CN106278857A - α, β unsaturated carbonyl tetralone derivative and application thereof - Google Patents
α, β unsaturated carbonyl tetralone derivative and application thereof Download PDFInfo
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- CN106278857A CN106278857A CN201610737655.6A CN201610737655A CN106278857A CN 106278857 A CN106278857 A CN 106278857A CN 201610737655 A CN201610737655 A CN 201610737655A CN 106278857 A CN106278857 A CN 106278857A
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- benzylidene
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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Abstract
The invention discloses a kind of α, β unsaturated carbonyl tetralone derivative and application thereof.There is following structural formula, wherein, R1Represent methylene or HC CH3；R2Represent hydrogen atom or methoxyl group；R3Represent hydrogen atom, chlorine atom, methoxyl group, bromine atoms, fluorine atom or nitro；R4Represent hydrogen atom or methoxyl group；R5Represent hydrogen atom, hydroxyl or methoxyl group；R’3、R’4Represent hydrogen atom or methoxyl group respectively；R’6Represent chlorine atom or bromine atoms.The compound of present invention synthesis has the pharmacologically active that anti-alzheimer's disease is relevant, is suitable as preventing, treating and diagnose the medicine of alzheimer's disease, has preferable potential application foreground.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of α, beta-unsaturated carbonyl tetralone derivative and should
With.
Background technology
Neurodegenerative diseases be by mulitpath control cell death the disease of a kind of complexity.Traditional location is treated
Method simply wherein one do not confirmed medicable method completely, and need a change assumed that researcher is set
Meter developing new drug.In our study, we have probed into a series of α, and beta-unsaturated carbonyl tetralone derivative is used for controlling
Treat the effect of Alzheimer disease.It addition, they have been also carried out research to the cytotoxicity of β amyloplaste induction.Following six chemical combination
Thing 3f, 3o, 3u, 3ae, 3af, and 3ag can protect neuron in PC12 cell to avoid cell death beta induced for A.Most
In vitro cell experiment proves that these compounds have potential suppression monoamine oxidase, MAO b, acetylcholinesterase and the A of auto-induction
The activity of β 1 42 self aggregation.Compound 3f demonstrate optimal acetylcholinesterase inhibitory activity (IC50=0.045 ±
0.02 μM), in addition, monoamine oxidase, MAO b also had inhibitory activity (IC50=0.88 ± 0.12 μM), it addition, chemical combination
The A beta of the A β self aggregation generation that thing 3f dispersibles auto-induction reaches 78.2 ± 4.8%.In a word, similar discovery demonstrates
The compound of this series can be as the potential poly functional reagent for treating Alzheimer disease.
Alzheimer disease, is a kind of neurodegenerative diseases caused owing to cognitive competence weakens.It is that the U.S. cannot control
One of ten big mortality rate diseases of system.Alzheimer disease gradually becomes United States residents common cause of death.But, former by other
Death because causing reduces the most in a large number, and data show that the mortality positive pole caused by Alzheimer disease increases severely and add, from 2000
Year, the dead quantity caused by Alzheimer disease rose 71%, and the mortality caused by heart disease declines by 2013
14%.If not taking direct measure prevention or treat this fatal disease, it is estimated that to the year two thousand fifty, 65 years old and above people
Three times will be had to have increased access to Alzheimer disease (5,100,000 rise to 13,800,000).
