CN105906608B - 8- aminoquinolines-epiphysin is miscellaneous conjuncted and its pharmaceutical composition - Google Patents
8- aminoquinolines-epiphysin is miscellaneous conjuncted and its pharmaceutical composition Download PDFInfo
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- 0 *c(cc1)cc2c1[n]cc2CCO Chemical compound *c(cc1)cc2c1[n]cc2CCO 0.000 description 2
- OHHDRXWXUMVRLW-UHFFFAOYSA-N C(CNc1cccc2c1nccc2)c1c[nH]c2c1cccc2 Chemical compound C(CNc1cccc2c1nccc2)c1c[nH]c2c1cccc2 OHHDRXWXUMVRLW-UHFFFAOYSA-N 0.000 description 1
- WREVVZMUNPAPOV-UHFFFAOYSA-N Nc1c2ncccc2ccc1 Chemical compound Nc1c2ncccc2ccc1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 1
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- 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
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Abstract
8 aminoquinoline epiphysins are miscellaneous conjuncted and its pharmaceutical composition.The present invention relates to 8 aminoquinoline epiphysins of synthesis are miscellaneous conjuncted, there is formula（Ⅰ）Structural formula, these compounds on the one hand can selectively chelate copper ion；On the other hand, good neural neuroprotective is played, the symptom of AD is improved.The invention further relates to include miscellaneous conjuncted or its pharmaceutically acceptable salt the pharmaceutical composition or Neuroprotective Agents.The invention further relates to the miscellaneous conjuncted pharmaceutical applications.
Description
Technical field
The present invention relates to synthesizing, a series of 8- aminoquinolines-epiphysins are miscellaneous conjuncted.Shown in structural formula such as formula (I).They
It is connected by connector appropriate.On the one hand copper ion can selectively be chelated；On the other hand, while good nerve nerve is played
First protective effect improves the symptom of AD so that they become the candidate of drug development.
Background technology
Alzheimer disease (Alzheimer's disease, AD) is a kind of neurodegenerative disease that the cause of disease is unknown,
Onset is hidden and process is slowly irreversible, clinically mainly characterized by recognizing with Memory Impairment.The main pathology of AD is special
Senile plaque (the senile that sign has the atrophy of cerebral cortex diffusivity, neuron to largely reduce, beta-amyloid protein is formed
Plaques, SPs) and Protein tau Hyperphosphorylationof formed nerve fibril knot (neurofibrillary tangles,
NFTs).In addition, also found that the reduction of cholinergic nerve fibers number and the function of cholinergic neuron subtract in AD patient's intracerebral
It is weak, prompt the retrogression of cholinergic neuron that may also participate in the generation of AD.At present still not very about the pathogenesis of AD
It is clear, there are A β cascades hypothesis, Protein tau hypothesis, cholinergic deficiency, gene theory, trace element and estrogen to change, blood vessel source
The Different types of etiopathogenises hypothesis such as property hypothesis, but any type hypothesis all cannot make comprehensive explanation to the pathogenic process of AD.
Recent study personnel gradually have found that metal ion plays a key effect in the occurrence and development of AD pathology, gold
The imbalance for belonging to homeostasis is considered as the key factor for leading to AD diseases.Metallic copper is trace element necessary to our human bodies,
It is the component part of cuprein.Copper ion is the transition metal ions for having redox active, in organism, copper ion energy
With multiple proteins side group coordination atom be coordinated, to maintain energetic supersession, connective tissue generations, radicals scavenging, iron activate and
The physiological functions such as neurotransmission are most important.Research finds that the copper ion Redox homeostasis balance of AD patient's brain is destroyed, copper
It is enriched in space between cells, the copper in histocyte is opposite to be lacked.The shortage of copper can influence AD patient's body in turn in brain tissue cell
The activity of interior copper-binding protein, including copper-zinc superoxide dismutase, cytochrome C oxidase, tyrosinase and dopamine
B-hydroxylase etc., and the metabolic processes of these enzymes and brain are closely related.In the Cu of appropriateness2+Concentration and physiological pH condition
Under, A β show antioxidation and inhibit Cu first2+The oxidation of the biomolecule of catalysis, the two is with 1:1 ratio is quickly formed
Reversible compound, the generations of lipid peroxidation product 4- Hydroxynonenals (4-hydroxynonenal, 4-HNE) obviously by
Inhibit, but works as excessive Cu2+In the presence of and/or pH value decline when, A β and Cu2+Form insoluble strong oxidizing property compound.A β knots
Close Cu2+Later, by Cu2+It is reduced into Cu+Generate H simultaneously2O2, then generated by Fenton reactions and Haber-Weiss reactions
With highly toxic free radical, oxidative stress and the death of neuron are eventually led to.Enteroquinol
(clioquinol) the brain A β precipitations that can reduce AD mouse models, improve the cognitive function of animal and improve holistic health shape
Condition becomes first anti-AD metal ion chelation agent for entering clinical research.8-hydroxyquinoline derivative PBT-2 can be significantly reduced
A β in AD animals cerebrospinal fluid (CSF)42It is horizontal.In the phase ii clinical trial of PBT-2, the tolerance of drug is very good, treatment drop
A β in low patient CSF42Content, and improve the health status of patient.The clinical efficacy of PBT-2 shows with 8- hydroxyl quinolines
Quinoline and 8- aminoquinolines are that core skeleton is that basic development of metallic ion regulating agent is used to AD treat to be practicable AD new drugs
Development strategy.
Epiphysin (melatonin) is a kind of fat-soluble neuro-endocrinology hormone mainly secreted by pineal body, also known as
Epiphysin, it is the derivative of 5-hydroxyryptophan, and chemical name is N- acetyl -5-MT 5-methoxytryptamine (N-acetyl-5-
methoxytryptamine).The biosynthesis of epiphysin with tryptophan (tryptaphan) be raw material, by being hydroxylated, taking off
Carboxylic, N- acetylations and oxygen methylate, and are eventually converted into epiphysin.It synthesizes later epiphysin and is not stored in pineal body,
But passively enter blood circulation immediately.Epiphysin is easy to enter brain tissue through blood-brain barrier, has and promotes sleep, adjusts
It saves the time difference, anti-aging, adjust the multinomial physiological function such as immune, antitumor.1992, the researchs such as Reiter found the elderly's synthesis
The hypofunction of epiphysin is secreted, and the reduction of epiphysin level and the destruction of circadian rhythm disorders and cognitive function are apparent
It is related.AD patients serums, ventricles of the brain CSF epiphysin compared with normal person's secretion level reduce, be accompanied by pathological change AD patient
Epiphysin level reduction in CSF is more obvious, and the CSF epiphysin levels with 4/4 genotype patients of APOE ε are bright
It is aobvious to be less than the patient that genotype is APOE ε 3/4, and 4 genotype of APOE ε is the well-known risks and assumptions of AD.It grinds in recent years
Study carefully and finds that epiphysin can protect neuron from the neurotoxic injury of A β.In the transgene mouse model of AD, pine nut
Voxel inhibits the aggregation of A β to a certain extent, reduces the abnormal nitrification of some protein, while can be by inhibiting internal mistake
The radical reaction of degree reduces brain inflammation cytokine levels and increases the stability of anti-inflammatory molecule.Therefore, epiphysin
This apparent neuroprotection provides a kind of new research direction for the treatment of AD diseases.
