CN105646289B - A kind of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds and its preparation method and application - Google Patents
A kind of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds and its preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- 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
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- 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
- C07D295/12—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 or doubly bound nitrogen atoms
- C07D295/125—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- 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
- C07D295/16—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 acylated on ring nitrogen atoms
- C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
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Abstract
The invention discloses 3 methoxycinnamate acid amide alkylamide compounds of a kind of 4 carbamate and its preparation method and application, the including but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease shape, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Description
Technical field
The present invention relates to medicinal chemistry arts, more particularly, to a kind of 4- carbamates -3- methoxycinnamate acid amide alkane
Base amides compound and its preparation method and application.
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, main clinical manifestation includes:Cognitive ability, the decline of memory and social-life ability and emotion,
The change of personality is a kind of chronic progressive disease.It is senile dementia in the Asian countries such as China, Japan vascular 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, seriously affects work and the quality of life of the elderly, and to society and family bring heavy economy and
Mental burden.Therefore, VD has become current gerontology and an important research hotspot in psychologic medicine field.Vascular is silly
It stays due to pathogenesis complexity, there is no the drug that disease can be blocked to develop, clinical treatment is to improve brain blood cycle at present
It is metabolized, reinforces based on brain nutrition with brain.
In recent years, studies at home and abroad show that, 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, ACh concentration in VD Cerebrospinal Fluid in Patients are significantly lower than normal level, and the degree that reduces of its concentration and dementia is 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
The recovery of neurotrosis and brain function after blood.This shows that acetylcholinesterase inhibitor can also be used for the treatment of vascular dementia.
Alzheimer's disease (Alzheimer ' s disease, AD) is incidence and the highest disease of lethality in the elderly
One of disease.Alzheimer's disease international association (Alzheimer ' s disease International, ADI) publication《2015
Global Alzheimer's disease report》It points out, the whole world in 2015 has had more than 46,000,000 people and suffered from dementia, it was predicted that 2050
Year, the whole world will have 1.315 hundred million populations to be perplexed by dementia, wherein the incidence 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 novel 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 drug
Volume will be up to 600,000,000,000 dollars;In China, with the rapid rising of senile dementia incidence, the market of this kind of drug is also quickly 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 neurodegenerative disease, key pathological feature are that beta amyloid peptide (β-amyloid peptide, A β) largely deposits
The neurofibrillary tangles that senile plaque (Senile plaque, SP), the Protein tau Hyperphosphorylationof of formation are formed
(Neurofibrillary tangle, NFT), and the degeneration etc. of the apoptosis and nerve synapse with neuron.In recent years, many
Researcher is dedicated to disclosing the pathogenesis of AD 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, Protein tau Hyperphosphorylationof, inflammation, free-radical oxidation, metal ion etc., therefore,
The novel therapeutic approach and means developed for these pathogenesis will be hopeful to alleviate and improve the state of an illness of AD patient.
Clinically effectively there are two main classes for the drug for the treatment of AD at present:(1) being based on neurotransmitter acetylcholine deficiency causes
The cholinergic hypothesis of cognitive function imbalance, improves patient's intracerebral levels of acetylcholine, such as using acetylcholinesterase inhibitor:
Tacrine、Donepezil、Ravastigmine、Galantamine;(2) N-methyl-D-aspartate (NMDA) receptor is used
Inhibitor reduces damage of the glutamate to nerve cell, such as:Memantine Hydrochloride.But these drugs exist
The problems such as action target spot is single, toxic side effect is more, not good enough to the long-term efficacy of AD patient.
Therefore, research and development with novel chemical structure, novel 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.
Invention content
In view of this, in view of the deficiencies of the prior art, it is an object of the present invention to provide a kind of 4- carbamates -3- methoxies
Base Chinese cassia tree acid amide alkylamide compound and its preparation method and application realizes and prepares the secondary work of multiaction target spot, low toxicity
The purpose of anti-neurodegenerative disease therapeutic agent, including but not limited to vascular dementia, Alzheimer's disease, pa gold
Gloomy disease, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, green light
The neurodegenerative diseases such as eye.
