CN105777614A - Cyclamine alkylamide ferulate compound as well as preparation method and application thereof - Google Patents
Cyclamine alkylamide ferulate compound as well as preparation method and application thereof Download PDFInfo
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- 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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Abstract
The invention belongs to the technical field of organic synthesis and particularly relates to a cyclamine alkylamide ferulate compound as well as a preparation method and application thereof. The preparation method comprises the following steps: enabling potassium phthalimide serving as a start raw material to react with 1-substituted-4-haloalkyl piperidine under the effects of a solvent and alkali to obtain a phthalimide alkylamine compound; performing hydrazinolysis of the phthalimide alkylamine compound and hydrazine hydrate to obtain a primary amine compound; and adding ferulic acid, a condensing agent and a solvent into the primary amine compound for a condensation reaction to obtain a product of cyclamine alkylamide ferulate compound. The cyclamine alkylamide ferulate compound provided by the invention is of a simple chemical structure, the chemical reactions in the preparation process are thorough, the product yield is high, the operation is convenient, the cost is low, and the product can be used for perfectly treating the neurodegenerative diseases.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of ferulic acid cyclammonium alkylamide compound and
Preparation method and purposes.
Background technology
Vascular dementia (Vascular Dementia, VD) be by ischemic cerebrovascular, hemorrhagic apoplexy,
Facing of the intelligence caused by various types of cerebrovascular disease such as acute and chronic Hypoxic cerebrovascular disease and cognitive dysfunction
Bed syndrome, its main clinical manifestation includes: going down and emotion, personality of cognitive competence, memory and social-life ability
Change, be a kind of chronic progressive disease.It is the first of senile dementia at Asian countries's vascular dementia such as Chinese, Japanese
Position reason；Along with world population is to the continuous propelling of aging, cerebrovascular is increasing, and Onset of Vascular Dementia rate has gradually
The trend risen, has a strong impact on work and the quality of life of old people, and brings heavy economy and spirit to society and family
Burden.Therefore, VD has become current geriatrics and an important study hotspot in psychologic medicine field.Vascular dementia by
Complicated in pathogenesis, there is no the medicine that can block disease development, current clinical treatment is to improve brain blood circulation and brain
Metabolism, it is main for strengthening brain nutrition.
In recent years, research both at home and abroad shows, is also often accompanied by cholinergic while VD patient shows cerebral damage
The exception of system.VD patient's hippocampus ChAT positive neuron and fibre density reduce, in brain under the ChAT activity of different parts
Fall, the ACh concentration in VD Cerebrospinal Fluid in Patients be significantly lower than normal level, and its concentration reduce degree with dementia serious
Degree is proportionate；And acetylcholine esterase active rises in cerebral ischemia can cause brain；Simultaneously it has also been found that acetylcholinesterase
Inhibitor is such as: HuperzineA and Revastigmine can protect the neuronal damage that ischemia causes, and can promote that brain lacks
Nerve injury and the recovery of brain function after blood, this shows that acetylcholinesteraseinhibitors inhibitors can also be used for the treatment of vascular dementia.
Alzheimer's disease (Alzheimer ' s disease, AD) is sickness rate and the highest disease of fatality rate in old people
One of sick.Alzheimer's disease international association (Alzheimer ' s disease International, ADI) issue " 2015
Whole world Alzheimer's disease report " point out, within 2015, dementia is suffered from more than 46,000,000 people in the whole world, it was predicted that to 2050
Year, the whole world will have 1.315 hundred million populations to be perplexed by dementia, and wherein the sickness rate of China Dementia patients has reached 6.61%.
Along with the prolongation of existent age per capita, primary disease has developed into the main burden of society and medical health system, and be society, trouble
Person and family members bring heavy spirit and economic pressures.Thus, research and develop novel senile dementia medicine significant.
From the point of view of the market demand, Alzheimer's disease international association predicts, to the global marketing of the year two thousand fifty curing senile dementia medicine
Volume will reach 600,000,000,000 dollars；In China, along with the rapid rising of senile dementia sickness rate, the market of this kind of medicine is the most swollen
Swollen.
