CN106632181B - Aurone Mannich alkaloid compound, preparation method and use - Google Patents
Aurone Mannich alkaloid compound, preparation method and use Download PDFInfo
- Publication number
- CN106632181B CN106632181B CN201610868702.0A CN201610868702A CN106632181B CN 106632181 B CN106632181 B CN 106632181B CN 201610868702 A CN201610868702 A CN 201610868702A CN 106632181 B CN106632181 B CN 106632181B
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- Prior art keywords
- acid
- aurone
- compound
- pharmaceutically acceptable
- mannich
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- 229930013930 alkaloid Natural products 0.000 title claims abstract description 45
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- 101710083761 Cholinesterase Proteins 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- 240000000203 Salix gracilistyla Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- HUGQNTGOVJKASF-UHFFFAOYSA-M [SH-].[I+] Chemical compound [SH-].[I+] HUGQNTGOVJKASF-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 231100000880 dysequilibrium Toxicity 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001857 fluorescence decay curve Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007986 glycine-NaOH buffer Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052603 melanterite Inorganic materials 0.000 description 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 1
- 229960000967 memantine hydrochloride Drugs 0.000 description 1
- 230000009225 memory damage Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- CIJQGPVMMRXSQW-UHFFFAOYSA-M sodium;2-aminoacetic acid;hydroxide Chemical compound O.[Na+].NCC([O-])=O CIJQGPVMMRXSQW-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of novel aurone Mannich alkaloid compound (I) and its pharmaceutically acceptable salt, preparation method, pharmaceutical composition and the purposes in preparation treatment and/or prevention nervus retrogression related disease drug, the including but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma；
Description
Technical field
The invention belongs to field of medicinal chemistry, it is related to a kind of novel aurone Mannich alkaloid compound (I) and its pharmaceutically
Acceptable salt, preparation method, pharmaceutical composition and preparation treatment and/or prevention nervus retrogression related disease drug in
Purposes, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders,
The neurodegenerative diseases such as multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Background technique
Alzheimer's disease (Alzheimer ' s disease, AD, senile dementia) is one kind with progressive cognitive disorder
With the central nervous system degenerative disease based on memory damage, disease incidence becomes in trend is risen year by year and is only second to the heart
The high incidence disease of angiosis and cancer, having gone up in developed countries such as America and Europes is the 4th of the cause of death.According to world health
Organisation Report, global over-65s old man have 10% dysnoesia, and wherein half occurs dull-witted, fall ill within 85 years old or more
Rate nearly 50%.The AD patient numbers about 600-700 ten thousand in China, disease incidence are more than 5%.With adding for population in the world aging process
Fastly, disease incidence is in obvious ascendant trend, is announced according to Alzheimer's Disease International in December, 2013
" global implication of Alzheimer's disease: 2013-2050 " report in point out, AD will become the coming few decades whole world face most
Big Health challenges, to the year two thousand thirty, patient numbers will rise to 76,000,000 by 44,000,000 in 2013, to the year two thousand fifty, this numerical value
It is up to surprising 1.35 hundred million.Due to AD clinical manifestation be memory capability, capacity of orientation, thinking and judgement decline, and
Activity of daily living reduces, or even abnormal Behavioral and psychological symptom occur etc., keep patient care difficulty larger, to society and family's band
Carry out heavy burden.The drug that approved is used to treat light/moderate AD at present has acetylcholinesterase (AChE) inhibitor, Yi Jiyong
In severe AD treatmentNMethyl-DAspartic acid (NMDA) receptor antagonist, but clinical use shows that these drugs can pass through
It improves patient's body levels of acetylcholine or inhibits the exitotoxicity of excitatory amino acid to alleviate AD symptom, but cannot be effective
Prevent or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, nausea, hepatotoxicity, loss of appetite and
The serious toxic side effect such as stool frequency, thus long-term efficacy is not satisfactory.Therefore, clinically there is an urgent need to research and develop with novel work
With the AD therapeutic agent of mechanism.