The approach of one crucial treatment Alzheimer disease is by using acetylcholinesteraseinhibitors inhibitors to increase in brain
Acetylcholine concentration.The curative effect of cholinesterase inhibitor is to maintain about 50% brain in patients function 1 year.Acetylcholine ester
Enzyme (AChE) and butyrylcholine esterase (BChE) maintain the hydrolysis of acetylcholine.Root according to the literature, acetylcholinesterase
(AChE) it is the main enzyme of central nervous system (CNS), is considered " the cholinomimetic target " for treating Alzheimer disease.Cause
This, the pivotal role played in cholinomimetic neurotransmission due to acetylcholinesterase (AChE), major part is about treatment Ah hereby
The silent disease in sea research all focus on acetylcholinesterase (AChE), but recent studies have shown that the butyryl gallbladder that getting up early is thought
Alkali esterase (BChE) viewpoint of not vital effect in the neurotransmission of cholinomimetic should be corrected, because butyryl
Acetylcholine esterase (BChE) is also proved to be the important moderator in the neurotransmission of cholinomimetic.It addition, butyrylcholine esterase
(BChE) at endotheliocyte, neurogliocyte and neuron are expressed.Up-to-date document report also indicates that acetylcholinesterase
(AChE) regulate in the growth course of the nervus centralis of multiple species (including rodent) with butyrylcholine esterase (BChE)
Neurite outgrowth and cell proliferation.Butyrylcholine esterase (BChE) may also function to important work in normal central nervous system
With.
Therefore, it can developing new drug synthesis strategy.In this regard, an important strategy assumes that and determines with multiple target
" single molecule, multiple target " is realized based on part (MTDL) method.This method has attracted the note of a lot of research team
Meaning, and have found several about the compound acting on multiple enzyme and receptor while Alzheimer disease.Treatment Ah hereby
One of the silent disease in sea it is crucial that monoamine oxidase, MAO (MAO) takes off because it can regulate the oxidation of multiple xenobiotic and biogenic amine
Amino effect, produces hydrogen peroxide simultaneously, and this is the poisonous oxygen radical species produced by Fenton's reaction.Monoamine oxygen
Change enzyme (MAO) and contain flavin adenine dinucleotide (FAD) (FAD), and be attached to the line of neuroglia, neuron and other cells
On plastochondria adventitia.MAO-A and MAO-B is two isozymes of monoamine oxidase, MAO, has the aminoacid sequence of uniqueness, to pressing down
The sensitivity of preparation and substrate specificity.MAO-A mainly oxidation 5-hydroxy tryptamine and norepinephrine, chlorgyline can
It is suppressed with selective；MAO-B mainly makes dopamine deaminizating, can be by the permanent suppression of L-deprenyl.Major part is faced
Tranquilizer and antidepressants that bed uses can optionally suppress MAO-A, but the inhibitor of MAO-B can be used to slow down handkerchief gold
The indication that gloomy disease is relevant with Alzheimer disease.
The neuritic speckle in extracellular (or senile plaque, SP) and intracellular neurofibrillary tangles are Alzheimer disease pathology
The most special.Senile plaque (compact deposition composition A β is major part) is especially included in mesencephalic region regulation memory and cognition.Literary composition
Offer the irregular A β of report excess and cause nerve cell death and clinical symptoms with fibers form at extracellular accumulation.Cause
This, we generally believe that the medicine of this gathering of can dissociating can be used for the treatment of Alzheimer disease.
In conjunction with acetylcholinesteraseinhibitors inhibitors and other treatment reagent in Alzheimer disease pathological research at not same order
Effective result that section plays a role, uses the potential compound that can hit multiple pharmacological target permissible as single molecule
It it is considered as the strategy of practicality.Our seminar and other researchers find some compounds have anticholinesterase activity and
Other neurological symptom correlation properties that Alzheimer disease is relevant.
Summary of the invention
It is an object of the invention to provide a kind of α, beta-unsaturated carbonyl tetralone derivative, it has and anti-A Erzi
The pharmacologically active that the silent disease in sea is relevant, is suitable as preventing, treating and diagnose the medicine of alzheimer's disease.
For reaching above-mentioned purpose, use technical scheme as follows:
α, beta-unsaturated carbonyl tetralone derivative, there is following structural formula:
Wherein, R1Represent methylene or-HC-CH3；R2Represent hydrogen atom or methoxyl group；R3Represent hydrogen atom, chlorine atom, first
Epoxide, bromine atoms, fluorine atom or nitro；R4Represent hydrogen atom or methoxyl group；R5Represent hydrogen atom, hydroxyl or methoxyl group；R’3、
R’4Represent hydrogen atom or methoxyl group respectively；R’6Represent chlorine atom or bromine atoms.