In order to achieve the above objectives, the present invention uses following technical scheme:
A kind of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds, the chemical constitution of the compound
General formula is such as shown in (I):
In formula:M indicates 1-12;
R1Indicate H, C1~C12Alkyl;
R2Indicate C1~C12Alkyl, benzyl, substituted benzyl;
R1NR2Nafoxidine base, morpholinyl, piperidyl, 4- are also illustrated that by C1~C12Piperidyl that alkyl is replaced, 4-
Piperidyl that position is replaced by benzyl or substituted benzyl, piperazinyl, 4- by C1~C12Piperazinyl that alkyl is replaced, 4- quilts
The piperazinyl that benzyl or substituted benzyl are replaced;
R3、R4Each independently represent H, C1~C12Alkyl or R3NR4Indicate morpholine ring, piperidine ring, 4- benzyl piepridines ring,
Piperazine ring, 4- by C1~C12Alkyl-substituted piperazine ring or nafoxidine ring;
The substituted benzyl refers to the benzyl replaced by 1-4 groups selected from the group below on phenyl ring:F、Cl、Br、I、
C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, these substituent groups can be in the arbitrary possibility of phenyl ring
Position.
Preferably, the chemical structure of general formula of the compound such as (I) is shown:
In formula:M indicates 1-8;
R1Indicate H, methyl, ethyl;
R2Indicate methyl, ethyl, benzyl, 2- methoxy-benzyls, 2- trifluoro-methoxybenzyls, 2- methylbenzyls, 2- trifluoros
Methylbenzyl, 2- chlorobenzyls;
R1NR2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4- ethyl piperidines base, 4- benzyl piepridines base, piperazinyl,
4- methyl piperazines base, 4- benzyl diethylenediamines base, 4- [(2- methoxyl groups) benzyl] piperazinyl;
R3、R4Each independently represent H, C1~C12Alkyl or R3NR4Indicate morpholine ring, piperidine ring, 4- benzyl piepridines ring,
Piperazine ring, 4- by C1~C12Alkyl-substituted piperazine ring or nafoxidine ring.
A kind of pharmaceutically acceptable salt of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds,
The pharmaceutically acceptable salt be above-mentioned 4- carbamate -3- methoxycinnamate acid amide alkylamide compounds with
Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, amber
Acid, tartaric acid, citric acid, C1-6The salt of alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
The preparation method of above-mentioned 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds, including it is as follows
Step:
The first step:Using potassium phthalimide as starting material, with two under the first solvent and the first alkaline condition
Alkylhalide group compound is reacted, and corresponding halogen compound is obtained;
Second step:Corresponding halogen compound described in the first step is reacted with organic amine compound in the second solvent,
Obtain corresponding phthalimide alkyl amine compound;
Third walks:By corresponding phthalimide alkyl amine compound described in second step in third solvent with
Hydrazinolysis reaction occurs for hydrazine hydrate, obtains corresponding primary amine compound;
4th step:By third walk described in corresponding primary amine compound issued in the 4th solvent and condensing agent with ferulic acid
Raw condensation reaction, obtains corresponding ferulic amide class compound;
5th step:By corresponding ferulic amide class compound described in the 4th step in the 5th solvent and the second alkaline condition
It is lower to react with corresponding carbamyl chloride to get to 4- carbamate -3- methoxycinnamate acid amide alkylamides
Close object.
Preferably, in the first step, the first solvent is ether, tetrahydrofuran, n,N-Dimethylformamide, dimethyl
Sulfoxide, dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile or C5-8Alkane;It is preferred that the first solvent is N, N- dimethyl methyls
Amide, acetone, acetonitrile, tetrahydrofuran or toluene;
Alkali used in first alkaline condition is alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali gold
Belong to bicarbonate, alkali metal bicarbonates, C1-8Alkali metal salt, trimethylamine class or the quaternary amine bases of alcohol are (such as:Triethylamine, three
Butylamine, trioctylamine, pyridine, N-methylmorpholine, N- methyl piperidines, triethylene diamine, tetrabutylammonium hydroxide), preferably alkali is hydrogen
Potassium oxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide;
Potassium phthalimide: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 room temperature~150 DEG C, and preferable reaction temperature is room temperature~120 DEG C;
Reaction time is 1~72 hour, and preferred reaction time is 2~24 hours.
In the second step, the second solvent is ether, tetrahydrofuran, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), two
Chloromethanes, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane, preferably the second solvent are N, N- dimethyl methyls
Amide, acetone, acetonitrile, tetrahydrofuran or toluene;
Corresponding halogen compound:The molar feed ratio of organic amine compound is 1.0:1.0~10.0, preferably mole feed intake
Than being 1.0:1.0~5.0;
Reaction temperature is room temperature~150 DEG C, and preferable reaction temperature is room temperature~120 DEG C;
Reaction time is 1~72 hour, and preferred reaction time is 2~24 hours.
