CN105646289A - 4-Carbamate-3-methoxy cinnamate aminoalkyl amide compound and preparation method and application thereof - Google Patents

4-Carbamate-3-methoxy cinnamate aminoalkyl amide compound and preparation method and application thereof Download PDF

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CN105646289A
CN105646289A CN201610200308.XA CN201610200308A CN105646289A CN 105646289 A CN105646289 A CN 105646289A CN 201610200308 A CN201610200308 A CN 201610200308A CN 105646289 A CN105646289 A CN 105646289A
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benzyl
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CN105646289B (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
    • 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
    • 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
    • C07D295/12—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
    • 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 a 4-carbamate-3-methoxy cinnamate aminoalkyl amide compound and a preparation method and application thereof. This compound is used to treat neurodegenerative diseases, including, but not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV related dementia, multiple sclerosis, progressive amyotrophic lateral sclerosis, neuropathic pain, glaucoma and other neurodegenerative diseases.

Description

A kind of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound and its production and use
Technical field
The present invention relates to medicinal chemistry art, especially relate to a kind of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound and its production and use.
Background technology
Vascular dementia (VascularDementia, VD) it is the clinical syndrome of intelligence caused by various types of cerebrovascular disease (including ischemic cerebrovascular, hemorrhagic apoplexy, acute and chronic Hypoxic cerebrovascular disease etc.) and cognitive dysfunction, its main clinical manifestation includes: going down and the change of emotion, personality of cognitive competence, memory and social-life ability, is a kind of chronic progressive disease. In first reason that Asian countries's vascular dementia such as Chinese, Japanese is senile dementia; Along with world population is to the continuous propelling of aging, cerebrovascular is increasing, and Onset of Vascular Dementia rate has the trend being gradually increasing, and has a strong impact on work and the quality of life of old people, and brings heavy economy and mental burden to society and family. Therefore, VD has become current geriatrics and an important study hotspot in psychologic medicine field. Vascular dementia is complicated due to pathogenesis, there is no the medicine that can block disease progression, and current clinical treatment is to improve brain blood circulation and brain metabolism, and it is main for strengthening brain nutrition.
In recent years, research both at home and abroad shows, is also often accompanied by the exception of cholinergic system while VD patients's cerebral damage. VD patient's hippocampus ChAT positive neuron and fibre density reduce, the ChAT activity decrease of different parts in brain, and the ACh concentration in VD Cerebrospinal Fluid in Patients is significantly lower than normal level, and the degree that its concentration reduces is proportionate with the dull-witted order of severity; And cerebral ischemia can cause that in brain, acetylcholine esterase active rises; Simultaneously it have also been found that acetylcholinesteraseinhibitors inhibitors such as: HuperzineA and Revastigmine can protect the neuronal damage that ischemia causes, and the recovery of nerve injury and brain function after cerebral ischemia can be promoted. This shows that acetylcholinesteraseinhibitors inhibitors can also be used for the treatment of vascular dementia.
Alzheimer's disease (Alzheimer ' sdisease, AD) is one of sickness rate and the highest disease of fatality rate in old people. Alzheimer's disease international association (Alzheimer ' sdiseaseInternational, ADI) " 2015 whole world Alzheimer's disease report " issued is pointed out, the whole world in 2015 has suffers from dementia more than 46,000,000 people, it is predicted, to the year two thousand fifty, the puzzlement that the whole world will have 1.315 hundred million populations to be subject to dementia, wherein the sickness rate of China Dementia patients has reached 6.61%.Along with the prolongation of existent age per capita, primary disease has developed into the main burden of society and medical health system, and brings heavy spirit and economic pressures for society, patient and family members. Thus, research and develop novel senile dementia medicine significant. From the market demand, Alzheimer's disease international association predicts, the global marketing volume to the year two thousand fifty curing senile dementia medicine will reach 600,000,000,000 dollars; In China, along with the rapid rising of senile dementia sickness rate, the market of this kind of medicine also rapid expanding.
AD be a kind of chronic, with Progressive symmetric erythrokeratodermia memory and Cognitive function damage be feature multi-pathogenesis, too many levels participate in complicated neurodegenerative diseases, its key pathological feature is beta amyloid peptide (��-amyloidpeptide, A ��) senile plaque (Senileplaque of a large amount of formation of deposits, SP), the neurofibrillary tangles (Neurofibrillarytangle that Protein tau Hyperphosphorylationof is formed, NFT), and with the degeneration etc. of neuronic apoptosis and nerve synapse. In recent years, many researcheres are devoted to from molecule and cellular level to disclose the pathogeny of AD, propose multiple hypothesis, as: cholinergic neuron damage, the deposition of amyloid, Protein tau Hyperphosphorylationof, inflammation, free-radical oxidation, metal ion imbalance etc., therefore, the novel therapeutic approach developed for these pathogenesis and means, will be hopeful to alleviate and improve the state of an illness of AD patient.
The drug main effectively treating AD at present clinically to have two classes: the cholinergic hypothesis that (1) causes cognitive function to be lacked of proper care based on neurotransmitter acetylcholine deficiency, acetylcholinesteraseinhibitors inhibitors is adopted to improve levels of acetylcholine in patient's brain, as: Tacrine, Donepezil, Ravastigmine, Galantamine; (2) N-methyl-D-aspartate (NMDA) acceptor inhibitor is adopted to reduce the glutamate, Glu damage to neurocyte, as: MemantineHydrochloride. But these medicines exist, and action target spot is single, toxic and side effects is more, to the problem such as the long-term efficacy of AD patient is not good enough.
