CN105801448B - A kind of methoxy cinnamic acid benzamides compound of 4 amine alkoxy 3, preparation method and its usage - Google Patents

A kind of methoxy cinnamic acid benzamides compound of 4 amine alkoxy 3, preparation method and its usage Download PDF

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CN105801448B
CN105801448B CN201610203112.6A CN201610203112A CN105801448B CN 105801448 B CN105801448 B CN 105801448B CN 201610203112 A CN201610203112 A CN 201610203112A CN 105801448 B CN105801448 B CN 105801448B
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acid
compound
methoxy cinnamic
amine
cinnamic acid
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CN105801448A (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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of methoxy cinnamic acid benzamides compound of 4 amine alkoxy 3, preparation method and its usage, its preparation method comprises the following steps：The first step, using forulic acid as initiation material, under the conditions of the first solvent and condensing agent with substituted aniline react, obtain corresponding forulic acid benzamides compound；Second step, forulic acid benzamides compound are reacted under the second solvent and the first alkalescence condition with Dihaloalkyl compound, generate corresponding halogen compound；3rd step, halogen compound react in the 3rd solvent and organic amine compound, that is, the methoxy cinnamic acid benzamides compound of 4 amine alkoxy 3 obtained.The compound of the present invention is respectively provided with the effect of significantly inhibiting to acetylcholinesterase, its IC50For 0.01 μM~5 μM, the inhibitory activity to butyrylcholine esterase is much higher than to the inhibitory activity of acetylcholinesterase, illustrates that compound disclosed in this invention has certain selective inhibitory to acetylcholinesterase.

Description

A kind of 4- amine alkoxy -3- methoxy cinnamic acid benzamideses compound, preparation method And application thereof
Technical field
The present invention relates to one kind treatment and/or prevention nervus retrogression relevant disease medicine, and in particular to a kind of 4- amine alkane Epoxide -3- methoxy cinnamic acid benzamideses compound, preparation method and its usage.
Background technology
Vascular dementia (Vascular Dementia, VD) is by various types of cranial vascular diseases (including ischemic brain Angiosis, hemorrhagic cerebrovaseular disease, acute and chronic Hypoxic cranial vascular disease etc.) caused by intelligence and cognition dysfunction Clinical syndrome, its main clinical manifestation includes：Cognitive ability, the decline of memory and social-life ability and emotion, The change of personality, it is a kind of chronic progressive disease.In the Asian countries such as China, Japan, vascular dementia is senile dementia First reason；As world population is to the continuous propulsion of aging, cerebrovascular disease 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 the elderly, and to society and family bring heavy economy and Mental burden.Therefore, VD turns into current gerontology and an important study hotspot in psychologic medicine field.Vascular is crazy about Stay because pathogenesis is complicated, there is no the medicine that disease can be blocked to develop, clinical treatment is circulated with improving brain blood at present It is metabolized, strengthens based on brain nutrition with brain.
In recent years, research shows both at home and abroad, and cholinergic is also often accompanied by while VD patient shows cerebral damage The exception of system.VD patient's hippocampus ChAT positive neurons and fibre density reduce, under the ChAT activity of intracerebral different parts Drop, the ACh concentration in VD Cerebrospinal Fluid in Patients be significantly lower than normal level, and the degree that reduces of its concentration with it is dull-witted serious Degree is proportionate；And cerebral ischemia can cause intracerebral acetylcholine esterase active to rise；Simultaneously it has also been found that acetylcholinesterase Inhibitor is such as：HuperzineA and Revastigmine can protect neure damage caused by ischemic, and brain can be promoted to lack Neurotrosis 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 the incidence of disease and fatal rate highest disease in the elderly One of disease.Alzheimer's disease international association (Alzheimer ' s disease International, ADI) issue《2015 Global Alzheimer's disease report》Point out, the whole world has had more than 46,000,000 people and suffers from dementia within 2015, it was predicted that to 2050 Year, the whole world will have 1.315 hundred million populations to be perplexed by dementia, wherein the incidence of disease of Chinese Dementia patients has reached 6.61%. With the extension of existent age per capita, this disease has developed into the main burden of society and medical health system, and for society, suffer from Person and family members bring heavy spirit and economic pressures.Thus, it is significant to research and develop new senile dementia medicine. From the point of view of the market demand, Alzheimer's disease international association prediction, to the global marketing of the year two thousand fifty curing senile dementia medicine Volume will be up to 600,000,000,000 dollars；In China, with the rapid rising of the senile dementia incidence of disease, the market of this kind of medicine is also quick swollen It is swollen.
