CN1780613A

CN1780613A - Methods of preventing,treating and diagnosing disorders of protein aggregation

Info

Publication number: CN1780613A
Application number: CN 200480011335
Authority: CN
Inventors: 乔安妮·麦克劳林
Original assignee: Individual
Current assignee: Individual
Priority date: 2003-02-27
Filing date: 2004-02-27
Publication date: 2006-05-31
Anticipated expiration: 2024-02-27
Also published as: CN101385722A; CN100536837C

Abstract

Disclosed are methods of preventing, treating, or diagnosing in a subject a disorder in protein folding or aggregation., or amyloid formation., deposition, accumulation, or persistence consisting of administering to said subject a pharmaceutically effective amount of inositol stereoisomers, enantiomers or derivatives thereof.

Description

The method of prevention, treatment and diagnosing disorders of protein aggregation

Related application

The application requires the priority of U.S. Provisional Patent Application series number 60/451,363,60/520,958 and 60/523,534, and above-mentioned application is respectively at submitting on February 27th, 2003, on November 17th, 2003 and on November 19th, 2003.

Invention field

The present invention relates to treat the method for Alzheimer and other amyloidosis; More particularly, the present invention relates in the therapeutic of Alzheimer and other amyloidosis gets involved, suppress and reduce the method that amyloid fibrils forms.

Description of related art

The neuropathological feature of Alzheimer is amyloid beta deposition thing, neurofibrillary tangle and selective neuronal loss.The main component of amyloid beta deposition thing is amyloid-β (A β), and it is the peptide of a kind of 39-43 residue.The A β of the soluble form that is produced by the amyloid precursor protein cracking is metabolic normal product.The importance outstanding behaviours of residue 1-42 in the Alzheimer (A β 42) causes A β 42 to increase than A β 1-40 output in codon 717 sudden changes of having found amyloid precursor protein gene, presenilin 1 and presenilin 2 genes.These with ripe speckle and dispersivity amyloid in exist the relevant result of A β 42 to derive following hypothesis: the material of the more amyloids of this generation may be crucial factor in speckle forms.This hypothesis has obtained the support of the following fact: A β 42 depositions have surpassed A β 40 depositions at the mongolism of PS1 sudden change and in the hereditary cerebral hemorrhage of amyloidosis.

Many in vitro studies are verified, and A β can be neurovirulent or can increase the susceptibility that neuron is subjected to exitotoxicity, metabolism or oxidative damage.At first, people only think that the A of fibril form is toxic to neuron, but more fully the sign of A beta structure have been confirmed that the dimerization of A β and little aggregation also are neurovirulent.These Notes of Key Datas prevent that A β oligomerization from will be the prevention neurodegenerative suitable strategy relevant with AD.Several studies is verified, utilize to increase the neurotoxicity that the chemical compound of neuron resistance can cause at external elimination A β, this chemical compound is by the targeting cellular pathways relevant with natural death of cerebral cells, after the A that destroys the path is beta induced, block downstream pathway, perhaps block A β oligomerization and final fibril and form and increase the neuron resistance.Illustrate to play though await and induce neurovirulent A β site, can block its toxic action by various medicament.

In the AD process, it can be early stage interfered with step that A β-fibril is accommodated on neuron and the glial cell film.The formation of amyloid plaque, neurotoxicity and inflammation may be the result that A and the interaction of molecules that contains glycosyl group directly or indirectly cause.Early stage research is verified, and A β and aminopolysaccharide interact and cause the A beta peptide aggregation may increase its insoluble and speckle persistency.Aminopolysaccharide is also relevant with the microgliacyte activation with neurotoxicity.In addition, the interaction with glycolipid such as ganglioside causes stabilisation and prevents that the Ab fibril from forming and A β produces the site.On the other hand, phosphatidylinositols family causes quickening fibriilar formation.A base of phosphatidylinositols is an inositol, and it is a kind of naturally occurring simple sugars, and is relevant with the control of lipid biosynthesis, signal transduction and osmotic pressure.

It should be noted that equally, multiple other human diseases is alleged occurrence amyloid beta deposition and be usually directed to general organ (promptly being positioned at the organ or tissue of central nervous system periphery) also, and these organs are with causing organ dysfunction or depleted amyloid to gather.For Alzheimer and " general " amyloid disease, do not cure at present or effective Therapeutic Method, and patient is dead in the 3-10 of morbidity usually.