Therefore, research and development have novel chemical structure, novel mechanism of action, multiaction target spot, low toxic and side effects anti-neurodegenerative disease therapeutic agent not only conform with the urgent needs of social senilization's process, and there is good market prospect.
Summary of the invention
In view of this, it is an object of the invention to for the deficiencies in the prior art, a kind of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound and its production and use is provided, achieve the purpose of the anti-neurodegenerative disease therapeutic agent preparing multiaction target spot, low toxic and side effects, include but not limited to the neurodegenerative diseases such as vascular dementia, Alzheimer, Parkinson's disease, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain, glaucoma.
For reaching above-mentioned purpose, the present invention by the following technical solutions:
A kind of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound, the chemical structure of general formula of this compound is as shown in (I):
In formula: m represents 1-12;
R1Represent H, C1��C12Alkyl;
R2Represent C1��C12Alkyl, benzyl, substituted benzyl;
R1NR2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4-position are by C1��C12The replaced piperidyl of alkyl, 4-position by the replaced piperidyl of benzyl or substituted benzyl, piperazinyl, 4-position by C1��C12The replaced piperazinyl of alkyl, 4-position are by the replaced piperazinyl of benzyl or substituted benzyl;
R3��R4Represent H, C independently of one another1��C12Alkyl, or R3NR4Represent that morpholine ring, piperidine ring, 4-benzyl piepridine ring, piperazine ring, 4-position are by C1��C12The piperazine ring of alkyl replacement or nafoxidine ring;
Described substituted benzyl refer to by phenyl ring by 1-4 selected from the replaced benzyl of the group of lower group: F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxyl, trifluoromethyl, trifluoromethoxy, nitro, cyano group, these substituent groups can at any possible position of phenyl ring.
Preferably, the chemical structure of general formula of this compound is as shown in (I):
In formula: m represents 1-8;
R1Represent H, methyl, ethyl;
R2Represent methyl, ethyl, benzyl, 2-methoxy-benzyl, 2-trifluoro-methoxybenzyl, 2-methyl-benzyl, 2-trifluoromethyl benzyl, 2-chlorobenzyl;
R1NR2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4-ethyl piperidine base, 4-benzyl piepridine base, piperazinyl, 4-methyl piperazine base, 4-benzyl diethylenediamine base, 4-[(2-methoxyl group) benzyl] piperazinyl;
R3��R4Represent H, C independently of one another1��C12Alkyl, or R3NR4Represent that morpholine ring, piperidine ring, 4-benzyl piepridine ring, piperazine ring, 4-position are by C1��C12The piperazine ring of alkyl replacement or nafoxidine ring.
The pharmaceutically acceptable salt of a kind of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound, described pharmaceutically acceptable salt is above-mentioned 4-carbamate-3-methoxycinnamate acid amide alkylamide compound and hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, C1-6The salt of alkyl sulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-methyl benzenesulfonic acid.
The preparation method of above-mentioned 4-carbamate-3-methoxycinnamate acid amide alkylamide compound, comprises the steps:
The first step: with potassium phthalimide for initiation material, reacts with Dihaloalkyl compound under the first solvent and the first alkali condition, obtains corresponding halogen compound;
Second step: halogen compound corresponding described in the first step and organic amine compound are reacted in the second solvent, obtains corresponding phthalimide alkyl amine compound;
3rd step: phthalimide alkyl amine compound corresponding described in second step is reacted with hydrazine hydrate generation hydrazinolysis in the 3rd solvent, obtains corresponding primary amine compound;
4th step: condensation reaction is occurred under the 4th solvent and condensing agent for primary amine compound corresponding described in the 3rd step and ferulic acid, obtains corresponding ferulic amide compounds;
5th step: reacted with corresponding carbamyl chloride under the 5th solvent and the second alkali condition by ferulic amide compounds corresponding described in the 4th step, namely obtains 4-carbamate-3-methoxycinnamate acid amide alkylamide compound.
Preferably, in the described first step, the first solvent is ether, oxolane, DMF, dimethyl sulfoxide, dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile or C5-8Alkane; Preferably the first solvent is N,N-dimethylformamide, acetone, acetonitrile, oxolane or toluene;
Alkali used by first alkali condition is alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, trimethylamine class or quaternary amine bases (such as triethylamine, tri-n-butylamine, trioctylamine, pyridine, N-methylmorpholine, N-methyl piperidine, triethylene diamine, TBAH), it is preferable that alkali is potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or Feldalat NM;
Potassium phthalimide: Dihaloalkyl compound: the molar feed ratio of alkali is 1.0:1.0��10.0:1.0��10.0, it is preferable that molar feed ratio is 1.0:1.0��5.0:1.0��5.0;
Reaction temperature is room temperature��150 DEG C, it is preferable that reaction temperature is room temperature��120 DEG C;
Response time is 1��72 hour, it is preferable that the response time is 2��24 hours.
In described second step, the second solvent is ether, oxolane, DMF, dimethyl sulfoxide, dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane, it is preferable that the second solvent is DMF, acetone, acetonitrile, oxolane or toluene;
Corresponding halogen compound: the molar feed ratio of organic amine compound is 1.0:1.0��10.0, it is preferable that molar feed ratio is 1.0:1.0��5.0;
Reaction temperature is room temperature��150 DEG C, it is preferable that reaction temperature is room temperature��120 DEG C;
Response time is 1��72 hour, it is preferable that the response time is 2��24 hours.