Invention content
Based on the above research, metal ion plays a key effect in the occurrence and development of AD pathology, metal ion-chelant
Agent especially copper ion chelator is to research and develop one of the Critical policies of AD drugs.It has to be mentioned that metal ion such as copper ion,
Zinc ion, iron ion etc. are all being essential important meals ions in human body, are played to different physiological roles most important
Effect.Therefore, the drug for treating AD diseases cannot be single ion chelating agent, and must be good conditioning agent.
The present invention provides the compound or its tautomer, pharmaceutical salts, prodrug or solvate of formula (I).
Wherein,
R is selected from H, OH, OCH3、OCON(CH3)2With OCON (CH3)CH2CH3；
X is selected from NH, NHCONH and NHCOCH2NH。
Unless otherwise specified, the compound of the present invention is also meant to include differing only in the presence of one or more isotopes richnesses
The compound of the atom of collection.For example, with this structure in addition to replacing hydrogen, Huo Zheyong with deuterium or tritium13C or14The carbon of C- enrichments is former
Son replaces carbon atom, or15The nitrogen-atoms of N- enrichments replaces nitrogen-atoms, and compound is within the scope of the present invention.
Another aspect of the present invention provides a kind of pharmaceutical composition, and it includes any compound of the present invention or its medicines
Acceptable salt and pharmaceutically acceptable carrier on.
Another aspect of the present invention provides any compound of the present invention or its pharmaceutically acceptable salt is preparing treatment
Application in the drug of the disease of neuronal damage.Preferably, the disease of the neuronal damage is Alzheimer's disease or brain
Vascular dementia.
Another aspect of the present invention provides a kind of Neuroprotective Agents, it includes any compound of the present invention or its
Pharmaceutically acceptable salt.
The present invention also provides a kind of disease for treating neuronal damage or the methods for protecting neuron, and the method includes will
Any compound of the present invention or its pharmaceutically acceptable salt and neuronal contacts.In a preferred method, the neuron
It is internal neuronal cell, the brain neuroblastoma member cell preferably in human body.
8- aminoquinolines are good selective chelating copper ions conditioning agents, under certain physiological condition, cupric from
Son is reduced to univalent copper ion, loses the sequestering power with 8- aminoquinolines, to be released.On the other hand, have
Research shows that epiphysin has good neural neuroprotective, while it can smoothly penetrate blood-brain barrier.Therefore,
We devise 8- aminoquinolines and epiphysin hybrid, it is contemplated that in conjunction with the treatment speciality of the two, further introduce current
Effective pharmacophore in clinical treatment drug target anticholinesterase, to play a medicine " multiple target point, more work(in being treated in AD
The synergy of energy ".
There are two main units for the compound of the present invention：Epiphysin part and 8- aminoquinolines part, they are logical
Cross connector connection appropriate.On the one hand copper ion can selectively be chelated；On the other hand, while good neural neuron is played
Protective effect improves the symptom of AD so that they become the candidate of drug development.We have found that variation connector and length and
Whether substituted base can adjust selectivity and activity on ring.
Description of the drawings
Fig. 1 compounds induce the protective effect of HT22 cell deaths to L-glutamate and to the cell toxicants of HT22 cells
Property.
Fig. 2 compounds promote the cell viability of C17.2 neural stem cell.
Fig. 3 compounds lxg-P-22 are mutual with common metal ion in organism (copper, zinc, magnesium, calcium, manganese, cobalt, nickel)
The uv-visible absorption spectroscopy figure of effect.
The phase interaction of Fig. 4 compounds lxg-P-2 and common metal ion in organism (copper, zinc, magnesium, calcium, manganese, cobalt, nickel)
Uv-visible absorption spectroscopy figure.
Specific implementation mode
The following example is provided, the present invention is further illustrated, they should not be considered as the limit to the scope of the invention
It is fixed.
Scheme I
The synthetic route of compound lxg-P-11 and lxg-P-10
The synthesis of embodiment 1- compounds lxg-P-11
0.71g compounds 1,1.67mL i-Pr are added in 50mL round-bottomed flasks2NEt and 15mL tetrahydrofurans, in room temperature
Lower stirring fully dissolving, is then slowly added to 1.26g compounds 2 dropwise, continues that reaction 4 hours is stirred at room temperature after dripping.Instead
It answers and about 10mL water is added in system, extracted with 30mL ethyl acetate, detach organic phase, continue with water and saturated common salt washing one
It is secondary.Organic phase is detached, is dried with anhydrous magnesium sulfate, rotary evaporation removes solvent after filtering, and it is to change to obtain colorless oil as product
Object 3 is closed, weigh 1.52g, yield 95%.Product can be directly used in next step without being further purified.
0.64g compounds 3,0.32g compounds 4 and 15mL acetonitriles are added in 50mL round-bottomed flasks, is stirred at room temperature
Then 0.46g DBU are added in fully dissolving.Reaction system is heated to flowing back, and reacts 3.5 hours, is cooled to room temperature later, depressurizes
Rotation removes most of solvent.Ethyl acetate is added, is washed with water and is washed with saturated common salt.Organic phase is detached, anhydrous magnesium sulfate is used
Dry, rotary evaporation removes solvent after filtering.Obtained solid obtains compound as white solid with silica gel column chromatogram separating purification
Lxg-P-11, weigh 0.61g, yield 92%.
Fusing point：159-162℃.
