CN105801448A - 4-amino alkoxy-3-methoxy cinnamic acid benzamide compounds as well as preparation methods and applications thereof - Google Patents

4-amino alkoxy-3-methoxy cinnamic acid benzamide compounds as well as preparation methods and applications thereof Download PDF

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CN105801448A
CN105801448A CN201610203112.6A CN201610203112A CN105801448A CN 105801448 A CN105801448 A CN 105801448A CN 201610203112 A CN201610203112 A CN 201610203112A CN 105801448 A CN105801448 A CN 105801448A
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acid
compound
methoxy cinnamic
cinnamic acid
amine
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CN105801448B (en
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桑志培
柳文敏
于林涛
马勤阁
陈长中
潘万里
李涛
高利敏
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Nanyang Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • 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
    • C07D211/10—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to 4-amino alkoxy-3-methoxy cinnamic acid benzamide compounds as well as preparation methods and applications thereof. The preparation methods of the compounds comprise the following steps: step 1, ferulic acid is taken as a starting material and subjected to a reaction with substituted aniline under the conditions of a first solvent and a condensing agent, and corresponding ferulic acid benzamide compounds are obtained; step 2, the ferulic acid benzamide compounds are subjected to a reaction with a dihalogenated alkyl compound under the condition of a second solvent and a first alkaline condition, and a corresponding halogen compounds are obtained; step 3, the halogen compounds are subjected to a reaction with an organic amine compound under the condition of a third solvent, and the 4-amino alkoxy-3-methoxy cinnamic acid benzamide compounds are obtained. The compounds have a remarkable inhibiting effect on acetylcholinesterase, the IC50 is 0.01 mu M-5 mu M, and the inhibitory activity on acetylcholinesterase is greatly higher than that on butyrylcholinesterase, so that the compounds have certain selective inhibiting effect on acetylcholinesterase.

Description

A kind of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound, preparation method And application thereof
Technical field
The present invention relates to a kind for the treatment of and/or prevention nervus retrogression relevant disease medicine, be specifically related to a kind of 4-amine alkane Epoxide-3-methoxy cinnamic acid benzamides compound, preparation method and its usage.
Background technology
Vascular dementia (Vascular Dementia, VD) is (to be included ischemic brain by various types of cerebrovascular disease Angiopathy, hemorrhagic apoplexy, acute and chronic Hypoxic cerebrovascular disease etc.) caused by intelligence and cognitive dysfunction Clinical syndrome, its main clinical manifestation includes: cognitive competence, memory and social-life ability go down and emotion, The change of personality, is a kind of chronic progressive disease.It is senile dementia at Asian countries's vascular dementia such as Chinese, Japanese First reason；Along with world population is to the continuous propelling of aging, cerebrovascular is increasing, and Onset of Vascular Dementia rate has The trend being gradually increasing, has a strong impact on work and the quality of life of old people, and give society and family bring heavy economy and Mental burden.Therefore, VD has become current geriatrics and an important study hotspot in psychologic medicine field.Vascular is crazy about Staying owing to pathogenesis is complicated, there is no the medicine that can block disease development, current clinical treatment is to improve brain blood circulation With 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.
Therefore, research and development have novel chemical structure, novel mechanism of action, multiaction target spot, low toxic and side effects anti- Neurodegenerative disease therapeutic agent not only conforms with the urgent needs of social senilization's process, and before there is good market Scape.
Summary of the invention
The invention provides a kind of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound, preparation method and Purposes, develop a kind for the treatment of and/or prevention nervus retrogression relevant disease medicine, include but not limited to vascular dementia, Alzheimer, Parkinson's disease, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, Progressive symmetric erythrokeratodermia funiculus lateralis medullae spinalis are hard Change the neurodegenerative diseases such as disease, neuropathic pain, glaucoma.
For solving above-mentioned technical problem, the technical solution used in the present invention is:
A kind of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound, it is characterised in that: the chemistry of this compound General structure is as shown in (I):
In formula: m represents 1-12；
R1Represent H, C1～C12Alkyl；
R2Represent C1～C12Alkyl, benzyl, substituted benzyl；
R1NR2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4-position are by C1～C12Alkyl substituted piperidyl, 4- Piperidyl, piperazinyl that position is replaced by benzyl or substituted benzyl, 4-position is by C1～C12The substituted piperazinyl of alkyl, 4-position quilt Benzyl or the substituted piperazinyl of substituted benzyl；
X represents C1～C12The benzene that the group being selected from lower group by 1-4 on alkyl, benzyl or substituted benzyl, phenyl ring is replaced Base: F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxyl, trifluoromethyl, trifluoromethoxy, nitro, cyano group, substituent group can be at phenyl ring Arbitrarily possible position.