Preferably, in the 3rd described step, the 3rd solvent is oxolane, DMF, dimethyl sulfoxide, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane, it is preferable that the 3rd solvent is toluene, ethanol;
Corresponding phthalimide alkyl amine compound: the molar feed ratio of hydrazine hydrate is 1.0:1.0��20.0, it is preferable that molar feed ratio is 1.0:2.0��10.0;
Reaction temperature is room temperature��150 DEG C, it is preferable that reaction temperature is room temperature��120 DEG C;
Response time is 1��72 hour, it is preferable that the response time is 2��24 hours.
In the 4th described step, the 4th solvent is oxolane, DMF, dimethyl sulfoxide, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, dichloromethane, chloroform, C1-8Alcohol or C5-8Alkane, it is preferable that the 4th solvent is acetone, oxolane, toluene, dichloromethane or chloroform;
Condensing agent is: dicyclohexylcarbodiimide, dicyclohexylcarbodiimide and DMAP, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole, it is preferable that condensing agent is dicyclohexylcarbodiimide and DMAP or 1-ethyl-(3-dimethylaminopropyl) 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, it is preferable that ingredient proportion is 1.0:1.0��5.0:1.0��5.0;
Reaction temperature is room temperature��100 DEG C, it is preferable that reaction temperature is room temperature��50 DEG C;
Response time is 1��72 hour, it is preferable that the response time is 2��24 hours.
Preferably, in the 5th described step, the 5th solvent is C3-8Aliphatic ketone, N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, glycol dimethyl ether, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, dichloromethane, chloroform, 1,2-dichloroethanes, benzene,toluene,xylene, chlorobenzene, o-dichlorohenzene, acetonitrile, dimethyl sulfoxide or pyridine, preferably the 5th solvent is ether, acetonitrile, acetic acid, acetone, DMF, toluene, oxolane or pyridine;
Alkali used by second alkali condition is alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, alkali metal or alkali metal bicarbonates, C1-6The combination of fatty acid alkali metal salt, piperidines, nafoxidine, triethylamine, tri-n-butylamine, trioctylamine, pyridine, N-methylmorpholine, N-methyl piperidine, triethylene diamine or TBAH or above-mentioned various alkali, it is preferable that alkali is: potassium carbonate, sodium carbonate, sodium bicarbonate, potassium acetate, pyridine, triethylamine, N-methylmorpholine;
Corresponding ferulic amide compounds: acylating agent acyl chlorides: the molar feed ratio of alkali is 1.0:1.0��60.0:1.0��100.0, it is preferable that molar feed ratio is: 1.0:1.0��20.0:1.0��50.0;
Reaction temperature is-20 DEG C��130 DEG C, it is preferable that reaction temperature is 0 DEG C��80 DEG C;
Response time is 1��120 hour, it is preferable that the response time is 2��48 hours.
Above-mentioned 4-carbamate-3-methoxycinnamate acid amide alkylamide compound or its pharmaceutically acceptable salt purposes in preparation treatment and/or prevention nervus retrogression relevant disease medicine, include but not limited to the neurodegenerative diseases such as vascular dementia, Alzheimer, Parkinson's disease, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain, glaucoma.
Preferably, described medicine, it is characterised in that include pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier or excipient of described 4-carbamate-3-methoxycinnamate acid amide alkylamide compound or described 4-carbamate-3-methoxycinnamate acid amide alkylamide compound.
The invention has the beneficial effects as follows:
(1) acetylcholinesterase is respectively provided with the effect of significantly inhibiting by the compound of the present invention, its IC50It is 0.01 ��M��5 ��Ms, and apparently higher than corresponding ferulic acid fatty amine alkylamide compound and ferulic acid alpha substituted benzylamine alkylamide compound, and the IC that positive control medicine Rivastigmine is to acetylcholine ester enzyme level50It it is 6.3 ��Ms; The inhibitory activity of acetylcholinesterase is much higher than the inhibitory activity to butyrylcholine esterase by the compound of the present invention, illustrates that acetylcholinesterase is had certain selective inhibitory by compound disclosed in this invention.
(2) the PC12 cell injury of hydrogen peroxide-induced is all had significant protective effect by the compound of the present invention, and 10-5Antioxidant activity under mol/L concentration is all better than ferulic acid.
(3) compound of the present invention is to A ��1-42The gathering of auto-induction is respectively provided with the effect of significantly inhibiting, its IC50Be 0.01 ��M��5 ��Ms, it is suppressed that rate 60-95%, and positive control medicine curcumin and ferulic acid under 25 ��Ms of concentration to A ��1-42The suppression ratio respectively 56.2% and 28.3% that auto-induction is assembled.
(4) compound of the present invention is respectively provided with good blood brain barrier through ability, and is better than ferulic acid fatty amine alkylamide compound that corresponding 4-position is free hydroxyl group and 4-position is the ferulic acid alpha substituted benzylamine alkylamide compound of free hydroxyl group.
(5) scopolamine is caused mice and obtains dysmnesia and have the improvement result of dose dependent by the compound of the present invention, compare with model group and be respectively provided with significant difference (p < 0.01), and be better than ferulic acid fatty amine alkylamide compound that corresponding 4-position is free hydroxyl group and 4-position is the ferulic acid alpha substituted benzylamine alkylamide compound of free hydroxyl group.
(6) ethanol induced mice memory representational role obstacle is respectively provided with the effect of being obviously improved by the compound of the present invention, all there is significant difference (p < 0.01) compared with model group, and be better than ferulic acid fatty amine alkylamide compound that corresponding 4-position is free hydroxyl group and 4-position is the ferulic acid alpha substituted benzylamine alkylamide compound of free hydroxyl group.