1H NMR(400MHz,CDCl3) δ 8.92 (s, 1H), 8.69 (dd, J=4.2,1.6Hz, 1H), 8.56 (dd, J=
7.7,1.0Hz, 1H), 8.12 (dd, J=8.3,1.6Hz, 1H), 8.08 (brs, 1H), 7.66 (d, J=7.8Hz, 1H), 7.51
(t, J=8.0Hz, 1H), 7.40-7.36 (m, 3H), 7.20 (dd, J=11.1,4.0Hz, 1H), 7.12 (t, J=7.2Hz,
1H), 7.07 (d, J=2.2Hz, 1H), 4.95 (t, J=5.5Hz, 1H), 3.70 (dd, J=12.7,6.6Hz, 2H), 3.07 (t,
J=6.7Hz, 2H)
13C NMR(100MHz,CDCl3)δ155.1,147.6,138.2,136.4,136.4,135.8,128.1,127.6,
127.3,122.2,122.2,121.4,119.5,119.5,118.8,114.8,113.1,111.2,40.6,25.9.
HRMS ESI(+)m/z calculated for C20H19N4O[M+H]+331.1559,found 331.1557.
The synthesis of embodiment 2- compounds lxg-P-10
By scheme prepare compound 3 described in embodiment 1,0.64g compounds 3,0.38gization are added in 50mL round-bottomed flasks
Object 5 and 15mL acetonitriles are closed, abundant dissolving is stirred at room temperature, 0.46g DBU are then added.Reaction system is heated to flowing back, instead
It answers 3.5 hours, is cooled to room temperature later, decompression rotation removes most of solvent.Ethyl acetate is added, is washed with water and saturated common salt
Washing.Organic phase is detached, is dried with anhydrous magnesium sulfate, rotary evaporation removes solvent after filtering.Obtained solid silica gel column chromatography
It isolates and purifies to obtain compound as white solid lxg-P-10, weigh 0.61g, yield 84%.
Fusing point：188-191℃.
1H NMR(400MHz,CDCl3) δ 8.90 (s, 1H), 8.69 (d, J=3.3Hz, 1H), 8.55 (d, J=7.6Hz,
1H), 8.12 (d, J=8.1Hz, 1H), 7.99 (brs, 1H), 7.51 (t, J=8.0Hz, 1H), 7.39 (dd, J=8.2,
3.7Hz, 2H), 7.26 (t, J=4.2Hz, 2H), 7.10-7.01 (m, 2H), 6.86 (dd, J=8.8,2.2Hz, 1H), 4.98
(brs, 1H), 3.80 (s, 3H), 3.69 (q, J=6.4Hz, 2H), 3.04 (t, J=6.6Hz, 2H)
13C NMR(100MHz,CDCl3)δ155.1,154.2,147.6,138.1,136.4,135.8,131.5,128.1,
127.8,127.6,123.0,121.4,119.6,114.8,112.9,112.6,112.0,100.5,55.9,40.7,25.9.
HRMS ESI(+)m/z calculated for C21H21N4O2[M+H]+361.1665,found 361.1659.
Scheme II
The synthetic route of compound lxg-P-22, lxg-P-25 and lxg-P-26
The synthesis of embodiment 3- compounds lxg-P-22
0.72g compound lxg-P-10 and 10mL dry methylene chlorides are added in 25mL round-bottomed flasks, in nitrogen protection
Under be placed in ice bath and stir, the dichloromethane solution of the Boron tribromide for a concentration of 3M that 2mL is prepared in advance is slowly added dropwise.Reactant
System is stirred to react overnight, and sodium bicarbonate aqueous solution is added dropwise and terminates reaction.With THF/EA (1:2) mixed extractant solvent 2 times merges
Organic phase is washed with saturated common salt, and anhydrous magnesium sulfate drying, rotary evaporation removes solvent after filtering.Gained crude product silicagel column color
Spectrum isolates and purifies to obtain compound as white solid lxg-P-22, and weigh 0.47g, yield 68%.
Fusing point：201-204℃.
1H NMR(400MHz,CD3OD) δ 8.76 (dd, J=4.1,1.4Hz, 1H), 8.41 (d, J=7.5Hz, 1H), 8.18
(dd, J=8.3,1.3Hz, 1H), 7.48-7.40 (m, 3H), 7.17 (d, J=8.6Hz, 1H), 7.06 (s, 1H), 7.01 (d, J
=2.1Hz, 1H), 6.68 (dd, J=8.6,2.2Hz, 1H), 3.55 (t, J=7.3Hz, 2H), 2.95 (t, J=7.3Hz, 2H)
13C NMR(100MHz,MeOD)δ156.7,149.7,147.8,138.3,136.0,135.9,131.8,128.2,
128.1,126.8,122.9,121.3,119.4,114.3,111.3,111.2,111.0,102.2,40.3,25.8.
HRMS ESI(+)m/z calculated for C20H19N4O2[M+H]+347.1508,found 347.1504.
The synthesis of embodiment 4- compounds lxg-P-25
0.35g compound lxg-P-22 and 5mL dry pyridines are added in 25mL round-bottomed flasks, sequentially add 151mgization
Close object 6 and 0.35mL i-Pr2NEt, reaction system are heated to 70 DEG C of reactions overnight under nitrogen protection.It is cooled to room temperature, depressurizes
Rotation removes most of solvent.Dichloromethane is added, is washed with water and is washed with saturated common salt.Organic phase is detached, anhydrous magnesium sulfate is used
Dry, rotary evaporation removes solvent after filtering.Gained crude product obtains compound as white solid with silica gel column chromatogram separating purification
Lxg-P-25, weigh 0.33g, yield 80%.
Fusing point：110-113℃.
1H NMR(400MHz,CDCl3) δ 9.02 (s, 1H), 8.73-8.63 (m, 2H), 8.59 (d, J=7.7Hz, 1H),
8.09 (dd, J=8.3,1.4Hz, 1H), 7.48 (t, J=8.0Hz, 1H), 7.41-7.32 (m, 2H), 7.26 (brs, 1H),
7.15 (d, J=8.7Hz, 1H), 6.86 (dd, J=8.7,2.1Hz, 1H), 6.75 (d, J=1.7Hz, 1H), 5.45 (brs,
1H), 3.38 (dd, J=12.6,6.6Hz, 2H), 3.12 (s, 3H), 3.02 (s, 3H), 2.70 (t, J=6.8Hz, 2H)
13C NMR(100MHz,CDCl3)δ156.5,155.6,147.5,144.6,138.3,136.3,136.2,134.1,
128.1,127.6,123.5,121.3,119.3,116.3,114.9,112.9,111.5,111.1,40.1,36.8,36.5,
25.5.
HRMS ESI(+)m/z calculated for C23H24N5O3[M+H]+418.1879,found 418.1875.