United States Patent (USP) 4,847 discloses phytic acid, phytate, the isomer of phytic acid or the purposes that hydrolyzate is used for the treatment of Alzheimer No. 082.The isomer of phytic acid or phytate is also disclosed, its comprise six phosphoric acid myo-inositol esters, six phosphoric acid Cocositol esters, six phosphoric acid D-chirality-mesoinositols, six phosphoric acid L-chirality-mesoinositols, six phosphoric acid new-inositol (neo-inositol) ester and six phosphoric acid are sticking-inositol (muco-inositol) ester configuration.Phytic acid is inositol-six phosphate ester (IP6).

United States Patent (USP) 5,112 discloses phytic acid No. 814 and isomery is used for the treatment of parkinsonian purposes.With United States Patent (USP) 4,847, No. 082 is identical, the phytic acid isomer of this patent disclosure on six carbon inositol sugar, have six phosphate-based.

It should be noted that in follow-up open source literature, studied inositol-phosplate, inositol-1,4-bisphosphate and inositol-1,4, the 5-triguaiacyl phosphate suppresses the ability of amyloid-β peptide microfibre generation and finds that they are invalid (J.Mol.Biol.278:183-194,1998).

People such as Barak disclose the purposes that inositol is used for the treatment of Alzheimer (AD).(Prog Neuro-psychopamacol & Biol Psychiat.20：729-735，2000)。But this list of references does not disclose the purposes of inositol isomer.Between inositol treatment patient AD and placebo (glucose) treatment patient AD, aspect overall cognitive function mark (CAMCOG index), the patient of inositol treatment does not demonstrate evident difference, but exponential two the concrete inferior indexs of CAMCOG but demonstrate significant improvement the (orientation and language).

Levine J. has summarized people's such as above-mentioned Barak article and has particularly pointed out the inositol treatment and has been unfavorable for AD or the inductive cognitive impairment of ECT-(Eur Neuropsychoparm.1997; 7,147-155,1997).

With reference to people's such as above-mentioned Barak article, it is useless for Alzheimer that people such as Colodny further research and propose inositol, does not therefore have purposes (Altern Med Rev 3 (6): 432-47,1998) open or the isomer of suggestion inositol.

People such as McLaurin disclose the little micelle (J.Mol.Biol.278,183-194,1998) that myo-inositol can be stablized A β 42.In addition, people such as McLaurin discloses table-inositol and Cocositol but has not been that chirality-inositol can induce A β 42 to take place by random structural transformation to beta structure (the J BiolChem.6 month 16; 275 (24): 18495-502,2000; With J Struct Biol 130:259-270,2000).In addition, stereoisomer all can not be induced the structural transformation of A β 40.Ultramicroscope shows that inositol can be stablized the little accumulation of A β 42.The interaction that these lists of references also disclose inositol-A β has produced a kind of PC-12 cell and avirulent complex of former generation human neure culture to the nerve growth factor differentiation.

Alzheimer has been finished many work, but current known chemical compound or medicament seldom is used for the treatment of scheme and forms, deposits, gathers and/or retain to stop or to reverse the amyloid that takes place in Alzheimer or other amyloidosis.

Therefore, being starved of the noval chemical compound or the medicament that are used for the treatment of scheme forms, deposits, gathers and/or retains to stop or to reverse the amyloid that takes place in Alzheimer or other amyloidosis.

Summary of the invention

The invention provides a kind of treatment or prevention experimenter with protein folding or gather disorder or amyloid forms, deposits, gathers or retain the method for relevant central or peripheral nervous system or general organ disease, it comprises the chemical compound that is selected from following structure to the medical effective dose of described experimenter's administration:

Wherein, each R ₁, R _{1 '}, R ₂, R _{2 '}, R ₃, R _{3 '}, R ₄, R _{4 '}, R ₅, R _{5 '}, R ₆And R _{6 '}Be independently selected from following group:

(a) hydrogen atom;

(b) NHR ₇, wherein said R ₇Be selected from hydrogen; C ₂-C ₁₀Acyl group and C ₁-C ₁₀Alkyl;

(c) NR ₈R ₉, wherein said R ₈Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl, and described R ₉Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl;

(d) OR ₁₀, wherein said R ₁₀Be selected from no group, hydrogen, C ₂-C ₁₀Acyl group, C ₁-C ₁₀Alkyl and SO ₃H;

(e) C ₅-C ₇Glycosyl;

(f) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OH, NH ₂, SH, OSO ₃H and OPO ₃H ₂

(g) SR ₁₁, R wherein ₁₁Be selected from hydrogen, C ₁-C ₁₀Alkyl and O ₃H;

(h) randomly be selected from hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁The C that replaces of substituent group ₁-C ₁₀Alkyl; With

(i) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁,

Condition is that this chemical compound is not a myo-inositol.