Detailed description of the invention
Below in conjunction with the specific embodiment of the invention, technical scheme is clearly and completely described, it is clear that described embodiment is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art obtain under not making creative work premise, broadly fall into the scope of protection of the invention. In the embodiment of the present invention, moieties adopts following abbreviated form: N, dinethylformamide is abbreviated as DMF, dicyclohexylcarbodiimide is abbreviated as DCC, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and is abbreviated as EDC, and I-hydroxybenzotriazole is abbreviated as HOBT.
Embodiment 1-20
The preparation method of a kind of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound, comprises the following steps:
The first step: add the alkali used by potassium phthalimide, the first solvent, the first alkali condition and dibromo alkyl compound in reaction bulb, temperature rising reflux stirring reaction, after reaction terminates, filtered while hot, a small amount of washing with acetone filter cake, filtrate decompression is evaporated off solvent and excessive dibromo alkyl compound, and residue, through column chromatography purification (eluent: petroleum ether: acetone=30:1v/v), obtains phthalimide alkyl bromide;
Second step: be all dissolved in the second solvent by above-mentioned phthalimide alkyl bromide, adds organic amine compound, is warming up to return stirring reaction, and reaction process TLC follows the tracks of; After reaction terminates, remove solvent under reduced pressure, second solvent in residue, successively with 5% sodium hydrate aqueous solution and deionized water wash, organic layer filters after drying through anhydrous sodium sulfate, removing solvent under reduced pressure, residue, through column chromatography purification (eluent: petroleum ether: acetone=15:1v/v), obtains phthalimide alkyl amine compound;
3rd step: be all dissolved in the 3rd solvent by phthalimide alkyl amine compound, adds hydrazine hydrate N2H4.H2O, is warming up to return stirring reaction, and reaction process TLC follows the tracks of; After reaction terminates, sucking filtration while hot, a small amount of washing with alcohol filter cake, filtrate decompression is evaporated off solvent, and residue, through column chromatography purification (eluent: dichloromethane: methanol=15:1v/v), obtains corresponding alkylamine primary amine compound;
4th step: be all dissolved in the 4th solvent by above-mentioned corresponding alkylamine primary amine compound, adds condensing agent and ferulic acid, reaction is stirred at room temperature, and reaction process TLC follows the tracks of; After reaction terminates, remove the 4th solvent under reduced pressure, residue adds the 4th solvent, successively with saturated aqueous sodium carbonate and saturated sodium-chloride water solution washing, organic layer filters after drying through anhydrous sodium sulfate, removing the 4th solvent under reduced pressure, residue, through column chromatography purification (eluent: dichloromethane: methanol=10:1v/v), obtains corresponding ferulic acid alkylamine amides compound;
5th step: being all dissolved in the 5th solvent by above-mentioned corresponding ferulic acid alkylamine amides compound, add the alkali used by the second alkali condition and carbamyl chloride, be warming up to 60 DEG C of stirring reactions, reaction process TLC follows the tracks of; After reaction terminates, remove the 5th solvent under reduced pressure, residue adds the 5th solvent, successively with saturated aqueous sodium carbonate and saturated sodium-chloride water solution washing, organic layer filters after drying through anhydrous sodium sulfate, removes solvent under reduced pressure, and residue is through column chromatography purification (eluent: dichloromethane: methanol=10:1v/v), obtain corresponding 4-carbamate-3-methoxycinnamate acid amide alkylamide compound (I), the equal warp of chemical constitution1H-NMR,13C-NMR and ESI-MS confirms.
Table 1 first step process conditions and result
The yield of product is had serious impact by process conditions as shown in Table 1, selects suitable process conditions that product yield has the important meaning. First solvent adopts acetone as shown in Table 1, alkali used by first alkali condition adopts triethylene diamine, and potassium phthalimide: Dihaloalkyl compound: the molar feed ratio of triethylene diamine is 1:4:3 reaction temperature is 65 DEG C, when response time is 18h, yield is 95.3%, and yield is the highest.
Table 2 second step process conditions and result
The yield of product is had serious impact by process conditions as shown in Table 2, selects suitable process conditions that product yield has important impact. Second solvent adopts toluene as shown in Table 2, corresponding halogen compound: the molar feed ratio of organic amine compound is 1:2, reaction temperature is 120 DEG C, when response time is 12h, yield is 97.5%, yield is the highest, and changes an any of the above described condition and all can yield be had an immense impact on.
Table 3 three step process condition and result
The yield of product is had serious impact by process conditions as shown in Table 3, selects suitable process conditions that product yield has important impact. 3rd solvent adopts ethanol as shown in Table 3, and molar feed ratio is 1:6, and reaction temperature is 80 DEG C, and when the response time is 18h, yield is 97.5%, and yield is the highest, and changes an any of the above described condition and all can yield be had an immense impact on.
Table 4 the 4th step process condition and result
The yield of product is had serious impact by process conditions as shown in Table 4, selects suitable process conditions that product yield has important impact. 4th solvent adopts dichloromethane as shown in Table 4, condensing agent adopts EDC:HOBT=1:2 composite, molar feed ratio is 1:3:5, reaction temperature is 40, when response time is 18h, yield is 87.8%, and yield is the highest, and changes an any of the above described condition and all can yield be had an immense impact on.
Table 5 the 5th step process condition and result
The yield of product is had serious impact by process conditions as shown in Table 5, selects suitable process conditions that product yield has important impact. 5th solvent adopts N as shown in Table 4, dinethylformamide, alkali used by second alkali condition adopts potassium acetate, molar feed ratio is 1:10:25, reaction temperature is 60, and when the response time is 36h, yield is 97.8%, yield is the highest, and changes an any of the above described condition and all can yield be had an immense impact on.
