CN106831799B - Hydroxy styrenes pyridine Mannich alkaloid compound, preparation method and use - Google Patents
Hydroxy styrenes pyridine Mannich alkaloid compound, preparation method and use Download PDFInfo
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- CN106831799B CN106831799B CN201611181249.2A CN201611181249A CN106831799B CN 106831799 B CN106831799 B CN 106831799B CN 201611181249 A CN201611181249 A CN 201611181249A CN 106831799 B CN106831799 B CN 106831799B
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- acid
- pyridine
- compound
- hydroxystyrene
- reaction
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- -1 alkaloid compound Chemical class 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims description 38
- XLLXMBCBJGATSP-UHFFFAOYSA-N 2-phenylethenol Chemical class OC=CC1=CC=CC=C1 XLLXMBCBJGATSP-UHFFFAOYSA-N 0.000 title description 31
- 229930013930 alkaloid Natural products 0.000 title description 29
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- 238000002156 mixing Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
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- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
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- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical class CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical class COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PKYCWFICOKSIHZ-UHFFFAOYSA-N 1-(3,7-dihydroxyphenoxazin-10-yl)ethanone Chemical compound OC1=CC=C2N(C(=O)C)C3=CC=C(O)C=C3OC2=C1 PKYCWFICOKSIHZ-UHFFFAOYSA-N 0.000 description 1
- BIAWAXVRXKIUQB-UHFFFAOYSA-N 2-(2-phenylethenyl)pyridine Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=N1 BIAWAXVRXKIUQB-UHFFFAOYSA-N 0.000 description 1
- NTBLZMAMTZXLBP-UHFFFAOYSA-M 2-acetylsulfanylethyl(trimethyl)azanium;iodide Chemical class [I-].CC(=O)SCC[N+](C)(C)C NTBLZMAMTZXLBP-UHFFFAOYSA-M 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 1
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- 108090000322 Cholinesterases Proteins 0.000 description 1
- 229910021591 Copper(I) 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
- 206010012289 Dementia Diseases 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
- 101000694718 Homo sapiens Amine oxidase [flavin-containing] A Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 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
- 241001465754 Metazoa Species 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 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
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000005325 alkali earth metal hydroxides Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 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
- 230000004596 appetite loss Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- BUXYRJPVMAZQSY-UHFFFAOYSA-N benzene;methanamine Chemical class NC.C1=CC=CC=C1 BUXYRJPVMAZQSY-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000008422 chlorobenzenes Chemical class 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 229940048961 cholinesterase Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 150000004816 dichlorobenzenes Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 231100000880 dysequilibrium Toxicity 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 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
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000003694 hair properties Effects 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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052603 melanterite Inorganic materials 0.000 description 1
- 230000009225 memory damage Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 125000005936 piperidyl group Chemical group 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
- 125000006239 protecting group Chemical group 0.000 description 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 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
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010792 warming Methods 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一类新型的羟基苯乙烯吡啶曼尼希碱类化合物（I）及其药学上可接受的盐、其制备方法、药物组合物和在制备治疗和/或预防神经退行性相关疾病药物中的用途，包括但不限于血管性痴呆、阿尔茨海默氏症、帕金森症、亨廷顿症、HIV相关痴呆症、多发性硬化症、进行性脊髓侧索硬化症、神经性疼痛、青光眼等神经退行性疾病；。The invention discloses a new class of hydroxystyrene pyridine Mannich base compound (I) and its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and preparation for treating and/or preventing neurodegenerative related diseases Use in medicines including, but not limited to, vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma and other neurodegenerative diseases; .
Description
Technical field
The invention belongs to field of medicinal chemistry, are related to a kind of novel hydroxy styrenes pyridine Mannich alkaloid compound (I)
And its pharmaceutically acceptable salt, preparation method, pharmaceutical composition are related in preparation treatment and/or prevention nervus retrogression
Purposes in disease medicament, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV
The nervus retrogressions diseases such as related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma
Disease.