AD belongs to disease caused by many factors, and pathogenesis is complicated, does not illustrate its pathogenesis completely also so far, but study
Show patient's intracerebral levels of acetylcholine decline,βThe excessive generation and deposition, metal ion metabolism of amyloid protein are disorderly
Disorderly, Ca2+Dysequilibrium,tauNeurofibrillary tangles caused by protein hyperphosphorylation, glutamate receptor activity are excessively high, oxidation is answered
Swash a large amount of active oxygens (ROS) of generation and many factors such as free radical and Neuroinflammation play the part of weight in the pathogenic process of AD
Want role.For above-mentioned pathogenic factors, researcher is using traditional " one target of a medicine " drug design strategies, it was found that largely to certain
One target spot have high activity and highly selective drug, such as: anticholinesterase andNMethyl-DAspartate receptor antagonism
Agent etc., but that there are action target spots is single, clinical use toxic side effect is more, not good enough to the long-term efficacy of AD patient etc. for these drugs
Problem.
In recent years, with constantly illustrating to AD pathogenesis, it is found that the occurrence and development of AD have multimachine system, multifactor
It is the characteristics of effect, again interrelated between different mechanisms to influence each other, constitute complicated network during AD occurrence and development
Regulator 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, can produce synergistic effect to the effect of each target spot, is greater 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 and more
Medicine use in conjunction and the main distinction of compound medicine are: can reduce dosage, improve therapeutic effect, avoid between drug
Interaction and thus bring toxic side effect, uniform pharmacokinetic properties, be easy to use etc..Therefore, research and development tool
There are novel chemical structure, novel mechanism of action, and the anti-neurodegenerative disease treatment with multiple target effect, less toxic side effect
Drug not only conforms with the urgent need of social senilization's process, and has good market prospects.In early-stage study, we
For in AD pathogenic process oxidative stress,βThe excessive generation of amyloid protein and deposition and metal ion metabolic disorder etc. because
Element has designed and synthesized a kind of 4- hydroxyl aurone class compound (CN 105646417A), biological activity test the results show that this
A little compounds not only have preferable monoamine oxidase-B inhibitory activity, to Aβ 1-42Self assemble and Cu2+The A of inductionβ 1-42Aggregation also have compared with strong inhibitory activity, and also have compared with strong anti-oxidation stress with complexing of metal ion effect, but such
Compound is weaker to the inhibitory activity of acetylcholinesterase (inhibiting rate under 50.0 μM of concentration is respectively less than 50.0%), to lead
Cause these compounds not good enough to the curative effect of AD in animal model；And acetylcholinesterase inhibitor is clinically to use at present
Most commonly used AD therapeutic agent, though the long-term efficacy to AD patient is not good enough, to alleviation AD symptom definite effect.Therefore, if
It counts and finds that there is anti-acetylcholinesterase, anti-oxidation stress, complexing of metal ion, inhibition simultaneouslyβAmyloid protein it is excessive
Generating the multiple target point AD therapeutic agent balanced with deposition and various active is still research direction important at present.
Summary of the invention
Present invention aims at open a kind of novel aurone Mannich alkaloid compounds (I) and its pharmaceutically acceptable
Salt.
Another object of the present invention is to disclose such aurone Mannich alkaloid compound (I) and its pharmaceutically acceptable salt
Preparation method.
Another object of the present invention is to disclosures can connect comprising such aurone Mannich alkaloid compound (I) and its pharmaceutically
The pharmaceutical composition for the salt received.
Still a further object of the present invention is to disclose such aurone Mannich alkaloid compound (I) and its pharmaceutically acceptable salt
With multiple target effect, can be used for preparing treatment and/or prevent nervus retrogression related disease drug in purposes, including but
Be not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis,
The neurodegenerative diseases such as progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
The general formula of the chemical structure of aurone Mannich alkaloid compound (I) provided by the present invention are as follows:
In formula: R1、R2And R3Each independently represent H, OH, CF3O、C1~C12Alkoxy, NR6R7, R4、R5、R6And R7Respectively
Independently indicate C1~C12Alkyl, benzyl, substituted benzyl, NR4R5And NR6R7It may also indicate that nafoxidine base, morpholinyl, piperidines
Base, piperazinyl, 4- by C1~C12Piperazinyl replaced alkyl, the 4- piperazinyls replaced benzyl or substituted benzyl,
R1、R2、R3、-CH2NR4R5It can be in the arbitrarily possible position of phenyl ring with OH；
Above-mentioned term " substituted benzyl " refers to by the benzyl replaced 1-4 groups selected from the group below on phenyl ring: F, Cl,
Br、I、C1-4Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, nitro, cyano, these substituent groups can be
Any possible position of phenyl ring.