The present invention provides also that a kind of prevention experimenter abnormal protein is folding, abnormal protein gathers, amyloid forms, has deposited, gathers or retain or the interactional method of amyloid lipid, and it comprises the chemical compound that is selected from following structure to the medical effective dose of described experimenter's administration:

Wherein, each R ₁, R _{1 '}, R ₂, R ₂', R ₃, R _{3 '}, R ₄, R _{4 '}, R ₅, R _{5 '}, R ₆And R _{6 '}Be independently selected from following group:

(a) hydrogen atom;

(e) C ₅-C ₇Glycosyl;

Condition is that this chemical compound is not a myo-inositol.

The present invention also provides a kind of protein dissociation of the experimenter's of making abnormal accumulation and/or has made amyloid fibril or the amyloid dissolving or the disruptive method of pre-formation or pre-deposition, and it comprises the chemical compound that is selected from following structure to described experimenter's administration medicine effective dose:

(a) hydrogen atom;

(e) C ₅-C ₇Glycosyl;

Condition is that this chemical compound is not a myo-inositol.

The method that the present invention also provides the unusual folding or protein that gathers of a kind of experimenter of diagnosis and/or amyloid fibril or amyloid to exist, it comprises: (a) to described experimenter's administration radioactive compound or labelling the chemical compound that is allowing the material of emission detectable signal under described chemical compound and unusual folding or the protein that gathers and/or fibril or the bonded condition of amyloid of q.s, if the folding unusually or protein that gathers and/or fibril or amyloid exist; (b) detect from unusual folding or the protein that gathers and/or the radioactivity or the signal of fibril or the bonded chemical compound of amyloid, diagnose described experimenter unusual folding or the protein that gathers and/or the existence of amyloid fibril or amyloid thus, wherein said chemical compound has following structure:

(a) hydrogen atom;

(e) C ₅-C ₇Glycosyl;

Condition is that this chemical compound is not a myo-inositol.

The method that the present invention also provides the unusual folding or protein that gathers of a kind of experimenter of diagnosis and/or amyloid fibril or amyloid to exist, it comprises: (a) collect from described experimenter's sample; (b) made described sample and radioactive compound or labelling and contacted, if protein and/or amyloid fibril or amyloid existence folding unusually or that gather at the chemical compound that allows the material of emission detectable signal under described chemical compound and unusual folding or the protein that gathers and/or amyloid fibril or the bonded condition of amyloid; (c) detect from unusual folding or the protein that gathers and/or the radioactivity or the signal of fibril or the bonded chemical compound of amyloid, diagnose described experimenter unusual folding or the protein that gathers and/or the existence of amyloid fibril or amyloid thus, wherein said chemical compound has following structure:

(a) hydrogen atom;

(e) C ₅-C ₇Glycosyl;

Condition is that this chemical compound is not a myo-inositol.

Brief description

Figure 1A has provided the structure of myo-inositol, table-inositol and Cocositol, and Figure 1B-1H has shown the georeferencing memory models of the Mo Lisi water maze test that carries out at the TgCRND8 mice simultaneously.Myo-inositol treatment change cognitive function (1B).When 6 monthly ages, untreated TgCRND8 (n=10) demonstrates cognitive impairment (every group of n=10, not treatment group is than treatment group p＜0.02) with respect to non--Tg matched group (1C) and Cocositol (1D) treatment mice.The performance of the TgCRND8 mice of table-inositol treatment is compared still damage to some extent with the brood mice of non--Tg (1E), but the performance close (1F) of the performance of Cocositol TgCRND8 mice and non--brood mice of Tg.The behavior of non--brood mice of Tg is not subjected to the influence of table-inositol (1G) or Cocositol (1H) treatment.Vertical bar is represented standard error.

The speckle of the TgCRND8 of table-inositol and Cocositol treatment stockpiled and astrocytosis when Fig. 2 A-2I showed for 6 monthly ages.Control animal has high speckle load and astrocytosis in hippocampus (2A) and cerebral cortex (2B).Higher enlarged drawing confirm the star-shaped glial cell activation not only with speckle load relevant (2C).The treatment of table-inositol stockpiles the effect of moderate to amyloid, and has reduced astrocytosis (2D, 2E and 2F).Cocositol treatment has reduced significantly that amyloid stockpiles and gliosis (2G, 2H and 2I).Higher enlarged drawing demonstrates Cocositol treatment mice and has less average speckle size (2I).Also use anti--A β antibody to identify that speckle stockpiles with anti--GFAP antibody labeling star-shaped glial cell.The calibration lines are 450 microns (A, B, D, E, G, H) and 94 microns (C, F, I).

