CN105367553A - Tacrine-8-hydroxyl(amine)quinoline derivative and application thereof - Google Patents
Tacrine-8-hydroxyl(amine)quinoline derivative and application thereof Download PDFInfo
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- CN105367553A CN105367553A CN201510880590.6A CN201510880590A CN105367553A CN 105367553 A CN105367553 A CN 105367553A CN 201510880590 A CN201510880590 A CN 201510880590A CN 105367553 A CN105367553 A CN 105367553A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates a tacrine-8-hydroxyl(amine)quinoline derivative and applications thereof, and belongs to the technical field of biological medicines. The derivative comprises a compound of a formula I and a pharmaceutically acceptable salt thereof. A preparation method thereof comprises the step of: performing reductive amination and deprotection on the compounds Id and Ii and an intermediate In/In' to obtain a compound I, wherein the compound I can react in an alcohol solution to produce a salt. Pharmacological tests verify that the compound has the activity against Alzheimer's disease and can inhibit acetylcholinesterase and butyrylcholinesterase activity, and meanwhile can inhibit self-polymerization of the beta-amyloid protein, and has a certain chelating effect on metal ions, particularly Cu<2+> and Zn<2+>, so that the hydrolysis of the acetylcholinesterase and the self-polymerization of the beta-amyloid protein are retarded, the effect of the acetylcholinesterase on synapses is improved, and the metal ions in the brain is regulated, and therefore the compound is effective for treating Alzheimer's disease.
Description
Technical field
The present invention relates to a kind of tacrine-8-hydroxyl (amine) base quinoline and application thereof, be specifically related to a kind of tacrine-8-hydroxyl (amine) base quinoline and the application in anti-A Cihaimo disease drug thereof, belong to biomedicine technical field.
Background technology
A Cihaimo disease (Alzheimer ' sdisease, AD) be the nervous system degenerative disease that the Progressive symmetric erythrokeratodermia of a kind of onset concealment develops.The feature of AD is that cognitive function is such as remembered, thinks deeply, understands, calculates, the reduction gradually of language, learning capacity and judgement, is enough to be diagnosed as dementia when affecting personal daily life-form structure when being reduced to, and within 65 years old, sends out patient in the past, and claims presenile dementia; Within 65 years old, claim senile dementia with sequela person, it is a kind of multifactor disease caused, the definite cause of disease is still illustrated without conclusive so far, considerable evidence proves that several forms of AD have heritable tendency, family history, women, injury of head, low level of education, thyropathy, female reproduction age, the factor such as too high or too low, virus infection was fallen ill relevant with this disease, as a kind of common geriatric disease, the health of the elderly in serious threat.
This sick onset is slow or hide, patient and household are often unable to explain clearly when onset, are more common in more than 70 years old (average 73 years old of the male sex, women is 75 years old) old man, a few patients symptom after physical disease, fracture or spirit are upset is clear rapidly, women many compared with the male sex (female: man is 3: 1).Main manifestations is the decline gradually of decrease of cognitive function, mental symptom and behavior disorder, activity of daily living.Current Chinese patients is more than 5,600,000 according to statistics, and along with aging population process is in the situation increased fast.The health of AD not only serious harm the elderly, but also bring heavy mental burden to family numbers of patients, for society brings huge Health risk, more tremendous influence is caused to economy, thus cause the common concern of people.
Several large pathogenesis of generally acknowledging at present comprises the outer self aggregation of β-sample amyloid proteins (A β) born of the same parents and forms toxicity oligopolymer, formation neurofibrillary tangles assembled by Protein tau peroxophosphoric acid in born of the same parents, cholinergic nerve damage causes cholinergic conductive impairment, and in brain, concentration of metal ions is too high causes oxidative stress and A β can be induced to be polymerized formation toxic-complex etc.
The most effective medicine of current Clinical practice is the acetylcholinesterase depressant (AChEIs) using Pseudocholinesterase as target spot, comprise galanthamine (REMINYL), rivastigmine (EXELON), donepezil (ARICEPT).But due to only for the single cause of disease, can not reverse or cure diseases, there is the defects in various degree such as hepatotoxicity is large, bioavailability is low simultaneously.
Other target spot inhibitor comprise A beta peptide aggregation inhibitor, Protein tau peroxophosphoric acid inhibitor, metal ion chelation agent etc. and there is no medicine listing at present, but be subject to increasing attention, to the disease of the complicated cause of disease, Mutiple Targets Synergistic treatment is a better strategy, and at present for AD, the exploitation of Mutiple Targets drug candidate is its main direction of studying.
Chinese invention " oxine derivative ", application number 03821942.5 discloses a kind for the treatment of, improvement and/or prevents the compound of neurodegenerative disease, but is not the Mutiple Targets medicine for AD.
Summary of the invention
The object of the invention is searching one class can have high restraining effect to acetylcholinesterase and β-sample amyloid proteins polymerization simultaneously, and to metal ion (Cu
2+, Zn
2+) there is tacrine-8-hydroxyl (amine) the base quinoline of certain sequestering action, be used for the treatment of A Cihaimo disease, and preparation method and the purposes of this compounds are provided.
For achieving the above object, the technical solution used in the present invention is:
One class tacrine-8-hydroxyl (amine) base quinoline has following general formula: shown in I:
Wherein X is
, CH
2,
Y is O, NH;
M is integer 1,2,4,5;
R is hydrogen, chlorine, fluorine.
In said structure general formula:
When X is
time,
R is hydrogen, 5-chlorine, 5-fluorine, 6-chlorine, 5,7-dichloros,
m=1，
And physiologically acceptable salt;
When X is CH
2time,
R is hydrogen, 5-fluorine, 5,7-dichloros,
m=1，2，4，5，
And physiologically acceptable salt.