AD is a kind of chronic, characterized by progressive memory and Cognitive function damage multi-pathogenesis, too many levels participates in Complicated nerve degenerative diseases, its key pathological feature are that beta amyloid peptide (β-amyloid peptide, A β) largely deposits The neurofibrillary tangles that senile plaque expelling (Senile plaque, SP), the Protein tau Hyperphosphorylationof of formation are formed (Neurofibrillary tangle, NFT), and degeneration of apoptosis and nerve synapse with neuron etc..In recent years, it is many Researcher is directed to disclosing AD pathogenesis from molecule and cellular level, it is proposed that a variety of hypothesis, such as：Cholinergic neuron Damage, the imbalance of the deposition of amyloid, Protein tau Hyperphosphorylationof, inflammation, free-radical oxidation, metal ion etc., therefore, For these pathogenesis come the novel therapeutic approach and means that develop, it will be hopeful to alleviate and improve AD patient the state of an illness.Mesh Preceding clinically effective treatment AD medicine mainly has two classes：(1) cognitive function is caused to lose based on neurotransmitter acetylcholine deficiency The cholinergic hypothesis of tune, patient's intracerebral levels of acetylcholine is improved using acetylcholinesteraseinhibitors inhibitors, such as：Tacrine、 Donepezil、Ravastigmine、Galantamine；(2) subtracted using N-methyl-D-aspartate (NMDA) acceptor inhibitor Few damage of the glutamate to nerve cell, such as：Memantine Hydrochloride.But there is action target spot in these medicines Single, the problems such as toxic side effect is more, not good enough to the long-term efficacy of AD patient.
Therefore, research and development with novel chemical structure, new mechanism of action, multiaction target spot, less toxic side effect it is anti- Neurodegenerative disease therapeutic agent not only conforms with the active demand of social senilization's process, and with before good market Scape.
The content of the invention
The invention provides a kind of 4- amine alkoxy -3- methoxy cinnamic acid benzamideses compound, preparation method and its Purposes, develop it is a kind of treat and/or prevention nervus retrogression relevant disease medicine, including but not limited to vascular dementia, Alzheimer's, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive funiculus lateralis medullae spinalis are hard Change the nerve degenerative diseases such as disease, neuropathic pain, glaucoma.
In order to solve the above technical problems, the technical solution adopted by the present invention is：
A kind of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds, it is characterised in that：The chemistry of the compound General structure is such 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- positions by C1~C12Piperidyl that alkyl is substituted, 4- Piperidyl that position is substituted by benzyl or substituted benzyl, piperazinyl, 4- positions are by C1~C12Piperazinyl that alkyl is substituted, 4- positions quilt The piperazinyl that benzyl or substituted benzyl are substituted；
X represents C1~C12The benzene substituted on alkyl, benzyl or substituted benzyl, phenyl ring by the 1-4 groups being selected from the group Base：F、Cl、Br、I、C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano group, substituent can be in phenyl ring Any possible position.
Present invention provides a kind of can pharmaceutically connecing for 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds The salt received, described pharmaceutically acceptable salt be 4- amine alkoxy -3- methoxy cinnamic acid benzamides 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, butanedioic acid, wine Stone acid, citric acid, C1-6The salt that the reaction of alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid is generated.