Embodiment 21
Concrete technology condition and embodiment 11 are identical, difference again with investigate different substituents, concrete substituent group is in Table 6, gained 4-carbamate-3-methoxycinnamate acid amide alkylamide compound, the equal warp of its chemical constitution1H-NMR,13C-NMR and ESI-MS confirms.
Table 6 different substituents is tested
Embodiment 22
The preparation method of the pharmaceutically acceptable salt of a kind of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound, comprises the following steps:
Take the 4-carbamate-3-methoxycinnamate acid amide alkylamide compound in table 6 respectively and acetone is stirring evenly and then adding into corresponding acid, temperature rising reflux stirring reaction 15-30 minute, reaction is cooled to room temperature after terminating, remove solvent under reduced pressure, residue acetone recrystallization, filter the solid precipitated out, obtain the pharmaceutically acceptable salt of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound, its chemical constitution warp1HNR and ESI-MS confirms.
Embodiment 23
The product prepared by embodiment 11 is adopted to carry out bioactivity screening experiment.
(1) acetylcholinesterase and butyrylcholine esterase inhibitory activity
1.0mmol/L acetylthiocholine iodide or sulfo-BuCh (equal available from Sigma) 30 �� L it is sequentially added in 96 orifice plates, the PBS 40 �� L of pH7.4, testing compound solution 20 �� L (DMSO content is less than 1%) and 10 �� L acetylcholinesterase (rat brain cortex 5% homogenate supernatant, the phosphate buffer of pH7.4 makes homogenate medium), after finishing mixing, hatch 15min for 37 DEG C, adding mass fraction in each hole is the 5 of 0.2%, 5'-dithio-bis-(2-nitro) benzoic acid (DTNB, available from Sigma) solution 30 �� L colour developing, the optical density (OD value) in each hole, 405nm place is measured by microplate reader, compare with the blank well being not added with testing sample, the computerized compound suppression ratio [enzyme inhibition rate=(1-sample sets OD value/blank group OD value) �� 100%] to enzyme, select five to six concentration of compound, measure its enzyme inhibition rate, and with the suppression ratio linear regression of the negative logarithm of this compound molar concentration with enzyme, molar concentration when trying to achieve 50% suppression ratio is the IC of this compound50. Measurement result shows, acetylcholinesterase is respectively provided with the effect of significantly inhibiting by compound disclosed in the embodiment of the present invention, its IC50It is 0.05 ��M��5 ��Ms, and apparently higher than corresponding ferulic acid fatty amine alkylamide compound and ferulic acid alpha substituted benzylamine alkylamide compound, and the IC that positive control medicine Rivastigmine is to acetylcholine ester enzyme level50It it is 6.3 ��Ms; Measurement result also shows, the inhibitory activity of acetylcholinesterase is much higher than the inhibitory activity to butyrylcholine esterase by compound disclosed in this project implementation example, illustrates that acetylcholinesterase is had certain selective inhibitory by compound disclosed in this invention.
(2) compound is to H2O2The protective effect screening of the PC12 cell injury of induction
The PC12 cell DMEM culture fluid containing 10% calf serum, with 1 �� 105Individual/mL density is inoculated on 96 well culture plates, and inoculation volume is 100mL/ hole, is subsequently placed into containing 5%CO237 DEG C of constant incubators in cultivate. After cultivating 24 hours, administration group adds the compound (final concentration of 10 of respective concentration-5Mol/L, 10-6Mol/L) 10mL/ hole, 2 hours (matched group and damage group add 10 �� L/ hole PBS respectively so that it is volume keeps equal) of preincubate. After PC12 cell incubation 2 hours, in administration group with damage group, it is separately added into 100 �� �� H2O2Damage agent 10 �� L/ hole (matched group adds 10 �� L/ hole PBS), after 30 minutes, all changes the culture fluid of each group the RPMI1640 culture fluid without calf serum into and continues to put into constant incubator cultivation 24 hours, and culture fluid volume thinks 100 �� L/ holes. After continuing cultivation 24 hours, respectively group addition 5mg/mL, MTT100 �� L/ hole, carries out living cells dyeing. After 3 hours, each group adds 100%DMSO stop buffer 100 �� L/ hole, fully dissolves mixing. Measuring the OD value of each group under the wavelength of 490nm, test result repeats 3 times, and with Duncan ' stest method statistic, the numeric representation of each group is mean �� S.E.M., and with matched group for 100%, administration group and damage class value represent with the percentage ratio of matched group. Measurement result shows, in the embodiment of the present invention, the PC12 cell injury of hydrogen peroxide-induced is all had significant protective effect by disclosed compound, and 10-5Antioxidant activity under mol/L concentration is all better than ferulic acid.
(3) compound suppresses A beta peptide aggregation determination of activity
Take the A �� of 20 �� L1-42The testing compound solution of solution+20 �� L, 20 �� L A ��1-42Solution+20 �� LPBS buffer (containing 2%DMSO), 20 �� LPBS buffer (containing 2%DMSO)+20 �� LPBS buffer (containing 25%DMSO) in black 96 orifice plate, compound and A ��1-42Ultimate density be 25 ��Ms. Hatch 24h for 37 DEG C, it is subsequently adding the glycine-NaOH buffer (pH=8.5) of the 160 �� L 50mM containing 5 ��Ms of thioflavine Ts, after jolting 5s, launches mensuration fluorescent value under wavelength by VarioskanFlashMultimodeReader (ThermoScientific) multi-functional microplate reader in 446nm excitation wavelength and 490nm immediately; A ��1-42The fluorescent value of+testing compound is recorded as IFi, A ��1-42The fluorescent value of+PBS is recorded as IFc, it is recorded as IF containing only the fluorescent value having PBS0, compound suppress A ��1-42The suppression ratio computing formula of self assemble is: 100-(IFi-IF0)/(IFc-IF0) * 100. The each concentration of each compound measures two multiple holes. Measurement result shows, compound disclosed in the embodiment of the present invention is to A ��1-42The gathering of auto-induction is respectively provided with the effect of significantly inhibiting, its IC50Be 0.1 ��M��20 ��Ms, it is suppressed that rate 60-95% and positive control medicine curcumin and ferulic acid under 25 ��Ms of concentration to A ��1-42The suppression ratio respectively 56.2% and 28.3% that auto-induction is assembled.
