CN102143749A

CN102143749A - Methods and systems for evaluating memory agents

Info

Publication number: CN102143749A
Application number: CN2009801347276A
Authority: CN
Inventors: T·图利; L·达瓦契
Original assignee: Dart Neuroscience LLC
Current assignee: Dart Neuroscience LLC
Priority date: 2008-07-18
Filing date: 2009-07-17
Publication date: 2011-08-03
Also published as: WO2010009453A1; KR20110049801A; SG195572A1; EP2313098A4; IL210696A; EP2313098A1; JP5789511B2; CA2730940A1; AU2009270697A1; JP2011528667A; IL210696A0; MX2011000652A; BRPI0916228A2

Abstract

The present invention provides methods and systems for identifying, evaluating, and testing various compounds as memory agents and regimens as training protocols related to memory enhancement and/or impairment. Such methods and systems may test any compounds or protocols, including the memory agents and training protocols described herein. The methods can comprise combining training protocols with the general administration of memory agents. In some embodiments, the present invention may involve identifying, selecting, testing, evaluating or assessing a compound as a drug candidate for a memory agent, for example, as one effective for enhancing or impairing memory.

Description

The method and system of assess memory medicament

The cross reference of related application

The application requires in the priority of the U.S. Provisional Application 61/081,845 of submission on July 18th, 2008 according to 35U.S.C. § 119, and its full content integral body is quoted adding this paper.

Invention field

The present invention relates to assess, differentiate or estimate method and system to the effectiveness of the memory medicament of individual administration and/or training program.

Background of invention

Memory is to passing empirical memory.People can write down fresh information, with its storage and one day it is being recalled subsequently.Memory true and incident is represented conscious, the outer memory form that shows (explicit).People also can remember the technical ability that the property realized is lower, for example by bike, play an instrument or about rewarding or punish the association of simple clue, the more hidden form of this representative memory.As if for both of these case, the process that memory forms experiences three general stages.Obtain (study) and comprise new empirical initial perception.This newly obtains empirical impermanent memory and seems of short duration and unstable then.Under appropriate condition, often need to repeat and have a rest, empirical then impermanent memory can " consolidation " be more persistent longterm memory.

The daily example of this memory process comprises the use telephone number.When people found new telephone number for the first time, they to reciting several times to learn its (study) themselves.If do not divert one's attention, then people can successfully dial this number subsequently in several seconds to a few minutes.On the other hand, interrupt almost always causing people to forget this number.The a few minutes after the dialing numbers in several hours, people will no longer remember this number (impermanent memory) probably.Yet, if this telephone number corresponding to friend's new cell-phone, people may find that they can repeat to dial it about every day so.Through enough repetitions, people finally can remember this telephone number by longterm memory.

Human brain is evolved and is its internal and external environment of induction, also changes replying of it adaptively with the cause effect relation between the perceptible stimulus.In order to finish this fabulous task, the growth of the cellular network of self-regulation network commander's more than one hundred billion neuron (having 100,000,000,000,000 connections therebetween) of 40,000 genes.Such complexity is surprising.Yet the neurobiologist has begun partly to understand human brain and how to work by studying brain function in other animal.

New experience obviously can be very complicated, but when in laboratory, it being reduced to the simple controllable research of " association " between two stimulations (for example title study (Pavlovian learning)), can from insecticide to mammiferous multiple different animals, study the process that memory forms through identifying.These zooscopies have helped us that memory is formed the existing understanding how to carry out, have disclosed the neuroanatomy and the biochemical aspect of brain.It should be noted that these researchs confirm, even the neuroanatomy between species is slightly different, but many basic biochemistry that memory forms and behavior phenomenology are kept in the whole animal kingdom by evolution.

These zooscopies show that memory forms generally and undertaken by the temporary transient stages different on several functions.Obtaining (LRN) needs repetition usually, and is considered to recover the maximum participation of the so empirical potential neural circuit of normal recordings.In case learn, early memory often disappears fast, and to diverting one's attention and benumbing the destruction sensitivity that (anesthesia) cause and (promptly benumb sensitivity memory (anesthesia-sensitive memory); ASM).The genetic dissection of ASM in the fruit bat shows that ASM can further be decomposed into impermanent memory (STM) and intermediate memory (ITM).

By comparison, long-time memory (long-lasting memory) (is anti-paralysis memory (anesthesia-resistant memory) to the destruction tolerance that becomes; ARM) and last very long.Importantly, these zooscopies have shown that generally protein synthesis is essential for the appearance of longterm memory (LTM).Again, fruit bat research discloses: (i) LTM but not ARM needs protein synthesis, and (ii) ARM and LTM can be memory stage independently on several functions by genetic dissection.

Zooscopy also has been disclosed in the basic wiring diagram (wiring diagram) of the brain that occurs in the growth course.Yet it is natural and non-functional that the major part in the neuron connects (synapse).Need experience subsequently to connect, finely tune the function in various loops thus with these synapses of refine (refine).Also recombinate in adult's brain in the synapse of continuously active dependency.New empirical study causes neural activity, and it finally produces the synapse reorganization in the neuron of associated loop.These are distributed in neural circuit synapse everywhere and change the material base that (synaptic plasticity) is considered to longterm memory.

Experience dependency in the neural activity changes and cause complicated biochemical reaction in neuron.This biochemical final effect is to produce short-term (of short duration) and long-term (lastingly) synaptic plasticity.Proceed basic research and become the cytobiology on this synaptic plasticity basis to differentiate increasing signal pathway and other.First is found that the cAMP approach in the middle of these approach, its in the functional status of numerous protein with born of the same parents outer neurotransmitter to discharge transduction be the enzyme reaction cascade that changes in the born of the same parents.As if neurotransmitter, their corresponding receptor and Cytoplasm PKA regulate short-term plasticity, produce the activation that long-term plasticity then needs transcription factor CREB (cAMP response element binding protein).

In the research of all species up to now, the CREB gene is expressed with two kinds of opposite forms: the genetic transcription of the activator of catchment or repressor, CRE-mediation.The pivotal role of CREB in longterm memory forms determined in critical behavior experiment in the fruit bat (Drosophila) at first.Related between normal fruit bat can be learnt specific scent and the foot electric shock is punished.After a training period, when providing between it and the neutral abnormal smells from the patient when selecting in T type labyrinth, most of fly can have been avoided previous and the paired abnormal smells from the patient of electric shock.Study although it is so is very stable at first, but memory thereafter is of short duration, will disappear within one day.On the contrary, when experience ten training periods (have 15 minutes lounge every), can in normal fly, produce the real protein synthesis dependency LTM that continues to surpass a week therebetween.Produce on the genetic engineering in the fly of high-level CREB repressor, LTM is blocked specifically and study or early memory is not influenced.Produce on the genetic engineering in the fly of high-level CREB repressor, the LTM after the training is unaffected at interval, but surprisingly, it is only just induced after a training period.In brief, the quantity of inducing LTM (equivalent on the function of remembering as the photographing unit) to form required training period by minimizing of expressing excessively of CREB activator is come hypermnesis.Begun in several animal models, to carry out molecular studies and further explained plastic biochemistry and the each side that synaptic plasticity and memory form is interrelated, thereby produced the general points of view of following brain plasticity: in specific neural circuit, write down new experience with neururgic change.Still exploring biochemical reaction inside and outside the complicated born of the same parents that this neural activity causes.Yet some critical aspects of this process evolution conservative seemingly up to now.The stimulation of nmda receptor is induced for two kinds of lasting biochemical reaction (phosphorylation of CREB) in local of short duration biochemical reaction and the nucleus in the synapse and is all seemed most important.Some intracellular signal passages are seemingly undertaken inductive at first by neural activity, but seemingly main " catchment " target of CREB is regulated the conversion of early memory to long-time memory.The CREB downward modulation suppresses and CREB rise enhancing potential genetic transcription reaction in the synapse growth course, and it produces function and the structure plasticity that continues in synapse.As if in fact, CREB serves as the role of main switch, to determine when neural activity can produce persistent, structural change in the loop.The key factor that influences this switch is for repeating; When the CREB approach by last timing, the quantity that forms longterm memory required training period is reduced.

Four methods that " CREB approach " medicine is regulated in elementary object guiding screening.At first for efficient, screening must be high-throughout, can carry out machine operation in 96 orifice plates.Secondly, because the medicine of all discriminatings finally is used for the mankind, preferred target spot is endogenous (neuron) form of human CREB.The 3rd, when design this when screening, all the associated upstream district signalling channels that may destroy the CREB function in the memory forming process are still unknown.Therefore, the screening of the broad base expressed as the CREB dependent gene of the functional reading of CREB approach of monitoring as if more can comprise any lack but still may be important biochemical signals.At last, but this screening needs to differentiate separately the CREB function not have effect have synergistic medicine with the public affairs activation of cAMP signal.Designing this need be with the experiment of simulation primitive behavior.In fly, expressing excessively of independent CREB is like water off a duck's back to the behavior of fruit bat.Just the opposite, because the inductive neururgic increase of experience activates the cAMP approach, so need training itself to produce enhanced memory.

These considerations all are received in the high flux screening (HTS) of the human neuroblastoma cell of the stable transfection CRE-luciferase reporter gene of being cultivated.By this way, can pass through the change of the CREB dependent transcription of fluorescence monitoring luciferase.Relevant essential condition for simulation (under biochemical level) memory formation, luciferase activity does not change when seeking use separately, still produces the medicine of synergism (＞2 times) (as to neururgic effect in the body) with the Fu Sikelin of suboptimal dose activation cAMP approach.Use automatic system to screen these cells in the 96-orifice plate, a large amount of medical compoundss is screened effectively, produces a large amount of " active matter (active hit) ".In order to prove conclusively, under four kinds of different concentration, estimate these active matters being with or without under the situation of Fu Sikelin subsequently.Several active matters through confirming appear from this screening process.

Interesting is that the effective molecular target of discovery is phosphodiesterase-4 (PDE4).Under common and particular case, this discovery is all meaningful.Most of bio-chemical pathway plays a role under the optimum condition of suitably regulating, and some of them molecular components (positive regulator) signal for faster is propagated, and other component (down regulator) then stops signal to be propagated.Consider the reverse functions of the inferior shape of CREB activator and repressor, this notion is applicable to the CREB switch adjusting in the longterm memory forming process.As gene mutation, most of medical compounds is in fact as the inhibitor of objective function (" hypomorph " of " antagonist " of medicine and sudden change).Therefore, but find that the medical compounds of the negative regulation thing of antagonism approach is used for the screening of enhancement function usually from expectability.The situation of this yes PDE inhibitor; Reduction PDE activity causes the increase by the normal synthetic cAMP of adenyl cyclase (AC), and the cAMP that raises causes CREB to activate by PKA.Yet, do not having the inductive AC of Fu Sikelin to activate under the condition of (or the inductive AC vivo activation of neural activity), but using PDE inhibitor expectability to have minimum effect separately.

Proved that the preceding PDE-4 inhibitor HT-0712 and other several CREB approach reinforcing agents except that HT-0712 are the granted chemical compound that is used for clinical development.Up to now, the behavior evaluation in the rodent models of memory formation and biochemical test has shown the effective hypermnesis of these chemical compounds.

Exploitation, differentiate and assess such chemical compound and therapy is very important.Such treatment may comprise the chemical compound that concrete training program and/or administration are such or comprise that described memory medicament can be the hypermnesia agent and the memory impairment agent (memory impairer) of raising the CREB approach specifically as the multiple chemical compound of the chemical compound of memory medicament.

Summary of the invention

The present invention includes method, described method comprises the step of evaluation to the effectiveness of the memory medicament of individual administration, and wherein said evaluation comprises to described individuality provides many groups to stimulate (sets of stimuli) and assess the reaction of described individuality to described stimulation.Described evaluation can comprise: the phase I, it comprise to described individuality provide association in groups (associated into sets) stimulation and assess described individuality to the reaction of described stimulation to set up standard; And second stage, it comprise to described individuality provide related in groups stimulation and assess described individuality the reaction of described stimulation successfully measured to set up for a long time.In some embodiments, second stage start from the phase I finish after at least about one day.The assessment of individual reaction can comprise described standard and described successfully the measurement are for a long time compared.Described many groups stimulate can comprise a plurality of couple stimulations.In some embodiments, described a plurality of couple stimulation can comprise positive unit (element) and/or negative unit separately.In other embodiments, described a plurality of couple stimulations can comprise a unit separately, its with described another right unit have can discern related.It is in some embodiments, described that to discern association can be face-names associate or word-word association.Described individuality can be an animal.In certain embodiments, described animal can be primate, mammal, mice or rat.In some embodiments, described primate can be the mankind, monkey, mongoose lemur, stump-tailed macaque or ape.In some embodiments, the phase I can be about one to about ten day.In some embodiments, second stage can be about one day.In some embodiments, a plurality of individualities can be arranged, it can comprise matched group and experimental group.In certain embodiments, described evaluation can comprise more described matched group and described experimental group.In some embodiments, the assessment of individual reaction comprises calculates and/or measures one or more aspects, described aspect is selected from: long-term successfully measurement keeps, desires to reach the required time quantum of specific criteria with ratio, the longterm memory of standard, and/or when keeping long-term constant, accurate constant (near-constant) or the ratio of successfully measuring with standard that improves, the time quantum between phase I and the second stage.

In other embodiments, the present invention can relate to method, and described method comprises: select the memory medicament as drug candidate, wherein said selection may further comprise the steps: to individual administration memory medicament; And provide many groups to stimulate and assess of the reaction of described individuality described stimulation to described individuality.Described evaluation may further include: the phase I, it comprise to described individuality provide related in groups stimulation and assess described individuality to the reaction of described stimulation to set up standard; And second stage, it comprise to described individuality provide related in groups stimulation and assess described individuality the reaction of described stimulation successfully measured to set up for a long time.In some embodiments, second stage start from the phase I finish after at least about one day.In certain embodiments, the assessment of individual reaction comprises calculates and/or measures one or more aspects, described aspect is selected from: long-term successfully measurement keeps, desires to reach the required time quantum of specific criteria with ratio, the longterm memory of standard, and/or when keeping long-term when successfully measuring, the time quantum between phase I and the second stage with the constant, accurate constant of standard or the ratio that improves.In some embodiments, described many group stimulations comprise a plurality of couple stimulations.In some embodiments, described individuality can be an animal, comprises mammal, for example primate, mice and rat.

In other embodiments, the present invention relates to method, described method comprises: test is as the memory medicament of longterm memory reinforcing agent, and wherein said test may further comprise the steps: to individual administration memory medicament; And provide many groups to stimulate and assess of the reaction of described individuality described stimulation to described individuality.In certain embodiments, described evaluation further comprises: the phase I, it comprise to described individuality provide related in groups stimulation and assess described individuality to the reaction of described stimulation to set up standard; And second stage, it comprise to described individuality provide related in groups stimulation and assess described individuality the reaction of described stimulation successfully measured to set up for a long time.In some embodiments, second stage start from the phase I finish after at least about one day.In some embodiments, the assessment of individual reaction comprises calculates and/or measures one or more aspects, described aspect is selected from: long-term successfully measurement keeps, desires to reach the required time quantum of specific criteria with ratio, the longterm memory of standard, and/or when keeping long-term when successfully measuring, the time quantum between phase I and the second stage with the constant, accurate constant of standard or the ratio that improves.In certain embodiments, described many group stimulations comprise a plurality of couple stimulations.In some embodiments, described individuality can be an animal, comprises the animal that is selected from primate, mammal, mice and rat.

In other embodiments, the present invention can be a method, described method comprises: estimate the effectiveness of memory medicament, wherein said evaluation may further comprise the steps: first individual and second individuality is provided, and wherein said first individuality is identical species with described second individuality; To the described first individual administration memory medicament; During the phase I, a plurality of couple stimulations are provided and assess of the reaction of described first individual and described second individuality, to set up described first individuality and described second individuality standard separately described stimulation to described first individual and described second individuality; During second stage, a plurality of couple stimulations are provided and assess of the reaction of described first individual and described second individuality, to set up the successfully measurement for a long time separately of described first individuality and described second individuality described stimulation to described first individual and described second individuality; The standard of more described first individuality and described second individuality and their successfully measurement for a long time separately.In some embodiments, second stage start from the phase I finish after at least about one day.In some embodiments, second stage start from the phase I finish after about 1 to about 10 days.What in certain embodiments, standard and long-term success were measured relatively comprises: determine the long-term successfully measurement of described first individuality and first ratio of the standard of described first individuality; Determine the long-term successfully measurement of described second individuality and second ratio of the standard of described second individuality; And more described first ratio and described second ratio.In certain embodiments, described many group stimulations comprise a plurality of couple stimulations.In some embodiments, described a plurality of couple stimulation comprises positive unit and/or negative unit.In other embodiments, described a plurality of couple stimulations comprise a unit separately, its with described another right unit have can discern related.In some embodiments, describedly discern association to be selected from face-names associate related with word-word.In some embodiments, described first individual and described second individuality animal that respectively does for oneself comprises the animal that is selected from primate (comprising the mankind, monkey, mongoose lemur, stump-tailed macaque and ape), mammal, mice and rat.In certain embodiments, the phase I comprises about one to about ten day.In some embodiments, second stage comprises about one day.In some embodiments, described first individual and described second individuality a plurality of individualities of respectively doing for oneself.

In some embodiments, the present invention includes and the above-mentioned similar method of those methods, but it focuses on assessment training program and non-memory medicament or removes and remember the medicament.Some embodiments relate to method, said method comprising the steps of: estimate the effectiveness of the training program of bestowing to individuality, wherein said evaluation comprises to described individuality to be provided many group stimulations and assesses the reaction of described individuality to described stimulation.Other embodiment relates to method, and described method comprises: test is as the training program of longterm memory reinforcing agent, and wherein said test may further comprise the steps: bestow training program to individuality; And provide many groups to stimulate and assess of the reaction of described individuality described stimulation to described individuality.Other embodiment relates to method, and described method comprises: estimate the effectiveness of training program, wherein said evaluation may further comprise the steps: first individual and second individuality is provided, and wherein said first individuality is identical species with described second individuality; Bestow training program to described first individuality; During the phase I, a plurality of couple stimulations are provided and assess their reactions, to set up described first individual and described second individuality standard separately described stimulation to described first individuality and described second individuality; During second stage, a plurality of couple stimulations are provided and assess their reactions, to set up the described first individual and described second individuality successfully measurement for a long time separately described stimulation to described first individuality and described second individuality; The standard of more described first individuality and described second individuality and their successfully measurement for a long time separately.