Fig. 3 A-3D has shown that the degree of A beta substance 1-42,1-40 and 1-38 and APP progress (3B) is difficult to differentiation in the TgCRND8 mice of contrast and treatment.In serial sagittal plane section, the blood vessel amyloid is stockpiled quantification with treatment and untreated TgCRND8 mice.The TgCRND8 mice has significant blood vessel amyloid and stockpiles, and this is with little relevant with medium sized blood vessel, the loading of the TgCRND8 mice of Cocositol treatment descend (3A).With do not treat with show-the TgCRND8 mice of inositol treatment compares (3C), the Cocositol treatment has reduced total blood vessel loading significantly.Obviously reduce (3D) of average speckle size illustrated that Cocositol has reduced plaque deposition.

Fig. 4 has shown the georeferencing memory models that uses the Mo Lisi water maze, and water is to the effect of TgCRND8 and non-Tg mice cognitive function in 3 days test examples.

Fig. 5 has shown the georeferencing memory models that uses the Mo Lisi water maze, and Cocositol is to the effect of TgCRND8 and non-Tg mice cognitive function in 3 days test examples.

Fig. 6 showed the georeferencing memory models that uses the Mo Lisi water maze, tested the effect of example invading the exterior-inositol to TgCRND8 and non-Tg mice cognitive function at 3 days.

Fig. 7 has shown the georeferencing memory models that uses the Mo Lisi water maze, and myo-inositol is to the effect of TgCRND8 and non-Tg mice cognitive function in 3 days test examples.

Fig. 8 has shown the georeferencing memory models that uses the Mo Lisi water maze, and Cocositol, table-inositol and myo-inositol compare to the effect of TgCRND8 cognitive function (learning period and memory test) and with wild-type mice in 3 days test examples.

Fig. 9 has shown the brain area percent that the mice of untreated TgCRND8 mice and Cocositol, table-inositol or myo-inositol treatment is relatively covered by speckle.

Figure 10 A and 10B have shown the survival rate relatively (10A) or compare (10B) with the survival rate of the TgCRND8 mice of Cocositol treatment of survival rate and the TgCRND8 mice of table-inositol or myo-inositol treatment of the TgCRND8 mice of water treatment.

Figure 11 A-D shown the TgCRND8 mice at 6 monthly ages through the result of the georeferencing memory models of mannitol treatment or untreated Mo Lisi water maze test (A, B).The TgCRND8 mice of mannitol treatment and untreated TgCRND8 mice do not have tangible difference (p=0.89; A).The performance of the TgCRND8 mice of mannitol treatment obviously is different from the brood mice (p=0.05 of non--Tg of mannitol treatment; B).Use the quantitative image analysis method analyzing proteins amount of stockpiling (C).When stockpiling quantitative determination as total speckle with the speckle counting, the TgCRND8 mice of mannitol treatment and untreated TgCRND8 mice as broad as long (p=0.87).Vertical bar is represented standard error.Drawn the Kaplan-Meier accumulation survival rate (D) of mannitol treatment or untreated TgCRND8 mice.Drawing between two treated animals (every group of n=35) by the Tarone-Ware statistical test does not have significant difference, p=0.87.

Figure 12 A and B have shown the treatment result of study of the georeferencing memory test that has carried out 3 days test examples.The performance of the TgCRND8 mice of Cocositol treatment can be comparable to the brood mice (p=0.38 of non--Tg of Cocositol treatment; A).As one man, treat after 2 months, the TgCRND8 mice of Cocositol treatment still with the as broad as long (p=0.67 of the brood mice of non--Tg; B).

Figure 13 A and B have shown to the TgCRND8 at 5 monthly ages mice and have been administered once the Cocositol of various dosage every day after 1 month, the A β content among the CNS.Under all dosage, soluble A β 42 content descend and obviously different with untreated matched group (A).On the contrary, under all conditions, insoluble A β 42 not significant different (B).Vertical bar is represented standard error.