Above-mentioned alpha, beta-unsaturated carbonyl tetralone derivative is:
2-(2-chloro-3-Methoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene (3a),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene (3b),
2-(2-bromo-3,4-Dimethoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene (3c),
2-(2-chloro-3-Methoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (3d),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (3e),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (3f),
2-(2-chloro-3-Methoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (3g),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (3h),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (3i),
2-(2-chloro-3-Methoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3j),
2-(2-chloro-3,4-Dimethoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3k),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3l),
2-(2-chloro-3-Methoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (3m),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (3n),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (3o),
2-(2-chloro-3-Methoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone (3p),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone (3q),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone (3r),
2-(2-chloro-3-Methoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (3s),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (3t),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (3u),
2-(2-chloro-3-Methoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (3v),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (3w),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (3x),
2-(2-chloro-3-Methoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3y),
2-(2-chloro-3,4-Dimethoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3z),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3aa),
2-(2-chloro-3-Methoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3ab),
2-(2-chloro-3,4-Dimethoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3ac),
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-(3ad),
2-(2-chloro-3-Methoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (3ae),
2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (3af) or
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (3ag).
Above-mentioned alpha, beta-unsaturated carbonyl tetralone derivative is as preventing, treating and diagnose alzheimer disease drug
Application.
Beneficial effects of the present invention is as follows:
The present invention has synthesized a series of α, beta-unsaturated carbonyl tetralone derivative, and surveys its biological activity
Fixed, it was demonstrated that the compound of present invention synthesis has the pharmacologically active that anti-alzheimer's disease is relevant, be suitable as prevention, treatment and
The medicine of diagnosis alzheimer's disease, has preferable potential application foreground.
Accompanying drawing explanation
A β self-induction in PC12 cell is assembled the Cytotoxic impact produced by Fig. 1: the present invention；
Fig. 2: the present invention is to A β1–42The inhibitory activity that self-induction is assembled.
Detailed description of the invention
Following example explain technical scheme further, but not as limiting the scope of the invention.
Alpha, beta-unsaturated carbonyl tetralone derivative preparation process of the present invention is as follows:
Mol ratio is that the ketone of 1:1 carries out claisen-schmidt condensation reaction in the basic conditions with aromatic aldehyde, obtains 33
Plant α, beta-unsaturated carbonyl tetralone derivative, be shown in Table 1.The compound of all synthesis is by recrystallization technology post color alive
Spectral technology is purified.Success synthesize noval chemical compound by mass spectrum,1H NMR、13C NMR and elementary analysis confirm.
For R1-R5&R'3-R'6see Table 1.
Table 1
First, the α of synthesis, the beta-unsaturated carbonyl tetralone derivative cytotoxicity to PC12 have been investigated.Pass through thiophene
Azoles indigo plant colorimetry concludes that the alpha, beta-unsaturated carbonyl tetralone derivative of variable concentrations is all nontoxic to PC12 cell
's.
With all tetralone derivatives of above synthesis, A β self-induction in PC12 cell is assembled the cell produced afterwards
The impact of toxicity detects, result such as Fig. 1.Found by MTT method, cell carried out A β self-induction gathering and processes,
The survival ability of cell declines 46%, and when cell is carried out pretreatment by the derivant of synthesized 1,2,3,4-Tetrahydrooxonaphthalene, but carefully
The survival ability of born of the same parents reaches 88%, and following six compound 3f, 3o, 3u, 3ae, 3af and 3ag show optimal protection cell
The Cytotoxic activity affected produced is not assembled by A β self-induction.Wherein 3ag best results, effect is substantially better than positive right
According to selegiline.1,2,3,4-Tetrahydrooxonaphthalene phenyl ring R3On when being substituted by nitro, activity higher (3ae, 3af and 3ag)；Work as R3On replacement
During for halogen, activity is substantially reduced (3j-3l, 3y-3ad)；R1Do not gathered by A β self-induction for protection cell also can be improved during methyl
The activity (3d-3f) of the Cytotoxic impact that collection produces；Totally compare to get off, when there being trimethoxy to replace on phenyl ring, live
Property can increase.