Present invention provides pharmaceutically can connecing of a kind of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound The salt being subject to, described pharmaceutically acceptable salt be 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound with 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, wine Stone acid, citric acid, C1-6The salt that the reaction of alkyl sulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-methyl benzenesulfonic acid is generated.
The preparation method of a kind of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound of the present invention, including such as Lower step:
The first step, with ferulic acid as initiation material, react with substituted aniline under the conditions of the first solvent and condensing agent, obtain Corresponding ferulic acid benzamides compound；
Second step, ferulic acid benzamides compound under the conditions of the second solvent and the first alkalescence with Dihaloalkyl compound Reaction, generates corresponding halogen compound；
3rd step, halogen compound react with organic amine compound at the 3rd solvent, the 4-amine alkoxyl-3-first i.e. obtained Epoxide cinnamic acid benzamides compound, its reaction equation is as follows:
Further, a preferred embodiment of the present invention is: in the described first step: the first solvent is: oxolane, N, N- Dimethylformamide, dimethyl sulfoxide, C3-8Aliphatic ketone, benzene, toluene, acetonitrile or C1-8Alkane, preferred solvent be dichloromethane or Toluene；
Condensing agent is: dicyclohexylcarbodiimide, DMAP, 1-ethyl-(3-dimethylaminopropyl) carbon One or more mixture in acyl diimmonium salt hydrochlorate and I-hydroxybenzotriazole；
Ferulic acid: substituted aniline: the molar feed ratio of condensing agent is that 1.0:1.0～10.0, preferably molar feed ratio are 1.0:1.0～5.0；
Reaction temperature is 25～150 DEG C, and preferable reaction temperature is 25～100 DEG C；
Response time is 1～72 hour, and the preferably response time is 1～24 hour.
Further, a preferred embodiment of the present invention is: in described second step: alkali used by the first alkalescence condition is: alkali Metal or alkaline earth metal carbonate, alkali metal or alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, triethylamine, tri-n-butylamine, Trioctylamine, pyridine, N-methylmorpholine, N-methyl piperidine, triethylene diamine and TBAH one or more than one Mixture, preferably alkali is potassium carbonate, sodium carbonate, triethylamine and the mixture of pyridine one or more than one；
Second solvent is ether, oxolane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C3-8 Aliphatic ketone, benzene, toluene, acetonitrile and C5-8One or more mixture of alkane, preferably reaction dissolvent is dichloromethane, first Benzene, acetonitrile and the mixture of chloroform one or more than one；
Ferulic acid benzamides compound: Dihaloalkyl compound: the molar feed ratio of alkali is 1.0:1.0～10.0:1.0 ～10.0, preferably molar feed ratio is 1.0:1.0～5.0:1.0～5.0；
Reaction temperature is 25～150 DEG C, and preferable reaction temperature is 25～100 DEG C；
Response time is 1～72 hour, and the preferably response time is 1～24 hour.
Further, a preferred embodiment of the present invention is: in the 3rd described step, the 3rd solvent is: ether, oxolane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol and C5-8Alkane The mixture of one or more than one in hydrocarbon, preferred solvent is acetonitrile, DMF or toluene；
Halogen compound: the molar feed ratio of organic amine compound is that 1.0:1.0～10.0, preferably molar feed ratio are 1.0:1.0～5.0；
Reaction temperature is 25～150 DEG C, and preferable reaction temperature is 25～100 DEG C；
Response time is 1～72 hour, and the preferably response time is 1～24 hour.
The system of the pharmaceutically acceptable salt of the 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound of the present invention Preparation Method, comprises the following steps:
4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound and acetone are stirring evenly and then adding into acid, heat up back Stream stirring reaction 15-30 minute, reaction is cooled to room temperature after terminating, and removes solvent, residue acetone recrystallization under reduced pressure, filters The solid separated out, obtains the pharmaceutically acceptable salt of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound.