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, monoamine oxidase B (MAO-B) activity increase
By force, glutamate receptor activity is excessively high, oxidative stress generates a large amount of active oxygens (ROS) and free radical and Neuroinflammation etc. are more
Kind factor is played an important role in the pathogenic process of AD.For above-mentioned pathogenic factors, researcher is using a traditional " medicine one
Target " drug design strategies, it was found that largely there is high activity and highly selective drug to a certain target spot, such as: cholinesterase suppression
Preparation andNMethyl-DAspartate receptor agonist etc., but that there are action target spots is single, clinical use is malicious secondary makees for these drugs
With it is more, not good enough to the long-term efficacy of AD patient the problems such as.
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..It designs and finds have simultaneously
There is acetylcholine esterase inhibition, inhibit monoamine oxidase B, anti-oxidation stress, the metal ion in selective complexation central tissues
(especially Cu2+And Fe2+), and the more balanced multiple target point AD therapeutic agent of multiple biological activities is current research hotspot.Cause
This, research and development have novel chemical structure, novel mechanism of action, and have multiple target point (or multi-functional) effect, low toxicity are secondary to make
Anti- neurodegenerative disease therapeutic agent not only conforms with the urgent need of social senilization's process, and has good city
Field prospect.
Summary of the invention
Present invention aims at open a kind of novel hydroxy styrenes pyridine Mannich alkaloid compounds (I) and its pharmacy
Upper acceptable salt；
Another object of the present invention is to disclose such hydroxy styrenes pyridine Mannich alkaloid compound (I) and its pharmaceutically
The preparation method of acceptable salt；
Another object of the present invention is to open comprising such hydroxy styrenes pyridine Mannich alkaloid compound (I) and its
The pharmaceutical composition of pharmaceutically acceptable salt；
Still a further object of the present invention is to disclose such hydroxy styrenes pyridine Mannich alkaloid compound (I) and its pharmaceutically
Acceptable salt has multiple target effect, in the drug that can be used for preparing treatment and/or prevention nervus retrogression related disease
It is purposes, including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, more
The neurodegenerative diseases such as hair property sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
The general formula of the chemical structure of hydroxy styrenes pyridine Mannich alkaloid compound (I) disclosed in this invention are as follows:
In formula: R1And R2Each independently represent C1~C12Alkyl, benzyl, substituted benzyl, propargyl；NR1R2Also illustrate that four
Hydrogen pyrrole radicals, morpholinyl, piperidyl, piperazinyl, 4- by C1~C12Piperazinyl replaced alkyl, 4- by benzyl or substitution
Piperazinyl replaced benzyl ,-CH2NR1R2It can be in the arbitrarily possible position of phenyl ring with OH；Ar be expressed as follows shown in (A) and
(B) any structure unit in；
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.
Hydroxy styrenes pyridine Mannich alkaloid compound (I) disclosed in this invention and its pharmaceutically acceptable salt can
It is prepared by the following method to obtain:
In formula: R1、R2Definition with Ar is identical as general formula of the chemical structure (I)；-CH2NR1R2Can arbitrarily may in phenyl ring with OH
Position；X indicates Cl or Br；R3Indicate C1-C12Alkyl.
With 5- (halogen methyl) -2,2,8- trimethyl -4H[1,3] dioxane [4,5-c] pyridine compounds and their (1) is
Beginning raw material, it is solvent-free or have under solvent condition with phosphite ester (P (OR3)3) reaction, obtain corresponding picolyl phosphoric acid easter class
It closes object (2)；Gained compound (2) is condensed under solvent and alkaline condition with hydroxy benzaldehyde compound (HO-PhCHO), is obtained
Isopropyl methene hydroxy styrenes pyridine compounds and their (3)；Obtained compound (3) is removed into isopropyl methene in acidic aqueous solution
Protecting group obtains hydroxy styrenes pyridine compounds and their (4)；Finally, by compound (3) or (4) in a solvent with formaldehyde, amine
Close object (HNR1R2) react through Mannich to get hydroxy styrenes pyridine Mannich alkaloid compound (I).