A kind of preparation method of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds of the present invention, including such as Lower step：
The first step, using forulic acid as initiation material, under the conditions of the first solvent and condensing agent with substituted aniline react, obtain Corresponding forulic acid benzamides compound；
Second step, forulic acid benzamides compound under the second solvent and the first alkalescence condition with Dihaloalkyl compound Reaction, generates corresponding halogen compound；
3rd step, halogen compound react in the 3rd solvent and organic amine compound, that is, the 4- amine alkoxy -3- first obtained Epoxide cinnamic acid benzamides compound, its reaction equation are as follows：
Further, a preferred embodiment of the present invention is：In the described first step：First solvent is：Tetrahydrofuran, N, N- Dimethylformamide, dimethyl sulfoxide (DMSO), C3-8Aliphatic ketone, benzene, toluene, acetonitrile or C1-8Alkane, preferred solvent be dichloromethane or Toluene；
Condensing agent is：Dicyclohexylcarbodiimide, DMAP, 1- ethyls-(3- dimethylaminopropyls) carbon One or more kinds of mixtures in acyl diimmonium salt hydrochlorate and I-hydroxybenzotriazole；
Forulic acid：Substituted aniline：The molar feed ratio of condensing agent is 1.0：1.0~10.0, preferably molar feed ratio is 1.0：1.0~5.0；
Reaction temperature is 25~150 DEG C, and preferable reaction temperature is 25~100 DEG C；
Reaction time is 1~72 hour, and preferred reaction time is 1~24 hour.
Further, a preferred embodiment of the present invention is：In described second step：Alkali used in 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, One or more than one kinds of trioctylamine, pyridine, N-methylmorpholine, N- methyl piperidines, triethylene diamine and TBAH Mixture, preferably alkali be potassium carbonate, sodium carbonate, triethylamine and pyridine one or more than one kinds of mixture；
Second solvent is ether, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, C3-8 Aliphatic ketone, benzene, toluene, acetonitrile and C5-8The one or more kinds of mixture of alkane, preferably reaction dissolvent are dichloromethane, first Mixture one or more than one kinds of benzene, acetonitrile and chloroform；
Forulic 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；
Reaction time is 1~72 hour, and preferred reaction time is 1~24 hour.
Further, a preferred embodiment of the present invention is：The 3rd solvent is in the 3rd described step：Ether, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol and C5-8Alkane One or more than one kinds of mixture in hydrocarbon, preferred solvent is acetonitrile, DMF or toluene；
Halogen compound：The molar feed ratio of organic amine compound is 1.0：1.0~10.0, preferably molar feed ratio is 1.0：1.0~5.0；
Reaction temperature is 25~150 DEG C, and preferable reaction temperature is 25~100 DEG C；
Reaction time is 1~72 hour, and preferred reaction time is 1~24 hour.
The system of the pharmaceutically acceptable salt of the 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds of the present invention Preparation Method, comprise the following steps：
4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds and acetone are stirring evenly and then adding into acid, heat up back Flow stirring reaction 15-30 minutes, reaction is cooled to room temperature after terminating, and removes solvent, residue acetone recrystallization, filtering under reduced pressure The solid of precipitation, produce the pharmaceutically acceptable salt of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds.
The pharmaceutically acceptable salt of the 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds of the present invention is used for Prepare the purposes in the medicine for the treatment of and/or prevention nervus retrogression relevant disease.
Further, a preferred embodiment of the present invention：4- amine alkoxy -3- methoxy cinnamic acid benzoyls in described medicine Aminated compounds accounts for gross weight than 10%~99.5%.
Invention also discloses one or more 4- amine alkoxy -3- first that a kind of pharmaceutical composition includes therapeutically effective amount Epoxide cinnamic acid benzamides compound or its pharmaceutically acceptable salt, the pharmaceutical composition can be further containing a kind of or more Kind pharmaceutically acceptable carrier or excipient." therapeutically effective amount " refers to cause researcher or the targeted group of doctor Knit, the medicine of biological or medical reaction or the amount of medicament of system or animal；" composition " refer to by by more than one The product that material or component mix；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, combination Thing or carrier, such as：Liquid or solid filler, diluent, excipient, solvent or packing material, they carry or transport certain Chemical substance.Its preferable ratio of pharmaceutical composition provided by the present invention is 4- amine alkoxy -3- methoxy cinnamic acid benzoyls Aminated compounds or its pharmaceutically acceptable salt account for gross weight than 10%~99.5% as active component, and remainder is to account for Gross weight is than less than 90%.
Initiation material potassium phthalimide, the secondary-amine compound of the present invention can use the common technical value in this area Obtain, including but not limited to the method 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。
According to 4- amine alkoxy -3- methoxy cinnamic acid benzamides compound (I) molecule of above-mentioned preparation method gained In contain amino, in alkalescence its materia medica can be made by pharmaceutically conventional salifying method with any suitable acid in the amino Upper acceptable salt.