AD be a kind of chronic, with Progressive symmetric erythrokeratodermia memory and Cognitive function damage be characterized multi-pathogenesis, too many levels participate in
Complicated neurodegenerative diseases, its key pathological feature is that beta amyloid peptide (β-amyloid peptide, A β) deposits in a large number
The neurofibrillary tangles that the senile plaque (Senile plaque, SP) of formation, Protein tau Hyperphosphorylationof are formed
(Neurofibrillary tangle, NFT), and with the apoptosis of neuron and the degeneration etc. of nerve synapse.In recent years, many
Researcher is devoted to from molecule and cellular level to disclose the pathogeny of AD, it is proposed that multiple hypothesis, such as: cholinergic neuron
Damage, the deposition of amyloid, Protein tau Hyperphosphorylationof, inflammation, free-radical oxidation, metal ion imbalance etc., therefore,
The novel therapeutic approach developed for these pathogenesis and means, will be hopeful to alleviate and improve the state of an illness of AD patient.Mesh
Before the most effectively treat the drug main of AD and to have two classes: (1) causes cognitive function to lose based on neurotransmitter acetylcholine deficiency
The cholinergic hypothesis adjusted, uses acetylcholinesteraseinhibitors inhibitors to improve levels of acetylcholine in patient's brain, such as: Tacrine,
Donepezil、Ravastigmine、Galantamine；(2) N-methyl-D-aspartate (NMDA) acceptor inhibitor is used to subtract
Few glutamate, Glu damage to neurocyte, such as: Memantine Hydrochloride.But there is action target spot in these medicines
Single, toxic and side effects is more, to the problem such as the long-term efficacy of AD patient is not good enough.
Summary of the invention
For overcoming drawbacks described above, the first object of the present invention is to provide a kind of ferulic acid cyclammonium alkylamide chemical combination
Thing.
The second object of the present invention also reside in the preparation method that a kind of ferulic acid cyclammonium alkylamide compound is provided.
The third object of the present invention also resides in a kind of medicine treating neurodegenerative diseases of offer, is crazy about for vascular
Slow-witted, Alzheimer, Parkinson's disease, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, Progressive symmetric erythrokeratodermia funiculus lateralis medullae spinalis
The neurodegenerative diseases such as sclerosis, neuropathic pain and glaucoma.
For achieving the above object, the present invention adopts the following technical scheme that
A kind of ferulic acid cyclammonium alkylamide compound, its chemical structure of general formula is:
Wherein: m is 1-12, R1Represent H, C1～C12Alkyl, benzyl or substituted benzyl.
Preferably, described substituted benzyl is-F ,-Cl ,-Br ,-I, C1-4Alkoxyl, trifluoromethyl, trifluoromethoxy, nitre
In base and cyano substituent any one, two kinds, three kinds or four kinds of groups are at the nuclear substituted benzyl of benzene.
The preparation method of a kind of ferulic acid cyclammonium alkylamide compound, comprises the following steps:
A. with potassium phthalimide as initiation material, under solvent and alkali effect ,-4-alkylhalide group piperazine is replaced with 1-
Pyridine is reacted, and obtains phthalimide alkyl amine compound；
B. phthalimide alkyl amine compound and hydrazine hydrate obtain primary amine compound by hydrazinolysis；
C. primary amine compound adds ferulic acid, condensing agent, solvent, carries out condensation reaction, obtains product ferulic acid cyclammonium
Alkylamide compound.
Its chemical reaction formula is:
Wherein: m is 1-12, R1Represent H, C1～C12Alkyl, benzyl or substituted benzyl.
Preferably, in described step a, alkali is alkaline earth metal hydroxide, alkali metal hydroxide, alkali carbonate, alkali
Earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, trimethylamine class or season
Amine base class；In described step a, solvent is ether, oxolane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chlorine
Imitative, C3-8Aliphatic ketone, benzene, toluene, acetonitrile and C5-8In alkane one or more.
Preferably, what potassium phthalimide in described step a, 1-replaced-4-alkylhalide group piperidines and alkali mole is
1.0:1.0～5.0:1.0～5.0, reaction temperature is 25～150 DEG C, and the response time is 1～72h.
Preferably, in described step b, solvent is oxolane, DMF, dimethyl sulfoxide, C3-8Fat
Ketone, benzene, toluene, acetonitrile, C1-8Alcohol and C5-8In alkane one or more.
Preferably, in described step b, phthalimide alkyl amine compound, the mol ratio of hydrazine hydrate are 1.0:
1.0～10.0, reaction temperature is 25～150 DEG C, and the response time is 1～72h.