The pharmaceutically acceptable salt of the 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound of the present invention is used for Purposes in the medicine of preparation treatment and/or prevention nervus retrogression relevant disease.
Further, a preferred embodiment of the present invention: 4-amine alkoxyl-3-methoxy cinnamic acid benzoyl in described medicine Aminated compounds accounts for gross weight ratio 10%～99.5%.
Invention also discloses a kind of pharmaceutical composition and include one or more 4-amine alkoxyl-3-first of therapeutically effective amount Epoxide cinnamic acid benzamides compound or its pharmaceutically acceptable salt, this pharmaceutical composition can contain a kind of or many further Plant pharmaceutically acceptable carrier or excipient.Described " therapeutically effective amount " refers to cause researcher or the targeted group of doctor Knit, system or the biology of animal or the medicine of medicine reaction or the amount of medicament；Described " compositions " refers to by by more than one The product that material or component mix；Described " pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, combination Thing or carrier, such as: liquid or solid filler, diluent, excipient, solvent or encapsulation material, they carry or transport certain Chemical substance.Its preferable ratio of pharmaceutical composition provided by the present invention is, 4-amine alkoxyl-3-methoxy cinnamic acid benzoyl Aminated compounds or its pharmaceutically acceptable salt account for gross weight ratio 10%～99.5% as active component, and remainder is for accounting for Gross weight ratio less than 90%.
The initiation material potassium phthalimide of the present invention, secondary-amine compound can use the technical value that this area is common , the method including, but not limited to disclosed in documents below: Sang, Z.et.al.Eur.J.Med.Chem., 2015,94, 348-366.Liu Q.et.al.Bioorg.Med.Chem.,2015,23,911-923。
4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound (I) molecule according to above-mentioned preparation method gained In containing amino, this amino is alkalescence, can prepare its materia medica with any suitable acid by the salifying method of pharmaceutically routine Upper acceptable salt.
Beneficial effects of the present invention:
The compound of the present invention is respectively provided with, to acetylcholinesterase, the effect of significantly inhibiting, and its IC50 is 0.01 μM～5 μMs, right The inhibitory activity of acetylcholinesterase is much higher than the inhibitory activity to butyrylcholine esterase, and chemical combination disclosed in this invention is described Thing 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.
Detailed description of the invention
Below in conjunction with the specific embodiment of the invention, technical scheme is clearly and completely described, aobvious So, described embodiment is only a part of embodiment of the present invention rather than whole embodiments.Based on the reality in the present invention Execute example, the every other embodiment that those of ordinary skill in the art are obtained under not making creative work premise, all belong to In the scope of protection of the invention.
Embodiment 1-15
The preparation method of a kind of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound, comprises the following steps:
The first step, addition ferulic acid, the first solvent, condensing agent and aniline, stirring reaction in reaction bulb, reaction process is used TLC follows the tracks of；After reaction terminates, remove solvent under reduced pressure, residue add dichloromethane, successively with saturated aqueous sodium carbonate and Saturated sodium-chloride water solution washs, and organic layer filters after drying through anhydrous sodium sulfate, removes solvent under reduced pressure, and residue is through column chromatography Purification (eluent: dichloromethane: methanol=30:1v/v), obtains corresponding ferulic acid benzamides compound；
Second step, above-mentioned ferulic acid benzamides compound is dissolved in the second solvent, adds used by the first alkalescence condition Alkali and Bromofume, temperature rising reflux stirs reaction, and reaction process TLC follows the tracks of, and after reaction terminates, pressure is evaporated off solvent and excess Bromofume, residue, through column chromatography purification (eluent: chloroform), obtains bromide intermediate
3rd step, bromide intermediate is dissolved in the 3rd solvent, there was added addition benzyimethylamine, be warming up to backflow and stir Mixing reaction, reaction process TLC follows the tracks of；After reaction terminates, remove solvent under reduced pressure, residue adds dichloromethane, uses successively 5% sodium hydrate aqueous solution and deionized water wash, organic layer filters after drying through anhydrous sodium sulfate, removes solvent under reduced pressure, residual Excess, through column chromatography purification (eluent: dichloromethane: methanol=15:1v/v), obtains corresponding 4-amine alkoxyl-3-methoxyl group meat Cinnamic acid benzamides compound, the equal warp of its chemical constitution1H-NMR,13C-NMR and ESI-MS confirms.
