFi, Aβ 1-42The fluorescent value of+PBS buffer solution is denoted as IFc, contain only
The fluorescent value of PBS buffer solution is denoted as IF0, compound inhibition Aβ 1-42The inhibiting rate of self assemble is：100-(IFi-IF0)/(IFc-
IF0)*100；Five to six concentration for selecting compound, measure its inhibiting rate；Each each concentration repetition measurement of compound three times, with
Curcumin is positive control.Measurement result shows the piperidines alkylbenzene phthalein compounds disclosed in the embodiment of the present invention（I）It is right
Aβ 1-42Self assemble all has remarkable inhibiting activity, to A under 20.0 μM of concentrationβ 1-42The inhibiting rate of self assemble is 30.0%
Between~55.0%；And clinically widely used anti-AD drugs：Donepezil, Rivastigmine, memantine hydrochloride, Yi Jishang
State control compound（II）（Y in its chemical structural formula indicates O, NH or S respectively）And control compound（III）At 25.0 μM
To A under concentrationβ 1-42The inhibiting rate of self assemble is respectively less than 10%.
（4）Piperidines alkylbenzene phthalein compounds（I）Platelet aggregation inhibitory activity
Male rabbit 3 is taken, with lidocaine local anaesthesia, operation separation arteria carotis communis takes blood, takes 3.8% sodium citrate 1：9
Anti-freezing is centrifuged 10 minutes with 500 r/min, prepares platelet rich plasma（PRP）, remainder again with 3000 r/min centrifuge,
Prepare platelet poor plasma（PPP）, platelet aggregation test is carried out by turbidimetry.Measure the PRP and 30 that 240 μ L are added in pipe
μ L various concentration test medicines, temperature is incubated 5 minutes, respectively with 30 μ L adenosine diphosphate (ADP)s（ADP）（Final concentration of 10 μm of ol/L）, 30
μ L fibrin ferments（Final concentration of 0.5 U/mL）With 30 μ L arachidonic acids（AA）（Final concentration of 1.0 mmol/L）For derivant,
Observe and record maximum aggregation rate in 5 minutes.Use physiological saline（NS）It compares, calculates the inhibiting rate of each test-compound（%）.It surveys
It is fixed the result shows that, the piperidines alkylbenzene phthalein compounds disclosed in the embodiment of the present invention（I）To ADP inductions, thrombin induction
Effect is significantly inhibited with the platelet aggregation of AA inductions, inhibiting rate is all higher than 15.0%.And it is clinically widely used anti-
AD drugs：Donepezil, Rivastigmine, memantine hydrochloride and above-mentioned control compound（II）（In its chemical structural formula
Y indicates O, NH or S respectively）And control compound（III）8.0% is respectively less than to the inhibiting rate of platelet aggregation.
Specific implementation mode
The present invention can be further described by the following examples, however, the scope of the present invention is not limited to
Following embodiments.One of skill in the art, can be right it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
The present invention carries out various change and modification.
Embodiment 1 works as A1-A2When indicating C=CH, piperidines alkylbenzene phthalein compounds（I）Preparation lead to method
By the corresponding 3- bromides of 2.0 mmol（1）, 2.4 mmol triphenylphosphines and 20 ml toluene be added in reaction bulb, heating
Return stirring reacts 12~24.0 hours（Reaction process is tracked with TLC）；After reaction, reaction solution is cooled to room temperature, filtered,
Filter cake is dry successively with toluene and petroleum ether, obtains corresponding 3- triphenylphosphines salt compound（2）, yield 60.0%-
88.0%, chemical constitution passes through1H-NMR is confirmed；
The 3- triphenylphosphine salt compounds that upper step is prepared（2）1.0 mmol, piperidines -4- alkyl aldehyde compounds（3）
1.2 mmol and 30 ml of dichloromethane are added in reaction bulb, are stirring evenly and then adding into 1.2 mmol of triethylamine, are then stirred at room temperature
Reaction 12~24.0 hours（Reaction process is tracked with TLC）；After reaction, it removes solvent under reduced pressure, 30 mL is added in residue
Deionized water adjusts reaction solution pH with 10% aqueous hydrochloric acid solution and adjusts reaction solution to highly acid, then with saturated sodium bicarbonate aqueous solution
PH is extracted to alkalescent with 120 mL dichloromethane in three times, and organic layer is washed after merging with saturated sodium-chloride water solution, through nothing
It is filtered after aqueous sodium persulfate drying, removes solvent under reduced pressure, residue isE/ZConfiguration mixture.By the mixture through silica gel column layer
Analysis purifying（Eluent：Dichloromethane:Methanol=20~60:1 v/v）, you can it obtains correspondingZFormula piperidines alkylbenzene phthaleins
Close object（I）（Yield：15.0%~22.0%）WithEFormula piperidines alkylbenzene phthalein compounds（I）（Yield：10.0%~20.0%）,
Chemical constitution passes through1H-NMR、13C-NMR and ESI-MS confirmations；The purity of gained object is all higher than 97.0% through HPLC measurement.