Preferably, in the described third step, third solvent be tetrahydrofuran, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO),
C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane, preferably third solvent are toluene, ethyl alcohol;
Corresponding phthalimide alkyl amine compound:The molar feed ratio of hydrazine hydrate is 1.0:1.0~20.0,
It is preferred that molar feed ratio is 1.0:2.0~10.0;
Reaction temperature is room temperature~150 DEG C, and preferable reaction temperature is room temperature~120 DEG C;
Reaction time is 1~72 hour, and preferred reaction time is 2~24 hours.
In 4th step, the 4th solvent is tetrahydrofuran, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), C3-8Fat
Ketone, benzene, toluene, acetonitrile, dichloromethane, chloroform, C1-8Alcohol or C5-8Alkane, preferably the 4th solvent are acetone, tetrahydrofuran, first
Benzene, dichloromethane or chloroform;
Condensing agent is:Dicyclohexylcarbodiimide, dicyclohexylcarbodiimide and 4-dimethylaminopyridine, 1- ethyls-(3-
Dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and 1-
Hydroxybenzotriazole, preferably condensing agent are dicyclohexylcarbodiimide and 4-dimethylaminopyridine or 1- ethyls-(3- dimethyl
Aminopropyl) phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole;
Corresponding primary amine compound:Ferulic acid:The molar feed ratio of condensing agent is 1.0:1.0~10.0:1.0~
10.0, preferably ingredient proportion is 1.0:1.0~5.0:1.0~5.0;
Reaction temperature is room temperature~100 DEG C, and preferable reaction temperature is room temperature~50 DEG C;
Reaction time is 1~72 hour, and preferred reaction time is 2~24 hours.
Preferably, in the 5th step, the 5th solvent is C3-8Aliphatic ketone, N,N-dimethylformamide, ether, isopropyl
Ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, glycol dimethyl ether, C1-6Aliphatic acid and C1-6The formed ester of fatty alcohol, dichloromethane,
Chloroform, 1,2- dichloroethanes, benzene,toluene,xylene, chlorobenzene, o-dichlorohenzene, acetonitrile, dimethyl sulfoxide (DMSO) or pyridine, the preferably the 5th
Solvent is ether, acetonitrile, acetic acid, acetone, N,N-dimethylformamide, toluene, tetrahydrofuran or pyridine;
Alkali used in second alkaline condition be alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate,
Alkali or alkaline earth metal bicarbonate, C1-6It is fatty acid alkali metal salt, piperidines, nafoxidine, triethylamine, tri-n-butylamine, three pungent
The combination of amine, pyridine, N-methylmorpholine, N- methyl piperidines, triethylene diamine or tetrabutylammonium hydroxide or above-mentioned various alkali,
It is preferred that alkali is:Potassium carbonate, sodium carbonate, sodium bicarbonate, potassium acetate, pyridine, triethylamine, N-methylmorpholine;
Corresponding ferulic amide class compound:Acylating agent acyl chlorides:The molar feed ratio of alkali is 1.0:1.0~60.0:1.0
~100.0, preferably molar feed ratio is:1.0:1.0~20.0:1.0~50.0;
Reaction temperature is -20 DEG C~130 DEG C, and preferable reaction temperature is 0 DEG C~80 DEG C;
Reaction time is 1~120 hour, and preferred reaction time is 2~48 hours.
Above-mentioned 4- carbamate -3- methoxycinnamate acid amide alkylamide compounds or its is pharmaceutically acceptable
Salt prepare treatment and/or prevent nervus retrogression relevant disease drug in purposes, including but not limited to vascular dementia, Ah
Er Cihai Mo's diseases, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral spinal sclerosis
The neurodegenerative diseases such as disease, neuropathic pain, glaucoma.
Preferably, the drug, it is characterised in that including the 4- carbamate -3- methoxycinnamate acid amide alkane
Base amides compound or the 4- carbamate -3- methoxycinnamate acid amide alkylamide compounds pharmaceutically may be used
The salt of receiving and one or more pharmaceutically acceptable carriers or excipient.
The beneficial effects of the invention are as follows:
(1) the compound of the present invention all has acetylcholinesterase the effect of significantly inhibiting, IC50It is 0.01 μM~5 μM,
And it is apparently higher than corresponding ferulic acid fatty amine alkylamide compound and ferulic acid alpha substituted benzylamine alkylamide compound,
The IC that and positive control medicine --- Rivastigmine inhibits acetylcholinesterase50It is 6.3 μM;The compound of the present invention pair
The inhibitory activity of acetylcholinesterase is much higher than the inhibitory activity to butyrylcholine esterase, illustrates chemical combination disclosed in this invention
Object has certain selective inhibitory to acetylcholinesterase.
