CN108218744A - A kind of coffee DOPA amide carbamate compound, preparation method and application - Google Patents

A kind of coffee DOPA amide carbamate compound, preparation method and application Download PDF

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CN108218744A
CN108218744A CN201810079029.1A CN201810079029A CN108218744A CN 108218744 A CN108218744 A CN 108218744A CN 201810079029 A CN201810079029 A CN 201810079029A CN 108218744 A CN108218744 A CN 108218744A
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acid
coffee
carbamate compound
substituted
dopa
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桑志培
王柯人
柳文敏
于林涛
程新峰
王慧娟
周毅
姬猛
马倩文
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Nanyang Normal University
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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
    • C07D211/16—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 acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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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  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of coffee DOPA amide carbamate compound, preparation method and applications, the coffee DOPA amide carbamate compound, which is characterized in that shown in its chemical structural formula such as following formula (I)；The coffee DOPA amide carbamate compound of the present invention can be used for preparing the pharmaceutical composition for the treatment of and/or prevention of neurodegenerative diseases.

Description

A kind of coffee DOPA amide carbamate compound, preparation method and application
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of coffee DOPA amide carbamate compound, its Preparation method and application.
Background technology
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 quick swollen It is swollen.
Alzheimer's disease (AD) is a kind of chronic, mostly sick characterized by progressive memory and Cognitive function damage The complicated neurodegenerative disease that cause, too many levels participate in, key pathological feature are beta amyloid peptide (β-amyloid Peptide, A β) largely deposit the senile plaque (Senile plaque, SP) formed, the nerve that Protein tau Hyperphosphorylationof is formed Fibre matting (Neurofibrillary tangle, NFT), and degeneration of apoptosis and nerve synapse with neuron etc..Closely Nian Lai, many researchers are dedicated to disclosing the pathogenesis of AD from molecule and cellular level, it is proposed that a variety of hypothesis, such as：Courage The damage of alkali serotonergic neuron, the deposition of amyloid protein, Protein tau Hyperphosphorylationof, inflammation, free-radical oxidation, metal ion lose Adjust etc., therefore, the novel therapeutic approach and means developed for these pathogenesis will be hopeful to alleviate and improve AD patient The state of an illness.Clinically the drug of effectively treatment AD mainly has two classes at present：(1) cause to recognize based on neurotransmitter acetylcholine deficiency Know the cholinergic hypothesis of functional disturbance, patient's intracerebral levels of acetylcholine is improved using acetylcholinesterase inhibitor, such as： Tacrine、Donepezil、Ravastigmine、Galantamine；(2) using N-methyl-D-aspartate (NMDA) receptor Inhibitor reduces damage of the glutamate to nerve cell, such as：Memantine Hydrochloride.But Long-term clinical uses Show that these drugs can alleviate the symptom of AD in a short time, but fundamentally effectively cannot prevent or reverse the course of disease, but also can lead Cause classical cholinergic toxicity, such as cause hallucinations, misunderstanding, dizziness, nausea, hepatotoxicity, loss of appetite and stool frequency It is numerous etc..Therefore, clinically there is an urgent need to research and develop the AD medicines with novel mechanism of action.
The AD causes of disease are complicated, not yet illustrate its pathogenesis completely so far, but research shows that, patient's intracerebral levels of acetylcholine Reduction, the excessive generation of beta-amyloid protein are excessive with deposition, metal ion metabolic disorder, Ca2+ dysequilibriums, tau- albumen Neurofibrillary tangles caused by phosphorylation, glutamate receptor activity are excessively high, oxidative stress generates a large amount of active oxygens (ROS) and free The many factors such as base and Neuroinflammation are played an important role in the pathogenic process of AD.For above-mentioned pathogenic factors, grind Personnel are studied carefully using traditional " one target of a medicine " drug design strategies, it was found that largely there is high activity and high selection to a certain target spot The drug of property, such as：Anticholinesterase and nmda receptor antagonist etc., these drugs there are action target spot it is single, clinical make It is more with toxic side effect, it is not good enough to the long-term efficacy of AD patient the problems such as.
