CN109665988A - The biphenyl dione compounds and application thereof that bipiperidine replaces - Google Patents
The biphenyl dione compounds and application thereof that bipiperidine replaces Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
The invention discloses novel bipiperidine replace biphenyl dione compounds under safe dose can it is dose-dependent inhibit cell histamine H 3 receptor activity, nerve cell can be protected as histamine H 3R antagonist；Mitigate nerve cell anoxia-induced apoptosis；Adjust neuroinflamation.Results of animal proves: compound I toxicity is lower, can pass through blood-brain barrier, can obviously improve vascular dementia caused by Bilateral Cervical always ligatures, can enhance learning and memory function, is expected to become the drug for preventing and/or treating the relevant disease of learning memory disorder.
Description
Technical field
The present invention relates to the bipiperidines with histamine H 3 receptor antagonistic effect, neurocyte protection effect, anti-inflammatory effect to take
The biphenyl dione compounds and its pharmaceutically acceptable salt and the compound and its pharmaceutically acceptable salt in generation are being treated
Learning memory disorder and senile dementia, vascular dementia, Parkinson's disease, the application in Huntington's disease.Belong to medical science neck
Domain.
Background technique
Histamine H 3 receptor (Histamine 3receptor, H3R) belongs to GPCR a member, can be mediated by G α i/o extensive
Signal transduction path.H3R is mainly expressed in cerebral cortex, hippocampus, amygdaloid nucleus, these are close with memory cognitive ability for corpus straitum etc.
Relevant region.In addition, H3R also regulates and controls the release of various neurotransmitters, so that it is more to adjust learning and memory, awakening and sleep etc.
The neural sexual behaviour of kind.So far, using H3R as target spot, the new drug of research and development treatment central nervous system disease becomes research hotspot.
In the recent period, a large amount of preclinical studies and clinical test show: H3 receptor antagonist has certain curative effect to AD disease.Group
The release of various neurotransmitters can be improved in amine H3 receptor antagonist, and the receptor activation after causing nerve synapse, this may be it
The basis for treating central nervous system cognitive disorder.In preclinical test, H3R antagonist can be improved by multiple confirmation dynamic
Ach in object cerebral cortex and hippocampus is horizontal and improves long-term memory, short-term memory and spatial memory capacity.In addition, grinding
Study carefully the transcriptional activity for showing that adenosine cyclophosphate response element binding protein (CREB) can be improved in H3R antagonist (ABT 239), and
And inhibit the Hyperphosphorylationof of Protein tau.These conclusions are in APP/A β transgenosis and APP/tau transgenic mice animal model
All confirmed.In conjunction with the Clinical symptoms of AD cognitive behavior dysfunction and the pathogenesis feature of progressive, using H3R as target
Point finds the new chemical entity that not only can effectively improve symptom simultaneously but also can delay pathogenesis, is research and development prevention and treatment AD new drug
One of feasible way.
Oxidativestress damage also can not be ignored in AD disease process, and the antioxygenic property for investigating compound is also explanationization
The important indicator of the anti-AD of object is closed, the inoxidizability that many H3R antagonists are shown during treating AD can help to the state of an illness
Improve；The more commonly used vehicles cells of experiment in vitro are SY5Y, the nerve such as APPsw-SY5Y, BV2 or spongiocyte, anoxia-induced apoptosis
Important function has been played in the pathogenesis of AD.The APPsw-SY5Y cell hypoxia damage model of glutamate induction is evaluationization
Close the common model that object protects neural cell hypoxia damage.Using APPsw-SY5Y cell as research object, examined by MTT colorimetric method
The protective effect of the sample cellular damage caused by glutamic acid in vitro.
In addition, neuroinflamation also plays important role in the occurrence and development process of AD.Investigate the anti-nerve of compound
The common counter of inflammation includes IL-6, TNF-α.The generation of neuroinflamation is mainly the activation of microglia, therefore is made using BV2
Reactive compound is investigated for vehicles cells, and inflammatory factor IL-6, TNF-α are secreted to the BV2 microglia after LPS stimulation activation
Influence.