Beneficial effects of the present invention：
The compound of the present invention is respectively provided with the effect of significantly inhibiting to acetylcholinesterase, and its IC50 is 0.01 μM~5 μM, right The inhibitory activity of acetylcholinesterase is much higher than the inhibitory activity to butyrylcholine esterase, illustrates chemical combination disclosed in this invention Thing has certain selective inhibitory to acetylcholinesterase.
The compound of the present invention has significant protective effect to the PC12 cellular damages of hydrogen peroxide-induced, and 10- 5Antioxidation activity under mol/L concentration is better than forulic acid.
The compound of the present invention is to A β1-42The aggregation of auto-induction is respectively provided with the effect of significantly inhibiting, its IC50For 0.1 μM~ 20μM。
Compound disclosed in this invention causes mouse to obtain memory disorders to hyoscine has the improvement of dose dependent Effect, significant difference (p is relatively respectively provided with model group<0.01).
Compound disclosed in this invention is respectively provided with the effect of being obviously improved to ethanol induced mice memory representational role obstacle, There is significant difference (p compared with model group<0.01).
Embodiment
Below in conjunction with the specific embodiment of the invention, technical scheme is clearly and completely described, shown So, described embodiment is only part of the embodiment of the present invention, rather than whole embodiments.Based on the reality in the present invention Example is applied, the every other embodiment that those of ordinary skill in the art are obtained under the premise of creative work is not made, is all belonged to In the scope of protection of the invention.
Embodiment 1-15
A kind of preparation method of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds, comprises the following steps：
The first step, forulic acid, the first solvent, condensing agent and aniline, stirring reaction are added in reaction bulb, reaction process is used TLC is tracked；After reaction terminates, remove solvent under reduced pressure, dichloromethane added in residue, successively with saturated aqueous sodium carbonate and Saturated sodium-chloride water solution washs, and organic layer filters after anhydrous sodium sulfate drying, removes solvent under reduced pressure, residue is through column chromatography Purify (eluent：Dichloromethane：Methanol=30：1v/v), corresponding forulic acid benzamides compound is obtained；
Second step, above-mentioned forulic acid benzamides compound is dissolved in the second solvent, added used in the first alkalescence condition Alkali and Bromofume, temperature rising reflux stirring reaction, reaction process are tracked with TLC, and after reaction terminates, solvent and excess is evaporated off in pressure Bromofume, residue purify (eluent through column chromatography：Chloroform), obtain bromide intermediate
3rd step, bromide intermediate is dissolved in the 3rd solvent, addition has addition benzyimethylamine, is warming up to backflow and stirs Reaction is mixed, reaction process is tracked with TLC；After reaction terminates, remove solvent under reduced pressure, dichloromethane is added in residue, is used successively 5% sodium hydrate aqueous solution and deionized water washing, organic layer filter after anhydrous sodium sulfate drying, remove solvent under reduced pressure, residual Excess purifies (eluent through column chromatography：Dichloromethane：Methanol=15：1v/v), corresponding 4- amine alkoxy -3- methoxyl group meat is obtained Cinnamic acid benzamides compound, its chemical constitution pass through1H-NMR,13C-NMR and ESI-MS confirmations.
Embodiment 1-15 concrete technology condition is shown in Table 1-3.
The first step process conditions of table 1 and result
Process conditions have serious influence to the yield of product as shown in Table 1, select suitable process conditions to product Yield has the important meaning.The first solvent uses dichloromethane as shown in Table 1：The volume ratio 2 of toluene:1, dicyclohexyl carbon two Imines：DMAP is 2:1, molar feed ratio 1:3, reaction temperature is 70 DEG C, under conditions of the reaction time is 6h, Yield is preferable, is 83.8%.When the first solvent uses dichloromethane：The volume ratio 2 of toluene:1, condensing agent uses dicyclohexyl carbon Diimine：DMAP:Zinc chloride is 2:1：0.05, molar feed ratio 1:3, reaction temperature is 70 DEG C, during reaction Between be 6h under conditions of, yield highest, be 87.8%.