The concrete technology condition of embodiment 1-15 is shown in Table 1-3.
Table 1 first step process conditions and result
Process conditions have serious impact to the yield of product as shown in Table 1, select suitable process conditions to product Yield has the important meaning.First solvent employing dichloromethane as shown in Table 1: volume ratio 2:1 of toluene, dicyclohexyl carbon two Imines: DMAP is 2:1, molar feed ratio is 1:3, and reaction temperature is 70 DEG C, under conditions of the response time is 6h, Yield is preferable, is 83.8%.When the first solvent uses dichloromethane: volume ratio 2:1 of toluene, condensing agent uses dicyclohexyl carbon Diimine: DMAP: zinc chloride is 2:1:0.05, molar feed ratio is 1:3, and reaction temperature is 70 DEG C, during reaction Between be 6h under conditions of, yield is the highest, is 87.8%.
Table 2 second step process conditions and result
Process conditions have serious impact to the yield of product as shown in Table 2, select suitable process conditions to product Yield has important impact.Second solvent employing dichloromethane as shown in Table 2: toluene: chloroform=2:1:2, the first alkalescence bar Alkali used by part is potassium carbonate: triethylamine: pyridine is 2:1:1, and molar feed ratio is 1:3:2, and reaction temperature is 70 DEG C, during reaction Between be 6h under conditions of, yield is 95.3%, and yield is the highest, and change an any of the above described condition all can to yield produce huge Big impact.
Table 3 three step process condition and result
Process conditions have serious impact to the yield of product as shown in Table 3, select suitable process conditions to product Yield has important impact.4th solvent uses dichloromethane as shown in Table 3: toluene is 2:1, and molar feed ratio is 1:3, instead Answering temperature is 70 DEG C, and under conditions of the response time is 12h, yield is 97.8%, and yield is the highest, and changes any of the above described one Yield all can be had an immense impact on by condition.
Embodiment 16
Concrete technology condition is same as in Example 7, difference again with investigate different substituents, concrete substituent group is shown in Table 4, Gained 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound, the equal warp of its chemical constitution1H-NMR,13C-NMR and ESI-MS confirms.
Table 4 different substituents is tested
Embodiment 17
A kind of preparation side of the pharmaceutically acceptable salt of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound Method, comprises the following steps:
Take the 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound in table 4 respectively and after acetone stirs Adding corresponding acid, temperature rising reflux stirring reaction 15-30 minute, reaction is cooled to room temperature after terminating, and removes solvent under reduced pressure, remaining Thing acetone recrystallization, filters the solid separated out, obtains the medicine of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound Acceptable salt on, its chemical constitution warp1HNR、13CNMR and ESI-MS confirms.
Embodiment 18
The product prepared by embodiment 7 is used to carry out bioactivity screening experiment
(1) acetylcholinesterase and butyrylcholine esterase inhibitory activity
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, Compound disclosed in the embodiment of the present invention is respectively provided with, to acetylcholinesterase, the effect of significantly inhibiting, its IC50It it is 0.01 μM～5 μM, and the IC that positive control medicine Rivastigmine is to acetylcholine ester enzyme level50It it is 6.3 μMs；Measurement result also table Bright, the inhibitory activity of acetylcholinesterase is much higher than butyrylcholine esterase by compound disclosed in this project implementation example Inhibitory activity, illustrate that compound disclosed in this invention has certain selective inhibitory to acetylcholinesterase.
(2) compound is to H2O2The protective effect screening of the PC12 cell injury of induction
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.After continuing to cultivate 24 hours, respectively group addition 5mg/mL, MTT100 μ L/ hole, carries out living cells dyeing.Treat 3 After hour, each group adds 100%DMSO stop buffer 100 μ L/ hole, fully dissolves mixing.Each group is measured under the wavelength of 490nm OD value, 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 is 100%, and administration group and damage class value represent with the percentage ratio of matched group.Measurement result shows, the embodiment of the present invention In disclosed compound the PC12 cell injury of hydrogen peroxide-induced is all had significant protective effect, and 10-5Mol/L concentration Under antioxidant activity be all better than ferulic acid.