The present invention also comprises system, comprises the system that uses with method disclosed herein.For example, in some embodiments, described system can comprise necessary all key elements of the embodiment of implementing the inventive method.System of the present invention can be used for selecting the memory medicament as drug candidate, estimate the effectiveness of memory medicament, estimate the effectiveness of training program, and/or test memory medicament, and/or test is with the memory medicament of training program as the longterm memory reinforcing agent as the longterm memory reinforcing agent.

In some embodiments, system of the present invention comprises how group stimulates, and wherein said many group stimulations are provided so that can assess the effectiveness that the training program of bestowing to described individuality is also estimated in the individual reaction that described many groups are stimulated thus.In some embodiments, described many group stimulations comprise a plurality of couple stimulations.In certain embodiments, described a plurality of couple stimulation comprises positive unit and/or negative unit separately.In some embodiments, described a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.In other embodiments, describedly discern association to be selected from face-names associate related with word-word.In other embodiments, described system can also comprise the dosage and the drug dosage schedule table of testing scheme, test plan table and/or memory medicament.

In other embodiments, system of the present invention comprises that many groups stimulate, and wherein said many groups stimulate and are provided so that and can assess the individual reactions that described many groups are stimulated and estimate effectiveness to the memory medicament of described individual administration thus.In some embodiments, described many group stimulations comprise a plurality of couple stimulations.In multiple embodiments, described a plurality of couple stimulations comprise positive unit and/or negative unit separately.In other embodiments, described a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.In certain embodiments, describedly discern association to be selected from face-names associate related with word-word.In other embodiments, described system can also comprise the dosage and the drug dosage schedule table of testing scheme, test plan table and/or memory medicament.

In some embodiments, method and system of the present invention uses the memory medicament, and it is one or more chemical compounds that are selected from the chemical compound with following structure:

Y wherein ₁, Y ₂, Y ₃And Y ₄Be independently of one another-H; Straight or branched C ₁-C ₇Alkyl, single fluoroalkyl or Polyfluoroalkyl; Straight or branched C ₂-C ₇Alkenyl or alkynyl; C ₃-C ₇Cycloalkyl or C ₅-C ₇Cycloalkenyl group;-F ,-Cl ,-Br or-I;-NO ₂-N ₃-CN;-OR ₄,-SR ₄,-OCOR ₄,-COR ₄,-NCOR ₄,-N (R ₄) ₂,-CON (R ₄) ₂Or-COOR ₄Aryl or heteroaryl; Perhaps be present in the Y on the adjacent carbon atom ₁, Y ₂, Y ₃And Y ₄In any two can constitute methylenedioxy group; Each R wherein ₄Be independently-H; Straight or branched C ₁-C ₇Alkyl, single fluoroalkyl or Polyfluoroalkyl; Straight or branched C ₂-C ₇Alkenyl or alkynyl; C ₃-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group, aryl or aryl (C ₁-C ₆) alkyl; Wherein A is A ', straight or branched C ₁-C ₇Alkyl, aryl, heteroaryl, aryl (C ₁-C ₆) alkyl or heteroaryl (C ₁-C ₆) alkyl; Wherein A ' is

R wherein ₁And R ₂Be independently of one another-H, straight or branched C ₁-C ₇Alkyl ,-F ,-Cl ,-Br ,-I ,-NO ₂Or-CN; R wherein ₃For-H, straight or branched C ₁-C ₇Alkyl ,-F ,-Cl ,-Br ,-I ,-NO ₂,-CN ,-OR ₆, aryl or heteroaryl; R wherein ₅Be straight or branched C ₁-C ₇Alkyl ,-N (R ₄) ₂,-OR ₄Or aryl; R wherein ₆Be straight or branched C ₁-C ₇Alkyl or aryl; Wherein B is an aryl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, the indolizine base, indole-4-base, indole-5-base, indole-6-base, indole-7-base, isoindolyl, benzo [b] furan-4-base, benzo [b] furan-5-base, benzo [b] furan-6-base, benzo [b] furan-7-base, benzo [b] thiophene-4-base, benzo [b] thiophene-5-base, benzo [b] thiophene-6-base, benzo [b] thiophene-7-base, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purine radicals, imidazo [2,1-b] thiazolyl, quinolyl, isoquinolyl, quinazolyl, 2,1, the 3-benzothiazolyl, furyl, thienyl, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group benzoxazolyl, the benzoisoxazole base, the cinnolines base, quinoxalinyl, 1, the 8-naphthyridinyl, pteridyl or phthaloyl imino; Yet its condition is that the adjacent one or more carbon atoms of imine linkage nitrogen-atoms only can be replaced by in the following group one or more :-F ,-Cl ,-Br ,-I ,-CN, methyl, ethyl or methoxyl group; Wherein n is the integer that comprises the 1-4 of end value; Wherein aryl is a phenyl or naphthyl, comprise by phenyl that one or more replaced and naphthyl in the following group :-F ,-Cl ,-Br ,-I ,-NO ₂,-CN, straight or branched C ₁-C ₇Alkyl, straight or branched C ₁-C ₇Single fluoroalkyl, straight or branched C ₁-C ₇Polyfluoroalkyl, straight or branched C ₂-C ₇Thiazolinyl, straight or branched C ₂-C ₇Alkynyl, C ₃-C ₇Cycloalkyl, C ₁-C ₇Single fluorine cycloalkyl, C ₃-C ₇Polyfluoro cycloalkyl, C ₅-C ₇Cycloalkenyl group ,-OR ₄, SR ₄,-OCOR ₄,-COR ₄,-NCOR ₄,-CO ₂R ₄,-CON (R ₄) ₂Or (CH ₂) _n-O-(CH ₂) _mCH ₃The perhaps acceptable salt of its pharmacy.

Wherein Me is a methyl, and cPent is a cyclopenta, and 3 and 5 carbon are the S configuration.

Description of drawings

Figure 1A-1B represents the result's of the embodiment of the present invention described in the embodiment 1 sketch map.The result is expressed as the average natural law ± standard error of mean (s.e.m) of each treatment, and * is with respect to carrier p＜0.05.

Fig. 2 A-2B represents the result's of the embodiment of the present invention described in the embodiment 1 sketch map.The result is expressed as average performance (performance) percentage ratio ± standard error of mean of each treatment.

Fig. 3 A-3B represents the result's of the embodiment of the present invention described in the embodiment 1 sketch map.The result is expressed as the average performance percentage ratio ± standard error of mean of each treatment.

Fig. 4 A-4D represents to can be used for the exemplary paired visual stimuli in the embodiment of the present invention described in the embodiment 1.

Fig. 5 represents the sketch map of the performance of the healthy geriatric volunteer in the embodiment of memory mensuration in pairs-related (face-title) described in the embodiment 2.Require 6 day time memory of body and function, one group of 40 pairs of face and title (occupation) (d2-d7).In training Day, the individual content of only browsing once 40 pairs of this groups.At first inquire their memory, provide correct option then to continue training.After the training, only use face-title that 1-20 is carried out the quantification (d10) that memory in three days keeps.These face-titles are carried out once more the quantification (d14b) of memory maintenance in seven days to 1-20.Also face-title is carried out the quantification (d14a and d14a2) that kept in twice seven days to 21-40,1 minute interval is arranged between recall period.

Detailed Description Of The Invention

In following paragraph, can in the mode of embodiment the present invention be described with reference to the accompanying drawings.In whole description, shown preferred embodiment and embodiment should be considered to example but not limitation of the present invention.This paper uses " the present invention " to be meant each embodiment and any equivalents of invention described herein.In addition, mention the various features of " the present invention " everywhere and do not mean that embodiment or method that all are claimed must comprise mentioned feature at this file.

Term used herein is only in order to describe the purpose of specific embodiments, and is not intended to limit the scope of the invention.Unless clear indicating arranged in the literary composition in addition, and singulative " a ", " an " and " the " that this paper and claims are used comprise that plural number refers to.Therefore, for example mention that " chemical compound " is meant one or more chemical compounds and comprises its equivalent well known by persons skilled in the art or the like.

Unless otherwise defined, all technical terms used herein have the implication identical with those skilled in the art's common sense with scientific terminology.Although described concrete grammar, device and material, all can be used in practice of the present invention or the test with those methods as herein described and materials similar or any method that is equal to and material.

The invention provides discriminating, assess and test multiple as the memory medicament chemical compound and as the method and system of the plan of training program.Such method and system can be tested any chemical compound or scheme, comprises memory medicament described herein and training program.Described method can comprise with training program with the memory medicament general administration combine.In some embodiments, the present invention can comprise discriminating, selection, test, assess or estimate the chemical compound as memory medicament drug candidate (for example medicine of the effective hypermnesis of conduct).

Drug candidate can be such chemical compound, and it is differentiated by the medicament research and development process, and synthesizes, characterizes, optimizes and/or screening or mensuration.In case (for example method of the application of the invention or system) proved that chemical compound has potential to given activity or effect, then it can be a drug candidate, can be the medicine of final business-like clinical trial by purpose promptly.

Differentiate, assess and test the method for memory medicament and training program

In some embodiments, the present invention includes the one or more aspects of memory ability that some task of use is estimated animal.Learning capacity, impermanent memory or the longterm memory that for example can test and/or estimate animal keep.Under the situation that does not have other modification (for example impermanent memory), term used herein " memory " refers to longterm memory.Term used herein " memory medicament " is meant hypermnesia agent (memory augmenting agent) or memory inhibitor (memory suppressing agent).Hypermnesia agent and memory inhibitor comprise but are not limited to for example at United States Patent (USP) 5,929,223,6,051,559,6,689,557 and 6,890,516 and U.S. Patent application 11/066, described in 125 those act on molecule, chemical compound and/or the medicament of CREB approach, and its disclosure integral body is separately quoted adding this paper.

Term used herein " animal " comprises mammal and other animal, vertebrates, invertebrates (for example birds, Fish, reptile, insecticide (for example fruit bat class)) and Mollusca (for example Carnis Rapanae thomasianae).Term used herein " mammal " and " mammiferous " are meant the vertebrates of their young baby of any nurture and viviparous (Eutheria (eutharian) or placental (placental mammal)) or oviparity (Metatheria (metatharian) or do not have placental mammals (nonplacental mammal)), comprise monotreme, marsupial and placental (placental).The example of mammal kind includes but not limited to human and primate (for example monkey, chimpanzee, the mankind, ape, mongoose lemur or stump-tailed macaque), rodent (for example rat, mice, Cavia porcellus) and ruminant animal (ruminent) (for example cattle, pig, horse).

Described animal can be have certain form or degree memory dysfunction animal or have the animal animal of the amnesia (memory failure) (any memory dysfunction or forfeiture) of form (promptly without any) of normal memory performance.Can use one or more animals, and such animal can place one or more groups (for example one or more matched groups and/or one or more experimental group).Described animal can be the age that is fit to arbitrarily.

Described task can comprise to individuality provides certain stimulation.Described stimulation can be the stimulus to the sense organ that is fit to arbitrarily, includes but not limited to audition, vision, sense of touch, olfactory sensation, the sense of taste and/or its combination.In some embodiments, described stimulation can be a visual stimulus, and is in symbol, letter, numeral, lines, shape, color, picture or its combination one or more.Described stimulation can association in groups, between this group membership, set up certain relation like this.Described stimulation can be related into about 2 groups, 3 groups, 4 groups, 5 groups, 6 groups, 7 groups, 8 groups, 9 groups or 10 groups.In some such embodiments, it is right that described stimulation is associated to.In some embodiments, the stimulation of each in described pairing is same type (being audition, vision or sense of touch); And in other embodiments, described pairing can be dissimilar.In some embodiments, unit in the described pairing has certain with another unit in this pairing and can discern related.Can discern association can be described right one or more unitary vision, audition, logic OR others, and it can make individuality that described paired unit and its corresponding unit are interrelated.In other embodiments, can not have to discern association.For example, described right to being word-word, one of them word can not discerned related (for example comb-Fructus Mali pumilae) with another word.The example of vision couple stimulation has been described among Fig. 4 A-4D.Have that can to discern related another right example of stimulation can be face-title to and/or occupation-face/title right.In some embodiments, also can have and of the occupation of face-title together listing.

In some embodiments, can provide one or more couple stimulations to described individuality.In some embodiments, can provide 2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,50,100,120,150 or the couple stimulation of other suitable quantity arbitrarily to described individuality.In some embodiments, a described right unit just is designated as, and this means that if this unit of described individual selection, then he can be awarded.In other embodiments, a described right unit is designated as negative, this means that if this unit of described individual selection, then he can receive negative feedback.In some embodiments, described individuality is selected described unit by touching this unit, but then can use other suitable system of selection arbitrarily in other embodiments.In some embodiments, described award can be a food, but in other embodiments, and described award can be pleasant sound, use the right of certain toy or article or be suitable for triggering anything of individual positive reaction.In some embodiments, described negative feedback is electric shock, sound, punishment or does not award privilege, and behavior of degenerative any appropriate etc. perhaps is provided to individuality.

Can adjust type of feedback, couple stimulation, form stimulation, the species of individuality and the selection at age more, and the different aspect of individual memory is tested and/or assessed to the others of described task.For example, use wherein each unit to have and to discern related stimulation can be used for assessing the associative memory (relational memory) of individuality with another unit.

In other embodiments, can use except that reward and/or the negative feedback appraisal procedure other appraisal procedure.For example, in some embodiments (for example described individuality is human embodiment), described stimulation can have dependency, described like this individuality can determine that this pairing or other association are correct or wrong (for example described stimulation are a couple stimulation, exist like this discerning of expection related) between another unit of unit of a centering and described centering.For example, if it is right to have taught individual face-title, then can provide the couple stimulation that mixes (scrambled), thereby it is right to destroy correct face-title to described individuality.Described then individuality can express face-title of offering him to whether be instructed to its correct face-title right.In such embodiments, discontinuous award is optional, and perhaps described award can be the direct feedback that the correctness of mankind's reaction is made.Can provide couple stimulation with the form of any appropriate.For example, can be at each test period with at random, organized or pseudorandom order administration.

Can test described individuality in the period that is fit to arbitrarily with the frequency that is fit to arbitrarily.For example, each test event can be to described individual test 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 50 times, 60 times, 75 times, 100 times, 150 times, 200 times, 250 times, 365 times or other number of times that is fit to arbitrarily (for example, if test is to carry out every day, then can to described individual test once, twice, three inferior).In such test, can be fit to the stimulation or the couple stimulation of quantity arbitrarily to individual body display.Individuality can be with every day, every other day, weekly, per two weeks, every month or any other suitable frequency accept test.In addition, can test the individuality that is fit to quantity arbitrarily.In some embodiments, test to utilize and individuality is instructed or its coding about the information that concerns between the described couple stimulation.Which for example, can test to instruct unit in this pairing of described individuality for just and/or negative unit.In other embodiments, can test to instruct the correct paired unit (for example correct face-names associate, occupation-names associate or occupation-face/names associate) in individual one group of stimulation.Can need the test in a plurality of stages in such embodiments.At first be the instruction stage, follow, the knowledge whether pairing that is provided by the suitable method inquiry of depending on described individual type (for example human to rat) in this stage correctly tests described individuality by second stage.

Can assess described individuality in the mode that is fit to arbitrarily.In some embodiments, provide one or more couple stimulations to described individuality, wherein this paired unit just is being designated as and/or this paired unit is designated as negative.In such embodiments, to this paired which unit of roger for just and/or negative unitary individual assessment its select just described and/or negative unit and/or do not select just described and/or negative unitary number of times.In other embodiments, described couple stimulation relevant (for example face-title relation, occupation-title relation, occupation-face/title relation, a pair of word, a group of letter or number, part picture or symbol) each other.In such embodiments, can assess, to redefine suitable pairing (for example the title unit being put together or the like with corresponding picture element unit cell) the ability of the individuality of correct relation between the described paired unit of roger.In some embodiments, can change this pairing by some modes, and can require the described individual described paired mode (for example, answer can " intact (intact) ", " rearranging ", " new " or " two all is new ") that changes of differentiating.

In some embodiments, can test individual longterm memory.In such embodiments, can set up standard results.Can set up such standard in many ways.For example, provide to individuality a pair of stimulation (wherein this paired unit for just and/or this paired unit for bearing) embodiment in, can provide this pairing (perhaps many assembly to) to differentiate described positive unit and/or negative unit with specific frequency to described individuality up to described individuality.This frequency subsequently can as the result after estimating can reference standard.Similarly, correctly set up the frequency that concerns between the unit of a pair of stimulation and also can be used for setting up standard.In some embodiments, assessment is individual reaches specific success rate until it.For example, about 50%, 55%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100% or other is fit to arbitrarily the standard of percentage ratio or the standard of correct number of results can be used as target.In other embodiments, can test specific number of times or certain period of time to individuality, and last assessment can be used for setting up standard.For example, about 1-23 hour or about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 50 days, 60 days, 75 days, 100 days, 150 days, 200 days, 250 days or 365 days or other hourage that is fit to arbitrarily or the time period of natural law can be used for setting up standard.Also can be to described individual test about 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 50 times, 60 times, 75 times, 100 times, 150 times, 200 times, 250 times, 365 times or other number of times that is fit to arbitrarily to set up standard.Can also utilize other statistical measure value of meansigma methods, intermediate value or individual actual result to set up described standard.

In some embodiments, in case set up described standard, then in the special time amount, do not assess described individuality or it is showed any couple stimulation that is used to set up described standard.Described time quantum can be about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 50 days, 60 days, 75 days, 100 days, 150 days, 200 days, 250 days, 365 days or other natural law that is fit to arbitrarily.After this period of delay, reuse the identical couple stimulation that is used to set up described standard and test described individuality.In some embodiments, can be equal to those environment that are used to set up described standard, repeat these tests under the similar or different environment.In addition, can be by set up the long-term performance of estimating described individuality of successfully measuring in the mode that is fit to arbitrarily.In some embodiments, set up mode that long-term success measures and can be similar to about setting up the described mode of standard, but be to use usually shorter time bar so that long-term memory of successfully measuring the described individuality of expression, rather than it learns relevant criterion once more.Can estimate described individuality by more described successfully the measurement for a long time subsequently with described standard.Statistical analysis or similar analysis can be used for assessing such result.

In some embodiments, method of the present invention can be used for assessing the effect of cryptanamnesia medicament and/or potential training program.For example, method of the present invention can be used for differentiating the minimizing of desiring to reach the required training burden of selected performance level.In such embodiments, can be at first individuality be assessed not existing under the situation of remembering medicament, then the individuality of administration memory medicament is assessed.Simultaneously, can use specific couple stimulation that the individuality of matched group is tested, and those results are compared with the group of individuals of the memory medicament of administration given dose.The assessment of memory medicament and/or training program can be taked multiple mode.For example, the memory medicament can reduce and sets up or reach time and/or the natural law that specific criteria or other effect that is fit to are arbitrarily measured required training period.