Then, carried out acetylcholinesterase, butyrylcholine esterase inhibitory activity, monoamine oxidase A and monoamine are aoxidized
Enzyme B inhibitory activity and A β1–42Self-induction assembles inhibitory activity detection, and the data obtained is shown in Table 2, and data are three independent experiments
Meansigma methods.
Table 2
Find after acetylcholinesterase and butyrylcholine esterase inhibitory activity are evaluated, most of α, beta-unsaturated carbonyl
Tetralone derivative is the inhibitor of acetylcholinesterase in various degree.Wherein compound 3f shows the strongest acetyl
Cholinesterase inhibition (IC50=0.045 ± 0.02 μM), it is better than positive control donepezil (IC50=0.059 ± 0.05 μ
M), (IC similar with tacrine50=0.032 ± 0.01 μM).Press down it addition, compound 3ag shows the strongest butyrylcholine esterase
System activity (IC50=6.2 ± 1.4 μMs), with positive control donepezil (IC50=6.5 ± 0.52 μM) similar.We have found that second
The inhibitory activity of acetylcholine esterase and the chemical constitution of compound have certain relation, R on 1,2,3,4-Tetrahydrooxonaphthalene skeleton1When replacing containing methyl
There is inhibiting activity of acetylcholinesterase (3d, 3e and 3f)；And this activity reduces (3a, 3b and 3c) when having methyl to replace on phenyl ring.
Then, 33 kinds of α of above synthesis, beta-unsaturated carbonyl tetralone derivative all shows good monoamine oxidation
Enzyme A and monoamine oxidase-B inhibitory activity.For the inhibitory activity of monoamine oxidase A, compound 3a-3f, 3n-3o and 3ab-
3ag shows the IC of 0.92 ± 0.12 to 47.2 ± 4.4 μMs of scopes50Value；For the inhibitory activity of monoamine oxidase-B, wherein 14
Plant compound and show the IC less than 10 μMs50Value, but neither one activity is higher than positive control tacrine (0.12 ± 0.7 μ
M).Repeat test and find that the activity of compound 3f with 3ag is similar with positive control.Similarly, this kind of tetralone derivative pair
The inhibitory activity of monoamine oxidase-B is also relevant with its chemical constitution.As R on 1,2,3,4-Tetrahydrooxonaphthalene ring5When having hydroxyl on Wei, its activity fall
Low；Its inhibitory activity to monoamine oxidase-B can be increased when having chlorine bromine or methoxy substitution.
Finally, 33 kinds of α of above synthesis, beta-unsaturated carbonyl tetralone derivative all shows good to A β1–42
Many how the inhibitory activity (10 μMs of lower suppression ratio are 19.2 ± 2.4 to 78.2 ± 4.8%) that self-induction is assembled, be superior to positive control
Piperazine is neat (10 μMs of lower suppression ratio are 14.96 ± 5.5%).Amount of activated stronger compound suppression ratio comparison diagram is as shown in Figure 2.Its
Middle compound 3e and 3f is to A β1–42The inhibitory activity that self-induction is assembled is the strongest, can respectively reach 66.4 at 10 μMs of lower suppression ratio
± 2.8% and 78.2 ± 4.8%%.It was found that work as R1On when having methyl to replace to A β1–42The inhibitory activity that self-induction is assembled
The highest (3d, 3e and 3f)；1,2,3,4-Tetrahydrooxonaphthalene part R5Hydroxyl (3g, 3h and 3i) and R is had on Wei3When having nitro (3ae-3ag) on Wei
Also show that preferable A β1–42The inhibitory activity that self-induction is assembled；R on 1,2,3,4-Tetrahydrooxonaphthalene phenyl ring3、R4Dimethoxy is had to replace on Wei
Time (3s, 3t and 3u) activity be greatly reinforced, be better than positive control；R2、R5Activity fall then can be made when having dimethoxy to replace on Wei
Low (3v-3x)；R3Also can reduce (3j-3l, 3y-3ad) for activity during halogen substiuted.