Its specific preparation method is described as follows:
(the halogen methyl) -2,2,8- of step a): 5- trimethyl -4H[1,3] dioxane [4,5-c] pyridine compounds and their (1)
It is solvent-free or have under solvent condition with phosphite ester (P (OR3)3) reaction, obtain corresponding picolyl phosphoric acid easter class compound (2)；
Wherein, solvent for use is reacted are as follows:N,NDimethylformamide, dimethyl sulfoxide, chlorobenzene, dichloro-benzenes, benzene,toluene,xylene or
Diphenyl ether；Compound (1): the molar feed ratio of phosphite ester be 1.0:1.0 ~ 100.0, preferably molar feed ratio be 1.0:1.0 ~
20.0；Reaction temperature is 50 ~ 250 DEG C, and preferable reaction temperature is 100 ~ 160 DEG C；Reaction time is 30 minutes ~ 24 hours, preferably
Reaction time is 1 ~ 12 hour.
Step b): the compound (2) being prepared by step a) under solvent and alkaline condition with hydroxy benzaldehyde class
Object (HO-PhCHO) condensation is closed, isopropyl methene hydroxy styrenes pyridine compounds and their (3) is obtained；Wherein, solvent for use is reacted are as follows:
C1-8Fatty alcohol, ethyl acetate, ether, tetrahydrofuran, 2- methyltetrahydrofuran,N,NDimethylformamide, dimethyl sulfoxide,
Methylene chloride, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane, preferred solvent are as follows: methanol, ethyl alcohol, isopropanol,N,NDimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or toluene；React alkali used are as follows: alkali metal hydroxide, alkali
Earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydride, C1-8It is the alkali metal salt of alcohol, organic
Tertiary amines or quaternary ammonium bases (such as: triethylamine, tri-n-butylamine, trioctylamine, pyridine,NMethyl morpholine,NMethyl piperidine, triethylene two
Amine, tetrabutylammonium hydroxide), preferred alkali are as follows: potassium hydroxide, sodium hydride, potassium carbonate, triethylamine or sodium methoxide；Compound (2):
Hydroxy benzaldehyde compound: the molar feed ratio of alkali is 1.0:0.9 ~ 5.0:1.0 ~ 10.0, and preferably molar feed ratio is 1.0:
1.0 ~ 3.0:1.0 ~ 6.0；Reaction temperature is -30 ~ 120 DEG C, and preferable reaction temperature is 0 ~ 100 DEG C；Reaction time is 1 ~ 24 hour,
Preferred reaction time is 2 ~ 12 hours.
Step c): the compound (3) being prepared by step b) removes isopropyl methene protecting group in acidic aqueous solution, obtains
Hydroxy styrenes pyridine compounds and their (4)；Wherein, solvent for use is reacted are as follows: water, C1-6Fatty alcohol,N,NDimethylformamide,
Tetrahydrofuran, C3-8Aliphatic ketone, acetonitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide, preferred solvent are as follows: water, methanol, ethyl alcohol, 1,
4- dioxane or tetrahydrofuran；Acid used are as follows: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, C1-6Fatty acid, C1-6
Alkyl sulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid, preferred acid are as follows: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, Loprazolam；Acid is in reactant
Mass fraction in system is 0.1%-98%, and preferred mass score is 10%-95%, and reaction temperature is 0 ~ 150 DEG C, preferable reaction temperature
For room temperature ~ 120 DEG C；Reaction time is 30 minutes ~ 24 hours, and preferred reaction time is 1 ~ 8 hour.