The object structure being prepared using above-mentioned logical method is as follows：
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Embodiment 2 works as A1-A2Indicate CH-CH2When, piperidines alkylbenzene phthalein compounds（I）Preparation lead to method
It will be according to the preparation-obtained piperidines alkylbenzene phthalein compounds of 1 method of embodiment（I）（I.e.：In chemical structure of general formula
A1-A2Indicate C=CH）'sE/Z1.0 mmol of configuration mixture, 25 ml of ethyl alcohol are added in reaction bulb, after stirring evenly, are added 10%
Pd/C 40mg, after leading to hydrogen displacement three times, logical hydrogen is stirred to react 2.0~24.0 hours under room temperature normal pressure（Reaction process is used
TLC is tracked）, after reaction, remove solvent under reduced pressure, residue is purified through silica gel column chromatography（Eluent：Dichloromethane:Methanol=
20~30:1 v/v）, obtain corresponding piperidines alkylbenzene phthalein compounds（I）（A1-A2Indicate CH-CH2）, yield 65.0%-
95.0%, chemical constitution passes through1H-NMR、13C-NMR and ESI-MS confirmations；The purity of gained object measures big through HPLC
In 97.0%.The object structure being prepared using above-mentioned logical method is as follows：
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3 piperidines alkylbenzene phthalein compounds of embodiment（I）It is prepared at salt with acid and leads to method
It is added in reaction bulb in accordance with the above-mentioned embodiment 1 or the piperidines alkylbenzene phthalein compounds of 2 gained（I）1.0 mmol and third
25 ml of ketone, is stirring evenly and then adding into that 4.0 mmol are sour accordingly, and temperature rising reflux is stirred to react 20 minutes, is cooled down after reaction
To room temperature, solvent is removed under reduced pressure, residue acetone recrystallization filters the solid of precipitation to get piperidines alkylbenzene phthaleins chemical combination
Object（I）Salt, chemical constitution warp1H NMR and ESI-MS confirmations.
Claims (8)
1. a kind of piperidines alkylbenzene phthalein compounds or its pharmaceutically acceptable salt, it is characterised in that the chemistry of such compound
General structure is such as（I）It is shown：
In formula：X indicates O, NR6Or S；A1-A2Indicate CH-CH2Or C=CH；Work as A1-A2When indicating C=CH, the compound isZFormula
Configuration,EFormula configuration orZFormula andEThe arbitrary proportion mixture of formula configuration；Work as A1-A2Indicate CH-CH2When, the compound
ForRConfiguration,SConfiguration or raceme；R2And R3Each independently represent H, OH, SH, C1~C12Alkyl, C1~C12Alkoxy, CN, halogen
Element, NR4R5Or C1~C12Alkylthio group；R4And R5Each independently represent H, C1~C12Alkyl；NR4R5Also illustrate that nafoxidine base,
Quinoline base or piperidyl；R2And R3It can be in the arbitrarily possible position of phenyl ring；R1Indicate H, C1~C12Alkyl, benzyl or substituted benzyl；R6
Indicate H, C1~C12Alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl；N indicates 0-12；Above-mentioned term " halogen " refer to F,
Cl, Br or I；" substituted-phenyl " or " substituted benzyl " refers to the phenyl replaced by 1-4 groups selected from the group below on phenyl ring
Or benzyl：F,Cl,Br,I,C1-4Alkyl, C1-4Alkoxy, NR7R8, trifluoromethyl, trifluoromethoxy, nitro, amino, carboxyl, hydroxyl
Base, cyano, R7And R8Each independently represent C1~C12Alkyl, NR7R8Also illustrate that nafoxidine base, morpholinyl or piperidyl；This
A little substituent groups can be in the arbitrary possible position of phenyl ring.