In recent years, with constantly illustrating to AD pathogenesis, finding the occurrence and development of AD has multimachine system, multifactor , there is the interrelated network tune for influencing each other, constituting AD occurrence and development process complexity in the characteristics of effect between different mechanisms Control system.Based on the above results, researcher proposes " multiple target point targeted drug (Multitarget-directed Ligands, MTDLs) " strategy researches and develops anti-neurodegenerative disease drug.So-called " multiple target point drug " refers to that single chemistry is real Body acts on multiple target spots in disease network simultaneously, and synergistic effect can be generated to the effect of each target spot, is more than gross effect each Single-action the sum of is answered, and such medicine is also referred to as " Multifunctional " or " Multipotential " drug.Multiple target point drug with it is more Medicine use in conjunction and the main distinction of compound medicine are：Dosage can be reduced, therapeutic effect is improved, avoids between drug Interaction and the toxic side effect thus brought, uniform pharmacokinetic properties, be easy to use etc..Therefore, research and development tool There are novel chemical structure, novel mechanism of action, the anti-neurodegenerative disease medicine with multiple target effect, less toxic side effect Object not only conforms with the active demand of social senilization's process, and with good market prospects.In early period is reported, it was found that Scutellarein carbamate derivates (CN10337956A, CN102603698A), talan or ethane amino first Acid esters compound (CN102816090A), isoflavones carbamate compound (CN102827131A), ferulic acid amino Formic ether compounds (CN105837497A, CA105601540A, CN105646289A) though these compounds have it is preferable Inhibiting activity of acetylcholinesterase and antioxidant activity, and have the inhibiting effect of any to A beta-aggregations, while to BuCh ester The inhibitory activity of enzyme is excessively poor, causes these compounds not good enough to the treatment curative effect of AD in animal model.Research shows that with The development of AD, AChE levels continuously decrease, and BuChE activity degrees increase the 165% of normal level, are knocking out AChE genes In Mice Body, selective AChE inhibitor does not have an impact ACh levels, and selectivity BuChE inhibitor then increases ACh levels 5 times, further animal experiments show that, selective BuChE inhibitor can avoid typical cholinergic toxicity, and normal condition The missing of lower BuChE is almost without the side effect in terms of health.Therefore, it designs and finds that there is acetylcholinesterase and fourth simultaneously The anti-AD medicines of multiple target point of acetylcholinesterase inhibitory activity, A beta-aggregations inhibitory activity and neuroprotection are important at present A research method.
Vascular dementia (Vascular Dementia, VD) be by ischemic cerebrovascular disease, hemorrhagic cerebrovaseular disease, Intelligence and cognition dysfunction caused by various types of cranial vascular diseases such as acute and chronic Hypoxic cranial vascular disease are faced Bed syndrome, main clinical manifestation include：Cognitive ability, the decline of memory and social-life ability and emotion, personality Change, be a kind of chronic progressive disease.It is the first of senile dementia in the Asian countries such as China, Japan vascular dementia Position reason；As world population is to the continuous propulsion of aging, cerebrovascular disease is increasing, and Onset of Vascular Dementia rate has gradually The trend of rising seriously affects work and the quality of life of the elderly, and brings heavy economy and spirit to society and family Burden.Therefore, VD has become current gerontology and an important research hotspot in psychologic medicine field.Vascular dementia by In pathogenesis complexity, there is no can block disease develop drug, at present clinical treatment with improve brain blood cycle and brain Metabolism is strengthened based on brain nutrition.
In recent years, both at home and abroad research shows that, VD patient show cerebral damage while be also often accompanied by cholinergic 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 is 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 Neurotrosis and the recovery of brain function after blood, this shows that acetylcholinesterase inhibitor can also be used for the treatment of vascular dementia.
Invention content
To solve defect in the prior art, the present invention provides a kind of coffee DOPA amide carbamates chemical combination Object, preparation method and application.
The present invention provides a kind of coffee DOPA amide carbamate compound, chemical structural formula such as following formula (I) It is shown：
Wherein, R represents H or CONR3R4；R3、R4Each independently represent C1~C12Alkyl, C1~C12Alkoxy, C3~C8 Cycloalkyl, phenyl, benzyl, substituted-phenyl or substituted benzyl are H, NR during four position R differences3R4It may also indicate that two allylamines Base, morpholinyl, pyrrole radicals, piperidyl, 4- benzyl piepridines base, 4- substituted benzyls piperidyl, 4- Phenylpiperidines base, 4- substituted-phenyls Piperidyl, benzyl diethylenediamine base, substituted benzyl piperazinyl, 4- by C1~C12Alkyl-substituted piperazinyl, 4- by C1~C12Alkane Piperidyl, the substituted-phenyl 1,2,3,4- tetrahydro isoquinolyls of base substitution；The substituted-phenyl and substituted benzyl are represented on phenyl ring Arbitrarily can substituted position replaced by 1-4 groups selected from the group below：F、Cl、Br、I、C1-4Alkyl, C1-4Alkoxy, three Methyl fluoride, trifluoromethoxy, nitro or cyano.