(4) blood brain barrier passes through merit rating (PAMPA-BBB)
Medulla sus domestica phospholipid (PBL, purchased from AvantiPolarLipids, Inc.) is dissolved in dodecane (Sigma) (20mg/mL), takes 4 �� L droppings on the lipotropy filter membrane of receptor hole with Biomimetic membrane. Receptor hole adds 350 �� LPBS/EtOH (70:30) buffer, for adding 200 �� L sample liquid in body opening, (compound dissolution obtains 5mg/mL storing solution in DMSO, then to be diluted to ultimate density with 50 times of PBS/EtOH (70:30) buffer be 100mg/mL. Place 96 hole filter plates and receive on plate (Millipore) in PVDF, immobilized artificial membrane is made can just to touch for body fluid, it is thusly-formed the confession body fluid that sandwich structure-bottom is determinand, centre is artificial phospholipid's film, drug molecule to be measured is from for diffusion body opening, through immobilized artificial membrane, enter in the receptor hole of upper strata. 25 DEG C of static 18h, after hatching, remove donor plate gently, draw by body fluid with for body fluid respectively, concentration, each sample four hole, independent test three times is measured by VarioskanFlashMultimodeReader microplate reader, test the OD value under 10 wavelength (250-450nm), draw effective transmissivity (P according to formulae). PAMPA effective permeability Pe(cm��s-1) it is calculated as follows:
Pe=-VdVa/[(Vd+Va)At]ln(1-drugacceptor/drugequilibrium)
Wherein, VdIt is the volume for body opening, VaBeing the volume of receptor hole, A is the area of artificial phospholipid's film, and t represents time of penetration, drugacceptor is the absorbance for body opening liquid, drugequilibrium is Theoretical Equilibrium absorbance, and result represents with mean value �� standard error (Standerror, S.E.). Test result shows, under this experiment condition, compound disclosed in this invention is respectively provided with good blood brain barrier through ability, and is better than ferulic acid fatty amine alkylamide compound that corresponding 4-position is free hydroxyl group and 4-position is the ferulic acid alpha substituted benzylamine alkylamide compound of free hydroxyl group.
(5) compound impact on scopolamine induced mice memory acquisition disturbance
SPF level ICR male mice, 25-30g, be randomly divided into: normal group, model group, by reagent high and low dose group (5.0,2.5mg/kg), often 10 animals of group.Disposable gavage gives test medicine, and blank group and model group give solvent 0.5%CMC-Na, and administration volume is 0.1ml/10g; 45min after medicine, normal group mouse peritoneal injecting normal saline, all the other each treated animals all inject scopolamine (5mg/kg), and administration volume is 0.1ml/10g; After modeling 30min, mice is put into non-electricity irritation Y labyrinth and carries out Behavior test. During test, mice is put in an arm end, it is allowed to condition in labyrinth and freely walks 8min, record its number of times entering each arm and alternate frequency, alternately rate is calculated: alternately rate %=[alternate frequency/(always entering number of times-2)] �� 100 according to below equation, result represents with mean �� standard deviation, and group difference adopts one factor analysis of variance. Measurement result shows, under this experiment condition, scopolamine is caused mice acquisition dysmnesia and has the improvement result of dose dependent by compound disclosed in this invention, compare with model group and be respectively provided with significant difference (p < 0.01), and be better than ferulic acid fatty amine alkylamide compound that corresponding 4-position is free hydroxyl group and 4-position is the ferulic acid alpha substituted benzylamine alkylamide compound of free hydroxyl group.
Behavioral experiment is complete takes brain by mice broken end immediately, uses pre-cooling normal saline flushing, is rapidly separated out cerebral hippocampal tissue on ice chest, weigh hippocampal tissue weight, adds 9 times of 4 DEG C of normal saline and make the homogenate of 10%, 3500r.min-1, 4 DEG C of centrifugal 15min ,-20 DEG C of storage supernatant are to be measured, measure total protein concentration by Coomassie brilliant blue. The method specified according to test kit measures AChE content under the wavelength of 412nm, and AChE vigor is expressed as U/mg. The vigor of ChAT is measured by the ACh synthetic reaction of ChAT catalysis. Operational approach, also according to the explanation of test kit, measures under 412nm wavelength, and the vigor U/mg of ChAT represents. Measurement result shows, under this experiment condition, compound disclosed in this invention can strengthen the vigor of acetylcholine transferase (ChAT), compare with blank group and be respectively provided with significant difference (p < 0.01), and be better than ferulic acid fatty amine alkylamide compound that corresponding 4-position is free hydroxyl group and 4-position is the ferulic acid alpha substituted benzylamine alkylamide compound of free hydroxyl group.