2. piperidines alkylbenzene phthalein compounds as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that institute
The pharmaceutically acceptable salt stated be such piperidines alkylbenzene phthalein compounds and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,
C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, sulphur are pungent
Acid, C1-6The salt of alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
3. the preparation side of piperidines alkylbenzene phthalein compounds or its pharmaceutically acceptable salt as described in claim any one of 1-2
Method, it is characterised in that the compound can be prepared by the following method to obtain：
In formula：X,R1、R2、R3Definition with n and piperidines alkylbenzene phthalein compounds（I）Chemical structure of general formula it is identical；
Step A)：With corresponding 3- bromides（1）For starting material, reacts, obtain accordingly with triphenylphosphine in appropriate solvent
3- triphenylphosphine salt compounds（2）；
Step B)：By step A) obtained 3- triphenylphosphine salt compounds（2）With piperidines -4- alkyl aldehyde compounds（3）?
Under appropriate solvent and alkaline condition respective compound is reacted to obtain through Wittig（4）'sE/ZConfiguration mixture, the mixture are available normal
Rule method respectively obtains corresponding through silica gel column chromatography separating purificationEFormula orZFormula configuration of compound；
Step C)：By step B) obtained compound（4）'sE/ZConfiguration mixture, directly through catalytic hydrogenation in appropriate solvent
Double bond is restored, corresponding piperidines alkylbenzene phthalein compounds are obtained（I）Raceme；It will be corresponding using conventional chiral HPLC chromatogram method
Piperidines alkylbenzene phthalein compounds（I）Raceme is detached, you can obtains corresponding optical isomer；
Utilize the piperidines alkylbenzene phthalein compounds of above method gained（I）Contain amino in molecule, which, can be in alkalinity
Its pharmaceutically acceptable salt is made by pharmaceutically conventional salifying method in any suitable acid.
4. the preparation method of piperidines alkylbenzene phthalein compounds as claimed in claim 3 or its pharmaceutically acceptable salt, special
Sign is the step A) in, reaction solvent for use is：C3-8Aliphatic ketone,N,NDimethylformamide, tetrahydrofuran, 2- methyl
Tetrahydrofuran, ethyl acetate, ether, benzene, toluene, acetonitrile, 1,4- dioxane, glycol dimethyl ether or C5-8Alkane；3- brominations
Object（1）：The molar feed ratio of triphenylphosphine is 1.0：1.0~10.0；Reaction temperature is 40 ~ 150 DEG C；Reaction time is 1 ~ 120 small
When.
5. the preparation method of piperidines alkylbenzene phthalein compounds as claimed in claim 3 or its pharmaceutically acceptable salt, special
Sign is the step B) in, reaction solvent for use is：C1-8Fatty alcohol, C3-8Aliphatic ketone, ether, tetrahydrofuran, 2- methyl four
Hydrogen furans,N,NDimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane
Hydrocarbon；Alkali is used in reaction：Alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate,
Alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, triethylamine, tri-n-butylamine, trioctylamine, pyridine,N-
Methyl morpholine,NMethyl piperidine, triethylene diamine, tetrabutylammonium hydroxide；3- triphenylphosphine salt compounds（2）：Piperidines -4-
Alkyl aldehyde compound（3）：The molar feed ratio of alkali is 1.0：1.0~10.0：1.0~10.0；Reaction temperature is 0 ~ 120 DEG C；Instead
It is 20 minutes ~ 48 hours between seasonable.
6. the preparation method of piperidines alkylbenzene phthalein compounds as claimed in claim 3 or its pharmaceutically acceptable salt, special
Sign is the step C) in, reaction solvent for use is：C1-6Fatty alcohol, C3-8Aliphatic ketone, C1-6Aliphatic acid, C1-6Aliphatic acid with
C1-6The formed ester of fatty alcohol, ether, isopropyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, glycol dinitrate
Ether, benzene, toluene or dimethylbenzene, hexane, heptane, octane；Catalytic hydrogenation used catalyst is：Raney Ni,PtO2、1%~30%
Pd-C、1%~30% Pd(OH)2-C；Compound（4）Mass ratio with catalyst is 1.0：0.01~1.0；Reaction pressure be normal pressure ~
10.0 MPa；Reaction temperature is room temperature ~ 150 DEG C；Reaction time is 1 ~ 96 hour.
7. a kind of pharmaceutical composition, it is characterised in that comprising such as claim 1-2 any one of them piperidines alkylbenzene phthaleins
Close object or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipient.
8. as prepared by claim 1-2 any one of them piperidines alkylbenzene phthalein compounds or its pharmaceutically acceptable salt
Purposes in treatment and/or prevention nervus retrogression relevant disease drug, this kind of nervus retrogression relevant disease are：Vascular is silly
Slow-witted, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive funiculus lateralis medullae spinalis
Sclerosis, neuropathic pain or glaucoma.
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