(3) compound suppression A beta peptide aggregation determination of activity
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, comprise 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, the present invention is real Execute compound disclosed in example to A β1-42The gathering of auto-induction is respectively provided with the effect of significantly inhibiting, its IC50It it is 0.1 μM～20 μ M, suppression ratio 65-90%, and positive control medicine curcumin and ferulic acid under 25 μMs of concentration to A β1-42Auto-induction gathers The suppression ratio of collection is respectively 56.2% and 28.3%.
(4) blood brain barrier passes through merit rating (PAMPA-BBB)
Medulla sus domestica phospholipid (PBL, purchased from Avanti Polar Lipids, Inc.) is dissolved in (20mg/ in dodecane (Sigma) ML), 4 μ L droppings are taken on the lipotropy filter membrane of receptor hole with Biomimetic membrane.350 μ L PBS/EtOH are added in receptor hole (70:30) buffer, for body opening adds 200 μ L sample liquid (compound dissolution obtains 5mg/mL storing solution in DMSO, then Being diluted to ultimate density with 50 times of PBS/EtOH (70:30) buffer is 100mg/mL.Place 96 hole filter plates and receive plate in PVDF (Millipore), on, make immobilized artificial membrane can just touch for body fluid, be thusly-formed the confession that sandwich structure-bottom is determinand Body fluid, centre is artificial phospholipid's film, and drug molecule to be measured spreads from for body opening, through immobilized artificial membrane, enters into upper strata receptor hole In.25 DEG C of static 18h, after hatching, remove donor plate gently, draw respectively by body fluid with for body fluid, use Varioskan Flash Multimode Reader microplate reader measures concentration, each sample four hole, independent test three times, tests 10 wavelength (250-450nm) the OD value under, draws effective transmissivity (P according to formulae).PAMPA effective permeability Pe(cm·s-1) calculate As follows:
Pe=-VdVa/[(Vd+Va)At]ln(1-drugacceptor/drugequilibrium)
Wherein, VdIt is the volume for body opening, VaBeing the volume of receptor hole, A is the area of artificial phospholipid's film, when t represents infiltration Between, drug acceptor is the absorbance for body opening liquid, and drug equilibrium is Theoretical Equilibrium absorbance, result with Mean value ± standard error (Stand error, S.E.) represents.Test result shows, presently disclosed under this experiment condition Compound be respectively provided with good blood brain barrier through ability, and be better than ferulic acid.
(5) compound impact on scopolamine induced mice memory acquisition disturbance
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, at this Under experiment condition, compound disclosed in this invention has dose dependent to scopolamine cause mice acquisition dysmnesia and changes Kind effect, compares with model group and is respectively provided with significant difference (p < 0.01).
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-1, 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).
(6) compound impact on ethanol induced mice reproducibility dysmnesia
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, compound disclosed in this invention reproduces merit to the memory of ethanol induced mice The effect of being obviously improved can be respectively provided with by obstacle, all have significant difference (p < 0.01) compared with model group.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention Within god and principle, any modification, equivalent substitution and improvement etc. made, should be included within the scope of the present invention.

Claims (9)

1. a 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound, it is characterised in that: the chemistry knot of this compound Structure formula is as shown in (I):
In formula: m represents 1-12；
R1Represent H, C1～C12Alkyl；
R2Represent C1～C12Alkyl, benzyl, substituted benzyl；
R1NR2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4-position are by C1～C12The substituted piperidyl of alkyl, 4-position quilt Benzyl or the substituted piperidyl of substituted benzyl, piperazinyl, 4-position are by C1～C12The substituted piperazinyl of alkyl, 4-position are by benzyl Or the substituted piperazinyl of substituted benzyl；
X represents C1～C12The phenyl that the group being selected from lower group by 1-4 on alkyl, benzyl or substituted benzyl, phenyl ring is replaced: F, Cl、Br、I、C1-4Alkyl, C1-4Alkoxyl, trifluoromethyl, trifluoromethoxy, nitro, cyano group, substituent group can any at phenyl ring Possible position.
2. pharmaceutically may be used of a 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound as claimed in claim 1 The salt accepted, it is characterised in that: described pharmaceutically acceptable salt is 4-amine alkoxyl-3-methoxy cinnamic acid benzamides Compound and hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, rich horse Acid, succinic acid, tartaric acid, citric acid, C1-6The reaction of alkyl sulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-methyl benzenesulfonic acid is generated Salt.