In some embodiments of the present invention, described memory medicament is assessed to observe it whether change natural law or the training issue that (for example reduce or increase) reaches performance standard.Term used herein " standard " is meant the tolerance of expected result and/or expectation performance level, and for example test is individual or the percentage ratio of the correct response (for example correct couple stimulation) of test group of individuals.Described standard can be as desired the changing or select of the manager of scheme, test, task and/or other embodiment of the present invention.Can be by for example changing the complexity that quantity that the pairing of described standard, desire stimulates and/or type, training natural law, training burden and/or training type are controlled the training of being bestowed in these embodiments.In other embodiments, using or do not using under the situation of described memory medicament, described training is enough to produce the CREB dependency and changes in longterm memory, and for example the CREB dependency of longterm memory strengthens.

In some embodiments, method of the present invention can be used for the effectiveness of assess memory damage agent.Such embodiment can comprise the step similar or identical with the method for assess memory medicament.Yet in such embodiments, the labelling of being assessed can be different.For example, the memory impairment agent can increase sets up the required time of a certain standard, increases to desire the required training issue of the standard that reaches, and reduces the long-term ratio of successfully measuring with standard, perhaps the arbitrary content that can assess in any other suitable mode.

Can provide suitable arbitrarily memory medicament or memory impairment agent by the method that is fit to arbitrarily, the delivery plan harmony in the exterior dosage that is fit to arbitrarily by suitable arbitrarily delivery system and use.In addition, can use the training program that is fit to arbitrarily.With the lower part exemplary training program, memory medicament and memory impairment agent are being discussed specifically.

The present invention also comprises system, comprises the system that uses with method disclosed herein.For example, in some embodiments, described system can comprise necessary all key elements of the embodiment of implementing the inventive method.System of the present invention can be used for selecting the memory medicament as drug candidate, estimate the effectiveness of memory medicament, estimate the effectiveness of training program, test is as the memory medicament of longterm memory reinforcing agent, test is as the memory medicament of specific or general memory impairment agent, and/or test is with the memory medicament of training program as the longterm memory reinforcing agent.Such system can comprise using aforesaid the group to stimulate, to comprise aforesaid couple stimulation and test plan harmony in the exterior scheme more.

Training program

As described herein, use the evaluation of the inventive method and system can comprise two parts: (1) concrete training program, and the administration of (2) memory medicament.In some embodiments, only use training program.In other embodiments, the administration of training and memory medicament all has generation.This combination can be promoted training program in the following manner: reduce producing the required training period natural law of progressive performance with respect to the performance that only obtains by training, perhaps need shorter between training period or do not need lounge every to produce progressive performance.This combination also can be promoted training program in the following manner: reduce and induce neuronal activity pattern required persistent period training period and/or quantity in one or more specific neuronal circuits, perhaps reduce the persistent period of inducing ring AMP response element binding protein matter (CREB)-dependency long-term (lastingly promptly) structure/changing function required training period in the neuronal circuit synapse connects and/or the potential pattern of quantity or neuronal activity.By such mode, people can improve the efficient of existing training program, produce significant function and benefit and economic benefit thus.

Training program (for example concentrating training (massed training), training (spaced training) at interval) is used to learn newspeak or new musical instrument is played in study.The administering drug combinations of memory medicament and training has reduced progressive time and/or the quantity that shows required training period of generation.Therefore, need still less put into practice (training period) to learn newspeak or the new musical instrument of study performance.

Training program is used for the potential pattern of the neuronal activity in individuality repetitive stimulation neuronal activity or one or more specific neuronal circuits.Memory medicament and the administering drug combinations of training have reduced the time of desiring to reach given result (for example inducing CREB dependency (lastingly promptly) structure/changing function for a long time in the neuronal circuit synapse is connected) required training period and/or the potential pattern of quantity and/or neuronal activity.

These methods are the particular aspects of hypermnesis in this animal that needs (particularly human or other mammal or vertebrates) is arranged in the following manner: (a) to described animals administer memory medicament (for example strengthening the medicament of CREB approach function); And (b) produce the described animal of training under the progressive condition in the performance that is enough to make described animal to the memory tasks paid close attention to.In some embodiments, described memory medicament strengthens medicine for the CREB approach.

Described method can be used for treatment and central nervous system's (CNS) disease or the relevant amnesia of the patient's condition in the animal of the described treatment of needs in the following manner: (a) to described animals administer memory medicament (for example strengthening the medicament of CREB approach function); And (b) produce the described animal of training under the progressive condition in the performance that is being enough to make described animal to concrete memory tasks.The CNS disease or the patient's condition comprise the memory impairment that the age is relevant, neurodegenerative disease (Alzheimer for example, parkinson disease, Huntington Chorea (chorea), other alzheimer disease), psychosis is (for example depressed, schizophrenia, autism, attention deficit syndrome), wound dependency loss function (trauma dependent loss of function) (cerebrovascular disease (apoplexy for example for example, ischemia), cerebroma, head or brain injury), genetic defect (Rubinstein-Taybi syndrome for example, mongolism), learning disability and/or its combination.

Described method also is used in repetitive stimulation neuronal activity or neuronal activity pattern (for example potential pattern of the neuronal activity in one or more specific neuronal circuits) in the animal, and it comprises that (a) is to described animals administer memory medicament (for example strengthening the medicament of CREB approach function); And (b) be enough to the animal moderate stimulation or induce neuronal activity or the condition of neuronal activity pattern under the training described animal.

For the many tasks in many species (comprising the mankind), at interval training program (each have between a plurality of training periods lounge every) is than concentrated training program (do not have between a plurality of training periods lounge every) stronger, the more persistent memory of generation.The behavioral genetics research of the Pavlovian olfaction study in fruit bat is determined, concentrated training is created in the long-time memory that disappears at least four days, it is not that protein synthesis is dependent, do not destroyed by the expression of crossing of CREB repressor transgenic (CREB-repressor transgene), and destroyed (Tully in radish mutant (radish mutant), T. wait the people, Cell, 79 (1): 35-47 (1994); And Yin, people such as J.C., Cell, 79 (1): 49-58 (1994)).On the contrary, training produces the long-time memory that continues at least seven days at interval, and it is that protein synthesis is dependent, destroyed by the genetically modified expression excessively of CREB repressor, and be normal (Tully, people such as T. in the radish mutant, Cell, 79 (1): 35-47 (1994); And Yin, people such as J.C., Cell, 79 (1): 49-58 (1994)).In training at interval one day after, memory keeps being made up of protein synthesis dependency and CREB dependency early memory (ARM) and protein synthesis dependency and CREB dependency longterm memory (LTM).Concentrated undertrained in addition is to induce LTM (Tully, people such as T., Cell, 79 (1): 35-47 (1994); And Yin, people such as J.C., Cell, 79 (1): 49-58 (1994)).

More and more evidences extends to these results on the mammal from invertebrates.For example, the molecular manipulation that CREB expresses in Carnis Rapanae thomasianae similar in fly, in its inhibition or enhancing (i) cell culture at the LTM of the monosynaptic facilitation electrophysiologic response of sensorimotor (facilitatory electrophysiological response), and (ii) connect (Bartsch in the sensory neuron and the synapse between the motor neuron that apply facilitation stimulation back generation at interval usually, D. wait the people, Cell, 83 (6): 979-992 (1995)).In rat, antisense rna oligonucleotide injection is entered Hippocampus or corpus amygdaloideum (amygdala) have been blocked the LTM that depends on the active two kinds of different tasks in these anatomic regions respectively and has formed (Guzowski, J.F. wait the people, Proc.Natl.Acad.Sci.USA, 94 (6): 2693-2698 (1997); And Lamprecht, people such as R., J.Neurosci., 17 (21): 8443-8450 (1997)).In mice, it is defective (Bourtchuladze, people such as R., Cell, 79 (1): 59-68 (1994)) that the two LTM of inherent task and external task is formed in the CREB mutant mice.

In dependent frightened trained reflex of Hippocampus in context or the passive avoidance task, CA1 of Hippocampus and the CRE dependency reporter gene expression in the CA3 zone are induced in the training of the transgenic mice that carries CRE dependency reporter gene (beta galactosidase).In the frightened trained reflex task of corpus amygdaloideum dependency, the training of these mices is induced corpus amygdaloideum but not CRE dependency reporter gene expression in the Hippocampus.Therefore, the training program of inducing LTM to form also induces the CRE dependent gene in the particular anatomical zone of mammal brain to transcribe (Impey, people such as S., Nat.Neurosci., 1 (7): 595-601 (1998)) simultaneously.

Utilize these animal models, verified enhanced three the remarkable examples of LTM.At first, the genetically modified expression excessively of CREB activator cancelled a plurality of interval demand of training period, ground replaces, only (it seldom or not produced memory usually and keeps (Yin after 24 hours inducing LTM formation after the training period for it, J.C. wait the people, Cell, 81 (1): 107-115 (1995)).Secondly, the CREB activator transgenic injection of viral expression is entered the memory that the rat corpus amygdaloideum also is enough in concentrated training back enhancing fear be strengthened alarm response (fear-potentiated startle effect), its cancelled to the lounge in the training at interval every demand (Josselyn, S.A. wait the people, Society for Neuroscience, the 24th volume, Abstract 365.10 (1998)).Moreover, if mutant mice is accepted different interval training program (Kogan, people such as J.H., Curr.Biol., 7 (1): 1-11 (1997)), then the LTM in the mice that lacks CREB forms (Bourtchuladze, R. wait the people, Cell, 79 (1): 59-68 (1994)) can form usually.

As if CREB also relate to Developmental Plasticity and the plastic various ways of cell in the vertebrates brain.For example, neuronal activity increases CREB activity (Moore, people such as A.N., J.Biol.Chem., 271 (24): 14214-14220 (1996)) in the cortex.CREB also regulates Hippocampus (Murphy, people such as D.D., Proc.Natl.Acad.Sci.USA, 1482-1487 (1997)), somatosensory cortex (Glazewski 94 (4):, 249-256 (1999)), striatum (Liu S. wait the people, Cereb.cortex, 9 (3):, F.C. wait the people, Neuron, 1133-1144 (1996)) and look cortex (Pham, people such as T.A. 17 (6):, Neuron, 22 (1): the Developmental Plasticity 63-72 (1999)).

As if CREB be affected in human nerve's degenerative disease and brain injury.For example, CREB activates and/or is expressed in the Alzheimer be damaged (Ikezu, people such as T., EMBO J., 15 (10): 2468-2475 (1996); Sato, people such as N., Biochem.Biophys.Res.Commun, 232 (3): 637-642 (1997); And Yamamoto-Sasaki, people such as M., Brain.Res., 824 (2): 300-303 (1999)).CREB activates and/or expresses also be improved (Blendy, people such as J.A., Brain Res., 681 (1-2): 8-14 (1995) behind outbreak (seizure) or ischemia; And Tanaka, people such as K., Neuroreport, 10 (11): 2245-2250 (1999))." environmental enrichment " is neuroprotective, by be used for preventing cell death (Young, people such as D., Nat.Med., 5 (4): 448-453 (1999)) through CREB.

CREB works with giving up in the process at drug susceptibility.For example, CREB is subjected to ethanol (Pandey, people such as S.C., Alcohol Clin.Exp.Res., 23 (9): 1425-1434 (1999); Constantinescu, people such as A., J.Biol.Chem., 274 (38): 26985-26991 (1999); Yang, people such as X., Alcohol Clin.Exp.Res., 22 (2): 382-390 (1998); Yang, people such as X., J.Neurochem., 70 (1): 224-232 (1998); And Moore, M.S. wait the people, Cell, 997-1007 (1998)), cocaine (Carlezon 93 (6):, W.A., people such as Jr., Science, 2272-2275 (1998)), morphine (Widnell 282 (5397):, 306-315 (1996)), methamphetamine (Muratake K.L. wait the people, J.Pharmacol.Exp.Ther., 276 (1):, T. wait the people, Ann N.Y.Acad.Sci, 844:21-26 (1998)) and cannabinoid (Calandra, people such as B., Eur.J.Pharmacol, 374 (3): 445-455 (1999); And Herring, people such as A.C., Biochem.Pharmacol, 55 (7): influence 1013-1023 (1998)).

The signal transduction pathway that can stimulate CREB/CRE to transcribe approach is the cAMP regulating system.Corresponding to it, lack the two mice of adenyl cyclase 1 (AC1) and AC8 enzyme and can not learn (people such as Wong S.T., Neuron, 23 (4): 787-798 (1999)).In these mices, Fu Sikelin has repaired the learning and memory of Hippocampus dependency task to the CA1 of Hippocampus zone administration.In addition, the age dependency forfeiture and the cell long-period potentiation (Barad of the memory of Hippocampus dependency the treatment of senile rat have been improved with the medicine (for example rolipram and D1 receptor stimulating agent) that improves the cAMP level, M. wait the people, Proc.Natl.Acad.Sci.USA, 95 (25): 15020-15025 (1998)).These recent data show defective (Bach, people such as M.E., Proc.Natl.Acad.Sci.USA, 96 (9): 5280-5285 (1999)) of cAMP signal in the impaired senile rat of study.

More and more evidences shows that neuron continues propagation (Arsenijevic, people such as Y., Exp.Neurol., 170:48-62 (2001) in adult's brain; Vescovi, people such as A.L., Biomed.Pharmacother., 55:201-205 (2001); Cameron, H.A. and McKay, R.D., J.Comp.Neurol, 435:406-417 (2001); And Geuna, people such as S., Anat.Rec., 265:132-141 (2001)), and such propagation is as reaction (Nilsson, people such as M., J.Neurobiol, 39:569-578 (1999) to various experience; Gould, people such as E., Trends Cogn.Sci, 3:186-192 (1999); Fuchs, E. and Gould, E., Eur.J.Neurosci., 12:2211-2214 (2000); Gould, people such as E., Biol.Psychiatry, 48:715-720 (2000); And Gould, people such as E., Nat.Neurosci., 2:260-265 (1999)).Present ongoing experimental strategy is neuronal stem cell (neuron stem) to be transplanted to be used for multiple treatment indication (Kurimoto, people such as Y., Neurosci.Lett., 306:57-60 (2001) in adult's brain; Singh, G., Neuropathology, 21:110-114 (2001); And Cameron, H.A. and McKay, R.D., Nat.Neurosci., 2:894-897 (1999)).Known many about the interim neurogenetic content (Saitoe of embryonic development, M. and Tully, T., " Making connections between synaptic and behavioral plasticity in Drosophila ", In Toward a Theory of Neuroplasticity, J.McEachern and C.Shaw, Eds. (New York:Psychology Press.), 193-220 page or leaf (2000)).As if neuron differentiation (Neuronal Differentiation), neurite prolong and the conspicuous sign of initial burst other (initial synaptic target recognition) all takes place with the activity dependent enzymes form.Yet (ongoing) neuronal activity that outstanding generation subsequently and synapse growth needs continue to finely tune synapse in the relevant mode of function and connects.These discoveries show that the integrated effect of function (final) of the neuronal stem cell of being transplanted needs neuronal activity.Therefore, ACT can be used for taking exercise suitable neuronal circuit and connects, is divided into neuronic transplanting stem cell to finely tune the synapse of newly obtaining." temper suitable neuronal circuit " and mean at one or more suitable neuronal circuits and induce the neuronal activity pattern, it is corresponding to the activity that is produced by concrete cognitive training scheme.Described cognitive training scheme can be used for inducing such neuronal activity.Perhaps, can induce neuronal activity by stimulus of direct current to neuronal circuit." neuronal activity " and " neural activity " of this paper can exchange use.

Memory medicament (for example the CREB approach strengthens medicine) can strengthen CREB approach function, and it is essential for the information consolidation that will newly obtain for LTM." strengthen CREB approach function " and mean the ability that strengthens or improve the expression of CREB dependent gene.Generation that can be by increasing endogenous CREB (for example by directly or the indirect stimulation endogenous gene to produce the CREB of recruitment, perhaps by increasing functional (biologic activity) CREB) strengthen or improve the expression of CREB dependent gene.Referring to for example United States Patent (USP) 5,929,223; United States Patent (USP) 6,051,559; With international publication WO9611270 (announcement on April 18th, 1996), its integral body is quoted adding this paper.Administration memory medicament can reduce the progressive performance required training of generation for the performance that is only produced by training." progressive performance " means the improvement aspect the memory performance.

The invention provides (in some embodiments, have this to need) assessment, test and/or differentiate the enhanced method of the particular aspects of memory in the animal (particularly human or other mammal or vertebrates), wherein said enhancing can be realized by following mode: (a) remember medicament (for example strengthening the medicament of CREB approach function) to described animals administer; And (b) produce the described animal of training under the progressive condition in the performance that is being enough to make described animal to concrete memory tasks.

Training can comprise one or more training periods, and is the progressive training of performance that is suitable for producing the memory tasks of being paid close attention to.For example, obtain the aspect and obtain progressively if be desirably in language, then training can concentrate on language and obtains.If be desirably in the ability aspect acquisition progress that study plays an instrument, then training can concentrate on and learn to play an instrument.Obtain progress if be desirably in special exercise technical ability aspect, then training can concentrate on obtaining of special exercise technical ability.Certain memory task of being paid close attention to and suitable training are complementary.

The present invention also is provided at assessment in the animal, test and/or differentiates and shows enhanced method by repetitive stimulation neuronal activity or the caused memory of neuronal activity pattern (for example potential pattern of the neuronal activity in one or more specific neuronal circuits), and it comprises: the memory medicament that (a) strengthens CREB approach function to described animals administer; And (b) be enough to the animal moderate stimulation or induce neuronal activity or the condition of neuronal activity pattern under the training described animal.In this case, training is meant and is suitable at the animal moderate stimulation or induces neuronal activity or the training of neuronal activity pattern.

" a plurality of training period " means two or more a plurality of training period.Can before one or more training periods, during or administration afterwards memory medicament.In one embodiment, before each training period and during administration memory medicament.