Said structure general formula is synthesized obtained by following route:
Reaction formula 1:
The preparation of Compound I d: from commercial o-Cyanoaniline, imines is generated with pimelinketone condensation under boron trifluoride diethyl etherate effect, reaction solvent generally adopts toluene, chlorobenzene, dimethylbenzene etc., at 120 DEG C of reaction 3-4 hour, the imines generated is separated out in reaction solution, is directly used in lower step after filtration washing, then generates tacrine Ib in alkali effect backflow, alkali generally adopts the aqueous solution of sodium hydroxide, potassium hydroxide, and Ib direct filtration is washed, is drying to obtain; Ib can obtain Ic through chloroacetyl chloride acidylate again, and reaction adopts triethylamine, diisopropyl ethyl amine etc. as acid binding agent, carries out at-10-100 DEG C, and generally at 80 DEG C of reaction 4-5 hour, products therefrom can through proper method as column chromatography, recrystallization be purified; Ic is connected with piperazine again can obtain Id, and the general ethanol that adopts of reaction, as solvent, reacts under sodium iodide or potassiumiodide catalysis, 80 DEG C of reaction 2-3 hour, and products therefrom can through proper method as column chromatography, recrystallization be purified.
Reaction formula 2:
The preparation of Compound I i: from commercial anthranilic acid, 9-chlorine tacrine is generated with pimelinketone condensation under phosphorus oxychloride effect, 120 DEG C of reaction 3-4 hour, product can directly be separated out after alkalization, filter and get final product, then refluxing in inert solvent with hydramine obtains Compound Ig per, and described inert solvent adopts high boiling point inert solvent as Pentyl alcohol, phenol, toluene, chlorobenzene, dimethylbenzene etc., reaction is carried out between 60-150 DEG C, and products therefrom can be purified through column chromatography or recrystallization; Ig refluxes and namely obtains Compound I h in 3-4 hour in sulfur oxychloride, Ih is connected with piperazine again can obtain Ii, and the general ethanol that adopts, as solvent, reacts under sodium iodide or potassiumiodide catalysis, at 80 DEG C, react 2-3 hour, products therefrom can through proper method as column chromatography, recrystallization be purified.
Reaction formula 3:
The preparation of Compound I n/In ': from commercial Ortho-Aminophenol or aniline, generate 2-methyl-8 hydroxyl (amine) base quinoline Ik with acetaldehyde condensation cyclisation under acid catalysis, reaction is carried out at 60-120 DEG C, and products therefrom can be purified through column chromatography or recrystallization; Ik benzyl or tert.-butoxy two carbonic anhydride protect to obtain Compound I m or Im '; and then obtain 2-formyl radical-8-hydroxyl (amine) base quinoline In or In ' through tin anhydride oxidation 2-position methyl; general employing ethers is as tetrahydrofuran (THF), 1; 4-dioxane etc. are as solvent; temperature of reaction is advisable between 60-100 DEG C, and products therefrom can be purified through column chromatography or recrystallization.
Reaction formula 4:
Compound I d or Ii and In or In ' reduces with Sodium triacetoxyborohydride in suitable solvent, then deprotection can obtain final product I in acid.
In reduction step, reaction solvent generally can select methylene dichloride, tetrahydrofuran (THF), 1,2-ethylene dichloride etc., and optimum solvent is 1,2-ethylene dichloride, reacts to carry out between 0-50 DEG C, generally reacts at ambient temperature, and products therefrom can be purified through column chromatography for separation.In deprotection steps, benzyl generally adopts concentrated hydrochloric acid deprotection, and temperature of reaction is 100 DEG C, and tertiary fourth oxygen acyl group adopts trifluoroacetic acid or hydrochloric acid deprotection, and reaction is carried out at ambient temperature, and products therefrom can through proper method as column chromatography or recrystallization be purified.
Cholinesterase inhibition testing method:
Acetylcholinesterase enzyme source adopts electric ray lyophilized powder, and butyrylcholine esterase adopts horse serum lyophilized powder, tests front potassium phosphate buffer (PH=7.4) and is diluted to 0.2U/mL, with the inhibit activities of colorimetric method for determining AChE and BuChE.Reaction total volume is 250 μ L, include acetylthiocholine iodide or sulfur iodide for BuCh 25 μ L (1mmol/L), the potassium phosphate buffer 25 μ L of PH=7.4, compound solution 25 μ L, developer two (3-carboxyl-4-nitro) phenyl disulfide (i.e. Ellman ' s reagent, DTNB) 125 μ L (1mmol/L), finally add the enzyme solution of dilution, absorbancy is measured in 405nm paradigm microwell plate detector after 5 minutes 37 DEG C of insulations, 50 minutes test durations of setting, within every 5 minutes, read an absorbance data.The all parallel survey of all samples three times, not add the mensuration group absorbancy of compound as 100%, the mensuration group not adding compound and enzyme is react the Background absorbance that need deduct, the compound group absorbancy of mensuration with do not add compared with compound group, the percentage of reduction is enzyme inhibition rate.Each compound first carries out primary dcreening operation with several concentration, its enzyme inhibition rate of 6 to 8 concentration determinations of compound is selected by primary dcreening operation result, and carry out linear regression with the negative logarithm of this compound volumetric molar concentration and enzyme inhibition rate, volumetric molar concentration when trying to achieve 50% suppression is the IC of this compound
50value.
The self aggregation inhibit activities testing method of amyloid-beta:
Amyloid-beta (A β
1-42) lyophilized powder is dissolved in hexafluoroisopropanol, room temperature leaves standstill carries out depolymerization in 16 hours, more at room temperature blows down hexafluoroisopropanol by nitrogen gas stream, obtains the A β of depolymerization
1-42being mixed with concentration with DMSO dissolving is 200 μMs of solution, with the A β self aggregation inhibit activities of fluorescence spectrometry compound.Reaction total volume is 10 μ L, includes the DMSO solution 5 μ L (concentration is 200 μMs) of sample, the A β of depolymerization
1-42dMSO solution 5 μ L (concentration is 200 μMs), potassium phosphate buffer (PH=7.4) the solution 40 μ L (concentration is 200 μMs) of thioflavine T is added after 37 DEG C of insulation 72h, paradigm microwell plate detector reads fluorescent value, excitation wavelength is 485nm, is 435nm under emission wavelength.The all parallel survey of all samples three times, not add the mensuration group absorbancy of compound as 100%, the compound group fluorescent value of mensuration with do not add compared with compound group, the percentage of reduction is A β self aggregation inhibiting rate under 20 μMs of concentration.