Aurone Mannich alkaloid compound (I) proposed by the invention can be prepared by the following method to obtain:
In formula: R1~R5Definition it is identical as the general formula of the chemical structure of aurone Mannich alkaloid compound (I).
With corresponding benzofuran -3 (2H) -one class compound (1) and hydroxy benzaldehyde Mannich alkaloid compound (2) be
Starting material, the direct polycondensation under solvent and alkaline condition obtain corresponding aurone Mannich alkaloid compound (I).Wherein, it reacts
Alkali used are as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal carbon
Sour hydrogen salt, alkali metal bicarbonates, C1-8Alkali metal salt, trimethylamine class or the quaternary ammonium bases of alcohol are (such as: triethylamine, three fourths
Amine, trioctylamine, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene diamine, tetrabutylammonium hydroxide), preferred alkali are as follows: hydrogen-oxygen
Change potassium, sodium hydroxide, potassium carbonate, triethylamine or pyridine；React solvent for use are as follows: C1-8Fatty alcohol, ether, tetrahydrofuran, 2- first
Base tetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, 1,4- dioxane, benzene, toluene or second
Nitrile, preferred solvent are as follows: methanol, ethyl alcohol, isopropanol,N,NDimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or toluene；
Benzofuran -3 (2H) -one class compound (1): hydroxy benzaldehyde Mannich alkaloid compound (2): the molar feed ratio of alkali is
1.0:1.0 ~ 3.0:1.0 ~ 20.0, preferably molar feed ratio are 1.0:1.0 ~ 2.0:1.0 ~ 10.0；Reaction temperature is 0 ~ 150 DEG C,
Preferable reaction temperature is room temperature ~ 120 DEG C；Reaction time is 1 ~ 120 hour, and preferred reaction time is 2 ~ 72 hours.
Starting material of the invention --- benzofuran -3 (2H) -one class compound (1) and hydroxy benzaldehyde Mannich base
Class compound (2) can be made with the common technology in this field, including but not limited to the method disclosed in following documents: 1,
Nadri H. et al.Daru, Journal of Pharmaceutical Sciences2013, 21, 15；2,Wu D.et al.Tetrahedron Letters2015, 56(29), 4383-4387；3,Zhang M.et al.Journal of Heterocyclic Chemistry2015, 52(6), 1887-1892；4,Aissaoui H.et al.WO
2014072903；5,Fattorusso C.et al.Journal of Medicinal Chemistry2008, 51(5),
1333-1343；6,Karki S.S.et al.Journal of Medicinal Chemistry2016, 59(2), 763-
769；7,Torrente E.et al.Journal of Medicinal Chemistry2015, 58(15), 5900-
5915。
Contain amino in aurone Mannich alkaloid compound (I) molecule of gained according to the method described above, which is in alkalinity,
Its pharmaceutically acceptable salt, the acid can be made by pharmaceutically conventional salifying method with any suitable acid are as follows:
Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid (such as: formic acid, acetic acid, propionic acid), oxalic acid, benzoic acid, bigcatkin willow
Acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Alkyl sulfonic acid (such as: methane sulfonic acid,
Ethylsulfonic acid etc.), camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
Pharmaceutical composition disclosed in this invention includes one or more aurone Mannich bases chemical combination of therapeutically effective amount
Object (I) or its pharmaceutically acceptable salt, the pharmaceutical composition can further contain one or more pharmaceutically acceptable loads
Body or excipient." therapeutically effective amount ", which refers to, causes researcher or targeted tissue, system or the biology of animal of doctor
Or the amount of the medical drug reacted or medicament；Made of " composition " refers to by mixing more than one substances or component
Product；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable substance, composition or carrier, such as: liquid is solid
Body filler, diluent, excipient, solvent or packing substance, they carry or transport certain chemical substance.It is provided by the present invention
Pharmaceutical composition its ideal ratio be that aurone Mannich alkaloid compound (I) or its pharmaceutically acceptable salt are as living
Property ingredient account for total weight than 5%~99.5%, rest part is to account for total weight than 95% or less.