More than test result indicate that, 33 kinds of α of above synthesis, beta-unsaturated carbonyl tetralone derivative shows multiple
Effect, carries out structure optimization further and Exploration on mechanism to this compounds, it will develop have multi-functional anti-Ah
Write from memory disease drug in Wurz sea.
Embodiment 1
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone (3f):
4-methyl-tetrahydro naphthalenone (10mmol, 1eq) and 2-it is separately added into bromo-in the round-bottomed flask filling 15mL ethanol
3,4,5-Trimethoxybenzaldehyde (10mmol, 1eq), temperature is maintained at 5 DEG C.Afterwards, 40% sodium hydroxide ethanol is added molten
Liquid.Mixture stirs reaction 1-24h at 27 DEG C.The outward appearance of precipitation shows the generation of product with color change.Anti-to this with TLC
Should be monitored.When the reactions are completed, the ice cancellation reaction of acidifying is added.Carry out recrystallization afterwards or column chromatography procedure obtains pure
The product changed, productivity is 69%.
Mp:90-91℃；1H NMR(500MHz,CDCl3) δ: 7.69 (s, H), 7.27 (d, J=7.5Hz, H), 7.19 (d, J
=7.5Hz, H), 7.07 (t, J=7.5Hz, H), 6.91 (t, J=7.0Hz, H), 6.47 (s, H), 3.56 (s, 9H), 2.19 (d,
J=8.5Hz, 2H), 1.79 (m, H)；1.19 (d, J=8.5Hz, 3H)；13C NMR(500MHz,CDCl3)δ:184.5,
150.7,149.1,147.1,146.8,145.2,137.3,134.5,134.0,130.2,127.3,125.5,124.8,
106.9,98.7,56.9,56.1,55.8,30.4,29.7,21.8；HRMS(ESI)m/z:418.32[M+H]+,
Microanalysis calculated for C21H21BrO4(417.29), C:60.44%, H:5.07%.Found C:
60.52%, H:5.15%.
Embodiment 2
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone (3i):
Initiation material is 6-dihydroxy-tetrahydro naphthalenone (10mmol, 1eq) and the bromo-TMB of 2-
(10mmol, 1eq), the other the same as in Example 4, productivity is 72%.
Mp:94-95℃；1H NMR(500MHz,CDCl3) δ: 7.68 (s, H), 7.15 (d, J=7.5Hz, H), 7.02 (t, J
=7.0Hz, H), 6.90 (d, J=7.5Hz, H), 6.42 (s, H), 5.81 (s, H), 3.52 (s, 9H), 2.52 (t, J=8.0Hz,
2H), 2.13 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:184.9,159.6,149.2,147.2,146.1,
140.2,137.8,134.4,134.0,130.5,126.2,122.4,120.2,105.5,96.1,56.8,56.0,55.8,
31.2,27.8；HRMS(ESI)m/z:420.46[M+H]+,Microanalysis calculated for C20H19BrO5
(419.27), C:57.29%, H:4.57%.Found C:57.52%, H:4.65%.
Embodiment 3
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone (3o):
Initiation material is 7-methoxy-tetrahydro naphthalenone (10mmol, 1eq) and the bromo-TMB of 2-
(10mmol, 1eq), the other the same as in Example 4, productivity is 76%.
Mp:92-93℃；1H NMR(500MHz,CDCl3) δ: 7.80 (s, H), 7.21 (d, J=8.0Hz, H), 7.02 (s,
H), 6.85 (d, J=8.0Hz, H), 6.55 (s, H), 3.59 (s, 3H), 3.50 (s, 9H), 2.50 (t, J=8.0Hz, 2H),
2.18 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:185.3,159.9,148.9,147.4,146.3,
141.0,137.2,134.5,134.2,130.5,126.5,123.0,119.1,102.7,99.4,56.8,56.2,56.0,
55.8,30.6,25.9；HRMS(ESI)m/z:456.62[M+Na]+,Microanalysis calculated for
C21H21BrO5(433.29), C:58.21%, H:4.89%.Found C:58.51%, H:4.91%.