Step d): the compound (3) being prepared by step b) or the compound (4) being prepared by step c) are in solvent
In with formaldehyde, aminated compounds (HNR1R2) reacted through Mannich, hydroxy styrenes pyridine Mannich bases chemical combination can be obtained
Object (I)；Wherein, solvent for use is reacted are as follows: C1-8Fatty alcohol, ethyl acetate, ether, tetrahydrofuran, 2- methyltetrahydrofuran,N, NDimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, 1,4- dioxane, benzene, toluene, acetonitrile or C5-8Alkane, it is excellent
Select solvent are as follows: methanol, ethyl alcohol, isopropanol,N,NDimethylformamide, tetrahydrofuran, methylene chloride or toluene；Compound (3)
Or (4): formaldehyde: the molar feed ratio of aminated compounds is 1.0:1.0 ~ 10.0:1.0 ~ 10.0, and preferably molar feed ratio is 1.0:
1.0 ~ 5.0:1.0 ~ 5.0；Reaction temperature is 0 ~ 120 DEG C, and preferable reaction temperature is room temperature ~ 100 DEG C；Reaction time is 1 ~ 24 small
When, preferred reaction time is 2 ~ 12 hours.
Contain amino in hydroxy styrenes pyridine Mannich alkaloid compound (I) molecule of gained according to the method described above, it should
In alkalinity its pharmaceutically acceptable salt can be made by pharmaceutically conventional salifying method with any suitable acid in amino,
The 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, salicylic 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), camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
Pharmaceutical composition disclosed in this invention includes one or more hydroxy styrenes pyridine Mannies of therapeutically effective amount
Uncommon alkaloid compound (I) or its pharmaceutically acceptable salt, the pharmaceutical composition can further containing it is one or more pharmaceutically
Acceptable carrier or excipient." therapeutically effective amount " refer to cause researcher or the targeted tissue of doctor, system or
The amount of the biology of animal or the drug of medicine reaction or medicament；" composition " refers to by by more than one substances or component
Product made of mixing；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable substance, composition or carrier,
Such as: liquid or solid filler, diluent, excipient, solvent or packing substance, they carry or transport certain chemical substance.
Its ideal ratio of pharmaceutical composition provided by the present invention is, hydroxy styrenes pyridine Mannich alkaloid compound (I) or its
Pharmaceutically acceptable salt accounts for total weight than 2%~99.5% as active constituent, and rest part is to account for total weight than 98% or less.
Hydroxy styrenes pyridine Mannich alkaloid compound (I) disclosed in this invention and its pharmaceutically acceptable salt into
Following bioactivity screening is gone.
(1) suppression of the hydroxy styrenes pyridine Mannich alkaloid compound (I) to acetylcholinesterase and butyrylcholine esterase
System activity
Sequentially added into 96 orifice plates 1.0 mmol/L acetylthiocholine iodides or iodine bisulfide for 30 μ L of BuCh,
1%) and 10 μ L acetylcholinesterases 40 μ L of PBS buffer solution of pH7.4,20 μ L(DMSO content of testing compound solution are less than
(rat brain cortex 5% is homogenized supernatant, and the phosphate buffer of pH7.4 makees homogenate medium) or butyrylcholine esterase (rat blood serum
25% supernatant, pH7.4 phosphate buffer make homogenate medium) solution, after finishing mixing, 37 DEG C of incubation 15min, to each Kong Zhongjia
Enter the 5 of 0.2%, 5 '-two thio-bis- 30 μ L of (2- nitrobenzoic acid) (DTNB) solution colour developings are measured each at 405nm with microplate reader
The optical density (OD value) in hole calculates compound to the inhibiting rate (enzyme inhibition rate of enzyme compared with the blank well that sample to be tested is not added
(%)=(1- sample sets OD value/blank group OD value) × 100%)；Five to six concentration for selecting compound, measure its enzyme inhibition rate,
And with the inhibiting rate linear regression of the negative logarithm of the compound molar concentration and enzyme, molar concentration when acquiring 50% inhibiting rate is i.e.