The synthesis of embodiment 5- compounds lxg-P-26
0.35g compound lxg-P-22 and 5mL dry pyridines are added in 25mL round-bottomed flasks, sequentially add 169mgization
Close object 7 and 0.35mL i-Pr2NEt, reaction system are heated to 70 DEG C of reactions overnight under nitrogen protection.It is cooled to room temperature, depressurizes
Rotation removes most of solvent.Dichloromethane is added, is washed with water and is washed with saturated common salt.Organic phase is detached, anhydrous magnesium sulfate is used
Dry, rotary evaporation removes solvent after filtering.Gained crude product obtains compound as white solid with silica gel column chromatogram separating purification
Lxg-P-26, weigh 0.33g, yield 77%.
Fusing point：112-115℃.
1H NMR(400MHz,CDCl3) δ 9.00 (s, 1H), 8.68 (dd, J=4.2,1.7Hz, 1H), 8.66 (brs, 1H),
8.58 (dd, J=7.8,1.2Hz, 1H), 8.09 (dd, J=8.3,1.7Hz, 1H), 7.48 (t, J=8.0Hz, 1H), 7.35
(ddd, J=8.3,2.7,1.4Hz, 2H), 7.27 (d, J=8.3Hz, 1H), 7.17 (dd, J=8.4,3.7Hz, 1H), 6.87
(d, J=8.7Hz, 1H), 6.76 (d, J=2.1Hz, 1H), 5.37 (brs, 1H), 3.55-3.42 (m, 2H), 3.39 (d, J=
4.8Hz, 2H), 3.05 (d, J=34.7Hz, 3H), 2.71 (d, J=6.5Hz, 2H), 1.31-1.11 (m, 3H)
13C NMR(100MHz,CDCl3)δ156.2,155.6,147.6,144.6,138.3,136.3,136.2,134.1,
128.1,127.6,123.5,121.3,119.3,116.3,114.9,112.9,111.5,111.1,44.1,40.1,34.3,
33.8,25.5,13.3,12.6.
HRMS ESI(+)m/z calculated for C24H26N5O3[M+H]+432.2036,found 432.2031.
Scheme III
The synthetic route of compound lxg-P-06 and lxg-P-07
The synthesis of embodiment 6- compounds lxg-P-6
0.8g compounds 4 and 15mL dry tetrahydrofurans are added in 50mL round-bottomed flasks, is placed in ice under nitrogen protection
It is stirred in bath, 0.48mL compounds 8 is slowly added dropwise, 1.39mL triethylamines are then added, it is small that reaction system is placed in stirring 6 at room temperature
When.Add water to terminate reaction, be extracted with ethyl acetate, be washed with water and washed with saturated common salt, detaches organic phase, it is dry with anhydrous magnesium sulfate
Dry, rotary evaporation removes solvent after filtering.Compound as white solid 9 is obtained, weigh 1.14g, yield 96%.Product is directly used in
In next step.
0.47g compounds 9,0.29g compounds 1 and 6mL DMF are added in 25mL round-bottomed flasks, 0.7mL is then added
i-Pr2NEt and 0.36g sodium iodides.Reaction system is heated to 80 DEG C and reacts 8 hours.It is cooled to room temperature, water is added, with acetic acid second
Ester extracts.Organic phase is detached, is dried with anhydrous magnesium sulfate, rotary evaporation removes solvent after filtering.Gained crude product silicagel column color
Spectrum isolates and purifies to obtain compound as white solid lxg-P-6, and weigh 0.43g, yield 63%.
Fusing point：182-185℃.
1H NMR(400MHz,CDCl3) δ 8.72 (dd, J=4.2,1.6Hz, 1H), 8.12 (dd, J=8.3,1.6Hz,
1H), 7.65 (brs, 1H), 7.49 (d, J=7.9Hz, 1H), 7.43 (dd, J=8.3,4.2Hz, 1H), 7.33 (t, J=
7.9Hz, 1H), 7.24 (d, J=8.3Hz, 1H), 7.18 (d, J=7.6Hz, 1H), 7.12 (t, J=7.2Hz, 1H), 7.00 (t,
J=7.2Hz, 1H), 6.85 (brs, 1H), 6.61 (d, J=2.2Hz, 1H), 6.58 (d, J=7.2Hz, 1H), 6.55 (brs,
1H), 3.98 (d, J=6.0Hz, 2H), 3.61 (q, J=6.6Hz, 2H), 2.90 (t, J=6.8Hz, 2H)
13C NMR(100MHz,CDCl3)δ170.2,147.4,143.8,138.2,136.2,136.1,128.4,127.6,
127.1,122.0,121.9,121.7,119.4,118.6,116.0,112.6,111.1,106.0,48.6,39.2,25.3.
HRMS ESI(+)m/z calculated for C21H20N4ONa[M+Na]+367.1535,found
367.1528.
The synthesis of embodiment 7- compounds lxg-P-7
0.57g compounds 5 and 10mL dry tetrahydrofurans are added in 50mL round-bottomed flasks, is placed in ice under nitrogen protection
It is stirred in bath, 0.29mL compounds 8 is slowly added dropwise, 0.83mL triethylamines are then added, it is small that reaction system is placed in stirring 6 at room temperature
When.Add water to terminate reaction, be extracted with ethyl acetate, be washed with water and washed with saturated common salt, detaches organic phase, it is dry with anhydrous magnesium sulfate
Dry, rotary evaporation removes solvent after filtering.Compound as white solid 10 is obtained, weigh 0.74g, yield 93%.Product is directly used
In in next step.
0.53g compounds 10,0.29g compounds 1 and 6mL DMF are added in 25mL round-bottomed flasks, 0.7mL is then added
i-Pr2NEt and 0.36g sodium iodides.Reaction system is heated to 80 DEG C and reacts 8 hours.It is cooled to room temperature, water is added, with acetic acid second
Ester extracts.Organic phase is detached, is dried with anhydrous magnesium sulfate, rotary evaporation removes solvent after filtering.Gained crude product silicagel column color
Spectrum isolates and purifies to obtain light yellow solid Compound lxg-P-7, and weigh 0.57g, yield 76%.
Fusing point：158-161℃.