Embodiment 4
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone (3u):
Initiation material is 7,8-dimethoxy-tetrahydro naphthalenone (10mmol, 1eq) and 2-bromo-3,4,5-trimethoxy-benzene first
Aldehyde (10mmol, 1eq), the other the same as in Example 4, productivity is 72%.
Mp:98-99℃；1H NMR(500MHz,CDCl3)δ:7.89(s,H),7.12(s,H),6.75(s,H),6.25(s,
H), 3.58 (s, 6H), 3.64 (s, 9H), 2.54 (t, J=8.0Hz, 2H), 2.18 (t, J=8.5Hz, 2H)；13C NMR
(500MHz,CDCl3)δ:186.5,152.7,148.3,147.2,146.0,140.6,135.9,134.9,134.4,131.2,
125.2,122.6,119.6,102.2,93.2,56.1,55.9,55.5,55.3,55.0,29.4,21.2；HRMS(ESI)m/z:
464.72[M+H]+,Microanalysis calculated for C22H23BrO6(463.32), C:57.03%, H:
5.00%.Found C:57.25%, H:5.15%.
Embodiment 5
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone (3x):
Initiation material is 6,9-dimethoxy-tetrahydro naphthalenone (10mmol, 1eq) and 2-bromo-3,4,5-trimethoxy-benzene first
Aldehyde (10mmol, 1eq), the other the same as in Example 4, productivity is 69%.
Mp:98-99℃；1H NMR (500MHz, CDCl3) δ: 7.85 (s, H), 7.05 (d, J=7.5Hz, H), 6.82 (d,
J=7.5Hz, H), 6.24 (s, H), 3.72 (s, 15H), 2.52 (t, J=8.0Hz, 2H), 2.10 (t, J=8.0Hz, 2H)；13C
NMR(500MHz,CDCl3)δ:186.2,151.9,148.5,147.4,146.0,140.4,136.2,134.6,134.3,
131.0,125.4,123.1,119.5,102.5,94.0,56.2,55.9,55.4,55.2,55.0,29.8,21.6；HRMS
(ESI)m/z:464.36[M+H]+,Microanalysis calculated for C22H23BrO6(463.32),C:
57.03%, H:5.00%.Found C:57.24%, H:5.12%.
Embodiment 6
The synthesis of compound 2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (3af):
Initiation material is 8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (10mmol, 1eq) and 2-chloro-3,4-dimethoxy benzaldehyde
(10mmol, 1eq), the other the same as in Example 4, productivity is 62%.
Mp:94-95℃；1H NMR(500MHz,CDCl3) δ: 7.96 (s, H), 7.64 (d, J=8Hz, H), 7.32 (d, J=
8Hz, H), 7.12 (d, J=7.5Hz, H), 6.92 (d, J=7.5Hz, H), 6.52 (s, H), 3.89 (s, 6H), 2.82 (t, J=
8.0Hz, 2H), 2.24 (t, J=8.0Hz, 2H)；13C NMR(500MHz,CDCl3)δ:190.2,154.5,149.5,147.1,
146.6,138.5,132.1,130.5,129.3,127.5,125.2,124.6,120.8,100.6,94.4,56.8,56.6,
27.3,19.4；HRMS(ESI)m/z:374.80[M+H]+,Microanalysis calculated for C19H16ClNO5
(373.79), C:61.05%, H:4.31%, N:3.75%.Found C:61.46%, H:4.49%, N:3.54%.
Embodiment 7
The synthesis of compound 2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (3ag):
Initiation material is 8-nitro-1,2,3,4-Tetrahydrooxonaphthalene (10mmol, 1eq) and the bromo-TMB of 2-
(10mmol, 1eq), the other the same as in Example 4, productivity is 54%.