For the IC of the compound50.Measurement result shows the hydroxy styrenes pyridine Mannich bases disclosed in the embodiment of the present invention
It closes object (I) and all has the effect of significantly inhibiting, IC to acetylcholinesterase50It is 0.2 μM ~ 15.0 μM；And hydroxy styrenes pyrrole
Pyridine Mannich alkaloid compound (I) is significantly higher than the inhibitory activity to butyrylcholine esterase to the inhibitory activity of acetylcholinesterase
(selectivity is greater than 10 times) illustrates that compound disclosed in this invention has selective inhibitory to acetylcholinesterase.It surveys
Determine the parent nucleus that result is also shown that hydroxy styrenes pyridine Mannich alkaloid compound (I) --- compound (3) or (4) are to acetyl
Cholinesterase is almost without inhibiting effect, IC50It is all larger than 200 μM.
(2) inhibitory activity of the hydroxy styrenes pyridine Mannich alkaloid compound (I) to monoamine oxidase A and B
Recombined human MAO-A is made into 12.5 μ g/mL sample liquids with 7.4 kaliumphosphate buffer of pH of 100 mM, by MAO-B
It is made into 75 μ g/mL sample liquids.20 μ L of testing compound solution, 80 μ L of monoamine oxidase are added into 96 orifice plate of black, mixes
Even, 37 °C are incubated for 15 min in the place of being protected from light, and 200 μM of Amplex Red reagents, 2U/mL horseradish peroxidase, 2 mM are added
Uteramin (inhibiting MAO-A) or 2 mM benzene methanamines (inhibiting MAO-B) initiation reaction, 37 °C of 20 min of incubation, in more function
In energy microplate reader, to fix 545 nm of excitation wavelength, fluorescent emission intensity at 590 nm is surveyed, MAO- is replaced with kaliumphosphate buffer
A or MAO-B is blank；The inhibiting rate calculation formula of compound inhibition monoamine oxidase are as follows: 100- (IFi)/(IFc) * 100, formula
In, IFiAnd IFcRespectively there is the difference of the fluorescence intensity and blank fluorescence intensity under inhibitor and no inhibitor.Each compound
3 multiple holes of measurement every time, every group of experiment are independent in triplicate.Five to six concentration for selecting compound, measure its enzyme inhibition rate,
And with the inhibiting rate linear regression of the negative logarithm of the compound molar concentration and enzyme, molar concentration when acquiring 50% inhibiting rate is i.e.
For the IC of the compound50.Measurement result shows the hydroxy styrenes pyridine Mannich bases disclosed in the embodiment of the present invention
It closes object (I) and all has the effect of significantly inhibiting, IC to MAO-B50It is 0.5 μM ~ 25.0 μM；And to the IC that MAO-A inhibits50?
Higher than 50.0 μM, illustrate that compound disclosed in this invention has selective inhibitory to MAO-B.
(3) measurement of hydroxy styrenes pyridine 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 ultraviolet absorption curve of the mixture within the scope of 200-600 nm on multi-function microplate reader, and to be measured with 100 μ L
Compound solution and 100 μ L methyl alcohol mixed liquors are control, observe the maximum absorption band of metal ion and untested compound mixed liquor
Red Shift Phenomena and maximum absorption band intensity.Measurement result shows the hydroxy styrenes pyrrole disclosed in the embodiment of the present invention
Pyridine Mannich alkaloid compound (I) is shown to Cu2+And Fe2+With selective complexation effect, and to Zn2+And Al3+Almost without
Complexing.
(4) antioxidant activity (ORAC-FL method) of hydroxy styrenes pyridine 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 in multi-function microplate reader, in 485 nm excitation wavelengths
With 90 min of METHOD FOR CONTINUOUS DETERMINATION under 535 nm launch wavelengths.Area AUC under fluorescence decay curve is calculated, 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 isTroloxWork as
Amount, its calculation formula is: [(AUC Sample-AUC blank)/(AUCTrolox-AUC blank)]´
[(concentration of Trolox/ concentration of sample)], each compound measures 3 again every time
Hole, every group of experiment are independent in triplicate.Measurement result shows the hydroxy styrenes pyridine Manny disclosed in the embodiment of the present invention
The antioxidant activity of uncommon alkaloid compound (I) isTrolox1.5-4.0 times, illustrate that such compound is living with strong anti-oxidation
Property.