Figure 14 is administered once the Cocositol of various dosage every day after 1 month to the TgCRND8 mice, analyzes the content of brain A β 40.Under all proof loads, different between solvable A β 40 content (A) of the TgCRND8 mice that does not detect in untreated and Cocositol treatment and soluble A β 40 content (B).

Figure 15 has shown with the brood mice of non--transgenic and has compared, the cognitive function of the TgCRND8 mice at 6 monthly ages of different-inositol treatment.

Figure 16 A-D has shown the mice of Cocositol treatment when 2 monthly ages, and the speckle amount of stockpiling in TgPS1 * APP mice decreases.Control animal has high speckle load in hippocampus (A) and cerebral cortex (B).The Cocositol treatment has reduced amyloid significantly and has stockpiled (C, D).Use anti--A β antibody (brown) to identify that speckle stockpiles.The calibration lines are 300 μ m.

Figure 17 A-C has shown quantitative that speckle stockpiles in Cocositol treatment back TgPS1 * APP mice.The speckle brain covers percent (A), average speckle size (B) and speckle counting (C) significantly to be reduced.Vertical bar is represented standard error.

Detailed Description Of The Invention

The invention discloses the treatment that had and amyloid related disease such as Alzheimer of some inositol stereoisomer relevant novelty, unpredictalbe and unexpected character.

Be surprised to find, some stereoisomer of inositol and relevant chemical compound can be blocked A β-inductive carrying out property cognitive decline and brain amyloid plaque pathological changes, and, can improve survival rate during with the transgene mouse model of its administration of human Alzheimer in the sedimentary newborn stage of A β.

As above-mentioned disclosed, some (being not whole) inositol stereoisomers of the Notes of Key Data in the past may act on (people such as McLaurin, J.Biol.Chem.275 (24): 18495-18502 (2000)) to some extent to the amyloid aggregation of the neuronal cell of In vitro culture.The stereoisomer (myo-inositol, table-inositol, Cocositol and chirality-inositol) that those investigation do not provide any method to come predict what to study will have this effect, do not predict yet any other will have this effect.And those researchs can not predict whether any inositol isomer meeting acts on to some extent to amyloid beta deposition, cognitive defect or life-span in vivo.The invention describes following uncertain result: in the animal model of the disease relevant with amyloid, some inositol stereoisomer is only arranged, particularly Cocositol and different-inositol reduce the amyloid plaque burden, improve cognition and increase the life-span, other the isomer that is studied does not then have this effect.

Research in the past also only points out some inositol stereoisomer (for example table-inositol and Cocositol) can suppress external newborn amyloid aggregation.The invention describes following uncertain result: Cocositol suppresses established brain amyloid beta deposition, and also is like this in the brain of living.Previously disclosed vitro data is to this hint not, and these data are thought some the neuronal cell type that only acts on cultivation, but not the complex organization of the brain of living, and only points out inositol can suppress newborn and assemble, thus with established disease independent.

Vitro data in the past also points out administration table-inositol and Cocositol also to influence amyloid A β 40 content and A β 42 content.Dose study has disclosed following unpredictable result in the body of the present invention: and administration is different-and inositol or Cocositol especially reduce A β 42 content, yet to insoluble A β 42 and the not influence of solvable or insoluble A β 40 content.

Investigation of the present invention demonstrates the variation of the active and inflammation of neuroglia, and this is novelty and surprising, and can not by data prediction in the previously disclosed body to.

Investigation of the present invention confirms that Cocositol improves the life-span of transgenic models animal, and this also is novelty and surprising, can not increase survival rate and life-saving because there is the medicine of Alzheimer to demonstrate in the past in the body.

Preferably, chemical compound of the present invention is 1,2,3,4,5, the 6-cyclohexanhexanol, more preferably be selected from suitable-, table-, different-, sticking-, new-, shark-, D-chirality-and L-chirality-inositol.

Also preferred

compound

1,2,3,4,5-quercitol (quercitol), more preferably be selected from table-, vibo-, shark-, different-, Ta Luo-, gala-, suitable-, sticking-, new-, former-quercitol and enantiomer thereof.

Also preferred those are selected from the chemical compound of the enantiomer of the enantiomer of stereoisomer, cyclohexanetetraol of stereoisomer, the phloroglucite of cyclohexanetetraol, phloroglucite, cyclohexanetetraol and phloroglucite.

These chemical compounds can also be penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.

Also preferred, these chemical compounds are the inososes that are selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.

Also preferred, these chemical compounds are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.More preferably (-)-1-deoxidation-Cocositol single ketones.