Cranial vascular disease can cause multiple types and different degrees of cognitive disorder, currently used for studying blood vessel inquiry learning
The Global Ischemia Model of memory disorders mainly has two blood vessel methods, four blood vessel methods etc..Stable disease can be also obtained using two blood vessel methods
Reason changes, and easy to operate, and success rate is high.Make bilateral common carotid arteries using two blood vessel legal systems and permanently ligatures (2VO) model
Rat, and the rat model Spatial memory feature is observed by Morris water maze.
Had found in author's early-stage study of the invention biphenyl dione compounds that a novel bipiperidine replaces and its
Pharmaceutically acceptable salt has both histamine H 3 receptor antagonistic activity.
Summary of the invention
We have found that the compound of a kind of unique structure, has H3 receptor antagonist activity.Simultaneously have both protection nerve cell,
Improve the effect of oxidative damage.Neuroinflamation can also be adjusted, improve the functions such as learning memory disorder.
The present invention relates to the compound of Formulas I and its officinal salts, they are for cognitive illnesses and/or senile dementia, blood vessel
Property dementia, Parkinson's disease have potential purposes in Huntington's disease.
Wherein, compound I can with organic acid or inorganic acids, organic acid be selected from maleic acid, methanesulfonic acid, caffeic acid, Ah
Wei's acid or gallic acid, inorganic acid are selected from hydrochloric acid or sulfuric acid.
Compound I proposed by the invention can be prepared by the following method to obtain:
Synthetic route:
Using biphenyl as starting material, under the action of carbon disulfide and alchlor, intermediate 2 is generated with chlorobutanoylchloride,
Again under the action of carbon disulfide and alchlor with chlorpromazine chloride generate intermediate 3, then 3 and piperidines in Anhydrous potassium carbonate and third
It is reacted in ketone, obtains compound I, compound I, at salt, obtains compound I hydrochloride in ethanol solution hydrochloride.Compound I can
With inorganic acid or organic acid at salt.
Using amino is contained in the resulting compound I molecule of the above method, which, can be with any suitable acid in alkalinity
Its pharmaceutically acceptable salt is made by pharmaceutically conventional salifying method.
Inventor has found the compound of the present invention I and pharmaceutically acceptable salt H3 receptor antagonist activity with higher.
Therefore, on the other hand the compound of the present invention I and pharmaceutically acceptable salt are related to treatment, improve and H3 receptor antagonist activity phase
The method of the disease of pass.The method includes the Formulas I of therapeutically effective amount or pharmaceutically acceptable is given to patient in need for the treatment of
Salt compound or its pharmaceutical composition.
Further the results showed that the compound of the present invention I or pharmaceutically acceptable salt have antioxygenic property,
Help to prevent and treat the oxidativestress damage in dull-witted process.Due to having more serious neuron in AD or other degenerative disease processes
It loses or degree of impairment, the present invention demonstrates influence of the compound I to nerve cell in cellular level, find compound I or medicine
Acceptable salt not will cause neurotrosis under effective concentration on, and preferable acetylcholine is shown on the cell
Esterase active depression effect.Pass through Cu2+Induce APPsw-SY5Y cell generate A β metabolic disorder, analog neuron cell it is hereditary because
Element and the pathological state under environmental factor collective effect, find compound I or pharmaceutically acceptable salt to Cu2+Damage
APPsw-SY5Y cell has significant protective effect, more determines the anti-AD activity of compound I or pharmaceutically acceptable salt.
In addition, using cellular level simulate neuroinflamation model, by LPS stimulate BV2 Activated Microglia find compound I or
Pharmaceutically acceptable salt can inhibit BV2 microglia secretion IL-6, TNF-α inflammatory factor after activation, mitigate nerve and move back
Inflammation in row disease process.
Anti- dementia effect evaluation in vivo, selects the Model of Dementia of hyoscine induction.M cholinergic receptor-blocking agent hyoscine
(scopolamine, SCOP) is remarkably decreased intracerebral Ach level, can inhibit central cholinergic system access function, simulate AD's
Animal model, stablize induction animal learning memory disorder, according to training period and test the phase latent time and errors number come
Compound I or pharmaceutically acceptable salt are investigated to the improvement result of the pathological model, as a result, it has been found that, compound I or pharmaceutically
Acceptable salt relative model group can significantly improve the latent time of test phase and reduce training period and test the errors number of phase,
This shows that compound I or pharmaceutically acceptable salt have played corresponding anti-oxidant, anti-inflammatory as multi-target effect molecule, mentioned
High intracerebral acetyl choline content promotes the transmitting of cynapse signal, improves the effect of learning and memory
The invention shows compound I to have good histamine H 3 receptor antagonism, and the protection of nerve cell anoxia-induced apoptosis is made
With neuroinflamation adjustment effect can be effectively improved learning and memory function in whole animal level.Compound I can pharmaceutically connect
The not disclosed report of the salt received.