Activity Results according to aforesaid method test gained part of compounds is listed as follows:
Table 1: Pseudocholinesterase suppresses IC
50and A β self aggregation inhibiting rate
Metal ion (Cu
2+, Zn
2+) stability constant testing method:
On ultraviolet spectrophotometer, all-wave long (190-700nm) scans testing sample and the testing sample/M of 20 μMs respectively
n+spectroscopic data, determine the maximum absorption band wavelength of testing sample and the maximum absorption band wavelength of testing sample and chelate of metal ion, then under the maximum absorption wavelength of inner complex, (mol ratio is from 0-1.5 for metal ion/testing sample successively, sample total concn controls at 20 μMs) absorbance, find in experiment, after metal ion/testing sample mol ratio is greater than 0.5, absorbance change eases up, show that compound and metal ion are joined not than being 2:1, and verify by Jobs method, determine that coordination ratio is 2:1; After metal ion/testing sample mol ratio is greater than 1, absorbance remains unchanged substantially, can be similar to and think that complete coordination occurs testing sample.Then according to formula
K=
Calculate compound and Cu
2+, Zn
2+form stability constant K and the lgK of inner complex.Acquired results is as shown in the table:
Table 2: compound and metal ion form the stability constant lgK of inner complex
A.Clioquinol inner complex stability constant literature value (
neurotoxicology 2007,
28, 445)
From table at a glance, all compounds all have certain inhibit activities to Pseudocholinesterase, wherein compound
1-
6in micromole's level, compound
7-
17in sub-micromolar level, meanwhile, majority of compounds is also to A β
1-42self aggregation there is good effect; From table two, majority of compounds is to metal ion (Cu
2+, Zn
2+) all there is sequestering action.The activity data of comprehensive three aspects, compound
11,14there is good effect, be equal to or slightly better in tacrine, to A β to the inhibit activities of acetylcholinesterase and butyrylcholine esterase and tacrine
1-42self aggregation inhibiting rate up to 80.5% and 93.2%, meanwhile, can chelated metal ions as Cu
2+, Zn
2+, stability constant, between 9-10, is expected to the lead compound becoming the anti-A Cihaimo disease drug of Mutiple Targets.
The invention has the beneficial effects as follows: it is active that compound of the present invention has anti-A Cihaimo disease, can acetylcholine esterase inhibition and the activity of BuChE, the autohemagglutination of amyloid-beta can be suppressed to merge metal ion particularly Cu simultaneously
2+, Zn
2+there is certain sequestering action, thus play and delay the hydrolysis of vagusstoff and the auto-polymerization of amyloid-beta, improve the effect of vagusstoff in cynapse, and to regulate in brain metal ion to reach the object of symptomatic treatment A Cihaimo disease; There is the feature that hepatotoxicity is little, bioavailability is high simultaneously.
Embodiment
Be described in further details the present invention below by example, these examples are only used for the present invention is described, do not limit the scope of the invention.
Embodiment 1
Synthesis 2-[(4-(oxine)-2-methyl) piperidines]-N-(1,2,3,4-tetrahydro acridine-9-amido) ethanamide
1
Weigh Compound
id(0.5mmol) and compound
in(0.5mmol, R=H), in 25mL round-bottomed bottle, adds NaBH (OAc)
3(1.0mmol); DCE (dry, 5mL), is heated to 50 DEG C of reactions under argon shield; TLC monitors reaction and terminates rear cooling reaction solution to room temperature; add water washing, DCM extracts, and concentrates after doing and is separated through silicagel column; products therefrom adds 37%HCl (2mL); reflux 1h, adds water after cooling, K
2cO
3be adjusted to weakly alkaline, after DCM extraction, concentrated xeromenia silicagel column is separated to obtain compound
1, white solid, yield 66%.
1 (400MHz,CDCl
3)δ=9.22(s,1H),8.14(d,
J=10.0Hz,1H),8.00(d,
J=8.0Hz,1H),7.71(d,
J=8.4Hz,1H),7.66–7.61(m,2H),7.48–7.41(m,2H),7.32(d,
J=8.4Hz,1H),7.16(d,
J=7.6Hz,1H),3.88(s,2H),3.33(s,2H),3.15(t,
J=6.4Hz,2H),2.85–2.80(m,6H),2.70(brs,4H),1.99–1.95(m,2H),1.90–1.85ppm(m,2H);
13 CNMR(100MHz,CDCl
3,)δ=168.6,159.9,156.8,152.0,147.0,138.1,137.5,136.6,129.0,128.8,127.6,127.4,127.1,126.0,123.7,121.9,121.8,117.7,110.1,64.6,61.8,54.0,53.5,34.0,25.8,22.7,22.5ppm;purity:99.7%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.34min;ESI-MSm/z:504.2[M+Na]
+。
Embodiment 2
Synthesis 2-[(4-(5-chloro-8-hydroxyquinoline)-2-methyl) piperidines]-N-(1,2,3,4-tetrahydro acridine-9-amido) ethanamide
2
Compound
id(0.5mmol) and compound
in(0.5mmol, R=5-Cl), with reference to embodiment 1 operating process, is separated to obtain compound
2, white solid, yield 63%.
1 (400MHz,CDCl
3)δ=9.21(s,1H),8.49(d,
J=8.8Hz,1H),8.00(d,
J=8.4Hz,1H),7.76–7.70(m,2H),7.63(t,
J=7.2Hz,1H),7.49–7.45(m,2H),7.09(d,
J=8.8Hz,1H),3.89(s,2H),3.31(s,2H),3.15(t,
J=6.4Hz,2H),2.85–2.80(m,6H),2.70(brs,4H),2.01–1.86ppm(m,4H);
13 CNMR(100MHz,CDCl
3)δ=168.6,159.9,157.6151.2,146.9,138.1,137.9,133.9,128.9,128.8,127.1,126.0,125.5,123.7,122.5,121.8,120.4,110.2,64.3,61.8,53.9,53.5,34.0,25.8,22.7,22.5ppm;purity:99.6%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.37min;ESI-MSm/z:538.3[M+Na]
+。
Embodiment 3
Synthesis 2-[(4-(5-fluorine oxine)-2-methyl) piperidines]-N-(1,2,3,4-tetrahydro acridine-9-amido) ethanamide
3
Compound
id(0.5mmol) and compound
in(0.5mmol, R=5-F), with reference to embodiment 1 operating process, is separated to obtain compound
3, white solid, yield 60%.