(2) the compound of the present invention has a significant protective effect to the PC12 cellular damages of hydrogen peroxide-induced, and
10-5Antioxidant activity under mol/L concentration is better than ferulic acid.
(3) the compound of the present invention is to A β1-42The aggregation of auto-induction all has the effect of significantly inhibiting, IC50For 0.01 μ
M~5 μM, inhibiting rate 60-95%, and positive control medicine --- curcumin and ferulic acid are under 25 μM of concentration to A β1-42Itself
The inhibiting rate of induced aggregation is respectively 56.2% and 28.3%.
(4) the compound of the present invention all has good blood-brain barrier and penetrates ability, and it is free to be better than corresponding 4-
The ferulic acid fatty amine alkylamide compound and 4- of hydroxyl are the ferulic acid alpha substituted benzylamine alkylamides of free hydroxyl group
Compound.
(5) the compound of the present invention causes mouse to obtain memory disorders with dose-dependent improvement work hyoscine
With relatively all having significant difference (p with model group<0.01), and be better than corresponding 4- be free hydroxyl group orizanol
Fat amine alkylamide compound and 4- are the ferulic acid alpha substituted benzylamine alkylamide compounds of free hydroxyl group.
(6) the compound of the present invention all has the effect of being obviously improved to ethyl alcohol induced mice memory representational role obstacle, with
Model group, which is compared, significant difference (p<0.01), and be better than corresponding 4- be free hydroxyl group ferulic acid fatty amine alkyl
Amides compound and 4- are the ferulic acid alpha substituted benzylamine alkylamide compounds of free hydroxyl group.
Specific implementation mode
Below in conjunction with the specific embodiment of the invention, technical scheme of the present invention is clearly and completely described, is shown
So, described embodiments are only a part of the embodiments of the present invention, instead of all the 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 without creative efforts all belongs to
In the scope of protection of the invention.Moieties use following abbreviated form in the embodiment of the present invention:N,N-dimethylformamide contracts
It is written as DMF, dicyclohexylcarbodiimide is abbreviated as DCC, the contracting of 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate
It is written as EDC, I-hydroxybenzotriazole is abbreviated as HOBT.
Embodiment 1-20
A kind of preparation method of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds, including it is following
Step:
The first step:Potassium phthalimide, the first solvent, the alkali used in the first alkaline condition are added in reaction bulb
With dibromo alkyl compound, temperature rising reflux is stirred to react, and after reaction, is filtered while hot, and a small amount of acetone washs filter cake, and filtrate subtracts
Solvent and excessive dibromo alkyl compound is evaporated off in pressure, and residue purifies (eluent through column chromatography:Petroleum ether:Acetone=30:
1v/v), phthalimide alkyl bromide is obtained;
Second step:Above-mentioned phthalimide alkyl bromide is all dissolved in the second solvent, organic amine is added
Compound is warming up to return stirring reaction, and reaction process is tracked with TLC,;After reaction, solvent is removed under reduced pressure, in residue
Second solvent is washed with 5% sodium hydrate aqueous solution and deionized water successively, and organic layer filters after being dried over anhydrous sodium sulfate,
Remove solvent under reduced pressure, residue purifies (eluent through column chromatography:Petroleum ether:Acetone=15:1v/v), phthalimide is obtained
Alkyl amine compound;
Third walks:Phthalimide alkyl amine compound is all dissolved in third solvent, hydrazine hydrate is added
N2H4.H2O, is warming up to return stirring reaction, and reaction process is tracked with TLC;After reaction, it filters while hot, a small amount of ethyl alcohol washing
Solvent is evaporated off in filter cake, filtrate decompression, and residue purifies (eluent through column chromatography:Dichloromethane:Methanol=15:1v/v), phase is obtained
The alkylamine primary amine compound answered;
4th step:Above-mentioned corresponding alkylamine primary amine compound is all dissolved in the 4th solvent, be added condensing agent and
Ferulic acid, is stirred at room temperature reaction, and reaction process is tracked with TLC;After reaction, it removes the 4th solvent under reduced pressure, adds in residue
Enter the 4th solvent, washed successively with saturated aqueous sodium carbonate and saturated sodium-chloride water solution, organic layer is dry through anhydrous sodium sulfate
Filtering after dry, removes the 4th solvent under reduced pressure, and residue purifies (eluent through column chromatography:Dichloromethane:Methanol=10:1v/v),
Obtain corresponding ferulic acid alkylamine amides compound;
5th step:Above-mentioned corresponding ferulic acid alkylamine amides compound is all dissolved in the 5th solvent, is added the
Alkali used in two alkaline conditions and carbamyl chloride are warming up to 60 DEG C and are stirred to react, and reaction process is tracked with TLC;Reaction terminates
Afterwards, it removes the 5th solvent under reduced pressure, the 5th solvent is added in residue, uses saturated aqueous sodium carbonate and saturated sodium-chloride water successively
Solution washs, and organic layer filters after being dried over anhydrous sodium sulfate, and removes solvent under reduced pressure, and residue purifies (eluent through column chromatography:
Dichloromethane:Methanol=10:1v/v) to get corresponding 4- carbamates -3- methoxycinnamates acid amide alkylamide chemical combination
Object (I), chemical constitution passes through1H-NMR,13C-NMR and ESI-MS confirmations.