The second step process conditions of table 2 and result
Process conditions have serious influence to the yield of product as shown in Table 2, select suitable process conditions to product Yield has important influence.The second solvent uses dichloromethane as shown in Table 2：Toluene：Chloroform=2:1：2, the first alkaline bar Alkali used in part is potassium carbonate：Triethylamine：Pyridine is 2:1:1, molar feed ratio 1:3:2, reaction temperature is 70 DEG C, the reaction time Under conditions of 6h, yield 95.3%, yield highest, and change any of the above conditions all can to yield produce it is huge Influence.
The three step process condition of table 3 and result
Process conditions have serious influence to the yield of product as shown in Table 3, select suitable process conditions to product Yield has important influence.The 4th solvent uses dichloromethane as shown in Table 3：Toluene is 2:1, molar feed ratio 1:3, instead It is 70 DEG C to answer temperature, under conditions of the reaction time is 12h, yield 97.8%, and yield highest, and change any of the above Condition can all have an immense impact on to yield.
Embodiment 16
Concrete technology condition is same as Example 7, and for difference again with investigating different substituents, specific substituent is shown in Table 4, Gained 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds, its chemical constitution pass through1H-NMR,13C-NMR and ESI- MS is confirmed.
The different substituents of table 4 are tested
Embodiment 17
A kind of preparation side of the pharmaceutically acceptable salt of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds Method, comprise the following steps：
Take the 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds in table 4 respectively and after acetone stirs Corresponding acid is added, temperature rising reflux stirring reaction 15-30 minutes, reaction is cooled to room temperature after terminating, removes solvent under reduced pressure, remaining Thing acetone recrystallization, the solid of precipitation is filtered, produce the medicine of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds Acceptable salt on, its chemical constitution warp1HNR、13CNMR and ESI-MS confirmations.
Embodiment 18
Bioactivity screening experiment is carried out using the product prepared by embodiment 7
(1) acetylcholinesterase and butyrylcholine esterase inhibitory activity
1.0mmol/L acetylthiocholine iodides are sequentially added into 96 orifice plates or thio BuCh (is purchased from Sigma Company) 30 μ L, pH7.4 the μ L of PBS 40, the μ L of testing compound solution 20 (DMSO contents be less than 1%) and 10 μ L acetyl Cholinesterase (rat brain cortex 5% is homogenized supernatant, and pH 7.4 phosphate buffer makees homogenate medium), after finishing mixing, 37 DEG C be incubated 15min, into each hole add mass fraction be 0.2% thio-bis- (2- nitros) benzoic acid of 5,5'- bis- (DTNB, purchase From Sigma companies) solution 30 μ L colour developing, with ELIASA measure 405nm at each hole optical density (OD values), with being not added with testing sample Blank well compare, calculate compound to the inhibiting rate of enzyme [enzyme inhibition rate=(1- sample sets OD values/blank group OD values) × 100%]；Select five to six concentration of compound, determine its enzyme inhibition rate, and with the negative logarithm of the compound molar concentration with The inhibiting rate linear regression of enzyme, molar concentration when trying to achieve 50% inhibiting rate are the IC of the compound50.Measurement result shows, Compound disclosed in the embodiment of the present invention is respectively provided with the effect of significantly inhibiting to acetylcholinesterase, its IC50For 0.01 μM~5 μM, and positive control medicine --- ICs of the Rivastigmine to acetylcholine ester enzyme level50For 6.3 μM；Measurement result also table Bright, the compound disclosed in this project embodiment is much higher than to butyrylcholine esterase to the inhibitory activity of acetylcholinesterase 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 cellular damages of induction
DMEM nutrient solution of the PC12 cells containing 10% calf serum, with 1 × 105Individual/mL density is inoculated in the culture of 96 holes On plate, inoculation volume is 100mL/ holes, is subsequently placed into containing 5%CO237 DEG C of constant incubators in cultivate.After culture 24 hours, Add the compound (final concentration of 10 of respective concentration in administration group-5Mol/L, 10-6Mol/L) 10mL/ holes, preincubate 2 hours are (right Add 10 μ L/ hole PBS respectively with damage group according to group, its volume is kept equal).After PC12 cell incubations 2 hours, administration group with 100 μ Μ H are separately added into damage group2O2The μ L/ holes of agent 10 (control group adds 10 μ L/ hole PBS) are damaged, after 30 minutes, by each group The RPMI1640 nutrient solutions that nutrient solution changes no calf serum into continue to be put into constant incubator and cultivated 24 hours, cultivate liquid Product thinks 100 μ L/ holes.After continuing culture 24 hours, each group adds 5mg/mL, the μ L/ holes of MTT 100, carries out living cells dyeing.Treat The μ L/ holes of 100%DMSO terminate liquids 100 are added after 3 hours, in each group, fully dissolving mixes.Determined under 490nm wavelength each The OD values of group, test result is repeated 3 times, and with Duncan ' s test method statistics, each group numerical value is expressed as mean ± S.E.M., Using control group as 100%, administration group and damage class value are represented with the percentage of control group.Measurement result shows that the present invention is implemented Compound disclosed in example has significant protective effect to the PC12 cellular damages of hydrogen peroxide-induced, and 10-5Mol/L is dense Antioxidation activity under degree is better than forulic acid.