Shown in chemical structural formula such as following formula (I), and R is any one in structural formula (1)-(14)：
Wherein, pharmaceutically acceptable salt be the coffee DOPA amide carbamate compound 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, succinic acid, wine Stone acid, citric acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid salt.
The present invention also provides a kind of preparation method of coffee DOPA amide carbamate compound as described above, Include the following steps：
(a) it using caffeic acid and dopamine as starting material, is obtained under the conditions of solvent and condensing agent in coffee DOPA amide Mesosome；
(b) under solvent and alkaline condition with corresponding acylating agent acyl chlorides acylation reaction occurs for coffee DOPA amide intermediate, Obtain product coffee DOPA amide carbamate compound；
In the present invention, the acylating agent can use carbamyl chloride class compound, specifically can for example enumerate：
Specific mechanism is as follows：
Wherein, caffeic acid in the step (a), dopamine, condensing agent molar ratio be than 1.0:1.0~50.0:1.0~ 100.0, reaction temperature is -20 DEG C~130 DEG C, and the acylation reaction time is 1~72h；
In addition, the molar ratio of coffee DOPA amide intermediate in the step (b), acylating agent, alkali is than 1.0:1.0~ 50.0:1.0~100.0, reaction temperature is -20 DEG C~130 DEG C, and the acylation reaction time is 1~72h.
In addition, in step (a), the solvent is C3-8Aliphatic ketone, N,N-dimethylformamide, ether, isopropyl ether, first Base tertbutyl ether, tetrahydrofuran, glycol dimethyl ether, C1-6Aliphatic acid and C1-6Fatty alcohol formed ester, dichloromethane, chloroform, One kind or several in 1,2- dichloroethanes, benzene,toluene,xylene, chlorobenzene, o-dichlorohenzene, acetonitrile, dimethyl sulfoxide (DMSO) or pyridine Kind.
In addition, step (a) described in condensing agent for DCC (dicyclohexylcarbodiimide), DCC/DMAP (dicyclohexyl carbon Diimine/4-dimethylaminopyridine), EDCI (1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides), EDCI/ HOBT (1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides/I-hydroxybenzotriazole) blocks one in special condensing agent Kind is several.
In addition, solvent is C in step (b)3-8Aliphatic ketone, N,N-dimethylformamide, ether, isopropyl ether, methyl- tert fourth Base ether, tetrahydrofuran, glycol dimethyl ether, C1-6Aliphatic acid and C1-6Fatty alcohol forms ester, dichloromethane, chloroform, 1,2- bis- One or more of chloroethanes, benzene,toluene,xylene, chlorobenzene, o-dichlorohenzene, acetonitrile, dimethyl sulfoxide (DMSO) or pyridine.
In addition, alkali used is alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal or alkaline earth gold in stepb Belong to carbonate, alkali or alkaline earth metal bicarbonate, C1-6Fatty acid alkali metal salt, piperidines, nafoxidine, triethylamine, three fourths Amine, trioctylamine, pyridine, N-methylmorpholine, N- methyl piperidines, triethylene diamine or one kind or several in tetrabutylammonium hydroxide Kind.
The present invention also provides a kind of coffee DOPA amide carbamate compounds as described above to prepare for controlling Application in the pharmaceutical composition for the treatment of and/or prevention of neurodegenerative diseases, with 2~99.5 weights in described pharmaceutical composition The coffee DOPA amide carbamate compound or the acceptable salt of its pharmacology for measuring % are active ingredient, remaining is Pharmaceutical carrier or excipient.
Wherein, the neurodegenerative disease includes vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon Disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain or glaucoma.