3. a preparation method for 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound as claimed in claim 1, It is characterized in that: comprise the steps:
The first step, with ferulic acid as initiation material, react with substituted aniline under the conditions of the first solvent and condensing agent, obtain corresponding Ferulic acid benzamides compound；
Second step, ferulic acid benzamides compound are anti-with Dihaloalkyl compound under the conditions of the second solvent and the first alkalescence Should, generate corresponding halogen compound；
3rd step, halogen compound react with organic amine compound at the 3rd solvent, the 4-amine alkoxyl-3-methoxyl group i.e. obtained Cinnamic acid benzamides compound.
4. a preparation method for 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound as claimed in claim 3, It is characterized in that: in the described first step: the first solvent is: oxolane, N,N-dimethylformamide, dimethyl sulfoxide, C3-8 Aliphatic ketone, benzene, toluene, acetonitrile or C1-8Alkane, preferred solvent is dichloromethane or toluene；
Condensing agent is: dicyclohexylcarbodiimide, DMAP, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne two One or more mixture in inferior amine salt hydrochlorate and I-hydroxybenzotriazole；
Ferulic acid: substituted aniline: the molar feed ratio of condensing agent be 1.0:1.0～10.0, preferably molar feed ratio be 1.0:1.0 ～5.0；
Reaction temperature is 25～150 DEG C, and preferable reaction temperature is 25～100 DEG C；
Response time is 1～72 hour, and the preferably response time is 1～24 hour.
The preparation method of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound the most according to claim 3, its Be characterised by: in described second step: alkali used by the first alkalescence condition is: alkali metal or alkaline earth metal carbonate, alkali metal or Alkali metal bicarbonates, the alkali metal salt of C1-8 alcohol, triethylamine, tri-n-butylamine, trioctylamine, pyridine, N-methylmorpholine, N-methyl Piperidines, triethylene diamine and the mixture of TBAH one or more than one, preferably alkali are potassium carbonate, carbonic acid Sodium, triethylamine and the mixture of pyridine one or more than one；
Second solvent is ether, oxolane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C3-8 fat One or more mixture of fat ketone, benzene, toluene, acetonitrile and C5-8 alkane, preferably reaction dissolvent is dichloromethane, first Benzene, acetonitrile and the mixture of chloroform one or more than one；
Ferulic acid benzamides compound: Dihaloalkyl compound: the molar feed ratio of alkali be 1.0:1.0～10.0:1.0～ 10.0, preferably molar feed ratio is 1.0:1.0～5.0:1.0～5.0；
Reaction temperature is 25～150 DEG C, and preferable reaction temperature is 25～100 DEG C；
Response time is 1～72 hour, and the preferably response time is 1～24 hour.
The preparation method of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound the most according to claim 3, its Be characterised by: in described second step, the 3rd solvent is: ether, oxolane, N,N-dimethylformamide, dimethyl sulfoxide, Dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol and C5-8The mixing of one or more than one in alkane Thing, preferred solvent is acetonitrile, DMF or toluene；
Halogen compound: the molar feed ratio of organic amine compound be 1.0:1.0～10.0, preferably molar feed ratio be 1.0: 1.0～5.0；
Reaction temperature is 25～150 DEG C, and preferable reaction temperature is 25～100 DEG C；
Response time is 1～72 hour, and the preferably response time is 1～24 hour.
7. pharmaceutically may be used of a 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound as claimed in claim 2 The preparation method of the salt accepted, it is characterised in that comprise the following steps:
4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound and acetone are stirring evenly and then adding into acid, and temperature rising reflux stirs Mixing reaction 15-30 minute, reaction is cooled to room temperature after terminating, and removes solvent, residue acetone recrystallization under reduced pressure, filters and separate out Solid, obtain the pharmaceutically acceptable salt of 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound.
8. the 4-amine alkoxyl-3-methoxy cinnamic acid benzamides compound prepared by claim 7 is pharmaceutically acceptable Salt for prepare treatment and/or prevention nervus retrogression relevant disease medicine in purposes.
Purposes the most according to claim 8, it is characterised in that: described 4-amine alkoxyl-3-methoxy cinnamic acid benzoyl The pharmaceutically acceptable salt of aminated compounds accounts for gross weight ratio 10%～99.5% in medicine.
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