The specific training program that can assess according to the present invention is known in the art and is easy to obtain.Referring to for example Karni, A. and Sagi, D., " Where practice makes perfect in text discrimination:evidence for primary visual cortex plasticity ", Proc.Natl.Acad.Sci.USA, 88:4966-4970 (1991); Karni, A. and Sagi, D., " The time course of learning a visual skill ", Nature, 365:250-252 (1993); Kramer, A.F. wait the people, " Taskcoordination and aging:explorations of executive control processes in the task switching paradigm ", Acta Psychol. (Amst.), 101:339-378 (1999); Kramer, A.F. wait the people, " Training for executive control:Task coordination strategies and aging ", In Aging and Skilled Performance:Advances In Theory and Applications, people such as W.Rogers, eds. (Hillsdale, N.J.:Erlbaum) (1999); Rider, R.A. and Abdulahad, D.T., " Effects of massed versus distributed practice on gross and fine motor proficiency of educable mentally handicapped adolescents ", Percept.Mot.Skills, 73:219-224 (1991); Willis, S.L. and Schaie, K.W., " Training the elderly on the ability factors of spatial orientation and inductive reasoning ", Psychol.Aging, 1:239-247 (1986); Willis, S.L. and Nesselroade, C.S., " Long-term effects of fluid ability training in old-old age ", Develop.Psychol., 26:905-910 (1990); Wek, S.R. and Husak, W.S., " Distributed and massed practice effects on motor performance and learning of autistic children ", Percept.Mot.Skills, 68:107-113 (1989); Verhaehen, people such as P., " Improving memory performance in the aged through mnemonic training:a meta-analytic study ", Psychol.Aging, 7:242-251 (1992); Verhaeghen, P. and Salthouse, T.A., " Meta-analyses of age-cognition relations in adulthood:estimates of linear and nonlinear age effects and structural models ", Psychol.Bull, 122:231-249 (1997); Dean, C.M. wait the people, " Task-related circuit training improves performance of locomotor tasks in chronic stroke:a randomized; controlled pilot trial ", Arch.Phys.Med.Rehabil, 81:409-417 (2000); Greener, people such as J., " Speech and language therapy for aphasia following stroke ", Cochrane Database Syst.Rev., CD000425 (2000); Hummelsheim, H. and Eickhof, C, " Repetitive sensorimotor training for arm and hand in a patient with locked-in syndrome ", Scand.J.Rehabil.Med., 31:250-256 (1999); Johansson, B.B., " Brain plasticity and stroke rehabilitation.The Willis lecture ", Stroke, 31:223-230 (2000); Ko Ko, C, " Effectiveness of rehabilitation for multiple sclerosis ", Clin.Rehabil., 13 (supplementary issue 1): 33-41 (1999); Lange, G. wait the people, " Organizational strategy influence on visual memory performance after stroke:cortical/subcortical and left/right hemisphere contrasts ", Arch.Phys.Med.Rehabil., 81:89-94 (2000); Liepert, people such as J., " Treatment-induced cortical reorganization after stroke in humans ", Stroke, 31:1210-1216 (2000); Lotery, people such as A.J., " Correctable visual impairment in stroke rehabilitation patients ", Age Ageing, 29:221-222 (2000); Majid, people such as M.J., " Cognitive rehabilitation for memory deficits following stroke " (Cochrane review), Cochrane Database Syst.Rev., CD002293 (2000); Merzenich, M. wait the people, " Cortical plasticity underlying perceptual; motor; and cognitive skill development:implications for neurorehabilitation ", Cold Spring Harb.Symp.Quant.Biol., 61:1-8 (1996); Merzenich, people such as M.M., " Temporal processing deficits of language-learning impaired children ameliorated by training ", Science, 271:77-81 (1996); Murphy, E., " Stroke rehabilitation ", J.R.Coll.Physicians Lond., 33:466-468 (1999); Nagarajan, people such as S.S., " Speech modifications algorithms used for training language learning-impaired children ", IEEE Trans.Rehabil.Eng., 6:257-268. (1998); Oddone, people such as E., " Quality Enhancement Research Initiative in stroke:prevention, treatment, and rehabilitation ", Med.Care 38:192-1104 (2000); Rice-Oxley, M. and Turner-Stokes, L., " Effectiveness of brain injury rehabilitation ", Clin.Rehabil., 13 (supplementary issue 1): 7-24 (1999); Tallal, people such as P., " Language learning impairments:integrating basic science, technology, and remediation ", Exp.Brain Res., 123:210-219 (1998); Tallal, P. wait the people, " Language comprehension in language-learning impaired children improved with acoustically modified speech ", Science, 271:81-84 (1996), its integral body is quoted adding this paper.

Correspondingly, strengthen the method for longterm memory in the animal that the invention still further relates in the described treatment of needs (particularly human or other mammal or vertebrates), it comprises: (a) the memory medicament of differentiating, testing or assess through the method for estimating, assessing and/or testing memory medicament effectiveness to described animals administer, selection is perhaps tested the memory medicament as the longterm memory reinforcing agent as the memory medicament of medical compounds; And (b) be enough in described animal to strengthen the described animal of training under the condition of longterm memory.

In one embodiment, the invention still further relates to the method for relevant memory impairment of treatment age in the animal of the described treatment of needs, it comprises: (a) the memory medicament of differentiating, testing or assess through the method for estimating, assessing and/or testing memory medicament effectiveness to described animals administer, selection is perhaps tested the memory medicament as the longterm memory reinforcing agent as the memory medicament of medical compounds; And (b) be enough in described animal to strengthen the described animal of training under the condition of longterm memory.

In another embodiment, the present invention relates to treatment and the relevant letheral method of neurodegenerative disease (for example Alzheimer, parkinson disease, Huntington Chorea, other alzheimer disease) in the animal of the described treatment of needs, it comprises: (a) the memory medicament of differentiating, testing or assess through the method for estimating, assessing and/or testing memory medicament effectiveness to described animals administer, selection is perhaps tested the memory medicament as the longterm memory reinforcing agent as the memory medicament of medical compounds; And (b) be enough in described animal to strengthen the described animal of training under the condition of longterm memory.

In another embodiment, the present invention relates to treatment and the relevant letheral method of psychosis (for example depression, schizophrenia, autism, attention deficit syndrome) in the animal of the described treatment of needs, it comprises: (a) the memory medicament of differentiating, testing or assess through the method for estimating, assessing and/or testing memory medicament effectiveness to described animals administer, selection is perhaps tested the memory medicament as the longterm memory reinforcing agent as the memory medicament of medical compounds; And (b) be enough in described animal to strengthen the described animal of training under the condition of longterm memory.

In another embodiment, the present invention relates to the method for the memory impairment that treatment is relevant with wound dependency memory function forfeiture (for example cerebrovascular disease (for example apoplexy, ischemia), cerebroma, head or brain injury) in the animal of the described treatment of needs, it comprises: (a) the memory medicament of differentiating, testing or assess through the method for estimating, assessing and/or testing memory medicament effectiveness to described animals administer, selection is perhaps tested the memory medicament as the longterm memory reinforcing agent as the memory medicament of medical compounds; And (b) be enough in described animal to strengthen the described animal of training under the condition of longterm memory.

In another embodiment, the present invention relates to treatment and the relevant letheral method of genetic defect (for example Rubinstein-Taybi syndrome, mongolism) in the animal of the described treatment of needs, it comprises: (a) the memory medicament of differentiating, testing or assess through the method for estimating, assessing and/or testing memory medicament effectiveness to described animals administer, selection is perhaps tested the memory medicament as the longterm memory reinforcing agent as the memory medicament of medical compounds; And (b) be enough in described animal to strengthen the described animal of training under the condition of longterm memory.

The invention still further relates to the treatment letheral method relevant in the animal of accepting the neuronal stem cell processing with the CNS disease or the patient's condition, it comprises: (a) the memory medicament of differentiating, testing or assess through the method for estimating, assessing and/or testing memory medicament effectiveness to described animals administer, selection is perhaps tested the memory medicament as the longterm memory reinforcing agent as the memory medicament of medical compounds; And (b) be enough in described animal to strengthen the described animal of training under the condition of longterm memory." neuronal stem cell processing " means: (1) is transplanted to exogenous neuronal stem cell in the brain or spinal cord (spinal chord) of animal, and perhaps (2) are at the animal moderate stimulation or induce the hypertrophy of endogenous neuronal stem cell.With neuronal stem cell to be transplanted to the brain of animal or the method in the spinal cord be known in the art and be easy to obtain (referring to for example Cameron, H.A. and McKay, R.D., Nat.Neurosci., 2:894-897 (1999); Kurimoto, people such as Y., Neurosci.Lett., 306:57-60 (2001); And Singh, G., Neuropathology, 21:110-114 (2001)).The animal moderate stimulation or to induce the outgrowth method of endogenous neuronal stem cell be known in the art and be easy to obtain (referring to for example Gould, people such as E., Trends Cogn.Sci, 3:186-192 (1999); Gould, people such as E., Biol.Psychiatry, 48:715-20 (2000); Nilsson, people such as M., J.Neurobiol., 39:569-578 (1999); Fuchs, E. and Gould, E., Eur.J.Neurosci., 12:2211-2214 (2000); And Gould, people such as E., Nat.Neurosci., 2:260-265 (1999)).Neuronal stem cell is transplanted to the brain of animal or the concrete grammar in the spinal cord and at animal moderate stimulation or the outgrowth concrete grammar of inducing the endogenous neuronal stem cell for implementing the present invention and indecisive.

The invention still further relates to the method for in the animal that suffers from study, language or reading disorder or aforementioned combination in any improvement or hypermnesis and/or performance, it comprises: (a) the memory medicament of differentiating, testing or assess through the method for estimating, assessing and/or testing memory medicament effectiveness to described animals administer, selection is perhaps tested the memory medicament as the longterm memory reinforcing agent as the memory medicament of medical compounds; And (b) be enough in described animal to strengthen the described animal of training under the condition of longterm memory.

The memory medicament

Memory medicament used herein is that dysmnesia and/or memory dysfunction are had the chemical compound of pharmacological activity, and comprises medicine, chemical compound, ionic compound, organic compound, organic ligand (comprising cofactor, saccharide, recombinant and synthetic peptide), protein, class peptide, nucleotide sequence (comprising gene, nucleic acid product) and other molecule and compositions.The memory medicament can for example strengthen or damage short-term or longterm memory.For example, the memory medicament can be the title submitted on February 27th, 2007 U.S. Patent application 11/679,782 for " Therapeutic Piperazones "; Title in December in 2006 submission on the 8th is the U.S. Patent application 11/608,746 of " Indolone Compound Useful To Treat Cognitive Impairment "; And the title of submitting on February 27th, 2006 is the U.S. Patent application 11/679,775 of " Therapeutic Compound "; The title of submitting on June 8th, 2007 is any compound of mentioning in the U.S. Provisional Patent Application 60/942,992 of " Therapeutic Pyrazoloquinoline Urea Derivatives ", and adding this paper is quoted in above-mentioned patent application integral body separately.

Memory impairment agent used herein has the chemical compound of pharmacological activity for (retained memory) (for example post-traumatic stress disorder) remembered in reservation, and comprises medicine, chemical compound, ionic compound, organic compound, organic ligand (comprising cofactor, saccharide, recombinant and synthetic peptide), protein, class peptide, nucleotide sequence (comprising gene, nucleic acid product) and other molecule and compositions.Memory impairment agent of the present invention and hypermnesia agent can be in method and system of the present invention any one use.

For example, the memory medicament can be Premeabilisation of cells agent cAMP analog (for example 8-bromine cAMP); Adenyl cyclase 1 (AC1) activator (for example Fu Sikelin); Act on the medicament of G-protein coupled receptor, such as but not limited to adrenoreceptor and opioid recdptor and their part (for example phenethylamine class); Cellular calcium concentration regulator (for example thapsigargin, N-methyl-D-aspartate (NMDA) receptor stimulating agent); Be responsible for the phosphodiesterase inhibitor that cAMP decomposes (cAMP breakdown) (for example rolipram (it suppresses phosphodiesterase 4), isobutyl group-methyl-xanthine (iso-buto-1-metho-xanthine, IBMX) (it suppresses phosphodiesterase 1 and 2)); Protein kinase and/or phosphoprotein phosphatase regulator, it is regulated, and CREB protein activates and the CREB dependent gene is expressed.The memory medicament also can be exogenous CREB, CREB analog, CREB sample molecule, biological activity CREB fragment, CREB fusion rotein, and/or the nucleotide sequence of encoding exogenous CREB, CREB analog, CREB sample molecule, biological activity CREB fragment and/or CREB fusion rotein.

The memory medicament also can be the nucleotide sequence of CREB function regulator and/or coding CREB function regulator.CREB function regulator used herein has the ability of regulating CREB approach function." adjusting " means the ability of change (increase or reduce) or change CREB approach function.

The memory medicament can be the chemical compound that can strengthen the CREB function in CNS.Described chemical compound includes but not limited to influence the chemical compound that cell membrane stability and flowability and specific immunity stimulate.In one embodiment, the memory medicament can temporarily strengthen CREB approach function in CNS.

CREB analog or derivant are defined as the protein with the aminoacid sequence that is similar to endogenous CREB in this article.Similarly aminoacid sequence definition in this article means such aminoacid sequence, thereby itself and endogenous CREB aminoacid sequence have the physiologically active that enough homogeneity has endogenous CREB, but have one or more " reticent (silent) " to change in described aminoacid sequence.The CREB analog comprises mammiferous CREM, mammiferous ATF-1 and other CREB/CREM/ATF-1 subtribe member.

Term CREB sample molecule used herein is meant on the function protein that is similar to (simulation) CREB.CREB sample molecule needn't have the aminoacid sequence that is similar to endogenous CREB.

The example of memory medicament can comprise:

The example of memory medicament also can comprise:

Wherein " Me " means methyl, and " cPent " means " cyclopenta ".Following formula comprises two kinds of enantiomer and composition thereof.In a specific embodiments (HT-0712), 3 of following formula and 5 carbon are the S configuration.

Example also can comprise the chemical compound with following structure:

Y wherein ₁, Y ₂, Y ₃And Y ₄Be independently of one another-H; Straight or branched C ₁-C ₇Alkyl, single fluoroalkyl or Polyfluoroalkyl; Straight or branched C ₂-C ₇Alkenyl or alkynyl; C ₃-C ₇Cycloalkyl or C ₅-C ₇Cycloalkenyl group;-F ,-Cl ,-Br or-I;-NO ₂-N ₃-CN;-OR ₄,-OCOR ₄,-COR ₄,-NCOR ₄,-N (R ₄) ₂,-CON (R ₄) ₂Or-COOR ₄Aryl or heteroaryl; Perhaps be present in the Y on the adjacent carbon atom ₁, Y ₂, Y ₃And Y ₄In any two can constitute methylenedioxy group; Each R wherein ₄Be independently-H; Straight or branched C ₁-C ₇Alkyl, single fluoroalkyl or Polyfluoroalkyl; Straight or branched C ₂-C ₇Alkenyl or alkynyl; C ₃-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group, aryl or aryl (C ₁-C ₆) alkyl; Wherein A is A ', straight or branched C ₁-C ₇Alkyl, aryl, heteroaryl, aryl (C ₁-C ₆) alkyl or heteroaryl (C ₁-C ₆) alkyl; Wherein A ' is

R wherein ₁And R ₂Be independently of one another-H, straight or branched C ₁-C ₇Alkyl ,-F ,-Cl ,-Br ,-I ,-NO ₂Or-CN; R wherein ₃For-H, straight or branched C ₁-C ₇Alkyl ,-F ,-Cl ,-Br ,-I ,-NO ₂,-CN ,-OR ₆, aryl or heteroaryl; R wherein ₅Be straight or branched C ₁-C ₇Alkyl ,-N (R ₄) ₂,-OR ₄Or aryl; R wherein ₆Be straight or branched C ₁-C ₇Alkyl or aryl; Wherein B is C ₃-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group, adamantyl, aryl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, the indolizine base, indole-4-base, indole-5-base, indole-6-base, indole-7-base, isoindolyl, benzo [b] furan-4-base, benzo [b] furan-5-base, benzo [b] furan-6-base, benzo [b] furan-7-base, benzo [b] thiophene-4-base, benzo [b] thiophene-5-base, benzo [b] thiophene-6-base, benzo [b] thiophene-7-base, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purine radicals, imidazo [2,1-b] thiazolyl, quinolyl, isoquinolyl, quinazolyl, 2,1, the 3-benzothiazolyl, furyl, thienyl, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group benzoxazolyl, the benzoisoxazole base, the cinnolines base, quinoxalinyl, 1, the 8-naphthyridinyl, pteridyl or phthaloyl imino; Yet, its condition is if B is an aryl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, the indolizine base, indole-4-base, indole-5-base, indole-6-base, indole-7-base, isoindolyl, benzo [b] furan-4-base, benzo [b] furan-5-base, benzo [b] furan-6-base, benzo [b] furan-7-base, benzo [b] thiophene-4-base, benzo [b] thiophene-5-base, benzo [b] thiophene-6-base, benzo [b] thiophene-7-base, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purine radicals, imidazo [2,1-b] thiazolyl, quinolyl, isoquinolyl, quinazolyl, 2,1, the 3-benzothiazolyl, furyl, thienyl, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group benzoxazolyl, the benzoisoxazole base, the cinnolines base, quinoxalinyl, 1, the 8-naphthyridinyl, pteridyl or phthaloyl imino, then the adjacent one or more carbon atoms of imine linkage nitrogen-atoms only can be replaced by in the following group one or more :-F,-Cl,-Br,-I,-CN, methyl, ethyl or methoxyl group; Wherein n is the integer that comprises the 1-4 of end value, and wherein aryl is a phenyl or naphthyl, comprise by phenyl that one or more replaced and naphthyl in the following group :-F ,-Cl ,-Br ,-I ,-NO ₂,-CN, straight or branched C ₁-C ₇Alkyl, straight or branched C ₁-C ₇Single fluoroalkyl, straight or branched C ₁-C ₇Polyfluoroalkyl, straight or branched C ₂-C ₇Thiazolinyl, straight or branched C ₂-C ₇Thiazolinyl, C ₃-C ₇Cycloalkyl, C ₁-C ₇Single fluorine cycloalkyl, C ₃-C ₇Polyfluoro cycloalkyl, C ₅-C ₇Cycloalkenyl group ,-OR ₄, SR ₄,-OCOR ₄,-COR ₄,-NCOR ₄,-CO ₂R ₄,-CON (R ₄) ₂Or-(CH ₂) _n-O-(CH ₂) _m-CH ₃