The coffee DOPA amide carbamate compound or its pharmaceutically acceptable salt of the present invention, the pharmaceutical composition Object can further contain one or more pharmaceutically acceptable carriers or excipient.
Coffee DOPA amide carbamate compound or its pharmaceutically acceptable salt of the present invention, to acetyl Cholinesterase, butyrylcholine esterase, A beta-aggregations activity have preferable inhibitory activity, to A β1-42The SH-SY5Y cells damage of induction Wound has significant protective effect, has significant protective effect to the PC12 cellular damages of hydrogen peroxide-induced, is crazy about to rat It stays cognition dysfunction in model and there is good improvement result, coffee DOPA acyl of the invention to mouse memory acquired disturbance Amine carbamate class compound or its pharmaceutically acceptable salt can be used for preparing treatment and/or prevention of neurodegenerative diseases Pharmaceutical composition.
Heretofore described " composition " refers to the product mixed by more than one substances or component；" the medicine Acceptable carrier on " refers to pharmaceutically acceptable substance, composition or carrier, such as：Liquid or solid filler, dilution Agent, solvent or packing substance, they carry or transport certain chemical substance.It is ideal for pharmaceutical composition provided by the present invention Ratio is that coffee DOPA amide carbamate compound (I) or its pharmaceutically acceptable salt account for always as active constituent Weight ratio 2%~99.5%.
Specific embodiment
Technical solution of the present invention is discussed in detail, but the present invention is not limited to this with reference to embodiment.
Embodiment 1
10mmol caffeic acids 1,10mmol dopamine 2s, card special condensing agent 15mmol and 100mLDMF are added in reaction bulb, After being stirred overnight at room temperature, deionized water is added in, is extracted with ethyl acetate, evaporated under reduced pressure solvent, residue is pure through column chromatography Change (petroleum ether：Ethyl acetate=100:1v/v), corresponding amide intermediate 3 is obtained.Then, 10mmol amide intermediates 3, 30mmol is corresponding50mmol Anhydrous potassium carbonates and 50ml acetonitriles after stirring evenly, rise Temperature is refluxed reaction 10 hours (reaction process is tracked with TLC)；After reaction, evaporated under reduced pressure solvent, add in 80ml go from Sub- water is extracted in three times with 200mL dichloromethane, and organic layer is washed after merging with saturated sodium-chloride, is dried over anhydrous sodium sulfate Filtering, depressurizes coffee DOPA amide carbamate compound (I-1) solvent evaporated, and residue purifies (dichloro through column chromatography Methane：Acetone=100:1v/v), corresponding target compound coffee DOPA amide carbamate compound (I-1) is obtained, is received Rate 45%.The purity of gained object is all higher than 97% through HPLC measure.
1H NMR 7.48 (d, J=15.6Hz, 1H, CH=CH), 7.35-7.33 (m, 2H, 2 × Ar-H), 7.31 (s, 1H, ), Ar-H 7.20 (d, J=8.0Hz, 1H, Ar-H), 7.13 (d, J=8.0Hz, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 6.34 (d, J=115.6Hz, 1H ,=CH), 3.68-3.63 (m, 4H, phCH2+NCH2),3.62-3.58(m,2H,NCH2),3.54- 3.45(m,2H,2×NCH2),3.26(s,3H,NCH3),3.20(s,3H,NCH3),3.09(s,3H,NCH3),3.07(s,3H, NCH3),2.86-2.79(m,2H,CH2),1.44-1.38(m,6H,2×CH3),1.29-1.23(m,6H,2×CH3).
Embodiment 2
10mmol caffeic acids 1,10mmol dopamine 2s, card special condensing agent 15mmol and 100mLDMF are added in reaction bulb, After being stirred overnight at room temperature, deionized water is added in, is extracted with ethyl acetate, evaporated under reduced pressure solvent, residue is pure through column chromatography Change (petroleum ether：Ethyl acetate=100:1v/v), corresponding amide intermediate 3 is obtained.Then, 10mmol amide intermediates 3, 30mmol is corresponding50mmol Anhydrous potassium carbonates and 50ml acetonitriles, after stirring evenly, heat up back Stream is stirred to react 10 hours (reaction process is tracked with TLC)；After reaction, evaporated under reduced pressure solvent adds in 80ml deionized waters, It being extracted in three times with 200mL dichloromethane, organic layer is washed after merging with saturated sodium-chloride, is dried over anhydrous sodium sulfate filtering, Coffee DOPA amide carbamate compound (I-2) solvent evaporated is depressurized, residue purifies (dichloromethane through column chromatography： Acetone=100:1v/v), corresponding target compound coffee DOPA amide carbamate compound (I-2), yield are obtained 55%.The purity of gained object is all higher than 97% through HPLC measure.