(3) compound suppresses A beta peptide aggregation determinations of activity
Take 20 μ L A β1-42The A β of the μ of solution+20 L testing compound solution, 20 μ L1-42The μ L PBSs of solution+20 The μ L PBSs (containing 25%DMSO) of (containing 2%DMSO), 20 μ L PBSs (containing 2%DMSO)+20 are in the orifice plate of black 96 In, compound and A β1-42Ultimate density be 25 μM.37 DEG C of incubation 24h, then add 160 μ L and contain 5 μM of thioflavine Ts 50mM glycine-NaOH buffer (pH=8.5), Varioskan Flash Multimode are used immediately after shaking 5s Reader (Thermo Scientific) multi-function microplate readers determine fluorescence under 446nm excitation wavelengths and 490nm launch wavelengths 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, A β are suppressed by compound1-42The inhibiting rate calculation formula of self assemble is：100- (IFi-IF0)/(IFc-IF0)*100.Each compound two multiple holes of each concentration mensuration.Measurement result shows that the present invention is implemented Compound disclosed in example is to A β1-42The aggregation of auto-induction is respectively provided with the effect of significantly inhibiting, its IC50For 0.1 μM~20 μM, Inhibiting rate 65-90%, and positive control medicine --- curcumin and forulic acid are under 25 μM of concentration to A β1-42Auto-induction is assembled Inhibiting rate be respectively 56.2% and 28.3%.
(4) blood-brain barrier passes through merit rating (PAMPA-BBB)
Pig brain phosphatide (PBL, purchased from Avanti Polar Lipids, Inc.) is dissolved in (20mg/ in dodecane (Sigma) ML), 4 μ L are taken to be added dropwise on the lipophilicity filter membrane of receptor hole with Biomimetic membrane.350 μ L PBS/EtOH are added in receptor hole (70:30) buffer solution, added in donor hole 200 μ L samples liquid (compound, which is dissolved in DMSO, obtains 5mg/mL storing solutions, then With 50 times of PBS/EtOH (70:30) it is 100mg/mL that buffer solution, which is diluted to ultimate density,.96 hole filter plates are placed in PVDF receiver boards (Millipore) on, immobilized artificial membrane is just touched donor liquid, be thusly-formed the confession that sandwich structure-bottom is determinand Body fluid, centre are artificial phospholipid's films, and drug molecule to be measured spreads from donor hole, through immobilized artificial membrane, enter upper strata receptor hole In.25 DEG C of static 18h, after incubation, donor plate is gently removed, draws respectively by body fluid and donor liquid, uses Varioskan Flash Multimode Reader ELIASAs determine concentration, each hole of sample four, and independent test three times, tests 10 wavelength OD values under (250-450nm), effective transmissivity (P is drawn according to formulae).PAMPA effective permeabilities Pe(cm·s-1) calculate It is as follows：Pe=-VdVa/[(Vd+Va)At]ln(1-drugacceptor/drugequilibrium)
Wherein, VdIt is the volume in donor hole, VaIt is the volume of receptor hole, A is the area of artificial phospholipid's film, when t represents infiltration Between, drug acceptor are the absorbances of donor boreliquid, and drug equilibrium are Theoretical Equilibrium absorbances, as a result with Mean value ± standard error (Stand error, S.E.) represents.Test result shows, presently disclosed under the experiment condition Compound be respectively provided with good blood-brain barrier and pass through ability, and be better than forulic acid.