Aurone Mannich alkaloid compound (I) disclosed in this invention and its pharmaceutically acceptable salt have carried out following
Bioactivity screening.
(1) inhibitory activity of the aurone Mannich alkaloid compound (I) to acetylcholinesterase and butyrylcholine esterase
1.0 mmol/L acetylthiocholine iodides are sequentially added into 96 orifice plates or iodine bisulfide (is purchased from for BuCh
Sigma company) 1%) and 10 30 μ L, 40 μ L of PBS buffer solution of pH7.4,20 μ L(DMSO content of testing compound solution is less than
μ L acetylcholinesterase (rat brain cortex 5% is homogenized supernatant, and the phosphate buffer of pH7.4 makees homogenate medium) or BuCh
Esterase (25% supernatant of rat blood serum, pH7.4 phosphate buffer make homogenate medium) solution, after finishing mixing, 37 DEG C of incubations
0.2% 5,5 '-two thio-bis- (2- nitrobenzoic acid) (DTNB is purchased from Sigma company) solution are added into each hole by 15min
30 μ L colour developing, with the optical density (OD value) in each hole at microplate reader measurement 405nm, compared with the blank well that sample to be tested is not added, meter
Compound is calculated to the inhibiting rate (enzyme inhibition rate (%)=(1- sample sets OD value/blank group OD value) × 100%) of enzyme；Select compound
Five to six concentration, measure its enzyme inhibition rate, and linearly return with the inhibiting rate of the negative logarithm of the compound molar concentration and enzyme
Return, molar concentration when acquiring 50% inhibiting rate is the IC of the compound50.Measurement result shows that institute is public in the embodiment of the present invention
The aurone Mannich alkaloid compound (I) opened all has the effect of significantly inhibiting, IC to acetylcholinesterase50For 8.78 nM ~
10.0 µM；And aurone Mannich alkaloid compound (I) is significantly higher than to BuCh the inhibitory activity of acetylcholinesterase
The inhibitory activity (selectivity is greater than 10 times) of esterase, illustrates that compound disclosed in this invention has selection to acetylcholinesterase
Property inhibiting effect.Measurement result is also shown that the parent nucleus of aurone Mannich alkaloid compound (I) --- 2 '-hydroxyl aurone (R1、R2、
R3And CH2NR4R5Indicate H, OH is located at 2 ' positions), 3 '-hydroxyl aurone (R1、R2、R3And CH2NR4R5Indicate that H, OH are located at 3 '
Position) and 4 '-hydroxyl aurone (R1、R2、R3And CH2NR4R5Indicate that H, OH are located at 4 ' positions) to the IC of acetylcholinesterase inhibition50?
Greater than 500 μM.
(2) antioxidant activity (ORAC-FL method) of aurone Mannich alkaloid compound (I)
Reference literature (Qiang, X.M.et al.Eur. J Med. Chem.2014,76,314-331) reported
Method be measured, it may be assumed that 6- hydroxyl -2,5,7,8- tetramethyl primary colours alkane -2- carboxylic acids (Trolox) use pH7.4 PBS buffer solution
It is made into the solution of 10-80 μm of ol/L, fluorescein (fluorescein) is made into 250 nmol/L's with the PBS buffer solution of pH7.4
Solution, 2,2 '-azo diisobutyl amidine dihydrochlorides (AAPH) are made into 40 mmol/L's with the PBS buffer solution of pH7.4 using preceding
Solution.The compound solution and luciferin solution of 50-10 μm of ol/L are added into 96 orifice plates, mixes, 37 °C of incubation 15min add
Enter AAPH solution, make every 200 μ L of hole total volume, mixes, be immediately placed on Varioskan Flash Multimode Reader
In (Thermo Scientific) instrument, 90 min of METHOD FOR CONTINUOUS DETERMINATION under 485 nm excitation wavelengths and 535 nm launch wavelengths.It calculates
Area AUC under fluorescence decay curve out, wherein with 1-8 μm of ol/L'sTroloxAs standard, sample to be tested is not added as blank,
The antioxidant activity results expression of compound isTroloxEquivalent, its calculation formula is [(AUC Sample-AUC
blank)/(AUC Trolox-AUC blank)] ×[(concentration of Trolox/concentration of
Sample)], each compound measures 3 multiple holes every time, and every group of experiment is independent in triplicate.Measurement result shows present invention reality
The antioxidant activity for applying the aurone Mannich alkaloid compound (I) disclosed in example isTrolox1.0~3.0 times, illustrate this
Class compound has strong anti-oxidative activity.