1H NMR 7.49 (d, J=15.6Hz, 1H, CH=CH), 7.36-7.34 (m, 2H, 2 × Ar-H), 7.31 (s, 1H, ), Ar-H 7.20 (d, J=8.0Hz, 1H, Ar-H), 7.13 (d, J=8.0Hz, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 6.35 (d, J=115.6Hz, 1H ,=CH), 3.67-3.65 (m, 2H, phCH2),3.64-3.53(m,8H,4×NCH2),3.47-3.37 (m,8H,4×NCH2),2.87-2.79(m,2H,CH2),1.43-1.35(m,12H,4×CH3),1.28-1.21(m,12H,4× CH3).
Embodiment 3
10mmol caffeic acids 1,10mmol dopamine 2s, card special condensing agent 15mmol and 100mLDMF are added in reaction bulb, After being stirred overnight at room temperature, deionized water is added in, is extracted with ethyl acetate, evaporated under reduced pressure solvent, residue is pure through column chromatography Change (petroleum ether：Ethyl acetate=100:1v/v), corresponding amide intermediate 3 is obtained.Then, 10mmol amide intermediates 3, 30mmol is corresponding50mmol Anhydrous potassium carbonates and 50ml acetonitriles, after stirring evenly, temperature rising reflux It is stirred to react 10 hours (reaction process is tracked with TLC)；After reaction, evaporated under reduced pressure solvent adds in 80ml deionized waters, uses 200mL dichloromethane extracts in three times, and organic layer is washed after merging with saturated sodium-chloride, is dried over anhydrous sodium sulfate filtering, is subtracted Coffee DOPA amide carbamate compound (I-3) solvent evaporated is pressed, residue purifies (dichloromethane through column chromatography：Third Ketone=100:1v/v), corresponding target compound coffee DOPA amide carbamate compound (I-3), yield 55% are obtained. The purity of gained object is all higher than 97% through HPLC measure.
1H NMR 7.49 (d, J=16.0Hz, 1H, CH=CH), 7.36-7.33 (m, 2H, 2 × Ar-H), 7.31 (s, 1H, ), Ar-H 7.20 (d, J=8.0Hz, 1H, Ar-H), 7.14 (d, J=8.0Hz, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 6.33 (d, J=16.0Hz, 1H ,=CH), 3.65-3.58 (m, 2H, phCH2),3.10(s,3H,NCH3),3.09(s,3H,NCH3), 3.07(s,3H,NCH3),3.06(s,3H,NCH3),3.03(s,3H,NCH3),3.00(s,6H,2×NCH3),2.99(s,3H, NCH3),2.87-2.79(m,2H,CH2).
Embodiment 4-14
Other than replacing corresponding acylating agent, in the same manner as in Example 1, the chemical combination in embodiment 4-14 is made Object.
Test example
1. coffee DOPA amide carbamate compound lives to the inhibition of acetylcholinesterase and butyrylcholine esterase Property
1.0mmol/L acetylthiocholine iodides are sequentially added into 96 orifice plates or thio BuCh (is purchased from Sigma Company) 30 μ L, pH8.0 40 μ L of PBS buffer solution, testing compound solution) 20 μ L (DMSO contents be less than 1%) and 10 μ L electric eels Acetylcholinesterase (EeAChE) or horse serum butyrylcholine esterase (eqBuChE), after finishing mixing, 37 DEG C of incubation 15min, to It is molten that thio-bis- (2- nitros) benzoic acid (DTNB, purchased from Sigma companies) of 5,5'- bis- that mass fraction is 0.2% are added in each hole 30 μ L of liquid develop the color, and the optical density (OD values) in each hole at 412nm is measured with microplate reader, compared with the blank well for being not added with sample to be tested, Calculate inhibiting rate [enzyme inhibition rate=(1- sample sets OD value/blank group OD value) × 100%] of the compound to enzyme；Select chemical combination Five to six concentration of object measure its enzyme inhibition rate, and linear with the inhibiting rate of the negative logarithm of the compound molar concentration and enzyme It returns, molar concentration when acquiring 50% inhibiting rate is the IC of the compound50。
Measurement result shows compound disclosed in the embodiment of the present invention to acetylcholinesterase and butyrylcholine esterase It is respectively provided with the effect of significantly inhibiting, IC50Respectively 0.05 μM~50 μM, 0.05 μM~50 μM, and positive control medicine --- The IC that Rivastigmine inhibits acetylcholinesterase and butyrylcholine esterase50For 5.6 μM and 1.4 μM.