Detailed description of the invention
Fig. 1, compound I hydrochloride inhibit the amount effect curve of H3R
The influence of Fig. 2, compound I hydrochloride to APPsw-SY5Y cell viability
Fig. 3, compound I hydrochloride are to Cu2+The influence of the APPsw-SY5Y cellular damage model cell vigor of induction
Fig. 4, compound I hydrochloride are to the shadow of the APPsw-SY5Y cell hypoxia damage model cell viability of glutamate induction
It rings
The influence of Fig. 5, compound I hydrochloride to activation primary glia IL-6 secretion
The influence of Fig. 6, compound I hydrochloride to activation primary glia TNF-α secretion
Fig. 7 .1, water maze 1-5 days rats find the latent time of platform
The 6th day rat of Fig. 7 .2, water maze finds the number of target quadrant platform and in target quadrant residence time (###
Compared with normal group, p < 0.005；## is compared with normal group, p < 0.0 1；* is compared with model group, p < 0.01；* with model group ratio
Compared with p < 0.05)
The MS spectrum of Fig. 8, compound I hydrochloride
The HNMR spectrum of Fig. 9, compound I hydrochloride
Specific embodiment
The preparation of embodiment 1, compound I hydrochloride:
It in 250mL there-necked flask, is added biphenyl (3g, 19.5mmol), alchlor (3.9g, 29.2mmol) and curing
Carbon (80mL).Then 3- chlorpromazine chloride (3.7g, 29.2mmol) slowly is added dropwise.Drop finishes, and 40-50 DEG C are reacted 4 hours.Wait react
System is cooled to room temperature, and reaction system is poured into ice water (500mL), and methylene chloride extracts organic phase, washing, anhydrous sodium sulfate
It is 12 hours dry.Organic phase is concentrated in filtering, and residue is purified through silica gel chromatographic column (petrol ether/ethyl acetate=3:1), collects
Required component, is concentrated to give, 4.42g intermediate 2, yield 93.0%.Same operation method is added intermediate in 250mL there-necked flask
2 (2.4g, 10mmol), alchlor (3.9g, 29.2mmol) and carbon disulfide (80mL).Then 4- neoprene acyl is slowly added dropwise
Chlorine (4.1g, 29.2mmol).Drop finishes, and back flow reaction 2 hours.After reaction system is cooled to room temperature, reaction system is poured into ice
In water (500mL), there is solid matter precipitation.It filters, after ice ethanol washing, 50 DEG C are dried in vacuo 24 hours, obtain intermediate 3, white
Color solid, 3.22g, yield: 92.6%.
It in 100mL single port bottle, is added piperidines (0.77g, 9.0mmol), anhydrous K 2CO3 (0.83g, 6.0mmol) and second
Nitrile (40ml) stirs 15 minutes at 50 DEG C.It adds intermediate 3 (1.0g, 3.0mmol), 50 DEG C are reacted 1 hour.It filters, filtrate
Concentration, obtains faint yellow solid, purifies through silica gel chromatographic column (DCM/MeOH=100:1), obtains compound 4, white solid, 0.90g,
Yield: 67.3%.
Compound I (4.47g, 10mmol) is dissolved in the ethanol solution of hydrogen chloride, reaction 2h is stirred at room temperature, removes under reduced pressure
Solvent, residue obtain white crystalline solid compound I hydrochloride 3.89g, yield: 75% through ethyl alcohol recrystallization.