Preferably, in described step c, condensing agent is dicyclohexylcarbodiimide, DMAP, 1-ethyl-(3-
Dimethylaminopropyl) in phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole one or more；In described step c, solvent is
Oxolane, N,N-dimethylformamide, dimethyl sulfoxide, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, dichloromethane, chloroform, C1-8
Alcohol and C5-8In alkane one or more.
Preferably, in described step c, primary amine compound, ferulic acid, the mol ratio of condensing agent are 1.0:1.0～5.0:
1.0～5.0, reaction temperature is 25～100 DEG C, and the response time is 1～72h.
A kind of medicine treating neurodegenerative diseases, by above-mentioned ferulic acid cyclammonium alkylamide compound or by it
With acid synthesis salt and pharmaceutically acceptable carrier be prepared from, described ferulic acid cyclammonium alkylamide compound or
The salt percentage by weight synthesized by itself and acid is 10%～99.5%.
Preferably, described acid is hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid,
Salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, benzenesulfonic acid or to toluene
Sulfonic acid.
Preferably, described carrier is filler, diluent, excipient, solvent and encapsulation material.
The positive beneficial effect of the present invention:
1. the compound of the present invention is respectively provided with, to acetylcholinesterase, the effect of significantly inhibiting, its IC50It is 0.01 μM～5 μMs,
Illustrate that compound disclosed in this invention has certain selective inhibitory to acetylcholinesterase；
The compound of the present invention all has significant protective effect to the PC12 cell injury of hydrogen peroxide-induced, and 10- 5Antioxidant activity under mol/L concentration is all better than ferulic acid；
The compound of the present invention is to A β1-42The gathering of auto-induction is respectively provided with the effect of significantly inhibiting, its IC50Be 0.1 μM～
20μM；
Compound disclosed in this invention causes mice acquisition dysmnesia and has the improvement of dose dependent scopolamine
Effect, compares with model group and is respectively provided with significant difference (p < 0.01)；
Compound disclosed in this invention is respectively provided with, to ethanol induced mice memory representational role obstacle, the effect of being obviously improved,
Significant difference (p < 0.01) is all had compared with model group.
Ferulic acid cyclammonium alkylamide compound chemical constitution the most of the present invention is simple, and the reaction of preparation process chemical reaction is thorough
The end, product yield is high, easy to operate, with low cost, has good therapeutical effect to neurodegenerative diseases.
Detailed description of the invention
Below in conjunction with some detailed description of the invention, the present invention is further described.
A kind of ferulic acid cyclammonium alkylamide compound, its chemical structure of general formula is:
Wherein, in embodiment 1-60, m and R1Substituent group is shown in Table 1 in detail.
The preparation method of the ferulic acid cyclammonium alkylamide compound of above-described embodiment 1, comprises the following steps:
A. in reaction bulb, add 10mmol potassium phthalimide (1), 30mL acetone, 12mmol Anhydrous potassium carbonate
Replace-4-chlorine Alkylpiperidine (2) with 12mmol 1-, be warming up to 60 DEG C of return stirrings and react 20 hours, after reaction terminates, while hot
Filtering, a small amount of washing with acetone filter cake, filtrate decompression is evaporated off solvent, and residue, through column chromatography purification (eluent: chloroform), obtains adjacent benzene
Dicarboximide alkyl amine compound (3), yield is 97.5%；
B. above-mentioned intermediate (3) is all dissolved in 50mL ethanol, adds 30mmolN2H4.H2O, is warming up to 80 DEG C of backflows
Stirring reaction 8 hours, after reaction terminates, sucking filtration while hot, a small amount of washing with alcohol filter cake, filtrate decompression is evaporated off solvent, residue warp
Column chromatography purification (eluent: dichloromethane: methanol=15:1v/v), obtains corresponding alkylamino radical primary amine compound (5), yield
It is 85.7%；
C. above-mentioned intermediate (5) is all dissolved in the oxolane that 30mL is dried, adds 15mmol1-ethyl-(3-bis-
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate EDCI and 15mmol1-hydroxy benzo triazole HOBT, 11mmol ferulic acid
(6), reaction 24 hour is stirred at room temperature；After reaction terminates, remove solvent under reduced pressure, residue adds 70mL dichloromethane, successively
Washing with saturated aqueous sodium carbonate and saturated sodium-chloride water solution, organic layer filters after drying through anhydrous sodium sulfate, and decompression is steamed
Except solvent, residue, through column chromatography purification (eluent: dichloromethane: methanol=10:1v/v), obtains product ferulic acid cyclammonium alkane
Base amides compound (I), yield is 87.8%, the equal warp of its chemical constitution1H-NMR,13C-NMR and ESI-MS confirms.