1H NMR(400MHz,CDCl3) δ 8.72 (dd, J=4.2,1.7Hz, 1H), 8.10 (dd, J=8.3,1.7Hz,
1H), 7.79 (brs, 1H), 7.41 (dd, J=8.3,4.2Hz, 1H), 7.31 (t, J=7.9Hz, 1H), 7.16 (dd, J=8.2,
0.9Hz, 1H), 7.13 (d, J=8.8Hz, 1H), 6.95 (d, J=2.4Hz, 1H), 6.87 (brs, 1H), 6.79 (dd, J=
8.8,2.4Hz, 1H), 6.62-6.53 (m, 3H), 3.96 (d, J=6.0Hz, 2H), 3.80 (s, 3H), 3.58 (q, J=6.8Hz,
2H), 2.85 (t, J=6.9Hz, 2H)
13C NMR(100MHz,CDCl3)δ170.4,153.9,147.4,143.8,138.1,136.1,131.4,128.4,
127.6,127.5,122.8,121.7,116.1,112.3,112.2,111.9,106.1,100.3,55.9,48.6,39.1,
25.4.
HRMS ESI(+)m/z calculated for C22H22N4O2Na[M+Na]+397.1640,found
397.1635.
Scheme IV
The synthetic route of compound lxg-P-12, lxg-P-24 and lxg-P-17
The synthesis of embodiment 8- compounds lxg-P-12
0.75g compound lxg-P-7 and 10mL dry methylene chlorides are added in 25mL round-bottomed flasks, under nitrogen protection
It is placed in ice bath and stirs, the dichloromethane solution of the Boron tribromide for a concentration of 3M that 2mL is prepared in advance is slowly added dropwise.Reaction system
It is stirred to react overnight, sodium bicarbonate aqueous solution is added dropwise and terminates reaction.With THF/EA (1:2) mixed extractant solvent 2 times, is associated with
Machine is mutually washed with saturated common salt, and anhydrous magnesium sulfate drying, rotary evaporation removes solvent after filtering.Gained crude product silica gel column chromatography
It isolates and purifies to obtain compound as white solid lxg-P-12, weigh 0.51g, yield 71%.
Fusing point：121-124℃.
1H NMR (400MHz, DMSO) δ 10.46 (s, 1H), 8.78 (dd, J=4.1,1.6Hz, 1H), 8.58 (s, 1H),
8.23 (dd, J=8.3,1.5Hz, 1H), 8.16 (t, J=5.7Hz, 1H), 7.52 (dd, J=8.3,4.2Hz, 1H), 7.37 (t,
J=7.9Hz, 1H), 7.11 (dd, J=8.4,3.8Hz, 2H), 7.01 (d, J=2.1Hz, 1H), 6.93 (t, J=5.5Hz,
1H), 6.84 (d, J=2.1Hz, 1H), 6.58 (dd, J=8.6,2.3Hz, 1H), 6.50 (d, J=7.6Hz, 1H), 3.88 (d, J
=5.5Hz, 2H), 3.37 (dd, J=14.0,6.7Hz, 2H), 2.74 (t, J=7.5Hz, 2H)
13C NMR(100MHz,DMSO)δ169.7,150.6,147.6,144.6,138.0,136.4,131.3,128.7,
128.3,128.2,123.6,122.3,114.4,112.1,111.7,111.2,105.2,102.7,46.8,39.9,25.84.
HRMS ESI(+)m/z calculated for C21H20N4O2Na[M+Na]+383.1484,found
383.1479.
The synthesis of embodiment 9- compounds lxg-P-24
0.36g compound lxg-P-12 and 5mL dry pyridines are added in 25mL round-bottomed flasks, sequentially add 151mgization
Close object 6 and 0.35mL i-Pr2NEt, reaction system are heated to 70 DEG C of reactions overnight under nitrogen protection.It is cooled to room temperature, depressurizes
Rotation removes most of solvent.Dichloromethane is added, is washed with water and is washed with saturated common salt.Organic phase is detached, anhydrous magnesium sulfate is used
Dry, rotary evaporation removes solvent after filtering.Gained crude product obtains compound as white solid with silica gel column chromatogram separating purification
Lxg-P-24, weigh 0.32g, yield 75%.
Fusing point：97-100℃.
1H NMR(400MHz,CDCl3) δ 8.70 (dd, J=4.2,1.7Hz, 1H), 8.20 (s, 1H), 8.07 (dd, J=
8.3,1.6Hz, 1H), 7.38 (dd, J=8.3,4.2Hz, 1H), 7.32 (t, J=7.9Hz, 1H), 7.20 (d, J=2.2Hz,
1H), 7.16-7.12 (m, 1H), 7.09 (d, J=8.7Hz, 1H), 6.83 (dt, J=9.1,4.5Hz, 2H), 6.64 (t, J=
5.9Hz, 1H), 6.57-6.53 (m, 1H), 6.51 (d, J=2.2Hz, 1H), 3.93 (d, J=5.9Hz, 2H), 3.47 (q, J=
6.7Hz, 2H), 3.10 (s, 3H), 3.00 (s, 3H), 2.76 (t, J=6.9Hz, 2H)
13C NMR(100MHz,CDCl3)δ170.4,156.1,147.4,144.8,143.9,138.2,136.1,133.9,
128.5,127.6,127.4,123.4,121.7,116.4,115.9,112.5,111.4,110.9,106.0,48.5,39.3,
36.7,36.5,25.3.
HRMS ESI(+)m/z calculated for C24H26N5O3[M+H]+432.2036,found 432.2032.
The synthesis of embodiment 10- compounds lxg-P-17
0.29g compound lxg-P-12 and 4mL dry pyridines are added in 25mL round-bottomed flasks, sequentially add 136mgization
Close object 7 and 0.28mL i-Pr2NEt, reaction system are heated to 70 DEG C of reactions overnight under nitrogen protection.It is cooled to room temperature, depressurizes
Rotation removes most of solvent.Dichloromethane is added, is washed with water and is washed with saturated common salt.Organic phase is detached, anhydrous magnesium sulfate is used
Dry, rotary evaporation removes solvent after filtering.Gained crude product obtains compound as white solid with silica gel column chromatogram separating purification
Lxg-P-17, weigh 0.26g, yield 72%.
Fusing point：87-90℃.
1H NMR(400MHz,CDCl3) δ 8.71 (dd, J=4.2,1.7Hz, 1H), 8.10 (dd, J=8.3,1.7Hz,
1H), 7.91 (s, 1H), 7.40 (dd, J=8.3,4.2Hz, 1H), 7.33 (t, J=7.9Hz, 1H), 7.21 (brs, 1H), 7.15
(dd, J=13.0,4.8Hz, 2H), 6.86 (d, J=8.6Hz, 1H), 6.81 (t, J=5.8Hz, 1H), 6.63 (t, J=
5.9Hz, 1H), 6.56 (dd, J=5.9,1.6Hz, 2H), 3.96 (d, J=6.0Hz, 2H), 3.57-3.36 (m, 4H), 3.08
(s, 1.5H), 3.0 (s, 1.5H) 2.80 (t, J=6.8Hz, 2H), 1.25 (t, J=6.5Hz, 1.5H), 1.18 (t, J=
6.5Hz,1.5H).