In some embodiments, A is aryl, heteroaryl or heteroaryl (C ₁-C ₆) alkyl; And wherein aryl quilt-F ,-Cl ,-Br ,-I ,-NO ₂,-CN, straight or branched C ₁-C ₇Alkyl, straight or branched C ₁-C ₇Single fluoroalkyl, straight or branched C ₁-C ₇Polyfluoroalkyl, straight or branched C ₂-C ₇Thiazolinyl, straight or branched C ₂-C ₇Alkynyl, C ₃-C ₇Cycloalkyl, C ₃-C ₇Single fluorine cycloalkyl, C ₃-C ₇Polyfluoro cycloalkyl, C ₅-C ₇Cycloalkenyl group ,-N (R ₄) ₂,-OR ₄,-SR ₄,-OCOR ₄,-COR ₄,-NCOR ₄,-CO ₂R ₄,-CON (R ₄) ₂Or-(CH ₂) _n-O-(CH ₂) _m-CH ₃Replace.A also can be aryl, heteroaryl, heteroaryl (C ₁-C ₆) alkyl or-(CH ₂) _n-CC-R ₄Wherein said aryl is replaced by-OH.In other embodiments, wherein A is A ', and A ' is

In other embodiments, Y ₁, Y ₂, Y ₃And Y ₄Be independently of one another-H; Straight or branched C ₁-C ₇Alkyl ,-CF ₃,-F ,-Cl ,-Br ,-I ,-OR ₄,-N (R ₄) ₂Or-CON (R ₄) ₂Each R wherein ₄Be independently-H; Straight or branched C ₁-C ₇Alkyl ,-CF ₃Or phenyl; Wherein A is A ', straight or branched C ₁-C ₇Alkyl, aryl, heteroaryl, aryl (C ₁-C ₆) alkyl or heteroaryl (C ₁-C ₆) alkyl; And wherein A ' is

In certain embodiments, B is C ₃-C ₇Cycloalkyl or adamantyl.In other embodiments, B is a pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, the indolizine base, indole-4-base, indole-5-base, indole-6-base, indole-7-base, isoindolyl, benzo [b] furan-4-base, benzo [b] furan-5-base, benzo [b] furan-6-base, benzo [b] furan-7-base, benzo [b] thiophene-4-base, benzo [b] thiophene-5-base, benzo [b] thiophene-6-base, benzo [b] thiophene-7-base, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purine radicals, imidazo [2,1-b] thiazolyl, quinolyl, isoquinolyl, quinazolyl, 2,1, the 3-benzothiazolyl, furyl, thienyl, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group benzoxazolyl, the benzoisoxazole base, the cinnolines base, quinoxalinyl, 1,8-naphthyridinyl, pteridyl or phthaloyl imino.In other embodiments, B is an aryl or for phenyl, and described phenyl is randomly replaced by in the following group one or more :-F ,-Cl ,-Br ,-CF ₃, straight or branched C ₁-C ₇Alkyl ,-OR ₄,-COR ₄,-NCOR ₄,-CO ₂R ₄Or-CON (R ₄) ₂

Other example comprises the chemical compound with following structure:

Other example comprises the chemical compound with following structure:

R wherein ₁And R ₂Be independently of one another-H, straight or branched C ₁-C ₇Alkyl ,-F ,-Cl ,-Br ,-I ,-NO ₂Or-CN; R wherein ₃For-H, straight or branched C ₁-C ₇Alkyl ,-F ,-Cl ,-Br ,-I ,-NO ₂,-CN ,-OR ₆, aryl or heteroaryl; R wherein ₅Be straight or branched C ₁-C ₇Alkyl ,-N (R ₄) ₂,-OR ₄Or aryl; R wherein ₆Be straight or branched C ₁-C ₇Alkyl or aryl; Wherein B is an aryl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, the indolizine base, indole-4-base, indole-5-base, indole-6-base, indole-7-base, isoindolyl, benzo [b] furan-4-base, benzo [b] furan-5-base, benzo [b] furan-6-base, benzo [b] furan-7-base, benzo [b] thiophene-4-base, benzo [b] thiophene-5-base, benzo [b] thiophene-6-base, benzo [b] thiophene-7-base, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purine radicals, imidazo [2,1-b] thiazolyl, quinolyl, isoquinolyl, quinazolyl, 2,1, the 3-benzothiazolyl, furyl, thienyl, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group benzoxazolyl, the benzoisoxazole base, the cinnolines base, quinoxalinyl, 1, the 8-naphthyridinyl, pteridyl or phthaloyl imino; Yet its condition is that the adjacent one or more carbon atoms of imine linkage nitrogen-atoms only can be replaced by in following one or more :-F ,-Cl ,-Br ,-I ,-CN, methyl, ethyl or methoxyl group; Wherein n is the integer that comprises the 1-4 of end value; Wherein aryl is a phenyl or naphthyl, comprise by phenyl that one or more replaced and naphthyl in the following group :-F ,-Cl ,-Br ,-I ,-NO ₂,-CN, straight or branched C ₁-C ₇Alkyl, straight or branched C ₁-C ₇Single fluoroalkyl, straight or branched C ₁-C ₇Polyfluoroalkyl, straight or branched C ₂-C ₇Thiazolinyl, straight or branched C ₂-C ₇Alkynyl, C ₃-C ₇Cycloalkyl, C ₁-C ₇Single fluorine cycloalkyl, C ₃-C ₇Polyfluoro cycloalkyl, C ₅-C ₇Cycloalkenyl group ,-OR ₄, SR ₄,-OCOR ₄,-COR ₄,-NCOR ₄,-CO ₂R ₄,-CON (R ₄) ₂Or-(CH ₂) _n-O-(CH ₂) _m-CH ₃The perhaps acceptable salt of its pharmacy.In some embodiments, Y ₁, Y ₂, Y ₃And Y ₄Be independently of one another-H; Straight or branched C ₁-C ₇Alkyl ,-CF ₃,-F ,-Cl ,-Br ,-I ,-OR ₄,-N (R ₄) ₂Or-CON (R ₄) ₂

In some embodiments, A is aryl, heteroaryl, heteroaryl (C ₁-C ₆) alkyl or-(CH ₂) _n-CC-R ₄Wherein aryl is replaced by-OH.In other embodiments, A is aryl, heteroaryl or heteroaryl (C ₁-C ₆) alkyl; And wherein aryl quilt-F ,-Cl ,-Br ,-I ,-NO ₂,-CN, straight or branched C ₁-C ₇Alkyl, straight or branched C ₁-C ₇Single fluoroalkyl, straight or branched C ₁-C ₇Polyfluoroalkyl, straight or branched C ₂-C ₇Thiazolinyl, straight or branched C ₂-C ₇Alkynyl, C ₃-C ₇Cycloalkyl, C ₃-C ₇Single fluorine cycloalkyl, C ₃-C ₇Polyfluoro cycloalkyl, C ₅-C ₇Cycloalkenyl group ,-N (R ₄) ₂,-OR ₄,-SR ₄,-OCOR ₄,-COR ₄,-CO ₂R ₄,-CON (R ₄) ₂Or-(CH ₂) _n-O-(CH ₂) _m-CH ₃Replace.A also can be aryl or aryl (C ₁-C ₆) alkyl.In other embodiments, A is A ', straight or branched C ₁-C ₇Alkyl, aryl, heteroaryl, aryl (C ₁-C ₆) alkyl or heteroaryl (C ₁-C ₆) alkyl; And A ' is

Chemical compound as herein described can be that mapping is pure and/or diastereo-isomerism is pure.It also can be pure Z imine isomer or pure Z olefin isomer, perhaps pure E imine isomer or pure E olefin isomer.

Other example comprises:

Other example can comprise the chemical compound of following formula:

Or the acceptable salt of its pharmacy, wherein:

R ₁, R ₂, R ₃And R ₄Be selected from independently of one another hydrogen, hydroxyl, halogen, cyano group ,-CONR _aR _b,-NR _aR _b, hydroxyl (C ₁-C ₆) alkyl, aryl, heteroaryl, heterocycle, amino (C ₁-C ₆) the alkyl, (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkyl and the (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkoxyl;

R _aAnd R _bBe hydrogen, (C independently of one another ₁-C ₆) alkyl, aryl, (C ₁-C ₆) alkyl OC (O)-or aryl OC (O)-, perhaps R _aAnd R _bForm randomly by one or more R jointly with the nitrogen that links to each other with them _dThe heterocyclic group that replaces; Wherein said heterocyclic group randomly comprises one or more O of being selected from (oxygen), S (O) _zAnd NR _cGroup;

Z respectively does for oneself and is selected from 0,1 and 2 integer;

R _cBe hydrogen, (C independently of one another ₂-C ₆) thiazolinyl, (C ₂-C ₆) alkynyl ,-C (O) O (C ₁-C ₆) alkyl ,-C (O) O aryl, (C ₁-C ₆) alkoxyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkyl O (CH ₂) _m, hydroxyl (C ₁-C ₆) alkyl, aryl, heteroaryl, heterocycle, aryl O (C ₁-C ₆) alkyl ,-C (O) NR _g(C ₁-C ₆) alkyl ,-C (O) NR _gAryl ,-S (O), (C ₁-C ₆) alkyl ,-S (O), aryl ,-C (O) (C ₁-C ₆) alkyl, aryl C (O)-, randomly by 5 (C that fluorine replaces at the most ₁-C ₆) alkyl or the (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkoxyl;

M respectively does for oneself and is selected from 2,3,4,5 and 6 integer;

R _dBe selected from independently of one another hydrogen, halogen, oxo, hydroxyl ,-C (O) NR _aR _b,-NR _aR _b, hydroxyl (C ₁-C ₆) alkyl, aryl, aryl (C ₁-C ₆) the alkyl, (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkyl and the (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkoxyl;

R _cAnd R _rBe selected from hydrogen, (C independently of one another ₁-C ₆) alkyl, aryl ,-S (O) (C ₁-C ₆) alkyl ,-S (O) aryl ,-CONR _g(C ₁-C ₆Alkyl), (C ₁-C ₆) alkyl C (O)-, aryl C (O)-, (C ₁-C ₆) alkyl OC (O)-and aryl OC (O)-;

R _gBe hydrogen or (C ₁-C ₆) alkyl;

R ₅And R ₆Be selected from hydrogen, (C independently of one another ₁-C ₆) alkyl, (C ₂-C ₆) thiazolinyl, (C ₂-C ₆) alkynyl and aryl, perhaps R ₅And R ₆Form randomly by one or more R jointly with the nitrogen that links to each other with them _dThe heterocyclic group that replaces; Wherein said heterocyclic group randomly comprises one or more O of being selected from (oxygen), S (O) _zAnd NR _cGroup;

R ₇Be selected from hydrogen, hydroxyl, halogen, hydroxyl (C ₁-C ₆) the alkyl, (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkyl and the (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkoxyl;

Ar is for separately randomly by one or more R ₈The aryl or the heteroaryl that replace; And

R ₈Be hydrogen, halogen, CF independently of one another ₃, CF ₂H, hydroxyl, cyano group, nitro, (C ₁-C ₆) alkyl, hydroxyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-NR _aR _b, aryl, heteroaryl or heterocycle.

Other example comprises the chemical compound of following formula:

And the acceptable salt of pharmacy.

R ₅And R ₆Can be for example form tetrahydro-1,4-thiazine ring in piperidyl, pyrrolidinyl, morpholinyl or the following formula chemical compound jointly with the nitrogen that links to each other with them.

Other example comprises the chemical compound of following formula:

And the acceptable salt of pharmacy, wherein: X is N (R _c), O (oxygen), C (R _d) ₂Or S (O) _zZ is selected from 0,1 and 2 integer; R _dBe selected from independently of one another hydrogen, halogen, oxo, hydroxyl ,-C (O) NR _aR _b,-NR _aR _b, hydroxyl (C ₁-C ₆) alkyl, aryl, aryl (C ₁-C ₆) the alkyl, (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkyl and the (C that randomly replaced by 5 fluorine at the most ₁-C ₆) alkoxyl; And n is selected from 0,1 and 2 integer; Its condition is that X is C (R when n=0 _d) ₂

Other example comprises the chemical compound of following formula:

And the acceptable salt of pharmacy.

Other example comprises the chemical compound of following formula:

And the acceptable salt of pharmacy, wherein n is 0,1 or 2.

In some embodiments, R ₂Be methyl, fluorine or OMe.In some embodiments, R ₃Be methyl, fluorine or OMe.In some embodiments, R ₂And R ₃Be fluorine.In another embodiment, R ₂And R ₃Be methyl.

Other example comprises the chemical compound of following formula:

And the acceptable salt of pharmacy.

Other example comprises the chemical compound of following formula:

And the acceptable salt of pharmacy, wherein Y is N or C (R independently of one another ₈).In some embodiments, R ₅And R ₆Form separately randomly by one or more R jointly with the nitrogen that links to each other with them _dThe piperidyl, pyrrolidinyl, morpholinyl or the tetrahydro-1,4-thiazine ring that replace.

Other example comprises the chemical compound of following formula:

And the acceptable salt of pharmacy.

In some embodiments, n can be 0,1 or 2.In some embodiments, R ₂Can be methyl, fluorine or OMe.In some embodiments, R ₃Can be methyl, fluorine or OMe.In some embodiments, R ₂And R ₃It can be fluorine.In another embodiment, R ₂And R ₃It can be methyl.

Other example comprises the chemical compound of following formula:

And the acceptable salt of pharmacy.

Example also comprises the chemical compound of following formula:

Wherein: R ₁Be H, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, (C ₁-C ₆) alkanoyloxy, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, aryl, aryl (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkoxyl, aryl (C ₁-C ₆) alkanoyl, het, het (C ₁-C ₆) alkyl, het (C ₁-C ₆) alkoxyl or het (C ₁-C ₆) alkanoyl;

N is 1 or 2;

M is 1 or 2;

W is O, S or two hydrogen;

X is O or N-Y-R ₄

Y be direct key ,-CH ₂-,-C (=O)-,-C (=S)-,-O-,-C (=O) O-,-OC (=O)-,-C (=O) NR _a-,-S-,-S (=O)-,-S (=O) ₂-or-S (=O) ₂NR _a-;

R ₄Be H, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, hydroxyl, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, hydroxyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxy carbonyl group, carboxyl, aryl, aryl (C ₁-C ₆) alkyl, het, NR _dR _e,-C (=O) R _dR _e, NR _dR _e(C ₁-C ₆) alkyl or het (C ₁-C ₆) alkyl;

R _aBe H, (C ₁-C ₆) alkyl, (C ₃-C ₈) cycloalkyl, (C ₁-C ₆) alkoxyl (C ₂-C ₆) alkyl or (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl;

Z is that described substituent group is independently selected from (C by the phenyl ring that one or more substituent group replaced ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, halo (C ₁-C ₆) alkoxyl, (C ₃-C ₈) cycloalkyloxy and (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkoxyl; Perhaps Z be with saturated, part is undersaturated or the monocycle of aromatics or the condensed phenyl ring of bicyclic system, described monocycle or bicyclic system comprise about 3 to about 8 and are selected from carbon, oxygen and NR _bAtom, wherein the monocycle of Z or bicyclic system are randomly by one or more R _bReplace, and wherein randomly replaced by one or more substituent group with described monocycle or the condensed phenyl ring of bicyclic system, described substituent group is independently selected from (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, halo (C ₂-C ₆) alkoxyl, (C ₃-C ₈) cycloalkyloxy and (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkoxyl;

R _bFor do not exist, H, (C ₁-C ₆) alkyl, (C ₃-C ₈) cycloalkyl, (C ₁-C ₆) alkoxyl (C ₂-C ₆) alkyl or (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl;

Rc is (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, (C ₁-C ₆) alkanoyloxy, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, aryl, aryl (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkoxyl, aryl (C ₁-C ₆) alkanoyl, het, het (C ₁-C ₆) alkyl, het (C ₁-C ₆) alkoxyl or het (C ₁-C ₆) alkanoyl;

R _dAnd R _eBe H, hydroxyl, (C independently of one another ₁-C ₆) alkyl, (C ₁-C ₆) thiazolinyl, (C ₂-C ₆) alkynyl, (C ₁-C ₆) alkoxyl, (C ₂-C ₆) alkene oxygen base, (C ₂-C ₆) alkynyloxy group, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, aryl, aryl (C ₁-C ₆) alkyl, NR _fR _gOr aryl (C ₁-C ₆) alkoxyl; And

R _fAnd R _gBe H, (C independently of one another ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, aryl, aryl (C ₁-C ₆) alkyl or aryl (C ₁-C ₆) alkoxyl; Perhaps R _fAnd R _gForm pyrrolidinyl, piperidyl, piperazinyl, morpholinyl or tetrahydro-1,4-thiazine ring jointly with the nitrogen that links to each other with them;

Wherein any aryl or R ₁And R ₄Het randomly replaced by one or more substituent group, described substituent group is independently selected from (C ₁-C ₆) alkyl, phenyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, (C ₁-C ₆) alkanoyloxy, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, (C ₃-C ₈) cycloalkyloxy, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkoxyl, halo (C ₂-C ₆) alkoxyl, cyano group, nitro, halogen, carboxyl or NR _dR _e

And the ring that wherein contains X randomly on carbon by one or more halogens, (C ₁-C ₆) alkyl or (C ₁-C ₆) alkoxyl replaces.

Comprise the acceptable salt of its any pharmacy.