(5) influence of the compound to hyoscine induced mice memory acquisition disturbance
SPF level ICR male mices, 25-30g, are randomly divided into：Normal group, model group, by reagent high and low dose group (5.0, 2.5mg/kg), every group of 10 animals.Disposable gavage gives test medicine, and blank group and model group give solvent 0.5%CMC- Na, administered volume are 0.1ml/10g；45min after medicine, normal group mouse peritoneal injection physiological saline, remaining each group animal are equal Hyoscine (5mg/kg) is injected, administered volume is 0.1ml/10g；After modeling 30min, mouse is put into non-electro photoluminescence Y fans Palace carries out Behavior test.Mouse is put in an arm end during test, allows it freely to walk 8min in labyrinth, records its entrance The number and alternate frequency of each arm, alternately rate is calculated according to below equation：Alternately rate %=[alternate frequency/(always enter indegree- 2)] × 100, as a result represented with mean ± standard deviation, group difference uses one-way analysis of variance.Measurement result shows, at this Under experiment condition, compound disclosed in this invention causes mouse to obtain memory disorders to hyoscine, and there is dose dependent to change Kind effect, significant difference (p is relatively respectively provided with model group<0.01).
Behavioral experiment finishes takes brain by mouse broken end immediately, with precooling normal saline flushing, is rapidly separated out on ice chest Cerebral hippocampal tissue, hippocampal tissue weight is weighed, add 9 times of 4 DEG C of physiological saline that 10% homogenate, 3500r.min is made-1, 4 DEG C of centrifugations 15min, -20 DEG C of storage supernatants are to be measured, and total protein concentration is determined by Coomassie brilliant blue.Exist according to method as defined in kit AChE contents are determined under 412nm wavelength, AChE vigor is expressed as U/mg.The ACh that ChAT vigor is catalyzed by ChAT is synthesized React to determine.Operating method is determined under 412nm wavelength also according to the explanation of kit, ChAT vigor with U/mg come Represent.Measurement result shows, under the experiment condition, compound disclosed in this invention can strengthen acetylcholine transferase (ChAT) vigor, significant difference (p is relatively respectively provided with blank group<0.01).
(6) influence of the compound to ethanol induced mice reproducibility dysmnesia
SPF level ICR male mices, 25-30g, are randomly divided into：Normal group, model group, by reagent high and low dose group (5.0, 2.5mg/kg), Rivastigmine group (3mg/kg), every group of 10 animals.Daily gavage is given to test medicine, blank group and model group Give solvent 0.5%CMC-Na, administered volume is 0.1ml/10g, successive administration 32 days；During administration 1~24 day, daily medicine 30min afterwards, model group and each administration group gavage 0.1ml/10g ethanol (15%w/v), successive administration 24 days, remove ethanol entrance Ethanol cleans the phase, and medicine continues to give；Carry out animal Jumping test within 31,32 days in administration, 45min is trained or surveyed after medicine Examination experiment, allows mouse to be placed in diving tower instrument during training, puts down gently in being powered on platform, when animal is under platform up-regulation with biped simultaneously Copper grid are contacted to get an electric shock, are considered as wrong reaction, the normal avoiding reaction after mouse is shocked by electricity is to escape onto platform, is recorded small Mouse escapes the incubation period to platform, and records electric shock number in 5min, in this, as school grade.Surveyed after 24 hours Examination, record mouse jump off the time (incubation period) shocked by electricity and its number (errors number) to be shocked by electricity in 5min for the first time, with This is as memory representational role evaluation index.Test result represents that group difference uses single factor test variance with mean ± standard deviation Analysis.Test result shows that compound disclosed in this invention is remembered to ethanol induced mice under the experiment condition reproduces work( Energy obstacle is respectively provided with the effect of being obviously improved, and has significant difference (p compared with model group<0.01).
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention God any modification, equivalent substitution and improvements made etc., should be included in the scope of the protection with principle.

Claims (9)

  1. A kind of 1. 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds, it is characterised in that：The chemistry knot of the compound Structure formula is such as shown in (I)：
    In formula：M represents 1-12；
    R1Represent H, C1~C12Alkyl；
    R2Represent C1~C12Alkyl, benzyl；
    R1NR2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4- positions by C1~C12Piperidyl that alkyl is substituted, 4- positions quilt Piperidyl that benzyl is substituted, piperazinyl, 4- positions are by C1~C12The piperazine that piperazinyl that alkyl is substituted, 4- positions are substituted by benzyl Piperazine base；
    X represents C1~C12Alkyl, benzyl, the phenyl substituted by the 1-4 groups being selected from the group on phenyl ring：F、Cl、Br、I、 C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano group, substituent can be in any possible positions of phenyl ring.