(3) aurone Mannich alkaloid compound (I) is to Aβ 1-42The inhibitory activity of self assemble
Reference literature (Qiang, X.M.et al.Eur. J Med. Chem.2014,76,314-331) reported
Method be measured, it may be assumed that pretreated Aβ 1-42It is made into stock solution with DMSO, using preceding dilute with the PBS buffer solution of pH7.4
It releases to 50 μM；Untested compound is made into 2.5 mM stock solutions with DMSO, is diluted to accordingly using preceding with the PBS buffer solution of pH7.4
Concentration takes the A of 20 μ Lβ 1-42The A of the testing compound solution of+20 μ L of solution, 20 μ Lβ 1-42The PBS buffer solution of+20 μ L of solution (contains
2%DMSO) in 96 orifice plates, 37 °C are incubated for for 24 hours, and the glycine-NaOH for the 50mM that 160 μ L contain 5 μM of thioflavine Ts is then added
Buffer (pH=8.5) is surveyed under 446 nm excitation wavelengths and 490 nm launch wavelengths with multi-function microplate reader immediately after shaking 5s
Determine fluorescent value；Aβ 1-42The fluorescent value of+untested compound is denoted as IFi, Aβ 1-42The fluorescent value of+PBS buffer solution is denoted as IFc, contain only
The fluorescent value of PBS buffer solution is denoted as IF0, compound inhibition Aβ 1-42The inhibiting rate of self assemble are as follows: 100- (IFi-IF0)/(IFc-
IF0)*100；Five to six concentration for selecting compound, measure its inhibiting rate, each each concentration repetition measurement of compound three times, with
Curcumin is positive control.Measurement result shows that the aurone Mannich alkaloid compound (I) disclosed in the embodiment of the present invention is right
Aβ 1-42Self assemble all has remarkable inhibiting activity, to A under 25.0 μM of concentrationβ 1-42The inhibiting rate of self assemble is all larger than
50.0%；And inhibiting rate of the curcumin under same concentrations is 41.3%, clinically widely used anti-AD drug: donepezil,
The parent nucleus of Rivastigmine, memantine hydrochloride and compound (I) --- 2 '-hydroxyl aurone (R1、R2、R3And CH2NR4R5Equal table
Show that H, OH are located at 2 ' positions), 3 '-hydroxyl aurone (R1、R2、R3And CH2NR4R5Indicate that H, OH are located at 3 ' positions) and 4 '-hydroxyl aurones
(R1、R2、R3And CH2NR4R5Indicate H, OH is located at 4 ' positions) under 25.0 μM of concentration to Aβ 1-42The inhibiting rate of self assemble is equal
Less than 10%.
(4) measurement of aurone Mannich alkaloid compound (I) and complexing of metal ion effect
CuCl is dissolved with methanol2·2H2O、ZnCl2、FeSO4·7H2O、AlCl3And untested compound, it is made into 75 μm of ol/L
Solution, 100 μ L testing compound solutions and 100 μ L metal ion solutions are added into 96 orifice plates, mix, be stored at room temperature 30
Min records mixture on Varioskan Flash Multimode Reader (Thermo Scientific) instrument and exists
Ultraviolet absorption curve within the scope of 200-600 nm, and be pair with 100 μ L testing compound solutions and 100 μ L methyl alcohol mixed liquors
According to the Red Shift Phenomena of the maximum absorption band of observation metal ion and untested compound mixed liquor and the intensity of maximum absorption band.It surveys
The result shows that, the aurone Mannich alkaloid compound (I) disclosed in the embodiment of the present invention shows have choosing to copper ion calmly
Selecting property complexing.