The preparation method of the ferulic acid cyclammonium alkylamide compound of embodiment of the present invention 2-10 is similar to Example 1,
Same section does not repeats, and difference is shown in Table 2-4.
The preparation method of the ferulic acid cyclammonium alkylamide compound of above-described embodiment 11, comprises the following steps: this
The preparation method of the ferulic acid cyclammonium alkylamide compound of bright embodiment is similar to Example 1, and step a, b are identical, different
Part is that step c, parameter refer to table 4,
C. above-mentioned intermediate (5) is all dissolved in the 1-ethyl-3-methylimidazole ethyl-sulfate salt that 30mL is dried, adds
15mmol1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate EDCI and 15mmol1-hydroxy benzo triazole
HOBT, 12mmol ferulic acid (6), is stirred at room temperature reaction 12 hours；After reaction terminates, residue is water-soluble with saturated sodium carbonate successively
Liquid and saturated sodium-chloride water solution washing, organic layer filters after drying through anhydrous sodium sulfate, and residue is through column chromatography purification (eluting
Liquid: dichloromethane: methanol=10:1v/v), obtain product ferulic acid cyclammonium alkylamide compound (I), yield is
87.8%, the equal warp of its chemical constitution1H-NMR,13C-NMR and ESI-MS confirms.
The preparation method of the ferulic acid cyclammonium alkylamide compound of embodiment of the present invention 12-60 is shown in embodiment 1.
Table 1 embodiment of the present invention 1-60 ferulic acid cyclammonium alkylamide compound
One of table 2 embodiment of the present invention 1-10 ferulic acid cyclammonium alkylamide compound preparation method parameter
The two of table 3 embodiment of the present invention 1-10 ferulic acid cyclammonium alkylamide compound preparation method parameter
The three of table 4 embodiment of the present invention 1-11 ferulic acid cyclammonium alkylamide compound preparation method parameter
Ferulic acid cyclammonium alkylamide compound (I) is prepared with acid synthesis salt
Ferulic acid cyclammonium alkylamide compound (I) according to above-described embodiment 1 preparation is added in reaction bulb
2.0mmol and acetone 50ml, is stirring evenly and then adding into 6.0mmol tartaric acid, and temperature rising reflux stirring reaction 20min, reaction terminates
After be cooled to room temperature, remove solvent under reduced pressure, residue acetone recrystallization, filter the solid separated out, obtain ferulic acid cyclammonium alkane
The salt of base amides compound (I), its chemical constitution warp1HNR and ESI-MS confirms.
One treats neurodegenerative diseases medicine, by above-mentioned ferulic acid cyclammonium alkylamide compound (I) or by
It is prepared from salt and the pharmaceutically acceptable carrier of acid synthesis, described ferulic acid cyclammonium alkylamide compound (I)
Or the salt percentage by weight 95% synthesized with acid by it, described carrier is filler, diluent, excipient, solvent and bag
Capsule material.
Performance test
1. the ferulic acid cyclammonium alkylamide compound that prepared by the present invention is to inhibiting activity of acetylcholinesterase
In 96 orifice plates, it is sequentially added into 1.0mmol/L acetylthiocholine iodide or sulfur (is purchased from Sigma for BuCh
Company) the PBS 40 μ L, testing compound solution 20 μ L (DMSO content be less than 1%) of 30 μ L, pH7.4 and 10 μ L acetyl
Acetylcholine esterase (rat brain cortex 5% is homogenized supernatant, and the phosphate buffer of pH 7.4 makees homogenate medium), after finishing mixing, 37
DEG C hatching 15min, adding mass fraction in each hole is the 5 of 0.2%, and (DTNB purchases 5'-dithio-bis-(2-nitro) benzoic acid
From Sigma company) solution 30 μ L colour developing, measure the optical density (OD value) in each hole at 405nm by microplate reader, and be not added with testing sample
Blank well compare, computerized compound to the suppression ratio of enzyme [enzyme inhibition rate=(1-sample sets OD value/blank group OD value) ×
100%]；Select five to six concentration of compound, measure its enzyme inhibition rate, and with the negative logarithm of this compound molar concentration with
The suppression ratio linear regression of enzyme, molar concentration when trying to achieve 50% suppression ratio is the IC of this compound50。
Measurement result shows, acetylcholinesterase is had and significantly inhibits work by compound disclosed in the embodiment of the present invention
With, its IC50It is 0.01 μM～5 μMs, and replaces benzyl higher than corresponding ferulic acid fatty amine alkylamide compound and ferulic acid
Amine alkylamide compound, and the IC that positive control medicine Rivastigmine is to acetylcholine ester enzyme level50It is 6.3
μM；Measurement result is it is also shown that illustrate that compound disclosed in this invention has certain Selective depression to acetylcholinesterase
Effect.