Other example comprises the chemical compound of following formula:

Wherein: R ¹For not replacing or by one or more R _e(the C that is replaced ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl or aryl;

R ²And R ³In one do not exist, and another is not for replacing separately or by hydrogen, (C that one or more group replaced ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, hydroxyl (C ₁-C ₆) alkyl, (C ₃-C ₈) cycloalkyl, amino (C ₂-C ₆) alkyl or aryl, described group is selected from alkyl, halogen, haloalkyl or nitro, Het, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl, (C ₁-C ₆) or Het (C ₁-C ₆) alkyl;

B is aryl, thiophene, heteroaryl, furan or pyrroles;

X is-C (=O) ,-C (S) ,-C (R ⁴) ₂,-C (OH)-or-S (O) _z

Z is 0,1 or 2 independently of one another;

Y is R ⁴,-N (R ⁴) ₂,-OR ⁴,-SR ⁴Or-C (R ⁴) ₃

R ⁴Be selected from independently of one another not and replace or by hydrogen, (C that one or more substituent group replaced ₁-C ₆) alkyl, (C ₂-C ₆) thiazolinyl, (C ₂-C ₆) alkynyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl (C ₂-C ₆) alkyl, hydroxyl (C ₂-C ₆) alkyl, cyano group (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylthio group (C _z-C ₆) alkyl, aryl, aryl (C ₁-C ₆) alkyl, aryloxy group (C ₂-C ₆) alkyl, halo (C ₂-C ₆) alkyl, (C ₁-C ₆) alkoxy carbonyl group (C ₁-C ₆) alkyl, NR _aR _b, Het or Het (C ₁-C ₆) alkyl, perhaps two R ⁴Group and the common aryl that forms of the atom that links to each other with them, Het or saturated or unsaturated 3-8 unit's monocycle system or 8-12 unit bicyclic system, described member ring systems comprises carbon atom, and randomly comprises one or more O of being selected from, S (O) _zAnd NR _cOther hetero atom, wherein each member ring systems is randomly by one or more R _dReplace;

R _aAnd R _bBe hydrogen or (C independently of one another ₁-C ₆) alkyl;

R _cIndependently of one another for not replacing or by one or more substituent R _eThe hydrogen that is replaced, aryl, S (O) ₂, (C ₁-C ₆) alkanoyl, hydroxyl (C ₁-C ₆) alkyl, alkoxyl (C ₁-C ₆) alkyl, Het, (C ₁-C ₆) alkoxy carbonyl group or (C ₁-C ₆) alkyl;

R _dIndependently of one another for not replacing or by one or more substituent R _eThe halogen that is replaced, hydroxyl, cyano group, nitro, azido, amino, (C ₁-C ₆) alkyl amino, amino (C ₁-C ₆) alkyl, acylamino-, (C ₁-C ₆) alkyl amido, aromatic acylamino, carboxylic acid, (C ₁-C ₆) alkyl, hydroxyl (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, halo (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, carboxyl, (C ₁-C ₆) alkanoyloxy, Het, aryl, Het (C ₁-C ₆) alkyl or aryl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylaryl, sulfonyl, sulfonamido, carbamide, carbamate (carbamate), perhaps two R _dForm ketone or spiral shell carbocyclic ring or spiroheterocyclic jointly with the atom that links to each other with them, perhaps two R _dForm bicyclic carbocyclic ring or two heterocycle jointly with the atom that links to each other with them, wherein each volution or dicyclo are unsubstituted or by one or more halogens, hydroxyl, cyano group, nitro, azido, (C ₁-C ₆) alkyl, hydroxyl (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, halo (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, carboxyl, (C ₁-C ₆) alkanoyloxy, NR _fR _g, R _fR _gNC (=O)-, phenyl or phenyl (C ₁-C ₆) alkyl, sulfonyl, sulfonamido, carbamide, carbamate replace, R wherein _fAnd R _gDo not replace or by one or more substituent R with common formation of the nitrogen that links to each other with them _eThe piperidyl that is replaced, pyrrolidinyl, morpholinyl or tetrahydro-1,4-thiazine ring;

R _eBe selected from halogen, hydroxyl, cyano group, nitro, azido, (C independently of one another ₁-C ₆) alkyl, Het, aryl, (C ₁-C ₆) alkyl Het, (C ₁-C ₆) alkylaryl, (C ₁-C ₆) alkyl Het (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylaryl (C ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) halogenated alkoxy, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, carboxyl and (C ₁-C ₆) alkanoyloxy;

R ⁵Be H, (C ₁-C ₆) alkyl, (C ₁-C ₆) thiazolinyl, (C ₁-C ₆) alkynyl, aryl (C ₁-C ₆) alkyl; And

R ⁶H, (C respectively do for oneself ₁-C ₆) alkyl, amino, acylamino-, ketone group or aryl (C ₁-C ₆) alkyl, its condition is when B is thiophene, R ¹Be trifluoromethyl, R ²Be methyl, R ³And R ⁶There is not R ⁵Be H, X be C (=O), and Y is N (R ⁴) ₂, all R ⁴It all is not methyl.

Other example comprises the chemical compound of following formula:

R wherein ¹For not replacing or by one or more R _e(the C that is replaced ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl or aryl;

Z ¹, Z ²And Z ³Be C (R independently of one another ⁶) _p, N (R ⁶) _q, O or S, if Z wherein ¹Be N (R ⁶) _q, O or S, then Z ¹Or Z ²In at least one must be N (R ⁶) _q, O or S;

P is 0,1 or 2 independently of one another;

Q is 0 or 1 independently of one another;

X is-C (=O) ,-C (=S) ,-C (R ⁴) ₂Or-S (O) L;

Z is 0,1 or 2 independently of one another;

Y is R ⁴,-N (R ⁴) _z,-OR ⁴,-SR ⁴Or-C (R ⁴) ₃

R ⁴Be selected from hydrogen, (C independently of one another ₁-C ₆) alkyl, (C ₂-C ₆) thiazolinyl, (C ₂-C ₆) alkynyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, (C ₃-C ₈) cycloalkyl, (C ₃-C ₈) cycloalkyl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl (C ₂-C ₆) alkyl, hydroxyl (C ₂-C ₆) alkyl, cyano group (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylthio group (C ₂-C ₆) alkyl, aryl, aryl (C ₁-C ₆) alkyl, aryloxy group (C ₂-C ₆) alkyl, halo (C ₂-C ₆) alkyl, (C ₁-C ₆) alkoxy carbonyl group (C ₁-C ₆) alkyl, NR _aR _b, Het or Het (C ₁-C ₆) alkyl, wherein alkyl, aryl or Het respectively do for oneself unsubstituted or by one or more R _dReplace perhaps two R ⁴Group and the common aryl that forms of the atom that links to each other with them, Het or saturated or unsaturated 3-8 unit's monocycle system or 8-12 unit bicyclic system, described member ring systems comprises carbon atom, and randomly comprises one or more O of being selected from, S (O) _zAnd NR _cOther hetero atom, wherein each member ring systems is randomly by one or more R _dReplace;

R _aAnd R _bBe hydrogen or (C independently of one another ₁-C ₆) alkyl;

R _dIndependently of one another for not replacing or by one or more substituent R _eThe halogen that is replaced, hydroxyl, cyano group, nitro, azido, amino, (C ₁-C ₆) alkyl amino, amino (C ₁-C ₆) alkyl, acylamino-, (C ₁-C ₆) alkyl amido, aryl acylamino-, carboxylic acid, (C ₁-C ₆) alkyl, hydroxyl (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, halo (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, carboxyl, (C ₁-C ₆) alkanoyloxy, Het, aryl, Het (C ₁-C ₆) alkyl or aryl (C ₁-C ₆) alkyl, (C ₁-C ₆) alkylaryl, sulfonyl, sulfonamido, carbamide, carbamate, perhaps two R _dForm ketone or spiral shell carbocyclic ring or spiroheterocyclic jointly with the atom that links to each other with them, perhaps two R _dForm bicyclic carbocyclic ring or two heterocycle jointly with the atom that links to each other with them, wherein each volution or dicyclo are unsubstituted or by one or more halogens, hydroxyl, cyano group, nitro, azido, (C ₁-C ₆) alkyl, hydroxyl (C ₁-C ₆) alkyl, halo (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, halo (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkanoyl, (C ₁-C ₆) alkoxy carbonyl group, carboxyl, (C ₁-C ₆) alkanoyloxy, NR _fR _g, R _fR _gNC (=O)-, phenyl or phenyl (C ₁-C ₆) alkyl, sulfonyl, sulfonamido, carbamide, carbamate replace, R wherein _fAnd R _gDo not replace or by one or more substituent R with common formation of the nitrogen that links to each other with them _eThe piperidyl that is replaced, pyrrolidinyl, morpholinyl or tetrahydro-1,4-thiazine ring;

R ⁵Be H, (C ₁-C ₆) alkyl, aryl (C ₁-C ₆) alkyl; And

R ⁶H, (C respectively do for oneself ₁-C ₆) alkyl, amino, acylamino-, ketone group or aryl (C ₁-C ₆) alkyl; Its condition be when X be C (=O) time, Y is N (R ⁴) _z, Z ¹Be O, Z ²Be N, and Z ³Be CH, all R of Y ⁴All be not H.

The biologically active polypeptide fragment of CREB can only comprise the part of CREB full length amino acid sequence, still biologically active.Can be by c-terminus or aminoterminal disappearance and the such fragment of inner disappearance (internal deletion) generation.

Fusion rotein comprises CREB protein as described herein, and it is meant the first that links to each other with non-existent second portion in the CREB protein.Described second portion can be single amino acids, peptide or polypeptide or other organic group, such as but not limited to carbohydrate, lipid or inorganic molecule.

Nucleotide sequence is defined as the heteropolymer of nucleic acid molecules in this article.Described nucleic acid molecules can be two strands or strand, and can be deoxyribonucleotide (DNA) molecule, for example cDNA or genomic DNA or ribonucleotide (RNA) molecule.Like this, nucleotide sequence can for example comprise one or more exons, randomly comprises or does not contain intron, and comprise one or more suitable control sequences.In one example, described nucleic acid molecules contains the single opening code-reading frame of the desired nucleic acid product of coding.Nucleotide sequence can be operably connected with suitable promoter (operably link).

As at people such as for example Ausubel, Current Protocols in Molecular Biology, John Wiley ﹠amp; Sons, New York (1998); With people such as Sambrook, Molecular Cloning:A Laboratory Manual, second edition, Cold Spring Harbor University Press, described in the New York. (1989), can separate, from native sequences, modify or from the beginning prepare the nucleotide sequence of desired CREB protein, CREB analog (comprising CREM, ATF-1), CREB sample molecule, biological activity CREB fragment, CREB fusion rotein or CREB function regulator of coding from nature.Can merge by methods known in the art (for example develop and prepare compatible clone or restriction site) isolating nucleic acid and with it.

Usually, described nucleotide sequence can be the gene of desired CREB protein, CREB analog, CREB sample molecule, CREB fusion rotein or CREB function regulator of coding.Such gene is operably connected with the suitable control sequence (preferably in CNS) of the expression that can realize CREB protein or CREB function regulator usually.Term used herein " is operably connected " and is defined as gene (or nucleotide sequence) so that mode that can expressing said gene (or nucleotide sequence) is connected with control sequence.Generally speaking, being operably connected means in abutting connection with (contiguous), but is not that such was the case with.

Control sequence comprises the sequence of the termination that operation subsequence (operator sequence), the sequence of encoding suitable messenger RNA (mRNA) ribosome binding site and control that transcripting promoter, the optional control that exists are transcribed are transcribed and translated.In one embodiment, the recombination (or nucleotide sequence) of coding CREB protein, CREB analog, CREB sample molecule, biological activity CREB fragment, CREB fusion rotein or CREB function regulator can place under the adjusting control of the promoter that can be induced or suppress, and control greatly is provided with regard to the product level thus.

Term used herein " promoter " is meant usually the DNA sequence in the upstream (5 ') in structural gene coding district, the expression that it controls the coding region by the identification that RNA polymerase and startup are provided transcribe other factor that can need and binding site.Suitable promoter is well known in the art.Exemplary promoter comprises SV40 and human elongation factor (EFI).Other suitable promoter is that this area is easy to obtain (referring to people such as for example Ausubel, Current Protocols in Molecular Biology, John Wiley ﹠amp; Sons, Inc., New York (1998); People such as Sambrook, Molecular Cloning:A Laboratory Manual, second edition, Cold Spring Harbor University Press, New York. (1989); With United States Patent (USP) 5,681,735).

The memory medicament can strengthen CREB approach function by number of mechanisms.For example, the memory medicament can influence the inductive signal transduction pathway that causes that the CREB dependent gene is expressed.Rise that can be by for example CREB function positive effector and/or CREB function negative effector following transfers to realize that the CREB dependent gene expresses induces.The positive effector of CREB function comprises adenyl cyclase and CREB activator.The negative effector of CREB function comprises cAMP phosphodiesterase (cAMP PDE) and CREB repressor.

The memory medicament can be by acting on the proteinic biochemical upstream of CREB or directly acting on the proteinic activator of CREB or repressor form and/or act on the CREB protein that contains transcription complex and strengthen CREB approach function.For example, can influence CREB approach function in the following manner: transcribing ground, transcribing ground, back or transcribing and transcribe the latter two ground increases the CREB protein level; Change the affinity that other of CREB protein and transcription complex must component (for example CREB conjugated protein (CBP albumen)); In promoter region, change and contain the affinity of the CREB protein of transcription complex DNA CREB response element; Perhaps induce passive or active immunity to the CREB protein subtype.The memory medicament strengthens the concrete mechanism of CREB approach function for implementing the present invention and indecisive.

The memory medicament can be in many ways to the direct administration of animal.In one embodiment, will remember the administration of medicament whole body.Other route of administration is as known in the art, and comprise in the intravenous (comprising infusion and/or bolus injection), Intraventricular, sheath, approach such as parenteral, mucosa, implantation, intraperitoneal, oral, intradermal, percutaneous (for example with the release polymer form), intramuscular, subcutaneous, local, epidural administration.Also can use other suitable route of administration, for example realize absorbing by epithelial layer or mucocutaneous layer.The certain memory medicament also can pass through the gene therapy administration, and the dna molecular of wherein will encode particular treatment protein or peptide is to described animals administer (for example by carrier (vector)), and this causes expressing and secretion specified protein or peptide with treatment level in vivo.

Term carrier used herein is meant nucleic acid carrier, for example DNA plasmid, virus or other suitable replicon (for example viral vector).Viral vector comprises retrovirus retrovirus, adenovirus, parvovirus (for example adeno associated virus), coronavirus, minus-stranded rna virus (for example influenza virus (for example influenza virus)), rhabdovirus (for example rabies and vesicular stomatitis virus), paramyxovirus (for example measles and celestial platform), positive chain RNA virus (for example pico+ribonucleic acid+virus (picomavirus) and Alphavirus) and double-stranded DNA virus (comprise adenovirus, herpesvirus (for example 1 type and herpes simplex types 2 virus, Epstein-Barr virus, cytomegalovirus) and poxvirus (cowpox for example, fowlpox and canary pox)).Other virus for example comprises Norwalk virus, togavirus, banzi virus, reovirus, papovavirus, has a liking for liver property DNA viruses and hepatitis virus.The example of retrovirus retrovirus comprises: birds leukemia-sarcoma virus, mammal C-type, B-type virus, D-type virus, HTLV-BLV genus, lentivirus, Spumavirus (Coffin, J.M., Retroviridae:The viruses and their replication, In Fundamental Virology, the third edition, people such as B.N.Fields, Eds., Lippincott-Raven Publishers, Philadelphia, 1996).Other example comprise muroid leucovirus, muroid sarcoma virus, mice mammary tumour virus, bovine leukemia virus, feline leukaemia virus, cat sarcoma virus, avian leukosis virus, adult T-cell leukosis virus, baboon endogenous virus, gibbon ape leukemia virus, Mason-Pfizer monkey disease poison, simian immunodeficiency virus, simian sarcoma virus, Rous sarcoma virus and slow virus.For example people such as McVey, United States Patent (USP) 5,801 has been described other example of carrier in 030, and its instruction content is quoted adding this paper.

Can insert in the nucleic acid carrier (referring to people such as for example Ausubel according to the nucleotide sequence of method well known in the art coded protein or peptide (for example CREB protein, CREB analog (comprising CREM, ATF-I), CREB sample molecule, biological activity CREB fragment, CREB fusion rotein, CREB function regulator), Eds., Current Protocols in Molecular Biology, John Wiley ﹠amp; Sons, Inc., New York (1998); People such as Sambrook, Eds., Molecular Cloning:A Laboratory Manual, second edition, Cold Spring Harbor University Press, New York (1989)).

Administering mode is preferably in the position of target cell.In one embodiment, administering mode is to be administered to neuron.

The memory medicament can with the together administration of active other component of inanimate object, described other component is the acceptable surface activation agent of pharmacy or carrier (for example glyceride), excipient (for example lactose), stabilizing agent, antiseptic, wetting agent, lubricant, antioxidant, carrier, diluent and excipient for example.Also can optionally add certain sweeting agent, correctives and/or coloring agent.When making up with multiple non-activity composition, the memory medicament also can refer to pharmaceutical composition.

The memory medicament can be mixed with solution, suspensoid, Emulsion or with the lyophilized powder of the acceptable parenteral excipient composition of pharmacy.The example of such excipient is water, saline, Ringer's solution, isotonic sodium chlorrde solution, glucose solution and 5% human serum albumin.Also can use liposome and non-aqueous carrier (vehicle) (for example fixed oil).Described carrier or lyophilized powder can contain the additive that keeps etc. oozing (for example sodium chloride, mannitol) and chemical stability (for example buffer and antiseptic).Can common technology be sterilized by described preparation.Among the Remington ' s Pharmaceutical Sciences suitable pharmaceutical carrier has been described.

To the dosage of the memory medicament of animals administer is that (particularly in neuron) produces in the CREB dependent gene is expressed and change required amount.Can depend on multiple factor and change that to the dosage (comprising administration frequency) of animals administer described factor comprises pharmacodynamic properties, administering mode and the approach of concrete memory medicament; Receiver's size, age, sex, health, body weight and diet; The nature and extent of the nature and extent of symptom to be treated or the memory that will strengthen or regulate, the kind of therapeutic alliance, the frequency and the Expected Results of treatment.

Depend on the nature and extent such as symptom, the kind of therapeutic alliance and the factor of Expected Results, the memory medicament can be with single dose or broken dose (for example a series of dosage that separate with the interval of sky, week or the moon) or with the slow release form administration.Other therapeutic scheme or healing potion can be united use with the present invention.

The full content of all articles that this paper quotes, patent and patent application instruction is quoted adding this paper.

Embodiment 1

Study effect with check memory medicament (HT-0712).

Use 6 before to undergo training and carry out the research with the old male stump-tailed macaque of finishing the certain memory task (age is about 22 years old during the research beginning, and it is equal to human about 66 years old of the age).Use CANTAB system (Cambridge Neuropsychological Test Automated Battery) and new task evaluation memory performance.

Identification learning-long-term the general description (DL LTR) of extracting (retrieval) task

In this task, in the process of test every day, provide 2 pairs of stimulations (for example 1 pair of shape and 1 pair of lines) to animal.For every pair of stimulation, a stimulation at random just is appointed as stimulates (promptly touching this stimulation can be awarded).Every pair of stimulation provides 14 times at the test period of being made up of 28 tests every day.Provide described couple stimulation (shape or lines) in each testing period with pseudo-random fashion.In order to be subjected to following the sugar pill of the happy tone to reward, animal must touch " just " shape or lines.Touching another shape or lines causes the negative tone (negative tone), does not have sugar pill and do not have rest.Every day, test animal reached in the testing period every day performance standard of 85% correct response until them.When reaching this standard, animal was not accepted further test at 7 days subsequently.After reaching standard the 8th day, the long-term extraction of distinguishing of acquistion in order to estimate used the identical couple stimulation of having learnt before them to come animal is tested once more.

Drug administration

All medicines are oral administration in Althaea officinalis (marshmallow), and described animal is in specially designed test-cage.Carrier only is an Althaea officinalis.