(6) compound impact on ethanol induced mice reproducibility dysmnesia
SPF level ICR male mice, 25-30g, be randomly divided into: normal group, model group, by reagent high and low dose group (5.0,2.5mg/kg), Rivastigmine group (3mg/kg), often 10 animals of group. Every day, gavage was to test medicine, and blank group and model group give solvent 0.5%CMC-Na, and administration volume is 0.1ml/10g, successive administration 32 days; During administration 1��24 day, 30min after every day medicine, model group and each administration group gavage 0.1ml/10g ethanol (15%w/v), successive administration 24 days, remove ethanol and enter ethanol and clean the phase, medicine continues to give; Within 31,32 days, animal Jumping test is carried out in what be administered; after medicine, 45min is trained or test experiments; mice is allowed to be placed in diving tower instrument during training; put down gently and be energized on platform, when animal is raised from platform, contact copper grid with biped for getting an electric shock simultaneously, be considered as wrong reaction; mice shocked by electricity after normal avoidance response for escape to platform; record mice escapes the incubation period to platform, and records electric shock number of times in 5min, in this, as school grade. Testing after 24 hours, record mice first time jumps off the number of times (errors number) shocked by electricity in the time (incubation period) shocked by electricity and 5min thereof, in this, as memory representational role evaluation index.Test result represents with mean �� standard deviation, and group difference adopts one factor analysis of variance. Test result shows, under this experiment condition, ethanol induced mice memory representational role obstacle is respectively provided with the effect of being obviously improved by compound disclosed in this invention, all there is significant difference (p < 0.01) compared with model group, and be better than ferulic acid fatty amine alkylamide compound that corresponding 4-position is free hydroxyl group and 4-position is the ferulic acid alpha substituted benzylamine alkylamide compound of free hydroxyl group.
What finally illustrate is, above example is only in order to illustrate technical scheme and unrestricted, other amendments that technical scheme is made by those of ordinary skill in the art or equivalent replace, without departing from the spirit and scope of technical solution of the present invention, all should be encompassed in the middle of scope of the presently claimed invention.

Claims (9)

1. a 4-carbamate-3-methoxycinnamate acid amide alkylamide compound, it is characterised in that: the chemical structure of general formula of this compound is as shown in (I):
In formula: m represents 1-12;
R1Represent H, C1��C12Alkyl;
R2Represent C1��C12Alkyl, benzyl, substituted benzyl;
R1NR2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4-position are by C1��C12The replaced piperidyl of alkyl, 4-position by the replaced piperidyl of benzyl or substituted benzyl, piperazinyl, 4-position by C1��C12The replaced piperazinyl of alkyl, 4-position are by the replaced piperazinyl of benzyl or substituted benzyl;
R3��R4Represent H, C independently of one another1��C12Alkyl, or R3NR4Represent that morpholine ring, piperidine ring, 4-benzyl piepridine ring, piperazine ring, 4-position are by C1��C12The piperazine ring of alkyl replacement or nafoxidine ring;
Described substituted benzyl refer to by phenyl ring by 1-4 selected from the replaced benzyl of the group of lower group: F, Cl, Br, I, C1-4Alkyl, C1-4Alkoxyl, trifluoromethyl, trifluoromethoxy, nitro, cyano group, these substituent groups can at any possible position of phenyl ring.
2. 4-carbamate-3-methoxycinnamate acid amide alkylamide compound according to claim 1, it is characterised in that: the chemical structure of general formula of this compound is as shown in (I):
In formula: m represents 1-8;
R1Represent H, methyl, ethyl;
R2Represent methyl, ethyl, benzyl, 2-methoxy-benzyl, 2-trifluoro-methoxybenzyl, 2-methyl-benzyl, 2-trifluoromethyl benzyl, 2-chlorobenzyl;
R1NR2Also illustrate that nafoxidine base, morpholinyl, piperidyl, 4-ethyl piperidine base, 4-benzyl piepridine base, piperazinyl, 4-methyl piperazine base, 4-benzyl diethylenediamine base, 4-[(2-methoxyl group) benzyl] piperazinyl;
R3��R4Represent H, C independently of one another1��C12Alkyl, or R3NR4Represent that morpholine ring, piperidine ring, 4-benzyl piepridine ring, piperazine ring, 4-position are by C1��C12The piperazine ring of alkyl replacement or nafoxidine ring.
3. the pharmaceutically acceptable salt of a 4-carbamate-3-methoxycinnamate acid amide alkylamide compound as claimed in claim 1, it is characterised in that: described pharmaceutically acceptable salt is 4-carbamate-3-methoxycinnamate acid amide alkylamide compound and hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, C1-6The salt of alkyl sulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-methyl benzenesulfonic acid.
4. the preparation method of a 4-carbamate-3-methoxycinnamate acid amide alkylamide compound as claimed in claim 1, it is characterised in that comprise the steps:
The first step: with potassium phthalimide for initiation material, reacts with Dihaloalkyl compound under the first solvent and the first alkali condition, obtains corresponding halogen compound;
Second step: halogen compound corresponding described in the first step and organic amine compound are reacted in the second solvent, obtains corresponding phthalimide alkyl amine compound;
3rd step: phthalimide alkyl amine compound corresponding described in second step is reacted with hydrazine hydrate generation hydrazinolysis in the 3rd solvent, obtains corresponding primary amine compound;
4th step: condensation reaction is occurred under the 4th solvent and condensing agent for primary amine compound corresponding described in the 3rd step and ferulic acid, obtains corresponding ferulic amide compounds;
5th step: reacted with corresponding carbamyl chloride under the 5th solvent and the second alkali condition by ferulic amide compounds corresponding described in the 4th step, namely obtains 4-carbamate-3-methoxycinnamate acid amide alkylamide compound.