1 (400MHz,CDCl
3)δ=9.21(s,1H),8.38(d,
J=8.8Hz,1H),8.00(d,
J=8.4Hz,1H),7.74–7.70(m,2H),7.65–7.61(m,2H),7.63(t,
J=7.6Hz,1H),7.47(t,
J=7.6Hz,1H),7.13–7.03(m,2H),3.88(s,2H),3.33(s,2H),3.15(t,
J=6.4Hz,2H),2.86–2.80(m,6H),2.71(brs,4H),2.01–1.97(m,2H),1.90–1.86ppm(m,2H);
13 CNMR(100MHz,CDCl
3)δ=168.6,159.9,158.0,150.7(
J C-F =244.1Hz),148.2(
J C-F =2.7Hz),147.0,138.0,137.1,137.0,130.3(
J C-F =3.1Hz),129.0,128.9,127.1,125.9,123.7,121.8,121.8(
J C-F =1.9Hz),118.0(
J C-F =18.7Hz),110.4(
J C-F =20.5Hz),108.8(
J C-F =7.1Hz),64.5,61.8,54.0,53.5,34.0,25.8,22.7,22.5ppm;purity:94.2%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.33min;ESI-MSm/z:522.2[M+Na]
+。
Embodiment 4
Synthesis 2-[(4-(6-chlorine oxine)-2-methyl) piperidines]-N-(1,2,3,4-tetrahydro acridine-9-amido) ethanamide
4
Compound
id(0.5mmol) and compound
in(0.5mmol, R=6-Cl), with reference to embodiment 1 operating process, is separated to obtain compound
4, faint yellow solid, yield 59%.
1 (400MHz,CDCl
3)δ=9.21(s,1H),8.04(d,
J=8.4Hz,1H),8.00(d,
J=8.4Hz,1H),7.71–7.761(m,3H),7.49–7.46(m,1H),7.31(d,
J=2.0Hz,1H),7.14(d,
J=2.4Hz,1H),3.85(s,2H),3.33(s,2H),3.15(d,
J=6.4Hz,2H),2.85–2.81(m,6H),2.77–2.69(m,4H),1.99–1.98(m,2H),1.89–1..86ppm(m,2H);
13 CNMR(100MHz,CDCl
3)δ=168.6,159.9,157.1,152.8,147.0,138.1,136.2,135.8,133.1,129.0,128.9,127.9,127.1,126.0,123.7,122.9,121.8,116.5,111.5,64.5,61.8,54.0,53.5,34.0,25.8,22.7,22.5ppm;purity:99.2%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.39min;ESI-MSm/z:538.3[M+Na]
+。
Embodiment 5
Synthesis 2-[(4-(5,7-dichloro-8-hydroxyquinoline)-2-methyl) piperidines]-N-(1,2,3,4-tetrahydro acridine-9-amido) ethanamide
5
Compound
id(0.5mmol) and compound
in(0.5mmol, R=5,7-dichloro), with reference to embodiment 1 operating process, is separated to obtain compound
5, faint yellow solid, yield 65%.
1 (400MHz,CDCl
3)δ=9.19(s,1H),8.46(d,
J=8.8Hz,1H),8.00(d,
J=8.4Hz,1H),7.76(d,
J=8.8Hz,1H),7.70(d,
J=8.4Hz,1H),7.63(t,
J=8.0Hz,1H),7.57(s,1H),7.46(t,
J=7.6Hz,1H),3.88(s,2H),3.31(s,2H),3.15(t,
J=6.4Hz,2H),2.83–2.80(m,6H),2.68(brs,4H),2.01–1.95(m,2H),1.90–1.86ppm(m,2H);
13 CNMR(100MHz,CDCl
3,)δ=168.6,159.9,158.9,147.5,146.9,138.1,137.9,134.1,129.0,128.8,127.9,127.1,126.0,124.2,123.7,122.4,121.8,120.7,115.5,64.2,61.8,53.9,53.5,34.0,25.8,22.7,22.5ppm;purity:98.4%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.41min;ESI-MSm/z:572.2[M+Na]
+。
Embodiment 6
Synthesis 2-[(4-(8-amido quinoline)-2-methyl) piperidines]-N-(1,2,3,4-tetrahydro acridine-9-amido) ethanamide
6
Weigh Compound
id(0.5mmol) and compound
in '(0.5mmol, R=H), in 25mL round-bottomed bottle, adds NaBH (OAc)
3(1.0mmol), DCE (dry, 5mL), is heated to 50 DEG C of reactions under argon shield, and TLC monitors reaction and terminates rear cooling reaction solution to room temperature, adds water washing, and DCM extracts, and concentrate after doing and be separated through silicagel column, products therefrom adds CF
3cO
2h/DCM (2mL, v/v=1/1), adds water after stirring at room temperature 1h, K
2cO
3be adjusted to weakly alkaline, after DCM extraction, concentrated xeromenia silicagel column is separated to obtain compound
6, white solid, yield 66%.