Mp:98-99℃；1H NMR(500MHz,CDCl3) δ: 7.92 (s, H), 7.66 (d, J=8Hz, H), 7.14 (s, H),
6.89 (d, J=7.5Hz, H), 6.58 (s, H), 3.81 (s, 9H), 2.88 (t, J=8.0Hz, 2H), 2.19 (t, J=8.0Hz,
2H)；13C NMR(500MHz,CDCl3)δ:191.0,154.2,148.6,147.4,146.2,137.2,132.6,130.1,
128.8,127.1,125.3,124.6,121.2,99.4,95.5,56.9,56.6,55.8,25.4,20.2；HRMS(ESI)m/
z:449.50[M+H]+,Microanalysis calculated for C20H18BrNO6(448.26), C:53.59%, H:
4.05%, N:3.12%.Found C:53.64%, H:4.22%, N:3.06%.
Claims (3)
1. class α, beta-unsaturated carbonyl tetralone derivative, it is characterised in that there is following structural formula:
Wherein, R1Represent methylene or-HC-CH3；R2Represent hydrogen atom or methoxyl group；R3Represent hydrogen atom, chlorine atom, methoxyl group,
Bromine atoms, fluorine atom or nitro；R4Represent hydrogen atom or methoxyl group；R5Represent hydrogen atom, hydroxyl or methoxyl group；R’3、R’4Respectively
Represent hydrogen atom or methoxyl group；R’6Represent chlorine atom or bromine atoms.
2. class α, beta-unsaturated carbonyl tetralone derivative, it is characterised in that for
2-(2-chloro-3-Methoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-bromo-3,4-Dimethoxy-benzylidene)-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-chloro-3-Methoxy-benzylidene)-4-methyl-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-4-methyl-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-dihydroxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3,4-Dimethoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the chloro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3-Methoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7-methoxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6-methoxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-7,8-dimethoxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-6,9-dimethoxy-tetrahydro naphthalenone,
2-(2-chloro-3-Methoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3,4-Dimethoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the bromo-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3-Methoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3,4-Dimethoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-bromo-3,4,5-Trimethoxy-benzylidene) the fluoro-1,2,3,4-Tetrahydrooxonaphthalene of-8-,
2-(2-chloro-3-Methoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene,
2-(2-chloro-3,4-Dimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene or
2-(2-bromo-3,4,5-Trimethoxy-benzylidene)-8-nitro-1,2,3,4-Tetrahydrooxonaphthalene.
3. alpha, beta-unsaturated carbonyl tetralone derivative described in claim 1 or 2 is as preventing, treat and diagnose A Erzi sea
The application of silent disease drug.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111904956A (en) * | 2020-07-22 | 2020-11-10 | 华中农业大学 | Application of 1-tetralone compound in preparation of monoamine oxidase inhibitor |
| JP2020533328A (en) * | 2017-09-07 | 2020-11-19 | タイワンジェ ファーマシューティカルズ カンパニー リミテッドＴａｉｗａｎｊ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏ．， Ｌｔｄ． | Benzene condensed heterocyclic derivative and its pharmaceutical composition |
| CN114230457A (en) * | 2022-01-04 | 2022-03-25 | 中山大学 | 2-benzylidene tetralone derivatives and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020533328A (en) * | 2017-09-07 | 2020-11-19 | タイワンジェ ファーマシューティカルズ カンパニー リミテッドＴａｉｗａｎｊ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏ．， Ｌｔｄ． | Benzene condensed heterocyclic derivative and its pharmaceutical composition |
| JP7296948B2 (en) | 2017-09-07 | 2023-06-23 | ニューソアラ バイオファーマ カンパニー リミテッド | Benzene-fused heterocyclic derivative and pharmaceutical composition thereof |
| CN111904956A (en) * | 2020-07-22 | 2020-11-10 | 华中农业大学 | Application of 1-tetralone compound in preparation of monoamine oxidase inhibitor |
| CN114230457A (en) * | 2022-01-04 | 2022-03-25 | 中山大学 | 2-benzylidene tetralone derivatives and preparation method and application thereof |
| CN114230457B (en) * | 2022-01-04 | 2023-06-09 | 中山大学 | 2-benzylidene tetralone derivatives, and preparation method and application thereof |
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