13C NMR(100MHz,CDCl3)δ170.4,155.8,147.4,144.8,143.9,138.2,136.1,133.9,
128.5,127.7,127.4,123.4,121.7,116.4,115.9,112.5,111.4,110.9,106.0,48.5,44.0,
39.3,34.3,33.8,25.3,13.3,12.6.
HRMS ESI(+)m/z calculated for C25H28N5O3[M+H]+446.2192,found 446.2187.
Plan V
The synthetic route of compound lxg-P-02 and lxg-P-20
The synthesis of embodiment 11- compounds lxg-P-2
1.61g compounds 11 and 20mL acetonitriles are added in 50mL round-bottomed flasks, sequentially add 3.4g triphenylphosphines and
4.64g carbon tetrabromide.Reaction system is stirred at room temperature 3 hours, and ethyl acetate and water is added, is extracted with ethyl acetate 2 times, closes
And organic phase washing and saturated common salt are washed.Organic phase is detached, is dried with anhydrous magnesium sulfate, rotary evaporation removes molten after filtering
Agent.Gained crude product obtains compound as white solid 13 with silica gel column chromatogram separating purification, and weigh 2.02g, yield 90%.
0.67g compounds 13,0.43g compounds 1 and 10mL acetone are added in 25mL round-bottomed flasks, is then added
0.83g Anhydrous potassium carbonates.Reaction system is heated to reflux 10 hours, and water quenching is added after being cooled to room temperature and goes out reaction.Use ethyl acetate
Extraction, saturated common salt washing, separation organic phase are dried with anhydrous magnesium sulfate, and rotary evaporation removes solvent after filtering.Gained crude product
Light yellow solid Compound lxg-P-2 is obtained with silica gel column chromatogram separating purification, weigh 0.69g, yield 80%.
Fusing point：107-110℃.
1H NMR(400MHz,CDCl3) δ 8.68 (dd, J=4.2,1.6Hz, 1H), 8.04 (dd, J=8.3,1.5Hz,
1H), 8.03 (s, 1H), 7.66 (d, J=7.8Hz, 1H), 7.38 (t, J=7.9Hz, 1H), 7.34 (dd, J=7.6,5.2Hz,
2H), 7.20 (t, J=7.2Hz, 1H), 7.13 (t, J=7.4Hz, 1H), 7.05 (dd, J=12.0,5.0Hz, 2H), 6.73 (d,
J=7.6Hz, 1H), 6.29 (brs, 1H), 3.66 (t, J=7.2Hz, 2H), 3.23 (t, J=7.2Hz, 2H)
13C NMR(100MHz,CDCl3)δ146.8,144.8,138.3,136.4,136.0,128.7,127.9,127.5,
122.1,122.0,121.4,119.4,118.8,113.8,113.7,111.2,104.7,43.7,25.2.
HRMS ESI(+)m/z calculated for C19H18N3[M+H]+288.1501,found 288.1494.
The synthesis of embodiment 12- compounds lxg-P-20
0.57g compounds 12 and 10mL acetonitriles are added in 25mL round-bottomed flasks, sequentially add 1.02g triphenylphosphines and
1.39g carbon tetrabromide.Reaction system is stirred at room temperature 3 hours, and ethyl acetate and water is added, is extracted with ethyl acetate 2 times, closes
And organic phase washing and saturated common salt are washed.Organic phase is detached, is dried with anhydrous magnesium sulfate, rotary evaporation removes molten after filtering
Agent.Gained crude product obtains brown oil compound 14 with silica gel column chromatogram separating purification, and weigh 0.51g, yield 67%.
0.51g compounds 14,0.29g compounds 1 and 8mL acetone are added in 25mL round-bottomed flasks, 0.55g is then added
Anhydrous potassium carbonate.Reaction system is heated to reflux 10 hours, and water quenching is added after being cooled to room temperature and goes out reaction.It is extracted with ethyl acetate,
Saturated common salt is washed, and separation organic phase is dried with anhydrous magnesium sulfate, and rotary evaporation removes solvent after filtering.Gained crude product silica gel
Column chromatography separating purification obtains pale yellowish oil compound lxg-P-20, and weigh 0.35g, yield 55%.
1H NMR(400MHz,CDCl3) δ 8.67 (dd, J=4.2,1.7Hz, 1H), 8.03 (dd, J=8.3,1.6Hz,
1H), 7.95 (brs, 1H), 7.38 (t, J=7.9Hz, 1H), 7.33 (dd, J=8.3,4.2Hz, 1H), 7.22 (d, J=
8.8Hz, 1H), 7.07 (d, J=2.3Hz, 1H), 7.06-7.01 (m, 2H), 6.85 (dd, J=8.8,2.4Hz, 1H), 6.73
(d, J=7.6Hz, 1H), 6.31 (brs, 1H), 3.81 (s, 3H), 3.64 (t, J=7.1Hz, 2H), 3.19 (t, J=7.1Hz,
2H).
13C NMR(100MHz,CDCl3)δ154.0,146.8,144.8,138.3,136.0,131.5,128.8,127.9,
127.8,122.8,121.4,113.8,113.5,112.3,111.9,104.7,100.6,55.9,43.8,25.2.
HRMS ESI(+)m/z calculated for C20H20N3O[M+H]+318.1606,found 318.1601.
Plan V I
The synthetic route of compound lxg-P-23, lxg-P-27 and lxg-P-28
The synthesis of embodiment 13- compounds lxg-P-23
0.32g compound lxg-P-20 and 5mL dry methylene chlorides are added in 25mL round-bottomed flasks, under nitrogen protection
It is placed in ice bath and stirs, the dichloromethane solution of the Boron tribromide for a concentration of 3M that 1mL is prepared in advance is slowly added dropwise.Reaction system
It is stirred to react 6 hours, sodium bicarbonate aqueous solution is added dropwise and terminates reaction.With THF/EA (1:2) mixed extractant solvent 2 times merges
Organic phase is washed with saturated common salt, and anhydrous magnesium sulfate drying, rotary evaporation removes solvent after filtering.Gained crude product silicagel column color
Spectrum isolates and purifies to obtain yellow solid compound lxg-P-23, and weigh 0.25g, yield 82%.
Fusing point：191-194℃.