(5) aurone Mannich alkaloid compound (I) is to Cu2+The A of inductionβ 1-42The inhibitory activity of aggregation
By CuCl275 μM of solution are made into HEPES buffer solution, with HEPES buffer solution by compound stock solution (2.5 mM)
With 200 μM of Aβ 1-42Stock solution is diluted to 75 μM, takes 20 μ L Cu respectively2++ 20 μ L A of solutionβ 1-42+ 20 μ L to be measuredization of solution
Polymer solution, 20 μ L Cu2++ 20 μ L A of solutionβ 1-42+ 20 μ L HEPES buffer solution of solution and 60 μ L HEPES buffer solutions are in 96
It in orifice plate, mixes, then the glycine-NaOH buffer for the 50mM that 190 μ L contain 5 μM of thioflavine Ts is added in 37 °C of 24 h of incubation
(pH=8.5) measure fluorescence under 446nm excitation wavelength and 490nm launch wavelength with multi-function microplate reader immediately after shaking 5s
Value；Cu2++Aβ 1-42The fluorescent value of+untested compound is recorded as IFi, Cu2++Aβ 1-42The fluorescent value of+HEPES buffer solution is recorded as
IFc, the fluorescent value for containing only HEPES buffer solution is recorded as IF0, compound is to Cu2+The A of inductionβ 1-42The inhibiting rate of aggregation are as follows:
100-(IFi-IF0)/(IFc-IF0)*100.Each each three multiple holes of concentration mensuration of compound, using curcumin as positive control.
Measurement result shows that the aurone Mannich alkaloid compound (I) disclosed in the embodiment of the present invention is right under 25.0 μM of concentration
Cu2+The A of inductionβ 1-42The inhibiting rate of aggregation is all larger than 60.0%；And inhibiting rate of the curcumin under same concentrations is 52.1%, is changed
Close parent nucleus --- the 2 '-hydroxyl aurone (R of object (I)1、R2、R3And CH2NR4R5Indicate H, OH is located at 2 ' positions), 3 '-hydroxyl aurones
(R1、R2、R3And CH2NR4R5Indicate that H, OH are located at 3 ' positions) and 4 '-hydroxyl aurone (R1、R2、R3And CH2NR4R5Indicate H, OH
Positioned at 4 ' positions) inhibiting rate under same concentrations is less than 20.0%.
Specific embodiment
The present invention can be further described by the following examples, however, the scope of the present invention is not limited to
Following embodiments.One of skill in the art, can be right it is understood that under the premise of without departing substantially from the spirit and scope of the present invention
The present invention carries out various change and modification.
Method is led in the preparation of 1 aurone Mannich alkaloid compound (I) of embodiment
Be added in reaction flask the corresponding benzofuran of 2.0 mmol -3 (2H) -one class compound (1), 3.0 mmol are corresponding
Hydroxy benzaldehyde Mannich alkaloid compound (2) and 30 ml ethyl alcohol be added dropwise to 30% KOH aqueous solution 12.0 after mixing evenly
Mmol is stirred at room temperature reaction 3.0~40.0 hours (reaction process is tracked with TLC)；After reaction, it is cooled to room temperature, with 10%
Aqueous hydrochloric acid solution adjusts reaction solution pH to highly acid, then adjusts reaction solution pH to alkalescent with saturated sodium bicarbonate aqueous solution, subtracts
Ethyl alcohol is evaporated off in pressure, and 80 mL deionized waters are added in residual solution, are extracted in three times with 240 mL methylene chloride, after organic layer merges
It is washed, is filtered after being dried over anhydrous sodium sulfate, evaporating solvent under reduced pressure with saturated sodium-chloride water solution, residue is through column chromatographic purifying
(eluent: methylene chloride: acetone=10:1 v/v), obtains corresponding aurone Mannich alkaloid compound (I), yield 42.0%-
80.0%, chemical structure passes through1H-NMR、13C-NMR and ESI-MS confirmation；The purity of gained object measures big through HPLC
In 97.0%.The object structure being prepared using above-mentioned logical method is as follows:
；
。
2 aurone Mannich alkaloid compound (I) of embodiment and acid are prepared at salt leads to method
Be added in reaction flask gained in accordance with the above-mentioned embodiment 1 2.0 mmol of aurone Mannich alkaloid compound (I) and
50 ml of acetone, is stirring evenly and then adding into that 8.0 mmol are sour accordingly, and temperature rising reflux is stirred to react 20 minutes, cold after reaction
But to room temperature, evaporating solvent under reduced pressure, residue acetone recrystallization filters the solid of precipitation to get aurone Mannich bases
Close the salt of object (I), chemical structure warp1H NMR and ESI-MS confirmation.