(2) coffee DOPA amide carbamate 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, then add in 160 μ L 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 present invention implementation Compound disclosed in example is to A β1-42The aggregation of auto-induction is respectively provided with the effect of significantly inhibiting, to A under 25.0 μM of concentration β1-42The inhibiting rate of self assemble is all higher than 50.0%；And inhibiting rate of the curcumin under same concentrations is 43.1%.
(3) coffee DOPA amide carbamate compound prepared by the present invention is to A β1-42The SH-SY5Y cells of induction The protective effect screening of damage
SH-SY5Y cells are used containing 10% fetal calf serum, 100U.mL-1Penicillin, the DMEM of 100mg.L-1 streptomysins are complete Culture medium is at 37 DEG C, 5%CO2Constant incubator in cultivate.2d is once passed on, and growth period cell of taking the logarithm is tried It tests.A β 1-42 are dissolved in buffer solution, 4 DEG C of incubation 48h agings.SH-SY5Y is with 1 × 105A/mL density is inoculated in 96 well culture plates On, after 37 DEG C are incubated 12h, blank control group cell culture fluid is changed to serum-free DMEM culture solutions, model group and untested compound After serum-free DMEM culture solutions of the group containing 5 μm of ol.L-1, continue after being incubated 48h, each group addition 5mg/mL, MTT solution, 37 DEG C 4h is incubated, abandons culture medium, 150 μ LDMSO are added in per hole, fully dissolve mixing.The OD values of each group are measured under the wavelength of 490nm, Test result is repeated 3 times, and with Duncan ' s test method statistics, each group numerical value is expressed as mean ± S.E.M., using control group as 100%, administration group and damage class value are represented with the percentage of control group.
Measurement result shows that compound is 10 disclosed in the embodiment of the present invention-4Mol/L~10-6To A under mol/L concentration β1-42The SH-SY5Y cellular damages of induction have significant protective effect.
(4) coffee DOPA amide carbamate compound prepared by the present invention is to H2O2The PC12 cellular damages of induction Protective effect screening
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 100mL/ holes, is subsequently placed into containing 5%CO237 DEG C of constant incubators in cultivate.After culture 24 hours, Add the compound (final concentration of 10 of respective concentration in administration group-5Mol/L, 10-6Mol/L) 10mL/ holes, preincubate 2 hours are (right Add 10 μ L/ hole PBS respectively with damage group according to group, its volume is made to keep equal).After PC12 cell incubations 2 hours, administration group with 100 μ Μ H are separately added into damage group2O210 μ L/ holes 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 μ L/ holes.After continuing culture 24 hours, each group adds in 5mg/mL, and 100 μ L/ holes of MTT carry out living cells dyeing.It treats 100 μ L/ holes of 100%DMSO terminate liquids are added in after 3 hours, in each group, fully dissolve mixing.It is measured under the wavelength of 490nm each The OD values of group, test result is repeated 3 times, and with Duncan ' s test method statistics, each group numerical value is expressed as mean ± S.E.M., Using control group as 100%, administration group and damage class value are represented with the percentage of control group.
Measurement result shows that compound is 10 disclosed in the embodiment of the present invention-4Mol/L~10-6It is right under mol/L concentration The PC12 cellular damages of hydrogen peroxide-induced have significant protective effect.
(5) coffee DOPA amide carbamate compound causes A β the shadow of cognition dysfunction in Model of Dementia in Rats It rings.