1 first step process conditions of table 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 acetone as shown in Table 1, and alkali used in the first alkaline condition uses triethylene two
Amine, and potassium phthalimide:Dihaloalkyl compound:The molar feed ratio of triethylene diamine is 1:4:3 reaction temperatures
It is 65 DEG C, under conditions of the reaction time is 18h, yield 95.3%, yield highest.
2 second step process conditions of table 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 toluene, corresponding halogen compound as shown in Table 2:Organic amine compound
Molar feed ratio is 1:2, reaction temperature is 120 DEG C, under conditions of the reaction time is 12h, yield 97.5%, and yield highest,
And changing any of the above conditions can all have an immense impact on to yield.
3 third step process condition of table 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.Third solvent uses ethyl alcohol, molar feed ratio 1 as shown in Table 3:6, reaction temperature is 80 DEG C,
Under conditions of reaction time is 18h, yield 97.5%, yield highest, and changing any of the above conditions all can be to receiving
Rate has an immense impact on.
The 4th step process condition of table 4 and result
Process conditions have serious influence to the yield of product as shown in Table 4, select suitable process conditions to product
Yield has important influence.The 4th solvent uses dichloromethane, condensing agent to use EDC as shown in Table 4:HOBT=1:2 compoundings,
Molar feed ratio is 1:3:5, reaction temperature 40, under conditions of the reaction time is 18h, yield 87.8%, yield highest, and
And any of the above conditions of change can all have an immense impact on to yield.
The 5th step process condition of table 5 and result
Process conditions have serious influence to the yield of product as shown in Table 5, select suitable process conditions to product
Yield has important influence.The 5th solvent uses n,N-Dimethylformamide as shown in Table 4, and alkali used in the second alkaline condition is adopted
With potassium acetate, molar feed ratio 1:10:25, reaction temperature 60, under conditions of the reaction time is 36h, yield 97.8%,
Yield highest, and change any of the above conditions and can all have an immense impact on to yield.
Embodiment 21
Concrete technology condition is identical as embodiment 11, difference again with investigate different substituents, specific substituent group is shown in Table
6, gained 4- carbamate -3- methoxycinnamate acid amide alkylamide compounds, chemical constitution passes through1H-NMR,13C-
NMR and ESI-MS confirmations.
6 different substituents of table are tested
Embodiment 22
A kind of pharmaceutically acceptable salt of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds
Preparation method includes the following steps:
4- carbamate -3- methoxycinnamate acid amide the alkylamide compounds in table 6 and acetone stirring are taken respectively
Corresponding acid is added after uniformly, temperature rising reflux is stirred to react 15-30 minutes, is cooled to room temperature after reaction, removes under reduced pressure molten
Agent, residue acetone recrystallization filter the solid of precipitation to get 4- carbamate -3- methoxycinnamate acid amide alkyl acyls
The pharmaceutically acceptable salt of aminated compounds, chemical constitution warp1HNR and ESI-MS confirmations.
Embodiment 23
Bioactivity screening experiment is carried out using the product prepared by embodiment 11.
(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 40 μ L of PBS buffer solution, 20 μ L of testing compound solution (DMSO contents be less than 1%) and 10 μ L acetyl
Cholinesterase (rat brain cortex 5% is homogenized supernatant, and the phosphate buffer of pH 7.4 makees homogenate medium), after finishing mixing, 37
DEG C be incubated 15min, into each hole be added mass fraction be 0.2% thio-bis- (2- nitros) benzoic acid of 5,5'- bis- (DTNB, purchase
From Sigma companies) 30 μ L colour developing of solution, the optical density (OD values) in each hole at 405nm is measured with microplate reader, and is not added with sample to be tested
Blank well compare, calculate compound to the inhibiting rate of enzyme [enzyme inhibition rate=(1- sample sets OD values/blank group OD values) ×
100%];Five to six concentration for selecting compound, measure 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 acquiring 50% inhibiting rate are the IC of the compound50.Measurement result shows
Compound disclosed in the embodiment of the present invention all has acetylcholinesterase the effect of significantly inhibiting, IC50It is 0.05 μM~5
μM, and it is apparently higher than corresponding ferulic acid fatty amine alkylamide compound and ferulic acid alpha substituted benzylamine alkylamide chemical combination
Object, and positive control medicine --- the IC that Rivastigmine inhibits acetylcholinesterase50It is 6.3 μM;Measurement result also table
Bright, the compound disclosed in this project embodiment is much higher than to butyrylcholine esterase the inhibitory activity of acetylcholinesterase
Inhibitory activity, illustrate compound disclosed in this invention to acetylcholinesterase have certain selective inhibitory.