1H-NMR (400MHz, CDCl3) δ 10.64 (s, 1H), 10.44 (s, 1H), 8.09-8.02 (m, 4H), 7.94-
7.98 (m, 4H), 3.74 (t, J=7.4Hz, 2H), 3.51 (m, 2H), 3.42 (m, 4H), 3.25 (t, J=7.4Hz, 2H), 3.07
(m, 2H), 2.88 (m, 4H), 2.07 (m, 2H), 1.80 (m, 8H), 1.70 (m, 2H), 1.49 (m, 2H)；ESI-MS (m/z):
447.51[M+H]+。
Embodiment 2, compound I hydrochloride are in vitro to the inhibitory activity of histamine H 3R
Method: this experiment select through transfection H3R- transcription factor (Gal4-VP16) fusion protein, Beta-arrestin2,
The H3-bla-U2OS cell of Beta- lactams hydrolase.Screening principle: it after agonist ligand is in conjunction with H3 histamine receptor, raises
Collect Beta-arrestin2, TEV protease hydrolyzes H3 histamine receptor and Gal4-VP16 transcription factor fusion albumen therewith, makes
Gal4-VP16 transcription factor falls off into core, expresses Beta-lactamase (bla) reporter gene.Substrate is then added
LiveBLAzerTM-FRET B/G Substrate (CCF2-AM or CCF4-AM) is incubated for.This substrate includes cephalosporin nuclear
With umbelliferone, FRET phenomenon occurs for this two parts, at this time its green optical signal for having a 520nm, Beta-
After lactamase hydrolyzes beta-lactam ring, green optical signal disappears, and becomes the blue light signals under a 450nm.According to blue light and green
The signal of light judges that screening sample and the combination of H3, thiazole amide are positive control, calculates IC50.In triplicate, mean value is calculated
And SD value.
As a result: compound I hydrochloride has inhibiting effect to H3R, to the IC of H3R50In 0.09381 μm of ol/L, it is shown in Table 1, is changed
The amount effect curve that object I hydrochloride inhibits H3R is closed, sees Fig. 1.
Table 1, compound I hydrochloride inhibit the IC of H3R50(mean±SD)
Embodiment 3, compound I hydrochloride Cu anti-to nerve cell2+The A beta-aggregation Damage Evaluation of simulation
(1) to the cellulotoxic effect of wild type APPsw transgenosis SY5Y (APPsw-SY5Y) nerve cell
Method: wild type APPsw transgenosis SY5Y (APPsw-SY5Y) cell is to contain 10% fetal calf serum, 400ug/
The DMEM/F12 culture medium culture of mlG418, when cell is in logarithmic growth phase, by 5*104The density in the hole a/ml, 100ul/
It is inoculated in 96 well culture plates.It is changed for 24 hours with serum-free DMEM/F12 culture medium culture, is changed after 12h with various concentration compound I afterwards
The serum-free DMEM/F12 culture medium of (0.1-10 μm of ol/L), donepezil and Rivastigmine (final concentration of 10 μm of ol/L) processing
Identical, rear MTS method measures cell viability for 24 hours, and DTNB method detects AChE activity in cell conditioned medium.
As a result: compared with normal group, compound I hydrochloride is within the scope of administration concentration to wild type APPsw transgenosis
The vigor of SY5Y (APPsw-SY5Y) cell does not make significant difference, and is shown in Table 2 and Fig. 2.
The influence (mean ± SD) of table 2, compound I hydrochloride to APP-sw SY5Y cell viability
#Compared with normal group, p < 0.05
(2) Effect study of the compound I hydrochloride on AD cell model
1) method: APPsw-SY5Y cell is trained with the DMEM/F12 culture medium containing 10% fetal calf serum, 400ug/ml G418
It supports, when cell is in logarithmic growth phase, by 5*104The density in the hole a/ml, 100ul/ is inoculated in 96 well culture plates.After for 24 hours
It changes and continues to cultivate 12h with serum-free DMEM/F12 culture medium, the compound I hydrochloride and 10 μ of final concentration of 10 μm of ol/L is added
After the donepezil of mol/L, Rivastigmine preincubate 2h, the Cu of final concentration of 250 μm of ol/L is added2+Handle cell, for 24 hours after with
MTS method measures cell viability, checks Cu2+In the A β segment Aggregation Model for stimulating APPsw-SY5Y to simulate, compound I hydrochloride pair
The improvement effect of the stimulation
As a result: compared with normal group, Cu2+After processing for 24 hours, model group cell survival rate significantly reduces (p < 0.005).With mould
Type group is compared, and compound I hydrochloride group cell survival rate is improved, the cell of 10 μm of ol/L compound I hydrochloride administration groups
Survival rate is higher than positive control donepezil, Rivastigmine group.It is shown in Table 3 and Fig. 3.