Wistar rats (10 week old) weight 280 or so, is randomly divided into：Control group and dull-witted moulding group, dull-witted moulding group Animal is fixed on after anaesthetizing (40mg/kg, i.p.) with yellow Jackets on I-C type rat stereotaxic instruments, is cut after routine disinfection Skin is opened, exposure bregma is slowly injected into state of aggregation A β with micro syringe to rats with left hippocampus1-425.0 μ L, let the acupuncture needle remain at a certain point 5 points Then clock slowly removes needle and sews up a wound so that the abundant disperses of A β.Control group gives isometric physiological saline.A β next day is being injected, Dull-witted moulding group rat is randomly divided into 5 groups：Model group, by reagent high (8mg/kg), in (4mg/kg), low (2mg/kg), agent Amount group and positive controls donepezil (5mg/kg), every group 8, gastric infusion (give isometric molten by control group and model group Matchmaker), 1 day 1 time, continuous 4 weeks；In the 3rd week ability of learning and memory with Morris water mazes measure rat of administration.Measurement result Show compared with the control group, the incubation period of Model of Dementia group Morris water mazes test is obviously prolonged (P<0.01)；Drug height, The incubation period of middle dose group significantly shortens (P compared with Model of Dementia group<0.01), drug low dose group and donepezil group and dementia Model group has certain shortening trend but there was no significant difference (P compared to incubation period<0.05).
(6) influence of the coffee DOPA amide carbamate 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 during test, it is allowed freely to walk 8min in labyrinth, records its entrance The number and alternate frequency of each arm calculate alternately rate according to the following formula：Alternately rate %=[alternate frequency/(always into indegree- 2) it] × 100, is as a result represented with mean ± standard deviation, group difference uses one-way analysis of variance.
Measurement result shows that under the experiment condition compound disclosed in this invention causes mouse to obtain hyoscine Memory disorders have dose-dependent improvement result, and significant difference (p is relatively respectively provided with model group<0.01).
Behavioral experiment finishes takes brain by mouse broken end immediately, with precooling normal saline flushing, is rapidly separated out on ice chest Cerebral hippocampal tissue weighs hippocampal tissue weight, adds 9 times of 4 DEG C of physiological saline that 10% homogenate, 3500r/min, 4 DEG C of centrifugations are made 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 under 412nm wavelength also according to the explanation of kit, the vigor of ChAT with U/mg come It represents.Measurement result shows that under the experiment condition compound disclosed in this invention can enhance acetylcholine transferase (ChAT) vigor is relatively respectively provided with significant difference (p with blank group<0.01).

Claims (10)

  1. A kind of 1. coffee DOPA amide carbamate compound, which is characterized in that its chemical structural formula such as following formula (I) institute Show：
    Wherein, R represents H or CONR3R4；R3、R4Each independently represent C1~C12Alkyl, C1~C12Alkoxy, C3~C8Cycloalkanes Base, phenyl, benzyl, substituted-phenyl or substituted benzyl are H, NR during four position R differences3R4May also indicate that two allylaminos, Quinoline base, pyrrole radicals, piperidyl, 4- benzyl piepridines base, 4- substituted benzyls piperidyl, 4- Phenylpiperidines base, 4- substituted phenylpiperidines Base, benzyl diethylenediamine base, substituted benzyl piperazinyl, 4- by C1~C12Alkyl-substituted piperazinyl, 4- by C1~C12Alkyl takes Piperidyl, the substituted-phenyl 1,2,3,4- tetrahydro isoquinolyls in generation；The substituted-phenyl and substituted benzyl represent arbitrary on phenyl ring Can substituted position replaced by 1-4 groups selected from the group below：F、Cl、Br、I、C1-4Alkyl, C1-4Alkoxy, fluoroform Base, trifluoromethoxy, nitro or cyano.
  2. 2. coffee DOPA amide carbamate compound as described in claim 1, which is characterized in that chemical structural formula is such as Shown in following formula (I)s, and R is any one in structural formula (1)-(14)：
  3. 3. coffee DOPA amide carbamate compound as claimed in claim 1 or 2, which is characterized in that it is in pharmacy Upper acceptable salt be the coffee DOPA amide carbamate compound 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, succinic acid, tartaric acid, citric acid, C1-6Alkyl sulphur Acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid salt.