1H NMR(400MHz,CD3OD) δ 8.63 (d, J=2.7Hz, 1H), 8.11 (d, J=8.2Hz, 1H), 7.43-7.33
(m, 2H), 7.17 (d, J=8.6Hz, 1H), 7.10-6.95 (m, 3H), 6.78 (d, J=7.6Hz, 1H), 6.68 (d, J=
8.6Hz, 1H), 3.59 (t, J=7.0Hz, 2H), 3.11 (t, J=7.0Hz, 2H)
13C NMR(100MHz,CD3OD)δ149.7,146.5,144.6,138.1,135.9,131.8,128.9,128.1,
127.5,123.0,121.0,113.6,111.4,111.3,111.0,104.9,102.1,43.5,24.7.
HRMS ESI(+)m/z calculated for C19H18N3O[M+H]+304.1450,found 304.1446.
The synthesis of embodiment 14- compounds lxg-P-27
90mg compound lxg-P-23 and 1.8mL dry pyridines are added in 10mL round-bottomed flasks, sequentially add 45mgization
Close object 6 and 0.11mL i-Pr2NEt, reaction system are heated to 70 DEG C of reactions overnight under nitrogen protection.It is cooled to room temperature, depressurizes
Rotation removes most of solvent.Dichloromethane is added, is washed with water and is washed with saturated common salt.Organic phase is detached, anhydrous magnesium sulfate is used
Dry, rotary evaporation removes solvent after filtering.Gained crude product obtains yellow oily compound with silica gel column chromatogram separating purification
Lxg-P-27, weigh 78mg, yield 70%.
1H NMR(400MHz,CDCl3) δ 8.68 (dd, J=4.2,1.7Hz, 1H), 8.28 (s, 1H), 8.04 (dd, J=
8.3,1.6Hz, 1H), 7.38 (d, J=7.9Hz, 1H), 7.35-7.31 (m, 2H), 7.21 (d, J=8.7Hz, 1H), 7.03 (d,
J=7.5Hz, 1H), 6.95 (d, J=2.2Hz, 1H), 6.91 (dd, J=8.7,2.2Hz, 1H), 6.70 (d, J=7.5Hz,
1H), 6.24 (brs, 1H), 3.60 (dd, J=11.3,6.7Hz, 2H), 3.19-3.07 (m, 5H), 3.02 (s, 3H)
13C NMR(100MHz,CDCl3)δ156.1,146.8,144.9,144.8,138.3,136.0,134.1,128.7,
127.9,127.7,123.3,121.3,116.6,113.7,113.6,111.5,111.0,104.8,43.6,36.8,36.5,
25.1.
HRMS ESI(+)m/z calculated for C22H23N4O2[M+H]+375.1821,found 375.1815.
The synthesis of embodiment 15- compounds lxg-P-28
90mg compound lxg-P-23 and 1.8mL dry pyridines are added in 10mL round-bottomed flasks, sequentially add 51mgization
Close object 6 and 0.11mL i-Pr2NEt, reaction system are heated to 70 DEG C of reactions overnight under nitrogen protection.It is cooled to room temperature, depressurizes
Rotation removes most of solvent.Dichloromethane is added, is washed with water and is washed with saturated common salt.Organic phase is detached, anhydrous magnesium sulfate is used
Dry, rotary evaporation removes solvent after filtering.Gained crude product obtains yellow oily compound with silica gel column chromatogram separating purification
Lxg-P-28, weigh 79mg, yield 68%.
1H NMR(400MHz,CDCl3) δ 8.68 (dd, J=4.2,1.6Hz, 1H), 8.28 (s, 1H), 8.04 (dd, J=
8.3,1.6Hz, 1H), 7.41-7.29 (m, 3H), 7.22 (d, J=8.7Hz, 1H), 7.03 (d, J=7.8Hz, 1H), 6.97 (d,
J=2.1Hz, 1H), 6.92 (d, J=8.5Hz, 1H), 6.71 (d, J=7.4Hz, 1H), 6.25 (brs, 1H), 3.61 (d, J=
3.9Hz,2H),3.55–3.37(m,2H),3.20–3.13(m,2H),3.09(s,1.5H),3.01(s,1.5H),1.26(t,J
=6.9Hz, 1.5H), 1.20 (t, J=6.9Hz, 1.5H)
13C NMR(100MHz,CDCl3)δ155.8,146.8,144.9,144.7,138.2,136.0,134.0,128.7,
127.8,127.7,123.3,121.3,113.7,113.6,111.5,111.0,104.7,45.1,44.0,43.6,35.7,
25.1,12.8.
HRMS ESI(+)m/z calculated for C23H25N4O2[M+H]+389.1978,found 389.1973.
16-the compounds of this invention of embodiment inhibits the effect of L-glutamate inducing cytotoxics
Mouse hippocampal neuron cell strain HT22, with the DMEM complete mediums containing 10% fetal calf serum, at 37 DEG C, saturation
Humidity is 5%CO containing volume fraction2, 95% air carbon dioxide incubator in routine culture.Logarithmic growth phase cell,
After being digested with 0.25% pancreatin, complete medium is resuspended, under microscope cell counting board counts and adjust cell concentration for 10 ×
104A/ml, is inoculated with 96 porocyte culture plates, 100 holes μ L/, and overnight incubation keeps cell adherent.Culture medium in 96 orifice plates is inhaled
It walks, untested compound is dissolved with DMSO, is diluted with complete medium, is added in 96 orifice plates, 100 holes μ L/.Preincubate 30min
Afterwards, 2 μ L 100mM L-glutamate are added.Model group is not added with untested compound, is directly added into 2 μ L 100mM L-
glutamate.After being incubated for 24 hours, 10 μ L 5mg/mL MTT are added per hole, is incubated 2h, discards supernatant, add 100 holes μ L/ DMSO,
Oscillation makes product formazan fully dissolve, and each hole absorbance value is measured in microplate reader, measures wavelength 570nm.Using public affairs
Formula compound promotes survival rate (%)=100%* (A of cellUntested compound-AModel group)/(AModel group-ABlank) calculate cell survival rate.Knot
Fruit sees Fig. 1 and Fig. 2.
The interaction of 17-the compounds of this invention of embodiment and common metal ion in organism
The interaction of compound and metal ion (copper ion, zinc ion) by ultraviolet-visible spectrophotometer into
Row measures research.Experimental implementation：Untested compound mother liquor is placed in methanol dilution in 1cm cuvettes, ultraviolet-visible is carried out
Absorption spectromtry.Then metal ion solution (the high concentration deionized water of different proportion is gradually added dropwise into cuvette solution
Solution is added dropwise volume and is unlikely to influence ligand compound concentration in cuvette), measure different metal ions/change after appropriate stirring
UV-visible absorption spectrum under object (M/L) ratio of conjunction.As a result see Fig. 3 and Fig. 4.