Table 3, compound I hydrochloride are to Cu2+Influence (the mean of the APPsw-SY5Y cellular damage model cell vigor of induction
±SD)
###P < 0.005 compared with normal group；**P < 0.01 compared with model group
Embodiment 4, compound I hydrochloride evaluate the anoxia-induced apoptosis that nerve cell anti-glutamate is simulated
Method: APPsw-SY5Y cell is trained with the DMEM/F12 culture medium containing 10% fetal calf serum, 400ug/ml G418
It supports, when cell is in logarithmic growth phase, by 5*104The density in the hole a/ml, 100ul/ is inoculated in 96 well culture plates.After for 24 hours
It changes and continues to cultivate 12h with serum-free DMEM/F12 culture medium, be added the compound I's and 10 μm of ol/L of final concentration of 10 μm of ol/L
After donepezil, Rivastigmine preincubate 2h, be added final concentration of 40mmol/L glutamic acid processing cell, for 24 hours after with MTS method
Cell viability is measured, is checked in the hypoxia model of glutamic acid stimulation APPsw-SY5Y simulation, compound I hydrochloride is to the thorn
Sharp improvement effect.
As a result: compared with normal group, after glutamic acid processing for 24 hours, model group cell survival rate significantly reduces (p < 0.005).
Compared with model group, compound I hydrochloride group cell survival rate is improved, 10 μm of ol/L compound I hydrochloride administration groups
Cell survival rate is higher than positive control donepezil, Rivastigmine group.It is shown in Table 4 and Fig. 4.
The influence (mean ± SD) of table 4, compound I hydrochloride to the APPsw-SY5Y cell hypoxia damage of glutamate induction
###P < 0.005 compared with normal group；**P < 0.01 compared with model group
Embodiment 5, compound I hydrochloride are to the Effect study of neuroinflamation
Method: the compound I hydrochloride of final concentration of 10 μm of ol/L is incubated for jointly with the primary glia of new green tire mouse
After 2h, in addition to blank control group, final concentration of 1 μ g/ml LPS is added in model group and administration group, is continued to be incubated for and be collected afterwards for 24 hours
Cell conditioned medium, Elisa method measure IL-6, TNF-α content in cell supernatant.
As a result: compared with normal group, LPS stimulate rat primary spongiocyte for 24 hours after, IL- in model group cell supernatant
6, TNF-α content significantly increases (p < 0.005).Compound I hydrochloride can reduce the content of IL-6 in cell conditioned medium, TNF-α, give
When dose is 10 μm of ol/L, IL-6, TNF-α content significantly reduce (p < 0.01) compared with model group in cell conditioned medium.It is shown in Table 5 Hes
Fig. 5,6.
The influence (mean ± SD) of table 5, compound I hydrochloride to primary activation microglia born of the same parents IL-6, TNF-α secretion
###P < 0.005 compared with normal group,**P < 0.01 compared with model group,***P < 0.005 compared with model group
The research of embodiment 6, compound I hydrochloride on AD animal model
Method: always ligaturing the study of (2VO) simulated blood vessel dementia construction rat, dysmnesia model with rats with bilateral neck,
Using butylbenzene peptide as positive control medicine, the effect of compound I hydrochloride is observed.Learning and memory function is with Morris water maze
Behavioral indexes evaluation, compares the difference between Normal group, model group and medicine group.
1. experimental animal and grouping
Male SD rat, weight 330-350g, in light and shade alternating (12h:12h) cleaning grade animal house, room temperature is protected for raising
23~25 DEG C are held, ad lib drinking-water.It is randomly divided into sham-operation group (sham group) and chronic cerebral ischemia group (2VO
group).Chronic cerebral ischemia group ligatures bilateral common carotid arteries, and sham-operation group only separating blood vessel does not ligature arteria carotis communis.Postoperative 3rd
Week start Morris water maze laboratory, rat is screened, determines whether animal realizes cerebral ischemia according to school grade, arranges
Except the unconspicuous rat of ischemic.The significant rat of ischemic is randomly divided into 4 groups according to operating time and weight.It is respectively as follows: chemical combination
Object I hydrochloride group (30mg/kg), compound I hydrochloride group (60mg/kg), damage control group (2VO group) and positive drug fourth
Benzene peptide (100mg/kg) group.The daily gastric infusion of administration group animal is primary, until the experiment of Morris determined with Morris water terminates；Control
Group and sham-operation group give isometric solvent, and solvent for use is water.Morris water maze laboratory is carried out after administration 28 days.