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.
Embodiment 1
When Ar indicates (B) structural unit, method is led in the preparation of hydroxy styrenes pyridine Mannich alkaloid compound (I)
4.0 mmol 5- (chloromethyl) -2,2,8- trimethyls -4 are added in reaction flaskH[1,3] dioxane [4,5-
C] pyridine (1) and 25.0 mmol triethyl phosphites, temperature rising reflux be stirred to react 4.0 hours (reaction process is tracked with TLC)；
After reaction, excessive triethyl phosphite is removed under reduced pressure, residue is purified by silica gel column chromatography (eluent: petroleum ether-second
Acetoacetic ester=1:1 v/v), obtain 2,2,8- trimethyls -4H[1,3] dioxane [4,5-c] pyridine -5- methyl acid phosphate diethylester
(2), yield 93.2%；
By 2,2,8- trimethyl -4 made from upper stepH[1,3] dioxane [4,5-c] pyridine -5- methyl acid phosphate diethylester
(2) full dose is dissolved in 20 ml tetrahydrofurans, is cooled to 0~5 DEG C, and 8.0 mmol sodium hydrides are added, and insulated and stirred reacts 30 points
Then hydroxy benzaldehyde compound (HO-PhCHO) 4.0 mmol is added in clock, it is small to continue at 0~5 DEG C of insulated and stirred reaction 6-8
When；After reaction, 10% aqueous hydrochloric acid solution is added and terminates reaction, then with 10% soda solution neutralization reaction liquid to neutrality,
Remove tetrahydrofuran under reduced pressure, residual solution is extracted with 50 ml ethyl acetate, and organic layer filters after being dried over anhydrous sodium sulfate, decompression
Solvent is evaporated off, residue obtains corresponding isopropyl methene through column chromatographic purifying (eluent: petroleum ether-ethyl acetate=2:1 v/v)
Hydroxy styrenes pyridine compounds and their (3), yield 65.0%-80.0%；
(3) 1.0 mmol of isopropyl methene hydroxy styrenes pyridine compounds and their for taking above-mentioned steps to obtain is dissolved in 6 ml ethyl alcohol
In, 3.0 mmol of paraformaldehyde and corresponding aminated compounds (HNR is added1R2) 3.0 mmol, temperature rising reflux is stirred to react 3-10
Hour (reaction process is tracked with TLC), after reaction, evaporating solvent under reduced pressure is added 25 ml ethyl acetate in residue, uses
10 ml saturated common salt water washings, organic layer filter after being dried over anhydrous sodium sulfate, and evaporating solvent under reduced pressure, residue is chromatographed through column
It purifies (eluent: petroleum ether-ethyl acetate=1:3 v/v), obtains corresponding hydroxy styrenes pyridine Mannich alkaloid compound
(I), yield 25.0%-75.5%, chemical structure pass through1H-NMR、13C-NMR and ESI-MS confirmation, the purity of gained object
97.0% is all larger than through HPLC measurement.The object structure being prepared using above-mentioned logical method is as follows:
Embodiment 2
When Ar indicates (A) structural unit, method is led in the preparation of hydroxy styrenes pyridine Mannich alkaloid compound (I)
4.0 mmol 5- (bromomethyl) -2,2,8- trimethyls -4 are added in reaction flaskH[1,3] dioxane [4,5-
C] pyridine (1), 10.0 mmol Trimethyl phosphites and 25 ml chlorobenzenes, temperature rising reflux is stirred to react 5.0 hours, and (reaction process is used
TLC tracking)；After reaction, excessive Trimethyl phosphite and chlorobenzene are removed under reduced pressure, residue is purified by silica gel column chromatography
(eluent: petroleum ether-ethyl acetate=1:1 v/v), obtains 2,2,8- trimethyls -4H[1,3] dioxane [4,5-c] pyridine-
5- methyl-phosphoric acid dimethyl ester (2), yield 90.9%；
By 2,2,8- trimethyl -4 made from upper stepH[1,3] dioxane [4,5-c] pyridine -5- methyl-phosphoric acid dimethyl ester