18-the compounds of this invention of embodiment is to acetylcholinesterase (AChE) activity suppression
Ellman(Ellman,G.L.；Et al.Biochem.Pharmacol.1961.) report colorimetric method commented at 37 DEG C
Estimate AChE inhibitory activity.Test solution is made of the following terms：0.1M phosphate buffers pH8.0,0.5mM 5,5 '-two is thio
Bis- (2- nitrobenzoic acids) (DTNB, Ellman ' s reagents), 0.03 unit AChE (Sigma derives from electric eel) and 0.5mM second
Substrate of the acyl thiocholine iodide as enzymatic reaction.Compound to be detected is added and is measured in solution and with enzyme at 37 DEG C
After twenty minutes, substrate is added in lower precincubation.It is relatively more anti-with absorbance change of the spectrophotometer measurement at 412nm in 5 minutes
Rate is answered, the percentage for causing reaction rate to inhibit due to the presence of test compound is calculated.With at least triplicate measurement
Value, which calculates to divide, answers rate, calculates relative to the control without compound, percentage caused by the presence due to test compound presses down
System.Measure the compound concentration (IC for making AChE enzyme's reaction speedings reduce by 50%50).By IC50It is defined as after compound is added,
The concentration of this kind of compound when reducing by 50% relative to enzymatic activity under no inhibitor.It the results are shown in Table 1.
The activity of 1. compound acetylcholine esterase inhibition (AChE) of table
19-the compounds of this invention of embodiment inhibits butyrylcholine esterase (BuChE)
BuChE inhibitory activity is assessed at 37 DEG C by the Ellman colorimetric methods reported.Solution is measured to be made of the following terms：
0.05 unit derives from the BuChE of human serum, 0.1M phosphate buffers (pH8.0), 5,5 '-two thiobis (2- nitre of 0.3mM
Yl benzoic acid) substrate of (DTNB, Ellman ' s reagents) and 0.5mM Butyryl thiocholines iodide as enzymatic reaction.It will wait for
The compound of detection is added in measurement solution and after twenty minutes, substrate is added in precincubation at 37 DEG C with enzyme.Use spectrophotometer
The absorbance change at 412nm in 5 minutes is measured, reaction rate is compared, is calculated since the presence of test compound causes instead
The percentage for answering rate to inhibit.It is calculated to divide at least triplicate measured value and answers rate, calculated relative to without compound
Control, percentage caused by the presence due to test compound inhibit.Measure the change for making AChE enzyme's reaction speedings reduce by 50%
Close object concentration (IC50).By IC50It is defined as after compound is added, this kind when reducing by 50% relative to enzymatic activity under no inhibitor
The concentration of compound.It the results are shown in Table 2.
2. compound of table inhibits the activity of butyrylcholine esterase (BuChE)
20-the compounds of this invention of embodiment inhibits A β auto-induction aggtegation
Take the A β that hexafluoroisopropanol (HFIP) makes to be lyophilized after singulation(1-40)It is dissolved in DMSO with untested compound, is used
0.215M PBS (pH8.0) dilute.Test solution is made of the following terms：10μL Aβ(1-40)Solution and 10 μ L untested compounds
(final concentration of 20 μM) or 10 μ L 0.215M PBS (pH 8.0).After 37 DEG C are incubated for 24 hours, 180 μ L, 1.5 μM of thioflavin Ts are added
Solution, mixing scanned ((λ using 300 seconds fluorescence intensitiesexc=446nm；λem=490nm).Using formula inhibiting rate=100-
(IFi/IF0* 100] inhibiting rate that untested compound assembles A β auto-inductions is calculated.Wherein IF0And IFiRespectively A β groups, A β+
The measured value of untested compound group.It the results are shown in Table 3.
Table 3.Th-T fluorescence spectrometry compounds inhibit the formation of amyloid fiber A β
The in vitro blood-brain barrier transmitance of 21-the compounds of this invention of embodiment
1) it takes 4 μ L 2% (PBL) solution to be added in the hydrophobic membrane of 96 orifice plates of MAIPs4550, pays attention to moving during being added dropwise
Liquid pipette tips do not contact film surface to prevent destroying membrane structure；
2) rapid (in 10min) quantitatively draws 200 μ L analyte sample fluids (0.1mg/ml) and is added on the film in 96 orifice plates
Fang Zuowei be administered pond, the film other side be added 200 μ L PBS (pH=7.4) be acceptance pool, pays attention to holding acceptable solution and film it is abundant
Contact；
3) after the static 120min of room temperature, administration pond is carefully removed, with compound absorbance in UV spectrometers test acceptance pool
It is worth (250-500nm)；
4) 100 μ L analyte sample fluids are drawn to mix well with 100 μ L PBS, as Theoretical Equilibrium solution, tests its extinction
Angle value (250-500nm) needs to use acceptor board tests；
5) logP is calculated according to formulaeValue：
Vd is the volume of acceptance pool in formula, and Va is the volume of acceptance pool, and A is membrane area, and t is time of penetration,
[drug]acceptorIt is the absorbance of acceptance pool, [drug]equilibriumIt is Theoretical Equilibrium absorbance.
Note：Pe×10-6cm s-1Value is more than 5.3, then compound can penetrate blood-brain barrier, and being defined as less than 2.4 cannot
Through blood-brain barrier.4 are the results are shown in Table, is indicated with means standard deviation.
4. external PAMPA-BBB methods of table detect blood brain barrier transmissivity
Claims (5)
1. formula（Ⅰ）Compound or its pharmaceutically acceptable salt,
Formula（Ⅰ）
Wherein,
R is selected from OH, OCH3、OCON(CH3)2With OCON (CH3)CH2CH3；
X is selected from NH, NHCONH and NHCOCH2NH。
2. a kind of pharmaceutical composition, it includes any compound described in claim 1 or its pharmaceutically acceptable salts, and
Pharmaceutically acceptable carrier.
3. any compound described in claim 1 or its pharmaceutically acceptable salt are in the disease for preparing treatment neuronal damage
Drug in application.
4. application according to claim 3, wherein the disease of the neuronal damage is Alzheimer's disease or the cerebrovascular
It is dull-witted.
5. a kind of Neuroprotective Agents, it includes any compound described in claim 1 or its pharmaceutically acceptable salts.
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