2. the ferulic acid cyclammonium alkylamide compound that prepared by the present invention is to H2O2The protection of the PC12 cell injury of induction
Effect screening
The PC12 cell DMEM culture fluid containing 10% calf serum, with 1 × 105Individual/mL density is inoculated in 96 holes and cultivates
On plate, inoculation volume is 100mL/ hole, is subsequently placed into containing 5%CO237 DEG C of constant incubators in cultivate.After cultivating 24 hours,
Administration group adds the compound (final concentration of 10 of respective concentration-5Mol/L, 10-6Mol/L) 10mL/ hole, preincubate 2 hours is (right
10 μ L/ hole PBS are added respectively so that it is volume keeps equal) according to group and damage group.After PC12 cell incubation 2 hours, administration group with
Damage group is separately added into 100 μ Μ H2O2Damage agent 10 μ L/ hole (matched group adds 10 μ L/ hole PBS), after 30 minutes, by each group
Culture fluid all changes the RPMI1640 culture fluid without calf serum into be continued to put into constant incubator cultivation 24 hours, cultivates liquid
Long-pending think 100 μ L/ holes.Continuing to cultivate after 24 hours, each group adds 5mg/mL, MTT 100 μ L/ hole, carries out living cells dyeing.Treat
After 3 hours, each group adds 100%DMSO stop buffer 100 μ L/ hole, fully dissolves mixing.Measure each under the wavelength of 490nm
The OD value of group, test result is repeated 3 times, and with Duncan ' s test method statistic, the numeric representation of each group is mean ± S.E.M.,
With matched group for 100%, administration group and damage class value represent with the percentage ratio of matched group.
Measurement result shows, in the embodiment of the present invention, disclosed compound is equal to the PC12 cell injury of hydrogen peroxide-induced
There is significant protective effect, and 10-5Antioxidant activity under mol/L concentration is all better than ferulic acid.
3. the ferulic acid cyclammonium alkylamide compound suppression A β that prepared by the present invention1-42Aggregation activity measures
Take the A β of 20 μ L1-42The testing compound solution of solution+20 μ L, the A β of 20 μ L1-42Solution+20 μ L PBS
(containing 2%DMSO), 20 μ L PBS (containing 2%DMSO)+20 μ L PBS (containing 25%DMSO) are in black 96 orifice plate
In, compound and A β1-42Ultimate density be 25 μMs.Hatch 24h for 37 DEG C, be subsequently adding 160 μ L and contain 5 μMs of thioflavine Ts
The glycine-NaOH buffer (pH=8.5) of 50mM, immediately with Varioskan Flash Multimode after shaking 5s
Reader (Thermo Scientific) multi-functional microplate reader launches mensuration fluorescence under wavelength in 446nm excitation wavelength and 490nm
Value；Aβ1-42The fluorescent value of+testing compound is recorded as IFi, A β1-42The fluorescent value of+PBS is recorded as IFc, comprises only
The fluorescent value of PBS is recorded as IF0, compound suppress A β1-42The suppression ratio computing formula of self assemble is: 100-
(IFi-IF0)/(IFc-IF0)*100.The each concentration of each compound measures two multiple holes.
Measurement result shows, compound disclosed in the embodiment of the present invention is to A β1-42The gathering of auto-induction is respectively provided with
Significantly inhibit effect, its IC50It is 0.1 μM～20 μMs, suppression ratio 60-95%, and positive control medicine curcumin and ferulic acid
The suppression ratio assembled A β 1-42 auto-induction under 25 μMs of concentration is respectively 56.2% and 28.3%.