Claims (7)
1. a kind of aurone Mannich alkaloid compound or its pharmaceutically acceptable salt, it is characterised in that the chemistry of such compound
General structure is such as shown in (I):
In formula: R1、R2And R3Each independently represent H, OH, CF3O、C1~C12Alkoxy, NR6R7, R4And R5It each independently represents
C1~C12Alkyl, benzyl, substituted benzyl, R6And R7Each independently represent C1~C12Alkyl, NR4R5Also illustrate that nafoxidine base,
Quinoline base, piperidyl, piperazinyl, 4- by C1~C12Piperazinyl replaced alkyl, 4- replaced benzyl or substituted benzyl
Piperazinyl, NR6R7Also illustrate that nafoxidine base, piperidyl, R1、R2、R3、-CH2NR4R5It is any possible on corresponding phenyl ring with OH
Position；" substituted benzyl " refers to the benzyl replaced 1-4 groups selected from the group below on phenyl ring: F, Cl, Br, I, C1-4
Alkyl, C1-4Alkoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, these substituent groups arbitrarily may on the phenyl ring of benzyl
Position.
2. aurone Mannich alkaloid compound as described in claim 1 or its pharmaceutically acceptable salt, it is characterised in that institute
The pharmaceutically acceptable salt stated be such aurone Mannich alkaloid compound and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,
C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, sulphur are pungent
Acid, C1-6Alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid salt.
3. the preparation side of aurone Mannich alkaloid compound or its pharmaceutically acceptable salt as described in claim any one of 1-2
Method, it is characterised in that the compound can be prepared by the following method to obtain:
In formula: R1~R5Definition it is identical as the general formula of the chemical structure of aurone Mannich alkaloid compound (I)；
With corresponding benzofuran -3 (2H) -one class compound (1) and hydroxy benzaldehyde Mannich alkaloid compound (2) be starting
Raw material, the direct polycondensation under solvent and alkaline condition obtain corresponding aurone Mannich alkaloid compound (I)；Utilize the above method
Contain amino in the aurone Mannich bases compound molecule of gained, which can pass through medicine with any suitable acid in alkalinity
Its pharmaceutically acceptable salt is made in conventional salifying method on.
4. the preparation method of aurone Mannich alkaloid compound as claimed in claim 3 or its pharmaceutically acceptable salt, special
Sign is to react alkali used are as follows: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline-earth metal carbonic acid
Salt, alkali metal hydrogencarbonate, alkali metal bicarbonates, C1-8The alkali metal salt of alcohol, triethylamine, tri-n-butylamine, trioctylamine, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene diamine or tetrabutylammonium hydroxide；React solvent for use are as follows: C1-8Fatty alcohol, second
Ether, tetrahydrofuran, 2- methyltetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, 1,4- dioxy
Six rings, benzene, toluene or acetonitrile.
5. the preparation method of aurone Mannich alkaloid compound as claimed in claim 3 or its pharmaceutically acceptable salt, special
Sign be benzofuran -3 (2H) -one class compound (1): hydroxy benzaldehyde Mannich alkaloid compound (2): alkali mole feeds intake
Than for 1.0:1.0 ~ 3.0:1.0 ~ 20.0；Reaction temperature is 0 ~ 150 DEG C；Reaction time is 1 ~ 120 hour.
6. a kind of pharmaceutical composition, it is characterised in that comprising such as the described in any item aurone Mannich bases of claim 1-2
Close object or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipient.
7. as prepared by the described in any item aurone Mannich alkaloid compounds of claim 1-2 or its pharmaceutically acceptable salt
Purposes in treatment and/or prevention nervus retrogression related disease drug, this kind of nervus retrogression related disease are as follows: vascular is silly
Slow-witted, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive funiculus lateralis medullae spinalis
Sclerosis, neuropathic pain or glaucoma.
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| CN110003033B (en) * | 2018-01-05 | 2021-06-18 | 四川大学 | Flurbiprofen chalcone Mannich base compound, and preparation method and application thereof |
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| CN114149395B (en) * | 2021-12-10 | 2023-09-08 | 江西中医药大学 | Benzocyclopentenone derivative, preparation method and medical application thereof |
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