(2) compound is to H2O2The protective effect of the PC12 cellular damages of induction is screened
DMEM culture solution of the PC12 cells containing 10% calf serum, with 1 × 105A/mL density is inoculated in the culture of 96 holes
On plate, inoculation volume is the holes 100mL/, is subsequently placed into containing 5%CO237 DEG C of constant incubators in culture.After culture 24 hours,
Add the compound (final concentration of 10 of respective concentration in administration group-5Mol/L, 10-6Mol/L) the holes 10mL/, preincubate 2 hours are (right
Add 10 μ L/ hole PBS respectively with damage group according to group, its volume is made to keep equal).After PC12 cell incubations 2 hours, administration group with
100 μ Μ H are separately added into damage group2O210 holes μ L/ of agent (control group adds 10 μ L/ hole PBS) are damaged, after 30 minutes, by each group
The RPMI1640 culture solutions that culture solution changes no calf serum into continue to be put into constant incubator and cultivate 24 hours, cultivate liquid
Product thinks 100 holes μ L/.After continuing culture 24 hours, 5mg/mL is added in each group, and the holes MTT100 μ L/ carry out living cells dyeing.Wait for 3
100 holes μ L/ of 100%DMSO terminate liquids are added after hour, in each group, fully dissolve mixing.Each group is measured under the wavelength of 490nm
OD values, test result is repeated 3 times, and with Duncan ' s test method statistics, each group numerical value is expressed as mean ± S.E.M., with
Control group is 100%, and administration group and damage class value are indicated with the percentage of control group.Measurement result shows the embodiment of the present invention
Disclosed in compound have significant protective effect to the PC12 cellular damages of hydrogen peroxide-induced, and 10-5Mol/L concentration
Under antioxidant activity be better than ferulic acid.
(3) compound inhibits A beta-aggregation determinations of activity
Take the A β of 20 μ L1-42The testing compound solution of+20 μ L of solution, the A β of 20 μ L1-42+ 20 μ L PBS buffer solution of solution
(containing 2%DMSO), 20 μ L PBS buffer solution (containing 2%DMSO)+20 μ L PBS buffer solution (containing 25%DMSO) are in 96 orifice plate of black
In, compound and A β1-42Ultimate density be 25 μM.37 DEG C are incubated for 24 hours, and 160 μ L are then added and contain 5 μM of thioflavine Ts
The glycine-NaOH buffer (pH=8.5) of 50mM uses Varioskan Flash Multimode immediately after shaking 5s
Reader (Thermo Scientific) multi-function microplate readers measure fluorescence under 446nm excitation wavelengths and 490nm launch wavelengths
Value;Aβ1-42The fluorescent value of+untested compound is recorded as IFi, A β1-42The fluorescent value of+PBS buffer solution is recorded as IFc, contain only
The fluorescent value of PBS buffer solution is recorded as IF0, A β are inhibited 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 all has the effect of significantly inhibiting, IC50It is 0.1 μM~20 μM,
Inhibiting rate 60-95% and positive control medicine --- curcumin and ferulic 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 penetrates merit rating (PAMPA-BBB)
Pig brain phosphatide (PBL is purchased from Avanti Polar Lipids, Inc.) is dissolved in (20mg/ in dodecane (Sigma)
ML), 4 μ L is 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, be added in for body opening 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 enable just to touch the confession for being thusly-formed that sandwich structure-bottom is determinand for body fluid
Body fluid, centre are artificial phospholipid's films, and drug molecule to be measured is spread from for body opening, pass through immobilized artificial membrane, enter upper layer receptor hole
In.25 DEG C of static 18h after incubation, gently remove donor plate, are drawn respectively by body fluid and for body fluid, use Varioskan
Flash Multimode Reader microplate reader measured concentrations, four hole of each sample, independent test three times, test 10 wavelength
OD values under (250-450nm) obtain effective transmissivity (P 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 for body opening, VaIt is the volume of receptor hole, A is the area of artificial phospholipid's film, when t indicates 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.) indicates.Test result shows presently disclosed under the experiment condition
Compound all have good blood-brain barrier penetrate ability, and be better than corresponding 4- be free hydroxyl group ferulic acid fatty amine
Alkylamide compound and 4- are the ferulic acid alpha substituted benzylamine alkylamide compounds of free hydroxyl group.