1 (400MHz,CDCl
3)δ=9.24(s,1H),8.04(d,
J=8.4Hz,1H),8.00(d,
J=8.4Hz,1H),7.71(d,
J=8.0Hz,1H),7.63(t,
J=7.6Hz,1H),7.57(d,
J=8.4Hz,1H),7.46(t,
J=7.6Hz,1H),7.30(t,
J=7.6Hz,1H),7.13(d,
J=8.0Hz,1H),6.91(d,
J=7.2Hz,1H),4.99(brs,2H),3.88(s,2H),3.33(s,2H),3.15(t,
J=6.4Hz,2H),2.85–2.80(m,6H),2.80–2.72(m,4H),2.00–1.94(m,2H),1.89–1.85ppm(m,2H);
13 CNMR(100MHz,CDCl
3,)δ=168.7,159.9,156.0,147.0,143.7,138.1,137.5,136.5,128.9,128.8,127.9,127.1,125.9,123.7,121.9,121.2,115.9,110.2,65.0,61.9,54.1,53.4,34.0,25.8,22.7,22.5ppm;purity:99.8%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.27min;ESI-MSm/z:503.3[M+Na]
+。
Embodiment 7
Synthesis 2-[(4-(2-(1,2,3,4-tetrahydro acridine)-9-amido) ethyl) piperidine methyl] quinoline-8-phenol
7
Weigh Compound
ii(0.5mmol, n=1) and compound
in(0.5mmol, R=H), in 25mL round-bottomed bottle, adds NaBH (OAc)
3(1.0mmol); DCE (dry, 5mL), is heated to 50 DEG C of reactions under argon shield; TLC monitors reaction and terminates rear cooling reaction solution to room temperature; add water washing, DCM extracts, and concentrates after doing and is separated through silicagel column; products therefrom adds 37%HCl (2mL); reflux 1h, adds water after cooling, K
2cO
3be adjusted to weakly alkaline, after DCM extraction, concentrated xeromenia silicagel column is separated to obtain compound
7, pale yellow oil, yield 55%.
1 (400MHz,CDCl
3)δ=8.54(d,
J=8.4Hz,1H),8.18(d,
J=8.8Hz,1H),8.14(d,
J=8.8Hz,1H),7.68(t,
J=7.2Hz,1H),7.62(d,
J=8.8Hz,1H),7.46–7.40(m,2H),7.34–7.31(m,1H),7.18–7.16(m,1H),7.00(brs,1H),4.05–3.94(m,2H),3.90(s,2H),3.38–3.26(m,2H),2.81(t,
J=5.2Hz,2H),2.76–2.67(m,8H),2.57(t,
J=5.2Hz,2H),1.95–1.89ppm(m,4H);
13 CNMR(100MHz,CDCl
3)δ=155.6,153.8,151.0,150.9,136.5,136.4,135.6,131.1,126.5,126.4,123.9,122.9,120.9,120.8,116.6,115.0,109.9,109.1,63.6,55.0,52.5,51.3,42.5,27.6,22.5,21.0,19.9ppm;purity:96.5%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.18min;ESI-MSm/z:468.3[M+H]
+。
Embodiment 8
Synthesis 5-fluoro-2-[(4-(2-(1,2,3,4-tetrahydro acridine)-9-amido) ethyl) piperidine methyl] quinoline-8-phenol
8
Compound
ii(0.5mmol, n=1) and compound
in(0.5mmol, R=5-F), with reference to embodiment 7 operating process, is separated to obtain compound
8, pale yellow oil, yield 51%.
1 (400MHz,CDCl
3)δ=8.36(d,
J=8.4Hz,1H),8.04(d,
J=8.0Hz,1H),7.99(d,
J=8.4Hz,1H),7.70(d,
J=8.4Hz,1H),7.58–7.54(m,1H),7.36–7.32(m,1H),7.13–7.04(m,2H),5.39(brs,1H),3.88(s,2H),3.61(t,
J=4.8Hz,2H),3.15–3.05(m,2H),2.80–2.75(m,2H),2.64–2.59(m,10H),1.93–1.91ppm(m,4H);
13 CNMR(100MHz,CDCl
3)δ=158.1,157.7,151.5,150.7(
J C-F=244.3Hz),149.5,148.3(
J C-F=3.2Hz),146.4,137.1(
J C-F=2.6Hz),130.3(
J C-F=3.5Hz),128.8,123.7,122.9,121.8(
J C-F=2.2Hz),119.8,117.9(
J C-F=15.8Hz),115.4,110.4(
J C-F=20.1Hz),108.8(
J C-F=7.7Hz),64.7,57.4,53.6,52.6,45.0,33.3,24.8,23.0,22.6ppm;purity:99.5%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.37min;ESI-MSm/z:486.3[M+H]
+。
Embodiment 9
Synthesis 5,7-bis-chloro-2-[(4-(2-(1,2,3,4-tetrahydro acridine)-9-amido) ethyl) piperidine methyl] quinoline-8-phenol
9
Compound
ii(0.5mmol, n=1) and compound
in(0.5mmol, R=5,7-dichloro), with reference to embodiment 7 operating process, is separated to obtain compound
9, pale yellow oil, yield 56%.
1 (400MHz,CDCl
3)δ=8.45–8.41(m,1H),8.04–7.99(m,2H),7.74–7.70(m,1H),7.58–7.55(m,1H),7.36–7.32(m,1H),5.47(brs,1H),3.87–3.85(m,2H),3.70–3.55(m,2H),3.17–3.03(m,2H),2.80–2.73(m,2H),2.64–2.63(m,10H),1.98–1.82ppm(m,4H);
13 CNMR(100MHz,CDCl
3)δ=158.9,157.2,151.8,147.8,145.9,138.1,133.9,129.0,127.8,127.4,124.1,123.8,123.0,122.5,120.4,119.5,115.5,115.1,64.3,57.3,53.6,52.5,44.9,32.9,24.7,23.0,22.5ppm;purity:96.1%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.24min;ESI-MSm/z:536.2[M+H]
+。
Embodiment 10
Synthesis
n-[2-(4-(8-amido quinoline)-2-methyl) piperidines] ethyl-1,2,3,4-tetrahydro acridine-9-amine
10
Weigh Compound
ii(0.5mmol, n=1) and compound
in '(0.5mmol, R=H), in 25mL round-bottomed bottle, adds NaBH (OAc)
3(1.0mmol), DCE (dry, 5mL), is heated to 50 DEG C of reactions under argon shield, and TLC monitors reaction and terminates rear cooling reaction solution to room temperature, adds water washing, and DCM extracts, and concentrate after doing and be separated through silicagel column, products therefrom adds CF
3cO
2h/DCM (2mL, v/v=1/1), adds water after stirring at room temperature 1h, K
2cO
3be adjusted to weakly alkaline, after DCM extraction, concentrated xeromenia silicagel column is separated to obtain compound
10, pale yellow oil, yield 49%.