Shown the treatment plan table in the table 1.Impose treatment continuously to treat 1 beginning.Training period the duration, before behavior training beginning, carry out each treatment (administration HT-0712 or carrier), once a day and continue 4 days, continue 1 treatment (administration HT-0712 or carrier) subsequently every day, sent in preceding four hours in test.When each animal reaches the performance standard of at least 85% correct response in testing period every day, will train and administration stops seven days.Subsequently, after reaching standard the 8th day, once more to animal testing DL LTR task (keeping test).

After drug test is finished, use 3 animals of finishing 100mg/kg administration research at first to carry out second study on the carrier.

Behavioral data is analyzed

Record is tested the correct response percentage ratio of sum and is reached the required natural law of standard (at least 85% correct response in the single testing period) every day.Keep the correct response percentage ratio of test at whole maintenance duration of test record, and test 1-14 is carried out the Asia with respect to the performance difference of 15-28 analyze.

Utilize unidirectional ANOVA that the data of carrier test for data and drug test are compared.Utilize Bonferroni t check to make comparisons thus.

The result

During studying,, there is not the side effect on tangible behavior or the health with behind any given dose administration HT-0712.Prove five memory performances that show improvement in employed six animals by the minimizing that reaches the required natural law of standard.The animal (9 years old) of the HT-0712 of any dosage of administration does not show the task performance of improvement.From statistical analysis, remove data from this non-responder.

Vehicle treatment

During first study on the carrier, all times of 26.3 ± 4.6 days of animal via reach standard.The average value that is reached is 89.3 ± 1.8% correct response.Keep on average showing as 79.7 ± 5.9% correct response in the test.When dividing maintenance test card now between test 1 to 14 and the test 15 to 28, animal shows 77.5 ± 5.1% correct response and 82.3 ± 7.5% correct response respectively.

Use 3 animals of finishing drug test at first to carry out second (behind the drug research) study on the carrier.During second study on the carrier, 20.0 ± 4.5 days time of animal via reaches standard.Their average value is 86.3 ± 1.3% correct response.The meansigma methods that keeps the test performance is 64.0 ± 4.0% correct response.When dividing maintenance test card now between test 1 to 14 and the test 15 to 28, animal shows 59.3 ± 8.4% correct response and 69.0 ± 10.4% correct response respectively.

Before research and between the carrier result of the test of research back, do not find statistically-significant difference (t=1.168, (P=0.363)).

The memory pharmaceutical treatment

Under the lowest dose level (1mg/kg) of the HT-0712 that is used for this research, animal reaches standard with the performance level of 91.4 ± 1.8% correct response through 12.0 ± 3.6 days time.Animal on average shows as 85.8 ± 4.6% correct response in keeping test.When dividing maintenance test card now between test 1 to 14 and the test 15 to 28, animal shows the level of the correct response of 80.2 ± 6.2% correct response and 91.6 ± 3.4% respectively.

Under the median dose (10mg/kg) of the HT-0712 that is used for this research, 11.8 ± 2.3 days time of animal via reaches standard (90.0 ± 2.6% correct responses).These animals on average show as 79.2 ± 3.5% correct response in keeping test.When divide keeping test card now between test 1 to 14 and the test 15 to 28, animal show respectively 71.4 ± 3.4% correctly with 87.2 ± 4.8% correct level.

Under the maximum dose level (100mg/kg) that uses HT-0712,9.0 ± 2.8 days time of animal via reaches standard (86.4 ± 0.7% correct responses).These animals on average show as 65.0 ± 3.5% correct response in keeping test.When divide keeping test card now between test 1 to 14 and the test 15 to 28, animal show respectively 58.4 ± 4.1% correctly with 71.4 ± 6.1% correct level.

The therapeutic effect of the natural law that reaches standard be significant (repeated measure ANOVA, F (4,3)=6.327, p=0.008).Therefore utilize the comparison sheet of Bonferroni t-check to reveal significant difference (each p＜0.050 relatively) between the HT-0712 of carrier and every kind of dosage.

On the performance level that the standard natural law is reached, do not have notable therapeutic effect (F (4,3)=1.408, p=0.289).

Do not have on the performance level that in keeping test, reaches notable therapeutic effect (F (4,3)=3.199, p=0.062).Treatment also fails to reach significance,statistical (being respectively p=0.058 and p=0.167) to the therapeutic effect analysis that keeps the test performance in test 1-14 and test 15-28.

The use identification learning-extracting this new task of task (DL LTR) for a long time carries out this research, and described task is designed to the effect that evaluation experimental memory medicament keeps learning and memory in old non-human primate.

The vehicle Control result of study shows, that normal geriatric animals needs is long-time (ex.＞20 day) reaches 85% the correct response standard to this test.In addition, result after the pharmaceutical carrier test shows, do not caused by the raising of animal dexterity in this test with the viewed performance raising of HT-0712, perhaps the implementation result and the first study on the carrier result as the second vehicle Control result of the test significantly do not distinguish.

Five performances that behind administration HT-0712, show improvement in six animals being tested.This improvement is expressed as the remarkable minimizing of the natural law of the standard of reaching, and shows to have improved learning capacity when treating with HT-0712.

The reaction of described animal can be divided into 2 general groups.In first group (5 years old and 8 years old animal), the optimal dose that is used to improve performance is the HT-0712 of 1mg/kg dosage.When dosage was increased to 10mg/kg again to 100mg/kg from 1mg/kg, these animals demonstrated successively decreasing of performance.That is to say, along with the dosage of HT-0712 increases, animal need reach standard (promptly need respectively 4 days, 5 days and 10 days reach standard (5 years old) and needs reached standard (8 years old) in 3 days, 12 days and 18 days) for more time behind administration 1mg/kg, 10mg/kg or 100mg/kg.Second treated animal (1 years old, 2 years old and 7 years old) shows more representative dose response effect, wherein, dosage (, under the dosage of 1mg/kg, 10mg/kg and 100mg/kg, needs to reach in 21 days, 15 days and 3 days standard respectively to the animal of 1 years old, 2 years old and 7 years old along with increasing; Need reach standard in 17 days, 18 days and 11 days; And need reach standard in 15 days, 9 days and 3 days) and performance improves.

At first utilize to postpone the sampling coupling (delayed matching to sample, DMTS) and paired association learning (paired associative learning, PAL) cognitive defect of animal of the present invention is tested and estimated to these two tasks.According to the performance level of these animals in these tasks to they sort (be that each task sorts animal from 1 to 6, the 1st, best shower, 6 then is the poorest (referring to table 10).This ordering shows arranges the 1st and arrange the 2nd in the performance of DMTS to the unresponsive animal of HT-0712 in the performance of PAL.Also has optimal representation in first study on the carrier that this same animal carries out in current planning.

In brief, this result of study shows, uses particular system of the present invention and method, and HT-071 has significantly improved the non-human primate's of normal age learning capacity and longterm memory.

Form

Table 2: comprise the descriptive statistic of the whole seminar of 9 years old NHP

	Meansigma methods	Standard deviation	Standard error
				Carrier reaches the natural law of C	26.333	11.237	4.587
The support C value	89.333	4.274	1.745
				Carrier keeps test	79.667	14.459	5.903
Carrier RT 1-14	77.500	12.486	5.097
				Carrier RT 15-28	82.333	18.468	7.540
Carrier 2 reaches the natural law of C	20.000	7.810	4.509
				Carrier 2C value	86.333	2.309	1.333
Carrier keeps test	64.000	7.000	4.041
				Carrier 2RT 1-14	59.333	14.572	8.413
Carrier 2RT 15-28	69.000	18.083	10.440
				1mg reaches the natural law of C	12.667	7.394	3.018
1mg C value	91.000	3.633	1.483
				1mg keeps test	82.833	11.788	4.813
1mg?RT?1-14	77.500	14.068	5.743

1mg?RT?15-28	88.167	10.852	4.430
				10mg reaches the natural law of C	14.000	7.043	2.875
10mg C value	89.333	5.428	2.216
				10mg keeps test	80.333	7.528	3.073
10mg?RT?1-14	73.833	8.976	3.664
				10mg?RT?15-28	87.000	9.633	3.933
100mg reaches the natural law of C	10.333	6.501	2.654
				100mg C value	86.333	1.366	0.558
100mg keeps test	66.000	7.430	3.033
				100mg?RT?1-14	59.333	8.477	3.461
100mg?RT?15-28	72.667	12.580	5.136

Code name: C: standard; RT: keep test; RT 1-14: keep test 1 to 14; RT 15-28: keep test 15 to 28

Table 3: the descriptive statistic of the whole seminar except that 9 years old NHP

	Meansigma methods	Standard deviation	Standard error
				Carrier 1 reaches the natural law of C	29.000	10.223	4.572
Carrier 1C value	88.600	4.336	1.939
				Carrier 1 keeps test	79.200	16.115	7.207
Carrier 1RT 1-14	77.200	13.936	6.232
				Carrier 1 RT 15-28	81.600	20.550	9.190
Carrier 2 reaches the natural law of C	22.000	9.899	7.000
				Carrier 2C value	85.000	0.000	0.000
Carrier 2 keeps test	64.000	9.899	7.000
				Carrier 2RT 1-14	67.500	4.950	3.500

Carrier 2RT 15-28	60.500	14.849	10.500
				1mg reaches the natural law of C	12.000	8.062	3.606
1mg C value	91.400	3.912	1.749
				1mg keeps test	85.800	10.378	4.641
1mg?RT?1-14	80.200	13.882	6.208
				1mg?RT?15-28	91.600	7.668	3.429
10mg reaches the natural law of C	11.800	5.070	2.267
				10mg C value	90.000	5.788	2.588
10mg keeps test	79.200	7.823	3.499
				10mg?RT?1-14	71.400	7.503	3.356
10mg?RT?15-28	87.200	10.756	4.810
				100mg reaches the natural law of C	9.000	6.285	2.811
100mg C value	86.400	1.517	0.678
				100mg keeps test	65.000	7.842	3.507
100mgRT?1-14	58.400	9.127	4.082
				100mgRT?15-28	71.400	13.631	6.096

The initial data of each treatment group

Table 4: carrier 1

Table 5:1mg/kg HT-0712

Table 6:10mg/kg HT-0712

Table 7:100mg/kg HT-0712

Table 8: carrier 2

Table 9: the description of used animal in the research

ID	The body weight of research beginning	Estimate the age	Sex
				1 year old	9.9kg	22 years old	Male
2 years old	9.65kg	22 years old	Male
				5 years old	8.4kg	22 years old	Male
7 years old	10.6kg	22 years old	Male
				8 years old	9.8kg	22 years old	Male
9 years old	11.15kg	22 years old	Male

Table 10: PAL of used animal and DMTS ordering in the research

	1 year old	2 years old	5 years old	7 years old	8 years old	9 years old
							PAL	4	5	6	2	3	1
DMTS	6	1	5	4	3	2
							Average ordering	5	3	5.5	3	3	1.5

Following to PAL and the ordering of DMTS task computation:

1.PAL: the average (3 stimulate/3 positions) of finishing the required by task test of difficult level.

2.DMTS: the average of correct response in than long delay.

Each task is animal from 1 to 6 ordering, 1 for the person of behaving oneself best 6 for the poorest.

Embodiment 2: the blind research of list in the old human individual of health

Research design

Can utilize the mankind carry out as described in example 1 above the use general approach and the research of drug administration.As described below, the task of extracting for a long time can utilize face-title to and/or occupation to the stimulation of form.Can show facial picture and people's name and/or occupation to the human individual.Can be to each title-face to listing occupation.In cataloged procedure, require the human individual to judge whether name and occupation match.In test process, show intact, that rearrange and new face-title to (do not provide occupation) to described human individual, and require its judge this face-title to be intact, rearrange or new.Use this test, can assess the human individual in mode as described in example 1 above subsequently.

In one embodiment, test unit point, double blinding, the three-dimensional crossing research of following three dosage regimens: (1) 45mg HT-0712, oral 7 days; (2) 45mg HT-0712, oral+the 2.5mg warfarin, oral 7 days; And (3) 2.5mg warfarin, oral 7 days.Arranged seven days day off between the administration phase.Individual in seven day day off three days (72 hours) hold mode (remain in-house) to study relevant operation.Individuality was not carried out clinical manipulation in four days in seven day offs.About the individual selection standard, be not used in this related in pairs comprising and/or exclusion standard of testing.

Development schedule

The individual HT-0712 that accepted 45mg dosage at the 1st, 2,3,4,5,6 and 7 day of I group; The HT-0712 that accepted 45mg dosage at the 15th, 16,17,18,19,20 and 21 day adds the warfarin of 2.5mg dosage; And accepted the warfarin of 2.5mg dosage at the 29th, 30,31,32,33,34 and 35 day.The individual HT-0712 that accepted 45mg dosage at the 1st, 2,3,4,5,6 and 7 day of II group adds the warfarin of 2.5mg dosage; Accepted the warfarin of 2.5mg dosage at the 15th, 16,17,18,19,20 and 21 day; And accepted the HT-0712 of 45mg dosage at the 29th, 30,31,32,33,34 and 35 day.The individual warfarin of accepting 2.5mg dosage at the 1st, 2,3,4,5,6 and 7 day of III group; Accepted the HT-0712 of 45mg dosage at the 15th, 16,17,18,19,20 and 21 day; And the HT-0712 that accepted 45mg dosage at the 29th, 30,31,32,33,34 and 35 day adds the warfarin of 2.5mg dosage.

Table 11: non-blind individual coding

The 1st group	The 2nd group	The 3rd group
			002	001	003
005	004	006
			008	007	009
012	011	010
			015	013	014
016	018	017
			019	020	021

The paired-associate test

Material: material thinks that by 21 All-China Federation of Taiwan Compatriots notebook computer forms.Every notebook computer is configured to eliminate all automatic configuration softwares and to reduce the setting that may disturb internal clock (internal clock) setting and E-Run software.E-Run (vl.2.1.68) is installed to carry out this paired-associate test on all notebook computers.With occupation (for example " the fireman ") pairing of 120 gray scale faces (masculinity and femininity) with two words (two-word).The gray scale facial image is to be drawn by the face data of Lund University Cognitive Science Lab..Only use two words or compound word (compound-word) occupation.With 120 face-titles to being divided into three groups, 40 pairs every group.Whole wheel all uses 40 identical face-titles right in each is taken turns.

Operation-administration time: beginning recall tests in about 6 hours after the administration.Finish all recall tests before the blood sampling in every day.As shown in Table 12, in the three-wheel of forming by 14 days (or part), train.In 42 days, test.At the 1st day that gives fixed wheel, make and individually be familiar with described computer and train its how use test software.Provided coding phase and extraction phase at the 2nd day to individuality.At 3-7 days, the individual memory of test every day.It is right at the 10th day individuality to be tested half face-title, and right to half face-title of individuality test residue at the 14th day, subsequently to being used for these all face-titles of taking turns to carrying out complete test.

Table 12: training and testing

Being familiar with of test operation:, make individuality be familiar with 5 computers to the analog code formed and extraction phase and train its how use test software by nine face-titles by accepting at the 1st day.Do not reexamine these pairings.

Coding and extraction: at the 2nd day, each participant accepted single encoded and extracts test:

Coding: in cataloged procedure, the participant on computer screen once ground see 40 with professional paired face.For example they see the occupation " skater " on a face and the right.They are to form lively perceptual image to the right task of each facial occupation, and wherein the personage on the picture is being engaged in the occupation that is shown in the right side.Therefore, for the paired face of skater, they may imagine the people who is doing highly difficult jump and drop action, and it is very happy owing to win the gold medal perhaps to imagine them.Observe this face occupation to 5 seconds after, point out them to form the complexity of this perceptual image with the grade evaluation of 1-3: if simply then be 1, if difficulty then be 2 is 3 if they can not successfully form perceptual image.After 2 seconds, show that next facial occupation is right.

Extract:, the participant is carried out them in cataloged procedure, seen right cued recall (cued-recall) test of 40 facial occupations of being in this part of experiment.In extracting test process, present face and do not present relevant occupation to individuality.Being close to face has a frame to allow them import in cataloged procedure and the paired occupation of this face.In case the participant imports an answer, then they receive the professional correct or wrong feedback of importing about them.If it is correct answering, then " correct! " together appear on the screen with suitable face and occupation pairing, it is right to carry out next one stimulation subsequently.If it is wrong answering, then on screen, present the correct face and the professional pairing conduct feedback in three seconds, it is right to present next stimulation then.In case whole 40 face-occupations finish to presenting, and just finish this test.Each of the research provided in 3-7 days once extracts test.

Longterm memory is estimated: after each final administration three days and before discharge (the 10th, 24 and 38 day) participant is carried out by 20 face-occupations the cued recall of forming being tested to measure the long-time stability that face-occupation is remembered.After each Drug therapy seven days (the 14th and 28 day and the 42nd day), provide 20 face-occupations before not testing right to the participant.At the 14th and 28 day and the 42nd day, present 20 face-occupations to after one minute rest period arranged.After this rest period of minute, provide 40 face-occupations of close set right to the participant.

Result: collect the data that the reflection participant recalls, and map as shown in Figure 5.These data show can utilize sufficient repetition training every day to set up the long-time memory of paired-associate task.

Blind method operation: this research is the double blinding placebo-controlled trial.Be responsible for keeping the individual treatment standard by the pharmacist.

Therefore, provide several different methods as can be seen.It will be understood by those skilled in the art that, the present invention also can be by being implemented except various embodiments mentioned in this description and the method the preferred embodiment, described various embodiment and preferred embodiment are the purposes unrestricted for explanation, and the present invention only is limited by the appended claims.The equivalent of the specific embodiments that should be noted that in this description to be discussed also can be implemented the present invention.

Though above described various embodiments of the present invention, be to be understood that they only are that mode by embodiment provides, and nonrestrictive.Similarly, various accompanying drawings can be described exemplary setting of the present invention (example configuration), and it is to understand feature that the present invention may comprise and functional for auxiliary.The present invention is not limited to illustrated exemplary setting, but can use multiple alternative setting to realize desired character.In fact, how to implement alternative functions, logic or physics setting and realize that desired character of the present invention it will be apparent to those skilled in the art that.In addition, about claim to a method, unless indicate in addition in the context, that the sequence of steps that this paper provided can not require to implement various embodiments with same order is described functional to realize.

Though above described various exemplary of the present invention and implementation (implementation), but be to be understood that, the various features described in one or more indivedual embodiments, aspect and functionally be not limited to be adapted in the specific embodiments that they are described, but can be separately or with various combining forms be adapted in one or more other embodiment of the present invention (whether no matter such embodiment described, and no matter such feature whether as the part of described embodiment and provide).Therefore degree of the present invention and scope should not be subjected to the restriction of any above-mentioned exemplary.