(5) influence of the compound to hyoscine induced mice memory acquisition disturbance
SPF grades of 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 to organize mouse peritoneal injecting normal saline, remaining each group animal is 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 when test, it is allowed to travel freely 8min in labyrinth, records its entrance
The number and alternate frequency of each arm calculate alternately rate according to following formula:Alternating rate %=[alternate frequency/(always into indegree-
2) it] × 100, is as a result indicated 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, which causes mouse to obtain memory disorders hyoscine, has dose-dependent change
Kind effect, significant difference (p is relatively all had with model group<0.01), and be better than corresponding 4- be free hydroxyl group asafoetide
Sour fatty amine alkylamide compound and 4- are the ferulic acid alpha substituted benzylamine alkylamide compounds of free hydroxyl group.
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 weighs hippocampal tissue weight, adds 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 measured by Coomassie brilliant blue.Exist according to method as defined in kit
AChE contents are measured under the wavelength of 412nm, AChE vigor is expressed as U/mg.The vigor of ChAT is synthesized by the ACh that ChAT is catalyzed
It reacts to measure.Operating method is measured also according to the explanation of kit under 412nm wavelength, the vigor of ChAT with U/mg come
It indicates.Measurement result shows that under the experiment condition, compound disclosed in this invention can enhance acetylcholine transferase
(ChAT) vigor relatively all has significant difference (p with blank group<0.01), and to be better than corresponding 4- be free hydroxyl group
Ferulic acid fatty amine alkylamide compound and 4- be free hydroxyl group ferulic acid alpha substituted benzylamine alkylamide chemical combination
Object.
(6) influence of the compound to ethyl alcohol induced mice reproducibility dysmnesia
SPF grades of 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
Solvent 0.5%CMC-Na is given, 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 ethyl alcohol (15%w/v), successive administration 24 days remove ethyl alcohol entrance
Ethyl alcohol cleans the phase, and drug continues to give;Carry out animal Jumping test within 31,32 days in administration, 45min is trained or surveys after medicine
Examination experiment, allows mouse to be placed in diving tower instrument when training, and puts down gently in being powered on platform, simultaneously with biped when animal is under platform up-regulation
It is to get an electric shock to contact copper grid, is 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.It is surveyed after 24 hours
Examination, the number (errors number) that record mouse jumps off the time (incubation period) shocked by electricity and its shocked by electricity in 5min for the first time, with
This is as memory representational role evaluation index.Test result indicates that group difference uses single factor test variance with mean ± standard deviation
Analysis.Test result shows that compound disclosed in this invention remembers ethyl alcohol induced mice under the experiment condition and reproduces work(
Energy obstacle all has the effect of being obviously improved, and has significant difference (p compared with model group<0.01), and it is better than 4- corresponding
Be free hydroxyl group ferulic acid fatty amine alkylamide compound and 4- be free hydroxyl group ferulic acid alpha substituted benzylamine alkyl
Amides compound.
Finally illustrate, the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, this field is common
Other modifications or equivalent replacement that technical staff makes technical scheme of the present invention, without departing from technical solution of the present invention
Spirit and scope, be intended to be within the scope of the claims of the invention.
Claims (8)
1. a kind of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds, it is characterised in that:The compound
Chemical structure of general formula is such as shown in (I):
In formula:M indicates 1-12;
R1Expression-CH3;
R2Expression-CH3、-CH2CH3、-CH2Ph、-CH2Ph(2’-OCH3)、-CH2Ph(2’-OCF3)、-CH2Ph(2’-CH3)、-
CH2Ph(2’-CF3)、-CH2Ph(2’-Cl);
R3、R4Each independently represent H, C1~C12Alkyl or R3NR4Indicate morpholine ring, piperidine ring, 4- benzyl piepridines ring, piperazine
Ring, 4- by C1~C12Alkyl-substituted piperazine ring or nafoxidine ring.
2. a kind of medicine of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds as described in claim 1
Acceptable salt on, it is characterised in that:The pharmaceutically acceptable salt is 4- carbamate -3- methoxy cinnamic acids
Amine alkylamide compound and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, bigcatkin willow
Acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid
The salt of synthesis.