1 (400MHz,CDCl
3)δ=8.48(d,
J=8.4Hz,1H),8.10(d,
J=8.8Hz,1H),7.97(d,
J=8.4Hz,1H),7.62–7.58(m,1H),7.48(d,
J=8.4Hz,1H),7.36–7.32(m,1H),7.23(t,
J=8.0Hz,1H),7.08–7.05(m,1H),7.02(brs,1H),6.87–6.85(m,1H),3.92(t,
J=5.2Hz,2H),3.83(s,2H),3.24(t,
J=5.2Hz,2H),2.74(t,
J=5.6Hz,2H),2.70–2.52(m,8H),2.48(t,
J=6.0Hz,2H),1.85–1.78ppm(m,4H);
13 CNMR(100MHz,CDCl
3)δ=155.5,155.0,151.6,143.7,139.3,137.5,136.4,132.2,127.8,127.2,125.0,123.9,121.5,121.3,115.9,115.8,110.8,110.2,64.9,56.0,53.4,52.3,43.5,28.4,23.5,22.0,20.8ppm;purity:99.1%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.18min;ESI-MSm/z:467.3[M+H]
+。
Embodiment 11
Synthesis 2-[(4-(3-(1,2,3,4-tetrahydro acridine)-9-amido) propyl group) piperidine methyl] quinoline-8-phenol
11
Compound
ii(0.5mmol, n=2) and compound
in(0.5mmol) with reference to embodiment 7 operating process, compound is separated to obtain
11, colorless oil, yield 53%.
1 (400MHz,CDCl
3)δ=8.39(d,
J=8.4Hz,1H),8.15(d,
J=8.4Hz,1H),8.06(d,
J=8.4Hz,1H),7.69(brs,1H),7.57–7.52(m,2H),7.35(t,
J=8.0Hz,1H),7.30–7.23(m,2H),7.10–7.08(m,1H),4.00(t,
J=5.2Hz,2H),3.81(s,2H),3.26–3.12(m,2H),2.65–2.60(m,10H),2.51–2.50(m,2H),1.90(t,
J=4.8Hz,2H),1.77–1.76ppm(m,4H);
13 CNMR(100MHz,CDCl
3)δ=156.4,155.4,152.0,151.4,139.6,137.5,136.6,131.8,127.6,127.5,124.6,124.4,121.9,121.5,117.7,116.1,110.9,110.2,64.7,58.3,53.9,52.7,50.0,28.7,25.6,25.4,21.8,20.9ppm;purity:96.8%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.11min;ESI-MSm/z:482.3[M+H]
+。
Embodiment 12
Synthesis 5-fluoro-2-[(4-(3-(1,2,3,4-tetrahydro acridine)-9-amido) propyl group) piperidine methyl] quinoline-8-phenol
12
Compound
ii(0.5mmol, n=2) and compound
in(0.5mmol, R=5-F), with reference to embodiment 7 operating process, is separated to obtain compound
12, pale yellow oil, yield 59%.
1 (400MHz,CDCl
3)δ=8.42(d,
J=8.4Hz,1H),8.30(d,
J=8.4Hz,1H),8.16(d,
J=8.8Hz,1H),7.74(s,1H),7.62–7.56(m,2H),7.31(t,
J=8.0Hz,1H),7.06–6.97(m,2H),4.03(t,
J=5.6Hz,2H),3.83(s,2H),3.22(t,
J=5.6Hz,2H),2.68–2.62(m,10H),2.53(t,
J=5.6Hz,2H),1.92(t,
J=4.8Hz,2H),1.81–1.78ppm(m,4H);
13 CNMR(100MHz,CDCl
3)δ=157.6,155.5,151.4,150.7(
J C-F=244.7Hz),148.2(
J C-F=3.3Hz),139.5,137.1(
J C-F=3.3Hz),132.0,130.4(
J C-F=1.8Hz),124.7,124.4,121.8(
J C-F=3.0Hz),121.5,117.9(
J C-F=18.8Hz),116.0,110.8,110.5(
J C-F=21.4Hz),108.9(
J C-F=7.4Hz),64.7,58.4,53.9,52.7,50.2,29.7,25.6,25.3,21.8,20.8ppm;ESI-MSm/z:500.3[M+H]
+。
Embodiment 13
Synthesis
n-[3-(4-(8-amido quinoline)-2-methyl) piperidines] propyl group-1,2,3,4-tetrahydro acridine-9-amine
13
Weigh Compound
ii(0.5mmol, n=1) and compound
in '(0.5mmol, R=H), in 25mL round-bottomed bottle, adds NaBH (OAc)
3(1.0mmol), DCE (dry, 5mL), is heated to 50 DEG C of reactions under argon shield, and TLC monitors reaction and terminates rear cooling reaction solution to room temperature, adds water washing, and DCM extracts, and concentrate after doing and be separated through silicagel column, products therefrom adds CF
3cO
2h/DCM (2mL, v/v=1/1), adds water after stirring at room temperature 1h, K
2cO
3be adjusted to weakly alkaline, after DCM extraction, concentrated xeromenia silicagel column is separated to obtain compound
13, colorless oil, yield 61%.
1 (400MHz,CDCl
3)δ=8.12(d,
J=8.4Hz,1H),8.04(d,
J=8.4Hz,1H),7.93(d,
J=8.4Hz,1H),7.48–7.43(m,2H),7.24–7.17(m,2H),7.02(d,
J=8.0Hz,1H),6.82(d,
J=7.6Hz,1H),6.72(brs,1H),4.97(brs,2H),3.77–3.72(m,4H),3.13–3.07(m,2H),2.68–2.35(m,12H),1.82–1.79(m,2H),1.77–1.73ppm(m,4H);
13 CNMR(100MHz,CDCl
3)δ=155.7,154.1,153.7,143.8,142.7,137.5,136.3,130.3,127.8,127.0,124.2,124.1,124.0,121.3,117.7,115.7,112.8,110.2,65.1,58.1,53.8,52.9,49.6,30.8,26.1,25.6,22.2,21.6ppm;purity:98.1%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.24min;ESI-MSm/z:481.3[M+H]
+。
Embodiment 14
Synthesis 2-[(4-(5-(1,2,3,4-tetrahydro acridine)-9-amido) amyl group) piperidine methyl] quinoline-8-phenol
14
Compound
ii(0.5mmol, n=4) and compound
in(0.5mmol, R=H), with reference to embodiment 7 operating process, is separated to obtain compound
14, pale yellow oil, yield 55%.