5. the preparation method of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound according to claim 4, it is characterized in that: in the described first step, first solvent is ether, oxolane, DMF, dimethyl sulfoxide, dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile or C5-8Alkane; Preferably the first solvent is N,N-dimethylformamide, acetone, acetonitrile, oxolane or toluene;
Alkali used by first alkali condition is alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, trimethylamine class or quaternary amine bases (such as triethylamine, tri-n-butylamine, trioctylamine, pyridine, N-methylmorpholine, N-methyl piperidine, triethylene diamine, TBAH), it is preferable that alkali is potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or Feldalat NM;
Potassium phthalimide: Dihaloalkyl compound: the molar feed ratio of alkali is 1.0:1.0��10.0:1.0��10.0, it is preferable that molar feed ratio is 1.0:1.0��5.0:1.0��5.0;
Reaction temperature is room temperature��150 DEG C, it is preferable that reaction temperature is room temperature��120 DEG C;
Response time is 1��72 hour, it is preferable that the response time is 2��24 hours.
In described second step, the second solvent is ether, oxolane, DMF, dimethyl sulfoxide, dichloromethane, chloroform, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane, it is preferable that the second solvent is DMF, acetone, acetonitrile, oxolane or toluene;
Corresponding halogen compound: the molar feed ratio of organic amine compound is 1.0:1.0��10.0, it is preferable that molar feed ratio is 1.0:1.0��5.0;
Reaction temperature is room temperature��150 DEG C, it is preferable that reaction temperature is room temperature��120 DEG C;
Response time is 1��72 hour, it is preferable that the response time is 2��24 hours.
6. the preparation method of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound according to claim 4, it is characterised in that: in the 3rd described step, the 3rd solvent is oxolane, DMF, dimethyl sulfoxide, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, C1-8Alcohol or C5-8Alkane, it is preferable that the 3rd solvent is toluene, ethanol;
Corresponding phthalimide alkyl amine compound: the molar feed ratio of hydrazine hydrate is 1.0:1.0��20.0, it is preferable that molar feed ratio is 1.0:2.0��10.0;
Reaction temperature is room temperature��150 DEG C, it is preferable that reaction temperature is room temperature��120 DEG C;
Response time is 1��72 hour, it is preferable that the response time is 2��24 hours.
In the 4th described step, the 4th solvent is oxolane, DMF, dimethyl sulfoxide, C3-8Aliphatic ketone, benzene, toluene, acetonitrile, dichloromethane, chloroform, C1-8Alcohol or C5-8Alkane, it is preferable that the 4th solvent is acetone, oxolane, toluene, dichloromethane or chloroform;
Condensing agent is: dicyclohexylcarbodiimide, dicyclohexylcarbodiimide and DMAP, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole, it is preferable that condensing agent is dicyclohexylcarbodiimide and DMAP or 1-ethyl-(3-dimethylaminopropyl) 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, it is preferable that ingredient proportion is 1.0:1.0��5.0:1.0��5.0;
Reaction temperature is room temperature��100 DEG C, it is preferable that reaction temperature is room temperature��50 DEG C;
Response time is 1��72 hour, it is preferable that the response time is 2��24 hours.
7. the preparation method of 4-carbamate-3-methoxycinnamate acid amide alkylamide compound according to claim 4, it is characterised in that: in the 5th described step, the 5th solvent is C3-8Aliphatic ketone, N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, glycol dimethyl ether, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, dichloromethane, chloroform, 1,2-dichloroethanes, benzene,toluene,xylene, chlorobenzene, o-dichlorohenzene, acetonitrile, dimethyl sulfoxide or pyridine, preferably the 5th solvent is ether, acetonitrile, acetic acid, acetone, DMF, toluene, oxolane or pyridine;
Alkali used by second alkali condition is alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, alkali metal or alkali metal bicarbonates, C1-6The combination of fatty acid alkali metal salt, piperidines, nafoxidine, triethylamine, tri-n-butylamine, trioctylamine, pyridine, N-methylmorpholine, N-methyl piperidine, triethylene diamine or TBAH or above-mentioned various alkali, it is preferable that alkali is: potassium carbonate, sodium carbonate, sodium bicarbonate, potassium acetate, pyridine, triethylamine, N-methylmorpholine;
Corresponding ferulic amide compounds: acylating agent acyl chlorides: the molar feed ratio of alkali is 1.0:1.0��60.0:1.0��100.0, it is preferable that molar feed ratio is: 1.0:1.0��20.0:1.0��50.0;
Reaction temperature is-20 DEG C��130 DEG C, it is preferable that reaction temperature is 0 DEG C��80 DEG C;
Response time is 1��120 hour, it is preferable that the response time is 2��48 hours.
8. a 4-carbamate-3-methoxycinnamate acid amide alkylamide compound as described in any one of claim 1-3 or its pharmaceutically acceptable salt purposes in preparation treatment and/or prevention nervus retrogression relevant disease medicine.
9. medicine according to claim 8, it is characterised in that include pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier or excipient of described 4-carbamate-3-methoxycinnamate acid amide alkylamide compound or described 4-carbamate-3-methoxycinnamate acid amide alkylamide compound.
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CN109678795A (en) * 2019-01-28 2019-04-26 南阳师范学院 4- carbamate-asafoetide amide -1,2,3,4- tetrahydroisoquinolicompounds compounds and its preparation method and application

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CN109678795A (en) * 2019-01-28 2019-04-26 南阳师范学院 4- carbamate-asafoetide amide -1,2,3,4- tetrahydroisoquinolicompounds compounds and its preparation method and application

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