  4. 4. a kind of preparation side of the coffee DOPA amide carbamate compound in 1-3 such as claim as described in any one Method, which is characterized in that include the following steps：
    (a) using caffeic acid and dopamine as starting material, coffee DOPA amide intermediate is obtained under the conditions of solvent and condensing agent；
    (b) coffee DOPA amide intermediate occurs acylation reaction with corresponding acylating agent, obtains product under solvent and alkaline condition Coffee DOPA amide carbamate compound；
    The molar ratio of caffeic acid, dopamine, condensing agent is than 1.0 in the step (a):1.0~50.0:1.0~100.0, instead It is -20 DEG C~130 DEG C to answer temperature, and the acylation reaction time is 1~72h；
    Coffee DOPA amide intermediate in the step (b), acylating agent, alkali molar ratio be than 1.0:1.0~50.0:1.0~ 100.0, reaction temperature is -20 DEG C~130 DEG C, and the acylation reaction time is 1~72h.
  5. 5. preparation method according to claim 4, which is characterized in that in step (a), the solvent is C3-8Aliphatic ketone, N,N-dimethylformamide, ether, isopropyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, glycol dimethyl ether, C1-6Aliphatic acid with C1-6Fatty alcohol forms ester, dichloromethane, chloroform, 1,2- dichloroethanes, benzene,toluene,xylene, chlorobenzene, o-dichlorohenzene, second One or more of nitrile, dimethyl sulfoxide (DMSO) or pyridine.
  6. 6. preparation method according to claim 4, which is characterized in that condensing agent described in step (a) is DCC, DCC/ DMAP, EDCI, EDCI/HOBT block one or more of in special condensing agent.
  7. 7. preparation method according to claim 4, which is characterized in that solvent is C in step (b)3-8Aliphatic ketone, N, N- bis- Methylformamide, ether, isopropyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, glycol dimethyl ether, C1-6Aliphatic acid and C1-6Fat Alcohol forms ester, dichloromethane, chloroform, 1,2- dichloroethanes, benzene,toluene,xylene, chlorobenzene, o-dichlorohenzene, acetonitrile, diformazan One or more of base sulfoxide or pyridine.
  8. 8. preparation method according to claim 4, which is characterized in that in stepb alkali used for alkali metal hydroxide, Alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate, alkali or alkaline earth metal bicarbonate, C1-6Fatty acid alkali Metal salt, piperidines, nafoxidine, triethylamine, tri-n-butylamine, trioctylamine, pyridine, N-methylmorpholine, N- methyl piperidines, triethylene two One or more of amine or tetrabutylammonium hydroxide.
  9. 9. the coffee DOPA amide carbamate compound in a kind of 1-3 such as claim as described in any one is preparing use Application in the pharmaceutical composition for the treatment of and/or prevention of neurodegenerative diseases, which is characterized in that in described pharmaceutical composition In using the coffee DOPA amide carbamate compound of 2~99.5 weight % or the acceptable salt of its pharmacology to have Ingredient is imitated, remaining is pharmaceutical carrier or excipient.
  10. 10. application according to claim 9, which is characterized in that the neurodegenerative disease include vascular dementia, Ah Er Cihai Mo's diseases, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral spinal sclerosis Disease, neuropathic pain or glaucoma.
CN201810079029.1A 2018-01-26 2018-01-26 A kind of coffee DOPA amide carbamate compound, preparation method and application Pending CN108218744A (en)

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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
CN113636949A (en) * 2021-09-13 2021-11-12 江苏弘和药物研发有限公司 Method for synthesizing caffeoyldopamine by one-pot method
CN115322109A (en) * 2022-08-26 2022-11-11 安徽恒星制药有限公司 Preparation method of dobutamine hydrochloride suitable for industrial production
CN116023305A (en) * 2022-12-28 2023-04-28 南阳市中心医院 Caffeic acid-dopamine-rivastigmine hybrid compound, preparation method and application

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN113636949A (en) * 2021-09-13 2021-11-12 江苏弘和药物研发有限公司 Method for synthesizing caffeoyldopamine by one-pot method
CN115322109A (en) * 2022-08-26 2022-11-11 安徽恒星制药有限公司 Preparation method of dobutamine hydrochloride suitable for industrial production
CN115322109B (en) * 2022-08-26 2024-02-27 安徽恒星制药有限公司 Preparation method of dobutamine hydrochloride suitable for industrial production
CN116023305A (en) * 2022-12-28 2023-04-28 南阳市中心医院 Caffeic acid-dopamine-rivastigmine hybrid compound, preparation method and application

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