4. scopolamine induced mice Memory acquisition is hindered by the ferulic acid cyclammonium alkylamide compound that prepared by the present invention
The impact hindered
SPF level ICR male mice, 25-30g, be randomly divided into: normal group, model group, by reagent high and low dose group (5.0,
2.5mg/kg), 10 animals are often organized.Disposable gavage gives test medicine, and blank group and model group give solvent 0.5%CMC-
Na, is administered volume and is 0.1ml/10g；45min after medicine, normal group mouse peritoneal injecting normal saline, remaining each treated animal is equal
Injection scopolamine (5mg/kg), is administered volume and is 0.1ml/10g；After modeling 30min, mice is put into non-electricity irritation Y fan
Palace carries out Behavior test.During test, mice is put in an arm end, allows it freely walk 8min in labyrinth, record it and enter
The number of times of each arm and alternate frequency, calculate alternately rate according to below equation: alternately rate %=[alternate frequency/(always enter number of times-
2)] × 100, result represents with mean ± standard deviation, and group difference uses one factor analysis of variance.
Measurement result shows, under this experiment condition, compound disclosed in this invention causes mice to scopolamine and obtains
Dysmnesia have the improvement result of dose dependent, compare with model group and are respectively provided with significant difference (p < 0.01), and are better than
Corresponding ferulic acid fatty amine alkylamide compound and ferulic acid alpha substituted benzylamine alkylamide compound.
Behavioral experiment is complete takes brain by mice broken end immediately, uses pre-cooling normal saline flushing, is rapidly separated out on ice chest
Cerebral hippocampal tissue, weighs hippocampal tissue weight, adds 9 times of 4 DEG C of normal saline and makes the homogenate of 10%, 3500r/min, and 4 DEG C are centrifuged
15min ,-20 DEG C of storage supernatant are to be measured, measure total protein concentration by Coomassie brilliant blue.The method specified according to test kit exists
Measuring AChE content under the wavelength of 412nm, AChE vigor is expressed as U/mg.The ACh that the vigor of ChAT is catalyzed by ChAT synthesizes
Reaction measures.Operational approach, also according to the explanation of test kit, measures under 412nm wavelength, and the vigor of ChAT U/mg comes
Represent.Measurement result shows, under this experiment condition, compound disclosed in this invention can strengthen acetylcholine transferase
(ChAT) vigor, compares with blank group and is respectively provided with significant difference (p < 0.01), and to be better than corresponding 4-position be free hydroxyl group
Ferulic acid fatty amine alkylamide compound and 4-position be the ferulic acid alpha substituted benzylamine alkylamide chemical combination of free hydroxyl group
Thing.
5. the ferulic acid cyclammonium alkylamide compound that prepared by the present invention is to ethanol induced mice reproducibility dysmnesia
Impact
SPF level ICR male mice, 25-30g, be randomly divided into: normal group, model group, by reagent high and low dose group (5.0,
2.5mg/kg), Rivastigmine group (3mg/kg), often 10 animals of group.Every day, gavage was to test medicine, and blank group and model group are given
Give solvent 0.5%CMC-Na, be administered volume and be 0.1ml/10g, successive administration 32 days；Be administered during 1～24 day, every day medicine
Rear 30min, model group and each administration group gavage 0.1ml/10g ethanol (15%w/v), successive administration 24 days, remove ethanol and enter
The phase cleaned by ethanol, and medicine continues to give；Within 31,32 days, carrying out animal Jumping test in be administered, after medicine, 45min is trained or surveys
Examination experiment, allows mice be placed in diving tower instrument during training, put down gently and be energized on platform, when animal is from platform raises with biped simultaneously
Contact copper grid, for getting an electric shock, are considered as wrong reaction, and the normal avoidance response after mice is shocked by electricity is to escape on platform, records little
Mus escapes the incubation period to platform, and records electric shock number of times in 5min, in this, as school grade.Survey after 24 hours
Examination, record mice jumps off the number of times (errors number) shocked by electricity in the time (incubation period) shocked by electricity and 5min thereof for the first time, with
This is as memory representational role evaluation index.Test result represents with mean ± standard deviation, and group difference uses single factor test variance
Analyze.