(2) full dose is dissolved in 20 ml toluene, is cooled to 0~5 DEG C, and 10.0 mmol sodium methoxides are added, and reaction 30 minutes is stirred at room temperature, so
Hydroxy benzaldehyde compound (HO-PhCHO) 4.0 mmol is added afterwards, is warming up to 50 DEG C and is stirred to react 5-12 hours；Reaction knot
Shu Hou is added 10% aqueous hydrochloric acid solution and terminates reaction, then removes first under reduced pressure to neutrality with 10% soda solution neutralization reaction liquid
Benzene, residual solution are extracted with 50 ml ethyl acetate, and organic layer filters after being dried over anhydrous sodium sulfate, evaporating solvent under reduced pressure, residue
Through column chromatographic purifying (eluent: petroleum ether-ethyl acetate=2:1 v/v), corresponding isopropyl methene hydroxy styrenes pyridines are obtained
Compound (3), yield 57.0%-68.0%；
15% aqueous hydrochloric acid solution 10 is added in isopropyl methene hydroxy styrenes pyridine compounds and their (3) full dose made from upper step
It in the mixed solution of 20 ml of ml and ethyl alcohol, is stirred at room temperature reaction 3.0~7.0 hours (reaction process is tracked with TLC), reaction knot
50 ml ethyl acetate are added in residue in Shu Hou, evaporating solvent under reduced pressure, and organic layer successively uses 25 ml, 5% sodium bicarbonate water-soluble
Liquid and the washing of 20 ml deionized waters, are filtered, evaporating solvent under reduced pressure, residue is through column chromatographic purifying after being dried over anhydrous sodium sulfate
(eluent: petroleum ether-ethyl acetate=2:1 v/v), obtains corresponding hydroxy styrenes pyridine compounds and their (4), yield 88%-
90%；
(4) 1.0 mmol of hydroxy styrenes pyridine compounds and their for taking above-mentioned steps to obtain is dissolved in 6 ml ethyl alcohol, is added
3.0 mmol of paraformaldehyde and corresponding aminated compounds (HNR1R2) 3.0 mmol, temperature rising reflux be stirred to react 3-10 hours it is (anti-
Process is answered to be tracked with TLC), after reaction, 25 ml ethyl acetate are added in residue in evaporating solvent under reduced pressure, full with 10 ml
And brine It, organic layer filter after being dried over anhydrous sodium sulfate, evaporating solvent under reduced pressure, residue (is washed through column chromatographic purifying
De- liquid: petroleum ether-ethyl acetate=1:3 v/v), obtain corresponding hydroxy styrenes pyridine Mannich alkaloid compound (I), yield
25.0%-75.5%, chemical structure pass through1H-NMR、13C-NMR and ESI-MS confirmation, the purity of gained object are surveyed through HPLC
Surely it is all larger than 97.0%.The object structure being prepared using above-mentioned logical method is as follows:
3 hydroxy styrenes pyridine Mannich alkaloid compound (I) of embodiment and acid are prepared at salt leads to method
It is added in reaction flask in accordance with the above-mentioned embodiment 1 or the hydroxy styrenes pyridine Mannich alkaloid compound of 2 gained
(I) 50 ml of 2.0 mmol and methanol, is stirring evenly and then adding into that 6.0 mmol are sour accordingly, and temperature rising reflux is stirred to react 10 minutes,
It is cooled to room temperature after reaction, evaporating solvent under reduced pressure, residue acetone recrystallization, filters the solid of precipitation to get hydroxyl
The salt of styryl pyridine Mannich alkaloid compound (I), chemical structure warp1H NMR and ESI-MS confirmation.
Claims (10)
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