Unless clearly demonstrate in addition, employed term and phrase and distortion thereof should be interpreted as open and nonrestrictive in presents.As above-mentioned example: term " comprises " and is interpreted as " including but not limited to " etc.; Term " example " is the illustrative examples that is used to provide item under discussion, but not its comprehensive or limited enumerating; Term " a " or " an " are interpreted as " at least one ", " one or more " etc.; And such as the adjective of " conventional ", " traditional ", " normally ", " standard ", " known " and term with similar meaning should not be interpreted as that described project is restricted to given time bar or till the preset time available project, and should be read as be included in now or that random time in the future can obtain or know is routine, traditional, normally or standard techniques.Similarly, be apparent to those skilled in the art or during known technology when mentioning in the presents, such technology comprise those now or random time in the future be apparent or known technology to those skilled in the art.

Unless clear statement is arranged in addition, with conjunction " with " one group of project linking to each other is not to be read as and needs those projects all to be present in this group with each separately, and should be read as " and/or ".Similarly, unless clear statement is arranged in addition, with conjunction " or " one group of project linking to each other is not to be read as the project that exclusively needs in this group, and also should be read as " and/or ".In addition, unless show clearly and be restricted to odd number, though project of the present invention, unit or component may be described or claimed with singulative, its plural form also is considered to be within its scope.

In some cases, should not be interpreted as under described expansion phrase may non-existent situation intention or require narrower situation such as the existence of expansion (broadening) word and expression of " one or more ", " at least ", " but being not limited to " or other similar phrase.What become apparent to those skilled in the art after reading presents is, can implement illustrated embodiment and their various distortion and is not limited to illustrated example.

Claims

1. method, it may further comprise the steps:

Evaluation is to the effectiveness of the memory medicament of individual administration, and wherein said evaluation comprises to described individuality provides many groups to stimulate; And

Assess of the reaction of described individuality to described stimulation.

2. the process of claim 1 wherein described stimulus effects CREB approach.

3. the method for claim 2, the longterm memory of the described individuality of wherein said stimulus effects.

4. the process of claim 1 wherein that described evaluation also comprises selects performance standard and assesses described individuality and desire to reach the required training natural law of described performance standard.

5. the process of claim 1 wherein that described many group stimulations comprise a plurality of couple stimulations.

6. the method for claim 5, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

7. the method for claim 6 is wherein saidly discerned association to be selected from face-names associate related with word-word.

8. the process of claim 1 wherein that described individuality is an animal.

9. the method for claim 8, wherein said animal is a mammal.

10. the method for claim 9, wherein said mammal is selected from primate, mice and rat.

11. the method for claim 10, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

12. the method for claim 11, wherein said primate are human.

13. the process of claim 1 wherein that described individuality is a plurality of individualities.

14. the method for claim 13, wherein said a plurality of individualities comprise matched group and experimental group.

15. the method for claim 14, wherein said evaluation comprise more described matched group and described experimental group.

16. the process of claim 1 wherein that described memory medicament is one or more chemical compounds that are selected from the chemical compound with following structure:

17. the process of claim 1 wherein that described memory medicament is one or more chemical compounds that are selected from the chemical compound with following structure:

18. method, it comprises the step of evaluation to the effectiveness of the memory medicament of individual administration, wherein said evaluation comprises: select performance standard, train described individuality by provide many groups to stimulate to described individuality, assess described individuality whether the reaction of described stimulation has been reached described performance standard to measure described individuality, and measure and desire to reach the required training natural law of described performance standard.

19. stimulating, the method for claim 18, wherein said many groups comprise a plurality of couple stimulations.

20. the method for claim 19, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

21. the method for claim 20 is wherein saidly discerned association to be selected from face-names associate related with word-word.

22. the method for claim 18, wherein said stimulus effects CREB approach.

23. the method for claim 18, the longterm memory of the described individuality of wherein said stimulus effects.

24. the method for claim 18, wherein said performance standard is the percentage ratio of the described individuality of expression to the quality of the reaction of described stimulation.

25. the method for claim 18, wherein said performance standard is represented obtaining of described individual longterm memory.

26. the method for claim 18, wherein said individuality are animal.

27. the method for claim 26, wherein said animal are mammal.

28. the method for claim 27, wherein said mammal is selected from primate, mice and rat.

29. the method for claim 28, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

30. the method for claim 29, wherein said primate are human.

31. the method for claim 18, wherein said individuality are a plurality of individualities.

32. the method for claim 31, wherein said a plurality of individualities comprise matched group and experimental group.

33. the method for claim 32, wherein said evaluation comprise more described matched group and described experimental group.

34. the method for claim 18, wherein said memory medicament are one or more chemical compounds that are selected from the chemical compound with following structure:

R wherein ₁And R ₂Be independently of one another-H, straight or branched C ₁-C ₇Alkyl ,-F ,-Cl ,-Br ,-I ,-NO ₂Or-CN; R wherein ₃For-H, straight or branched C ₁-C ₇Alkyl ,-F ,-Cl ,-Br ,-I ,-NO ₂,-CN ,-OR ₆, aryl or heteroaryl; R wherein ₅Be straight or branched C ₁-C ₇Alkyl ,-N (R ₄) ₂,-OR ₄Or aryl; R wherein ₆Be straight or branched C ₁-C ₇Alkyl or aryl; Wherein B is an aryl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, the indolizine base, indole-4-base, indole-5-base, indole-6-base, indole-7-base, isoindolyl, benzo [b] furan-4-base, benzo [b] furan-5-base, benzo [b] furan-6-base, benzo [b] furan-7-base, benzo [b] thiophene-4-base, benzo [b] thiophene-5-base, benzo [b] thiophene-6-base, benzo [b] thiophene-7-base, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purine radicals, imidazo [2,1-b] thiazolyl, quinolyl, isoquinolyl, quinazolyl, 2,1, the 3-benzothiazolyl, furyl, thienyl, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group benzoxazolyl, the benzoisoxazole base, the cinnolines base, quinoxalinyl, 1, the 8-naphthyridinyl, pteridyl or phthaloyl imino; Yet its condition is that the adjacent one or more carbon atoms of imine linkage nitrogen-atoms only can be replaced by in the following group one or more :-F ,-Cl ,-Br ,-I ,-CN, methyl, ethyl or methoxyl group; Wherein n is the integer that comprises the 1-4 of end value; Wherein aryl is phenyl or naphthyl, comprise by phenyl that one or more replaced and naphthyl in the following group :-F ,-Cl ,-Br ,-I ,-NO ₂,-CN, straight or branched C ₁-C ₇Alkyl, straight or branched C ₁-C ₇Single fluoroalkyl, straight or branched C ₁-C ₇Polyfluoroalkyl, straight or branched C ₂-C ₇Thiazolinyl, straight or branched C ₂-C ₇Alkynyl, C ₃-C ₇Cycloalkyl, C ₁-C ₇Single fluorine cycloalkyl, C ₃-C ₇Polyfluoro cycloalkyl, C ₅-C ₇Cycloalkenyl group ,-OR ₄, SR ₄,-OCOR ₄,-COR ₄,-NCOR ₄,-CO ₂R ₄,-CON (R ₄) ₂Or (CH ₂) _n-O-(CH ₂) _mCH ₃The perhaps acceptable salt of its pharmacy.

35. the method for claim 18, wherein said memory medicament are one or more chemical compounds that are selected from the chemical compound with following structure:

36. method, it comprises the step of evaluation to the effectiveness of the memory medicament of individual administration, wherein said evaluation comprises: select performance standard, train described individuality by provide many groups to stimulate to described individuality, assess described individuality whether the reaction of described stimulation has been reached described performance standard to measure described individuality, repeat described provide and assess until described individuality reach described performance standard, and measure described individuality and desire to reach the required training natural law of described performance standard.

37. the method for claim 36, wherein said stimulus effects CREB approach.

38. the method for claim 36, the longterm memory of the described individuality of wherein said stimulus effects.

39. stimulating, the method for claim 36, wherein said many groups comprise a plurality of couple stimulations.

40. the method for claim 39, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

41. the method for claim 40 is wherein saidly discerned association to be selected from face-names associate related with word-word.

42. the method for claim 36, wherein said individuality are animal.

43. the method for claim 42, wherein said animal are mammal.

44. the method for claim 43, wherein said mammal is selected from primate, mice and rat.

45. the method for claim 44, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

46. the method for claim 45, wherein said primate are human.

47. the method for claim 36, wherein said individuality are a plurality of individualities.

48. the method for claim 47, wherein said a plurality of individualities comprise matched group and experimental group.

49. the method for claim 48, wherein said evaluation comprise more described matched group and described experimental group.

50. the method for claim 36, wherein said memory medicament are one or more chemical compounds that are selected from the chemical compound with following structure:

Y wherein ₁, Y ₂, Y ₃And Y ₄Be independently of one another-H; Straight or branched C ₁-C ₇Alkyl, single fluoroalkyl or Polyfluoroalkyl; Straight or branched C ₂-C ₇Alkenyl or alkynyl; C ₃-C ₇Cycloalkyl or C ₅-C ₇Cycloalkenyl group;-F ,-Cl ,-Br or-I;-NO ₂-N ₃-CN;-OR ₄,-SR ₄,-OCOR ₄,-COR ₄,-NCOR ₄,-N (R ₄) ₂,-CON (R ₄) ₂Or-COOR ₄Aryl or heteroaryl; Perhaps be present in the Y on the adjacent carbon atom ₁, Y ₂, Y ₃And Y ₄In any two can constitute methylenedioxy group; Each R wherein ₄Be independently-H; Straight or branched C ₁-C ₇Alkyl, single fluoroalkyl or Polyfluoroalkyl; Straight or branched C ₂-C ₇Alkenyl or alkynyl; C ₃-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group, aryl or aryl (C ₁-C ₆) alkyl; Wherein A is A,, straight or branched C ₁-C ₇Alkyl, aryl, heteroaryl, aryl (C ₁-C ₆) alkyl or heteroaryl (C ₁-C ₆) alkyl; Wherein A ' is

51. the method for claim 36, wherein said memory medicament are one or more chemical compounds that are selected from the chemical compound with following structure:

52. method, it comprises: select the memory medicament as drug candidate, wherein said selection may further comprise the steps: estimate described memory medicament to the described memory medicament of individual administration; And provide many groups to stimulate and assess of the reaction of described individuality described stimulation to described individuality.

53. stimulating, the method for claim 52, wherein said many groups comprise a plurality of couple stimulations.

54. the method for claim 53, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

55. the method for claim 54 is wherein saidly discerned association to be selected from face-names associate related with word-word.

56. the method for claim 52, wherein said stimulus effects CREB approach.

57. the method for claim 52, the longterm memory of the described individuality of wherein said stimulus effects.

58. the method for claim 52, wherein said evaluation also comprises the selection performance standard, and described assessment comprises that measuring described individuality desires to reach the required quantity of stimulus of described performance standard.

59. the method for claim 58, wherein said performance standard is the percentage ratio of the described individuality of expression to the quality of the reaction of described stimulation.

60. the method for claim 59, wherein said performance standard is represented obtaining of described individual longterm memory.

61. the method for claim 52, wherein said individuality are animal.

62. the method for claim 61, wherein said animal are mammal.

63. the method for claim 62, wherein said mammal is selected from primate, mice and rat.

64. the method for claim 63, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

65. the method for claim 64, wherein said primate are human.

66. the method for claim 52, wherein said individuality are a plurality of individualities.

67. the method for claim 66, wherein said a plurality of individualities comprise matched group and experimental group.

68. the method for claim 67, wherein said evaluation comprise more described matched group and described experimental group.

69. the method for claim 52, wherein said memory medicament are one or more chemical compounds that are selected from the chemical compound with following structure:

70. the method for claim 52, wherein said memory medicament are one or more chemical compounds that are selected from the chemical compound with following structure:

71. method, it comprises:

Test is as the memory medicament of longterm memory reinforcing agent, and wherein said test may further comprise the steps:

To the described memory medicament of individual administration;

Provide many groups to stimulate to described individuality; And

Assess of the reaction of described individuality to described stimulation.

72. stimulating, the method for claim 71, wherein said many groups comprise a plurality of couple stimulations.

73. the method for claim 72, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

74. the method for claim 73 is wherein saidly discerned association to be selected from face-names associate related with word-word.

75. the method for claim 71, wherein said second individuality is an animal.

76. the method for claim 75, wherein said animal are mammal.

77. the method for claim 76, wherein said mammal is selected from primate, mice and rat.

78. the method for claim 77, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

79. the method for claim 78, wherein said primate are human.

80. the method for claim 71, wherein said individuality are a plurality of individualities.

81. the method for claim 80, wherein said a plurality of individualities comprise matched group and experimental group.

82. the method for claim 81, wherein said evaluation comprise more described matched group and described experimental group.

83. the method for claim 71, wherein said memory medicament are one or more chemical compounds that are selected from the chemical compound with following structure:

84. the method for claim 71, wherein said memory medicament are one or more chemical compounds that are selected from the chemical compound with following structure:

85. system, it comprises: many groups stimulate, and wherein said many groups stimulate and are provided so that and can assess the individual reactions that described many groups are stimulated and estimate effectiveness to the memory medicament of described individual administration thus.

86. stimulating, the system of claim 85, wherein said many groups comprise a plurality of couple stimulations.

87. the system of claim 86, wherein said a plurality of couple stimulations comprise positive unit or negative unit separately.

88. the system of claim 86, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

89. the system of claim 88 wherein saidly discerns association to be selected from face-names associate related with word-word.

90. the system of claim 85, wherein said individuality is an animal.

91. the system of claim 90, wherein said animal is a mammal.

92. the system of claim 91, wherein said mammal is selected from primate, mice and rat.

93. the method for claim 92, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

94. the method for claim 93, wherein said primate are human.

95. the system of claim 85, wherein said individuality is a plurality of individualities.

96. the system of claim 95, wherein said a plurality of individualities comprise matched group and experimental group.

97. the system of claim 96, wherein said evaluation comprises more described matched group and described experimental group.

98. the system of claim 85, wherein said memory medicament is one or more chemical compounds that are selected from the chemical compound with following structure:

99. the system of claim 85, wherein said memory medicament is one or more chemical compounds that are selected from the chemical compound with following structure:

100. method, it may further comprise the steps:

The effectiveness of the training program that evaluation is bestowed to individuality, wherein said evaluation comprise to described individuality to be provided many groups to stimulate and assesses the reaction of described individuality to described stimulation.

101. method, it comprises:

Test is as the training program of longterm memory reinforcing agent, and wherein said test may further comprise the steps:

Bestow training program to individuality; And

Many group stimulations are provided and assess of the reaction of described individuality to described individuality described stimulation.

102. system, it comprises: how group stimulates, and wherein said many group stimulations are provided so that can assess the effectiveness that the training program of bestowing to described individuality is also estimated in the individual reaction that described many groups are stimulated thus.

103. stimulating, the system of claim 102, wherein said many groups comprise a plurality of couple stimulations.

104. the system of claim 103, wherein said a plurality of couple stimulations comprise positive unit or negative unit separately.

105. the system of claim 103, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

106. the system of claim 105 wherein saidly discerns association to be selected from face-names associate related with word-word.

107. method, it may further comprise the steps:

Evaluation is to the effectiveness of the memory impairment agent of individual administration, and wherein said evaluation comprises to described individuality to be provided many group stimulations and assess the reaction of described individuality to described stimulation.

108. stimulating, the method for claim 107, wherein said many groups comprise a plurality of couple stimulations.

109. the method for claim 108, wherein said a plurality of couple stimulations comprise positive unit or negative unit separately.

110. the method for claim 108, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

111. the method for claim 110 is wherein saidly discerned association to be selected from face-names associate related with word-word.

112. the method for claim 107, wherein said individuality are animal.

113. the method for claim 112, wherein said animal are mammal.

114. the method for claim 113, wherein said mammal is selected from primate, mice and rat.

115. the method for claim 114, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

116. the method for claim 115, wherein said primate are human.

117. the method for claim 107, wherein said individuality are a plurality of individualities.

118. the method for claim 117, wherein said a plurality of individualities comprise matched group and experimental group.

119. the method for claim 118, wherein said evaluation comprise more described matched group and described experimental group.

120. method, it comprises:

Selection is as the memory impairment agent of drug candidate, and wherein said selection may further comprise the steps:

By estimating described memory impairment agent to the described memory impairment agent of individual administration; And

121. stimulating, the method for claim 120, wherein said many groups comprise a plurality of couple stimulations.

122. the method for claim 121, wherein said a plurality of couple stimulations comprise positive unit or negative unit separately.

123. the method for claim 121, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

124. the method for claim 123 is wherein saidly discerned association to be selected from face-names associate related with word-word.

125. the method for claim 120, wherein said individuality are animal.

126. the method for claim 125, wherein said animal are mammal.

127. the method for claim 126, wherein said mammal is selected from primate, mice and rat.

128. the method for claim 127, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

129. the method for claim 128, wherein said primate are human.

130. the method for claim 120, wherein said individuality are a plurality of individualities.

131. the method for claim 130, wherein said a plurality of individualities comprise matched group and experimental group.

132. the method for claim 131, wherein said evaluation comprise more described matched group and described experimental group.

133. system, it comprises: many groups stimulate, and wherein said many groups stimulate and are provided so that and can assess the individual reactions that described many groups are stimulated and estimate effectiveness to the memory impairment agent of described individual administration thus.

134. stimulating, the system of claim 133, wherein said many groups comprise a plurality of couple stimulations.

135. the system of claim 134, wherein said a plurality of couple stimulations comprise positive unit or negative unit separately.

136. the system of claim 134, wherein said a plurality of couple stimulations comprise a unit separately, its with described paired another unit have can discern related.

137. the system of claim 136 wherein saidly discerns association to be selected from face-names associate related with word-word.

138. the system of claim 133, wherein said individuality is an animal.

139. the system of claim 138, wherein said animal is a mammal.

140. the system of claim 139, wherein said mammal is selected from primate, mice and rat.

141. the system of claim 140, wherein said primate is selected from the mankind, monkey, mongoose lemur, stump-tailed macaque and ape.

142. the system of claim 141, wherein said primate is human.

143. the system of claim 133, wherein said individuality is a plurality of individualities.

144. the system of claim 143, wherein said a plurality of individualities comprise matched group and experimental group.

145. the system of claim 144, wherein said evaluation comprises more described matched group and described experimental group.