  2. 2. a kind of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds as claimed in claim 1 pharmaceutically may be used The salt of receiving, it is characterised in that：Described pharmaceutically acceptable salt is 4- amine alkoxy -3- methoxy cinnamic acid benzamideses Compound and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, rich horse Acid, butanedioic acid, tartaric acid, citric acid, C1-6What the reaction of alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid was generated Salt.
  3. 3. a kind of preparation method of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds as claimed in claim 1, It is characterized in that：Comprise the following steps：
    The first step, using forulic acid as initiation material, react, obtain corresponding with substituted aniline under the conditions of the first solvent and condensing agent Forulic acid benzamides compound；
    Second step, forulic acid benzamides compound are anti-with Dihaloalkyl compound under the second solvent and the first alkalescence condition Should, generate corresponding halogen compound；
    3rd step, halogen compound react in the 3rd solvent and organic amine compound, that is, the 4- amine alkoxy -3- methoxyl groups obtained Cinnamic acid benzamides compound.
  4. 4. a kind of preparation method of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds as claimed in claim 3, It is characterized in that：In the described first step：First solvent is：Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), benzene, Toluene, acetonitrile or C1-8Alkane；
    Condensing agent is：Dicyclohexylcarbodiimide, DMAP, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne two One or more kinds of mixtures in inferior amine salt hydrochlorate and I-hydroxybenzotriazole；
    Forulic acid：Substituted aniline：The molar feed ratio of condensing agent is 1.0：1.0~10.0；
    Reaction temperature is 25~150 DEG C；
    Reaction time is 1~72 hour.
  5. 5. the preparation method of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds according to claim 3, its It is characterised by：In described second step：Alkali used in first alkalescence condition is：Alkali carbonate, alkaline earth metal carbonate, alkali gold Belong to bicarbonate, alkali metal bicarbonates, the alkali metal salt of C1-8 alcohol, triethylamine, tri-n-butylamine, trioctylamine, pyridine, N- methyl Mixture one or more than one kinds of morpholine, N- methyl piperidines, triethylene diamine and TBAH；
    Second solvent is ether, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane, chloroform, benzene, first The one or more kinds of mixture of benzene, acetonitrile and C5-8 alkane；
    Forulic acid benzamides compound：Dihaloalkyl compound：The molar feed ratio of alkali is 1.0:1.0~10.0:1.0~ 10.0；
    Reaction temperature is 25~150 DEG C；
    Reaction time is 1~72 hour.
  6. 6. the preparation method of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds according to claim 3, its It is characterised by：The 3rd solvent is in described second step：Ether, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide (DMSO), Dichloromethane, chloroform, benzene, toluene, acetonitrile, C1-8Alcohol and C5-8One or more than one kinds of mixture in alkane；
    Halogen compound：The molar feed ratio of organic amine compound is 1.0：1.0~10.0；
    Reaction temperature is 25~150 DEG C；
    Reaction time is 1~72 hour.
  7. 7. a kind of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds as claimed in claim 2 pharmaceutically may be used The preparation method of the salt of receiving, it is characterised in that comprise the following steps：
    4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds and acetone are stirring evenly and then adding into acid, and temperature rising reflux stirs Mix reaction 15-30 minutes, reaction is cooled to room temperature after terminating, and removes solvent, residue acetone recrystallization under reduced pressure, and filtering separates out Solid, produce the pharmaceutically acceptable salts of 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds.
  8. 8. 4- amine alkoxy -3- methoxy cinnamic acid benzamides compounds prepared by claim 7 is pharmaceutically acceptable Salt be used for prepare treatment and/or prevention nervus retrogression relevant disease medicine in purposes.
  9. 9. purposes according to claim 8, it is characterised in that：Described 4- amine alkoxy -3- methoxy cinnamic acid benzoyls The pharmaceutically acceptable salt of aminated compounds accounts for gross weight than 10%~99.5% in medicine.
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