2. ability of learning and memory detects: starting the test of Morris water maze after administration 28 days.Every group of rat is continuously instructed
Practice 5 days, stomach-filling is uninterrupted, the 1st day it is trained when, selective calling platform opposite and adjacent quadrants are location into the pool, and rat is placed in quadrant side
Head enters water towards pool wall at 1/2 radian of edge, records required time (i.e. escape latency, escape that rat in 60s finds platform
latency).The person that do not find platform through 60s is led to platform, places 15s, guide its study, escape latency is recorded as
60s.Repetition in 2-5 days as above operates, using each group rat Morris water maze test in the 1-5 days escape latency as
Measure the index of its Spatial learning ability.Experiment takes rat brain to do pathological section and Electronic Speculum observation on the day of terminating.
3. statistical method
Each group numerical value is indicated with mean ± SEM, and the difference of dependence test index between each group is compared with SPSS statistical software；
Statistical analysis method uses one way ANOVA, and further analysis uses HSD or LSD method, detects level P=0.05, then
It is mapped with Graphpad software.
As a result: compound I hydrochloride can shorten the incubation period of 2VO rat water maze experiment, and latent time is shown in Table 6, figure
7.1；The number for increasing spanning platform position, is shown in Table 7, Fig. 7 .2；Extend in the residence time of target quadrant, is shown in Table 8, figure
7.2.Illustrate that compound I hydrochloride can improve the learning memory disorder of 2VO rat.
Table 6, compound I hydrochloride in first five day learning and memory of water maze laboratory to find platform incubation period to study remember
The influence (mean ± SD) recalled
Table 7, compound I hydrochloride pass through the number (mean ± SD) of target platform on the 6th day in water maze laboratory
P < 0.01 compared with model group ## p < 0.01 compared with normal group, * p < 0.05 compared with model group, * *
Table 8, compound I hydrochloride in water maze laboratory the 6th day at target quadrant residence time (mean ± SD)
#P < 0.05 compared with normal group,*P < 0.05 compared with model group.
Claims (10)
1. one kind is such as formula (I) compound represented and its pharmaceutically acceptable salt:
2. compound according to claim 1 and its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt
Selected from compound I and salt formed by organic acid or inorganic acid, organic acid is selected from maleic acid, methanesulfonic acid, caffeic acid, ferulic acid or does not have
Gallate-based, inorganic acid are selected from hydrochloric acid or sulfuric acid.
3. -2 described in any item compounds and its pharmaceutically acceptable salt according to claim 1, described pharmaceutically acceptable
Salt be selected from:
4. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition includes claim 1-3 described in any itemization
Close object and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or excipient.
5. the described in any item compounds of claim 1-3 and its pharmaceutically acceptable salt or drug as claimed in claim 4
Composition prevents and/or treats the application in the disease medicament characterized by learning memory disorder in preparation.
6. application according to claim 5, which is characterized in that the disease characterized by learning memory disorder includes old age
Dementia, vascular dementia, Huntington's disease.
7. the described in any item compounds of claim 1-3 and its pharmaceutically acceptable salt or drug as claimed in claim 4
Composition is preparing the application in histamine H 3 receptor antagonists drug.
8. the described in any item compounds of claim 1-3 and its pharmaceutically acceptable salt or drug as claimed in claim 4
Application of the composition in preparation protection nerve cell, improvement anoxia-induced apoptosis drug.
9. the described in any item compounds of claim 1-3 and its pharmaceutically acceptable salt or drug as claimed in claim 4
Composition adjusts the application in neuroinflamation drug in preparation.
10. the described in any item compounds of claim 1-3 and its pharmaceutically acceptable salt or drug as claimed in claim 4
Composition improves the application in learning and memory function drug in preparation.
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