Test result shows, under this experiment condition, the memory of ethanol induced mice is reproduced by compound disclosed in this invention
Dysfunction is respectively provided with the effect of being obviously improved, and all has significant difference (p < 0.01) compared with model group, and be better than corresponding Ah
Acid Wei fatty amine alkylamide compound and ferulic acid alpha substituted benzylamine alkylamide compound.
Claims (10)
1. a ferulic acid cyclammonium alkylamide compound, it is characterised in that its chemical structure of general formula is:
Wherein: m is 1-12, R1Represent H, C1～C12Alkyl, benzyl or substituted benzyl.
Ferulic acid cyclammonium alkylamide compound the most according to claim 1, it is characterised in that described substituted benzyl
For-F ,-Cl ,-Br ,-I, C1-4In alkoxyl, trifluoromethyl, trifluoromethoxy, nitro and cyano substituent any one, two
Kind, three kinds or four kinds of groups are at the nuclear substituted benzyl of benzene.
3. a preparation method for the ferulic acid cyclammonium alkylamide compound described in claims 1 or 2, its feature exists
In, comprise the following steps:
A. with potassium phthalimide as initiation material, under solvent and alkali effect ,-4-alkylhalide group piperidines is replaced with 1-anti-
Should, obtain phthalimide alkyl amine compound；
B. phthalimide alkyl amine compound and hydrazine hydrate obtain primary amine compound by hydrazinolysis；
C. primary amine compound adds ferulic acid, condensing agent, solvent, carries out condensation reaction, obtains product ferulic acid cyclammonium alkyl
Amides compound.
The preparation method of ferulic acid cyclammonium alkylamide compound the most according to claim 3, it is characterised in that described
In step a, alkali is alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth gold
Belong to bicarbonate, C1-8The alkali metal salt of alcohol, trimethylamine class or quaternary amine bases；In described step a, solvent is ether, tetrahydrochysene
Furan, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile and C5-8Alkane
In hydrocarbon one or more.
The preparation method of ferulic acid cyclammonium alkylamide compound the most according to claim 3, it is characterised in that described
What potassium phthalimide in step a, 1-replaced-4-alkylhalide group piperidines and alkali mole is 1.0:1.0～5.0:1.0～
5.0, reaction temperature is 25～150 DEG C, and the response time is 1～72h.
The preparation method of ferulic acid cyclammonium alkylamide compound the most according to claim 3, it is characterised in that described
In step b, solvent is oxolane, N,N-dimethylformamide, dimethyl sulfoxide, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8
Alcohol and C5-8In alkane one or more.
The preparation method of ferulic acid cyclammonium alkylamide compound the most according to claim 3, it is characterised in that described
In step b, phthalimide alkyl amine compound, the mol ratio of hydrazine hydrate are 1.0:1.0～10.0, and reaction temperature is
25～150 DEG C, the response time is 1～72 hour.
The preparation method of ferulic acid cyclammonium alkylamide compound the most according to claim 3, it is characterised in that described
In step c, condensing agent is dicyclohexylcarbodiimide, DMAP, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne
In diimmonium salt hydrochlorate and I-hydroxybenzotriazole one or more；In described step c, solvent is oxolane, N, N-dimethyl
Methanamide, dimethyl sulfoxide, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, dichloromethane, chloroform, C1-8Alcohol and C5-8In alkane a kind of or
Several.
The preparation method of ferulic acid cyclammonium alkylamide compound the most according to claim 3, it is characterised in that described
In step c, primary amine compound, ferulic acid, the mol ratio of condensing agent are 1.0:1.0～5.0:1.0～5.0, and reaction temperature is 25
～100 DEG C, the response time is 1～72h.
10. treat a medicine for neurodegenerative diseases, by ferulic acid cyclammonium alkylamide described in claims 1 or 2
Compound or the salt and the pharmaceutically acceptable carrier that are synthesized with acid by it are prepared from；Described ferulic acid cyclammonium alkyl acyl
Aminated compounds or by its with acid synthesis salt percentage by weight be 10%～99.5%, described acid be hydrochloric acid, hydrobromic acid,
Nitric acid, sulphuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lemon
Lemon acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-methyl benzenesulfonic acid, described carrier is filler, diluent, figuration
Agent, solvent and encapsulation material.
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