3. a kind of system of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds as described in claim 1
Preparation Method, which is characterized in that include the following steps:
The first step:Using potassium phthalimide as starting material, under the first solvent and the first alkaline condition with two alkyl halides
Based compound reacts, and obtains corresponding halogen compound;
Second step:Corresponding halogen compound described in the first step is reacted with organic amine compound in the second solvent, is obtained
Corresponding phthalimide alkyl amine compound;
Third walks:By corresponding phthalimide alkyl amine compound described in second step in third solvent with hydration
Hydrazinolysis reaction occurs for hydrazine, obtains corresponding primary amine compound;
4th step:By third walk described in corresponding primary amine compound contract under the 4th solvent and condensing agent with ferulic acid
Reaction is closed, corresponding ferulic amide class compound is obtained;
5th step:By corresponding ferulic amide class compound described in the 4th step under the 5th solvent and the second alkaline condition with
Corresponding carbamyl chloride reacts to get to 4- carbamate -3- methoxycinnamate acid amide alkylamide compounds.
4. the preparation of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds according to claim 3
Method, it is characterised in that:In the first step, the first solvent is ether, tetrahydrofuran, n,N-Dimethylformamide, diformazan
Base sulfoxide, dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile or C5-8Alkane;
Alkali used in first alkaline condition is alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal carbon
Sour hydrogen salt, alkali metal bicarbonates, C1-8Alkali metal salt, trimethylamine class or the quaternary amine bases of alcohol;
Potassium phthalimide:Dihaloalkyl compound:The molar feed ratio of alkali is 1.0:1.0~10.0:1.0~
10.0;
Reaction temperature is room temperature~150 DEG C;
Reaction time is 1~72 hour;
In the second step, the second solvent is ether, tetrahydrofuran, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane
Alkane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane;
Corresponding halogen compound:The molar feed ratio of organic amine compound is 1.0:1.0~10.0;
Reaction temperature is room temperature~150 DEG C;
Reaction time is 1~72 hour.
5. the preparation of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds according to claim 3
Method, it is characterised in that:In the third step, third solvent is tetrahydrofuran, n,N-Dimethylformamide, dimethyl Asia
Sulfone, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane;
Corresponding phthalimide alkyl amine compound:The molar feed ratio of hydrazine hydrate is 1.0:1.0~20.0;
Reaction temperature is room temperature~150 DEG C;
Reaction time is 1~72 hour;
In 4th step, the 4th solvent is tetrahydrofuran, n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), C3-8Aliphatic ketone,
Benzene, toluene, acetonitrile, dichloromethane, chloroform, C1-8Alcohol or C5-8Alkane;
Condensing agent is:1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole, two hexamethylenes
Base carbodiimide and 4-dimethylaminopyridine, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate or two rings
Hexyl carbodiimide;
Corresponding primary amine compound:Ferulic acid:The molar feed ratio of condensing agent is 1.0:1.0~10.0:1.0~10.0;
Reaction temperature is room temperature~100 DEG C;
Reaction time is 1~72 hour.
6. the preparation of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds according to claim 3
Method, it is characterised in that:In 5th step, the 5th solvent is C3-8Aliphatic ketone, N,N-dimethylformamide, ether, isopropyl
Ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, glycol dimethyl ether, C1-6Aliphatic acid and C1-6The formed ester of fatty alcohol, dichloromethane,
Chloroform, 1,2- dichloroethanes, benzene,toluene,xylene, chlorobenzene, o-dichlorohenzene, acetonitrile, dimethyl sulfoxide (DMSO) or pyridine;
Alkali used in second alkaline condition is alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate, alkali gold
Category or alkali metal bicarbonates, C1-6Fatty acid alkali metal salt, piperidines, nafoxidine, triethylamine, tri-n-butylamine, trioctylamine, pyrrole
Pyridine, N-methylmorpholine, N- methyl piperidines, triethylene diamine or tetrabutylammonium hydroxide;
Corresponding ferulic amide class compound:Acylating agent acyl chlorides:The molar feed ratio of alkali is 1.0:1.0~60.0:1.0~
100.0;
Reaction temperature is -20 DEG C~130 DEG C;
Reaction time is 1~120 hour.
7. a kind of 4- carbamates -3- methoxycinnamate acid amide alkylamide compounds as described in claim 1 or its
Purposes of the pharmaceutically acceptable salt in preparing treatment and/or preventing nervus retrogression relevant disease drug.
8. purposes according to claim 7, it is characterised in that:The drug is by the 4- carbamate -3- first
Oxygroup Chinese cassia tree acid amide alkylamide compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable loads
Body or excipient are prepared.
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