1 (400MHz,CD
3OD)δ=8.39(d,
J=8.4Hz,1H),8.22(d,
J=8.8Hz,1H),7.86–7.76(m,2H),7.60–7.56(m,2H),7.43–7.33(m,2H),7.10–7.08(m,1H),3.99–3.95(m,4H),3.33–3.30(m,2H),3.01–2.81(m,10H),2.71–2.69(m,2H),1.96–1.87(m,6H),1.74–1.70(m,2H),1.51–1.47ppm(m,2H);
13 CNMR(100MHz,CD
3OD)δ=156.6,155.3,152.8,150.5,138.4,137.9,136.7,132.7,128.2,127.2,125.1,125.0,121.5,118.8,117.5,115.8,111.6,110.8,63.0,57.0,51.8,50.9,48.4,29.7,28.0,24.3,23.7,23.6,21.6,20.5ppm;ESI-MSm/z:510.3[M+H]
+。
Embodiment 15
Synthesis 5-fluoro-2-[(4-(5-(1,2,3,4-tetrahydro acridine)-9-amido) amyl group) piperidine methyl] quinoline-8-phenol
15
Compound
ii(0.5mmol, n=4) and compound
in(0.5mmol, R=5-F), with reference to embodiment 7 operating process, is separated to obtain compound
15, pale yellow oil, yield 57%.
1 (400MHz,CDCl
3)δ=8.31(d,
J=8.0Hz,1H),8.26(d,
J=8.8Hz,1H),8.14(d,
J=8.8Hz,1H),7.58–7.52(m,2H),7.34(t,
J=8.0Hz,1H),7.03–6.93(m,2H),6.17(brs,1H),3.85(t,
J=6.8Hz,2H),3.81(s,2H),3.23–3.10(m,2H),2.72–2.57(m,12H),1.82–1.77(m,6H),1.66–1.61(m,2H),1.46–1.42ppm(m,2H);
13 CNMR(100MHz,CDCl
3)δ=156.3,154.3,150.8,149.6(
J C-F=244.1Hz),147.5(
J C-F=3.1Hz),138.3,136.2(
J C-F=3.3Hz),131.0,129.3(
J C-F=2.7Hz),124.0,123.2,120.7(
J C-F=2.2Hz),120.3,117.0(
J C-F=18.7Hz),115.1,110.2,109.5(
J C-F=21.0Hz),108.0(
J C-F=7.7Hz),63.1,56.5,51.6,51.0,47.0,29.5,27.8,24.2,23.2,23.0,21.0,19.8ppm;ESI-MSm/z:528.3[M+H]
+。
Embodiment 16
Synthesis 5-chloro-2-[(4-(5-(1,2,3,4-tetrahydro acridine)-9-amido) amyl group) piperidine methyl] quinoline-8-phenol
16
Compound
ii(0.5mmol, n=4) and compound
in(0.5mmol, R=5-F), with reference to embodiment 7 operating process, is separated to obtain compound
16, pale yellow oil, yield 58%.
1 (400MHz,CDCl
3)δ=8.43(d,
J=8.8Hz,1H),8.38(d,
J=8.8Hz,1H),8.23(d,
J=8.8Hz,1H),7.68–7.60(m,2H),7.45–7.38(m,2H),7.05(d,
J=8.4Hz,1H),6.38(brs,1H),3.97–3.90(m,2H),3.86(s,2H),3.24–3.23(m,2H),2.68–2.66(m,10H),2.52(t,
J=6.8Hz,2H),1.89–1.86(m,6H),1.64–1.62(m,2H),1.50–1.47ppm(m,2H);
13 CNMR(100MHz,CDCl
3)δ=157.4,155.1,151.9,151.4,139.7,138.0,133.8,131.7,127.0,125.4,124.9,124.3,122.5,121.5,120.2,116.4,111.5,110.3,64.1,57.8,52.8,52.6,48.1,30.7,29.1,25.7,24.4,24.2,22.1,20.9ppm;ESI-MSm/z:544.3[M+H]
+。
Embodiment 17
Synthesis
n-[5-(4-(8-amido quinoline)-2-methyl) piperidines] propyl group-1,2,3,4-tetrahydro acridine-9-amine
17
Weigh Compound
ii(0.5mmol, n=1) and compound
in '(0.5mmol, R=H), in 25mL round-bottomed bottle, adds NaBH (OAc)
3(1.0mmol), DCE (dry, 5mL), is heated to 50 DEG C of reactions under argon shield, and TLC monitors reaction and terminates rear cooling reaction solution to room temperature, adds water washing, and DCM extracts, and concentrate after doing and be separated through silicagel column, products therefrom adds CF
3cO
2h/DCM (2mL, v/v=1/1), adds water after stirring at room temperature 1h, K
2cO
3be adjusted to weakly alkaline, after DCM extraction, concentrated xeromenia silicagel column is separated to obtain compound
17, colorless oil, yield 62%.
1 (400MHz,CDCl
3)δ=8.30–8.25(m,1H),8.11(d,
J=8.8Hz,1H),7.93–7.91(m,1H),7.55–7.51(m,1H),7.45–7.42(m,1H),7.33–7.29(m,1H),7.19–7.17(m,1H),7.03–7.01(m,1H),6.84–6.82(m,1H),6.01(brs,1H),4.96(brs,2H),3.77–3.74(m,4H),3.14–3.13(m,2H),2.58–2.34(m,12H),1.78–1.76(m,6H),1.54–1.49(m,2H),1.41–1.38ppm(m,2H);
13 CNMR(100MHz,CDCl
3)δ=155.9,154.6,152.6,143.8,140.5,137.5,136.3,131.4,127.8,127.0,124.8,124.1,122.3,121.3,116.7,115.7,111.9,110.1,64.9,58.0,53.1,52.8,48.3,30.9,29.5,26.0,24.5,24.2,22.2,21.1ppm;purity:99.5%,determinedbyHPLCwithInertSustainC18column(5μm,4.6×150mm)at254nm[CH
3CN(contain0.05%CF
3CO
2H)/H
2O=95:5,flowrate=1.2mL/min],t
R=1.33min;ESI-MSm/z:509.3[M+H]
+。
Claims (5)
1. tacrine-8-hydroxyl (amine) base quinoline, is characterized in that: its structural formula is as shown in the formula shown in I: the salt comprising formula I and be pharmaceutically suitable for
Wherein X is
, CH
2,
Y is O, NH;
M is integer 1,2,4,5;
R is hydrogen, chlorine, fluorine.
2. a kind of tacrine-8-hydroxyl (amine) base quinoline according to claim 1, is characterized in that:
When X is
time,
R is hydrogen, 5-chlorine, 5-fluorine, 6-chlorine, 5,7-dichloros,
m=1，
And physiologically acceptable salt;
When X is CH
2time,
R is hydrogen, 5-fluorine, 5,7-dichloros,
m=1，2，4，5，
And physiologically acceptable salt.
3. a kind of tacrine-8-hydroxyl (amine) base quinoline according to claim 1, is characterized in that: the preparation method of described formula I, comprises the steps:
(1) preparation of Compound I d: o-Cyanoaniline and pimelinketone generate imines under boron trifluoride diethyl etherate catalysis, then obtain tacrine molecule I b by alkaline purification reflow treatment, obtain Compound I c through chloroacetyl chloride acidylate, then be connected to obtain Compound I d with piperazine;
(2) preparation of Compound I i: anthranilic acid and pimelinketone reflux and obtain 9-chlorine tacrine molecule I f in phosphorus oxychloride, and then nucleophilic substitution generates Ig in inert solvent with hydramine, then through thionyl chloride chloro, is connected obtains Compound I i with piperazine;
(3) Compound I n/In
'preparation: o-aminophenol (amine) and acetaldehyde in acid condition condensation obtain quinoline compound Ik, through benzyl chlorine or Boc
2o protects hydroxyl or amino, reoxidizes and obtains quinoline aldehyde cpd In/In
';
(4) preparation of Compound I: Compound I d and Ii and intermediate compound I n/In
'compound I is obtained through reduction amination, deprotection.
4. a kind of tacrine-8-hydroxyl (amine) base quinoline according to claim 3, is characterized in that: prepared Compound I prepares corresponding hydrochloride, acetate, trifluoroacetate to hydrochloric acid, acetic acid, trifluoroacetic acid in alcoholic solution.
5. an application for tacrine-8-hydroxyl (amine) base quinoline, is characterized in that: the medicine being applied to treatment A Cihaimo disease.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056780A (en) * | 2017-05-08 | 2017-08-18 | 中山大学 | The different dyad of the similar group of lipoic acid Tacrine and its application for treating alzheimer's disease |
| WO2018000047A1 (en) * | 2016-07-01 | 2018-01-04 | Prana Biotechnology Limited | Method of treating immunoglobulin light chain amyloidosis |
| CN108047202A (en) * | 2017-12-20 | 2018-05-18 | 东南大学 | A kind of aluminium ion response type compound and preparation method and application |
| RU2675794C1 (en) * | 2017-11-01 | 2018-12-25 | Федеральное Государственное Бюджетное Учреждение Науки Институт Физиологически Активных Веществ Российской Академии Наук (Ифав Ран) | Multifunctional conjugates of tacrine and its analogues with derivatives of 1,2,4-tiadiazole, the way of their synthesis and application for the treatment of neurodegenerative diseases |
| CN110041309A (en) * | 2019-04-04 | 2019-07-23 | 广东工业大学 | A kind of Tacrine -8- amino (hydroxyl) quinoline of 2- carboxypiperazin connection and preparation and application |
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| WO1995023137A1 (en) * | 1994-02-23 | 1995-08-31 | EGIS Gyógyszergyár Rt. | Acetic acid amide derivatives and process for the preparation thereof |
| CN1681791A (en) * | 2002-07-16 | 2005-10-12 | 普拉纳生物技术有限公司 | 8-hydroxy quinoline derivatives |
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| WO2018000047A1 (en) * | 2016-07-01 | 2018-01-04 | Prana Biotechnology Limited | Method of treating immunoglobulin light chain amyloidosis |
| CN109414437A (en) * | 2016-07-01 | 2019-03-01 | 普拉纳生物技术有限公司 | The method for treating light chain immunoglobulin amyloidosis |
| US11357770B2 (en) | 2016-07-01 | 2022-06-14 | Alterity Therapeutics Limited | Method of treating immunoglobulin light chain amyloidosis |
| CN107056780A (en) * | 2017-05-08 | 2017-08-18 | 中山大学 | The different dyad of the similar group of lipoic acid Tacrine and its application for treating alzheimer's disease |
| CN107056780B (en) * | 2017-05-08 | 2020-07-10 | 中山大学 | Lipoic acid-tacrine-like group heterodimer and application thereof in treating Alzheimer's disease |
| RU2675794C1 (en) * | 2017-11-01 | 2018-12-25 | Федеральное Государственное Бюджетное Учреждение Науки Институт Физиологически Активных Веществ Российской Академии Наук (Ифав Ран) | Multifunctional conjugates of tacrine and its analogues with derivatives of 1,2,4-tiadiazole, the way of their synthesis and application for the treatment of neurodegenerative diseases |
| CN108047202A (en) * | 2017-12-20 | 2018-05-18 | 东南大学 | A kind of aluminium ion response type compound and preparation method and application |
| CN108047202B (en) * | 2017-12-20 | 2021-06-11 | 东南大学 | Aluminum ion response type compound and preparation method and application thereof |
| CN110041309A (en) * | 2019-04-04 | 2019-07-23 | 广东工业大学 | A kind of Tacrine -8- amino (hydroxyl) quinoline of 2- carboxypiperazin connection and preparation and application |
| CN110041309B (en) * | 2019-04-04 | 2022-01-28 | 广东工业大学 | 2-carboxypiperazine-linked tacrine-8-amino (hydroxy) quinoline derivative and preparation and application thereof |
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