Also preferred, these chemical compounds are penta hydroxy group Ketohexamethylene (inosose) or its stereoisomer or enantiomer, more preferably are selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.

Randomly, these chemical compounds are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer, as (-)-1-deoxidation-Cocositol single ketones.

Also preferred, these chemical compounds are O-monomethyl-cyclohexanhexanol or its stereoisomer or enantiomer, more preferably are selected from D-pinitol, L-bornesitol and D-bornesitol.

In addition, these chemical compounds can be selected from an amino quercitol (inosamine), diaminourea cyclohexanetetraol (inositol diamidogen), diaminourea phloroglucite, its stereoisomer and enantiomer and its officinal salt, for example L-new-inosamine, D, L-table-inosamine-2, streptamine and deoxystreptamine.

Also preferred, these chemical compounds are single sulfydryl-quercitol or its stereoisomer or enantiomer, more preferably 1L-1-deoxidation-1-sulfydryl-8-O-methyl-chirality-inositol.

Most preferred compound of the present invention is different-inositol and Cocositol, wherein Cocositol most preferably.As implied above, inositol stereoisomer of the present invention does not comprise myo-inositol and does not comprise table-inositol.

Even administration after the amyloid pathological changes has formed the several months, these chemical compounds also can reverse brain A β effectively and gather and the amyloid pathological changes.

Therefore, find that these chemical compounds are useful among treatment or the prevention experimenter with protein folding or gather disorder or amyloid forms, deposits, gathers or retain the disease of relevant central or peripheral nervous system or general organ.Find that also these chemical compounds can be used for preventing that experimenter's abnormal protein is folding, abnormal protein gathers, amyloid forms, deposit, gather or retain or the amyloid lipid interacts, and make the protein dissociation of experimenter's abnormal accumulation and/or make amyloid fibril or the amyloid dissolving or the destruction of pre-formation or pre-deposition.

Preferably, the disease of described central or peripheral nervous system or general organ causes protein, protein fragments and the peptide form precipitation with beta-pleated sheet and/or fibril and/or aggregation.More preferably, the disease of described central or peripheral nervous system or general organ is selected from: Alzheimer, senilism and old and feeble formation; Amyloid blood vessel disease; Mild cognitive goes down; The dementia relevant with Alzheimer; The tau disease; Alpha-synapse albumen disease; Parkinson disease; Amyotrophic lateral sclerosis; Motor neuron; Spastic paraplegia (paraplagia); The Heng Yandun disease; Spinocebellar ataxia; Friedreich ataxia; With in the cell and/or the relevant neurodegenerative disease of gathering of neuron internal protein and polyglutamic amide, poly-alanine or other repeat body of causing by three in the corresponding gene or the unitary pathology expansion of tetranucleotide; Cerebrovascular disease; Mongolism; The head trauma that gathers with amyloid beta after the wound; With prion-related diseases; Familial Britain dementia; Familial Denmark dementia; Presenile dementia with spasmodic ataxia; Britain's type cerebral amyloid angiopathy; Presenile dementia with spasmodic ataxia; The danish type cerebral amyloid angiopathy; Has neurofilament but the familial encephalopathia (FENIB) of albumen inclusion body; Amyloid polyneuropathy; The inclusion body myositis that causes by amyloid beta; The familial amyloidosis Finnish type; The SA relevant with multiple myeloma; Familial Mediterranean fever; Chronic infection and inflammation; And with the relevant type ii diabetes of Diabetes-associated peptide (IAPP).

Also preferred, the dementia relevant with Alzheimer is vascular or Alzheimer, and the tau disease is selected from argentaffine grannles dementia (argyrophilic grain dementia), the cortex substrate degeneration, the dementia pugilistica, dispersivity neurofibrillary tangle with calcification, frontotemporal dementia with parkinson's syndrome, with prion-related diseases, Hallervorden Spatz, myotonia atrophica, C type Niemann-Pick disease, non-Guam motor neuron with neurofibrillary tangle, Pick disease, Ba Jinsen syndrome after the encephalitis, the prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear plasy, subacute sclerosing panencephalitis, only entanglement type dementia (tangle only dementia).

Also preferred, alpha-synapse albumen disease is selected from the dementia with the multiwalled corps ronds of centration, the multiple system atrophy with neurogliocyte matter inclusions, shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, has neural degeneration, heterosmia and amyotrophic lateral sclerosis that I type brain ferrum gathers.

Also preferred, motor neuron is relevant with neurofilament and/or superoxide dismutase albumen thread or the gathering shape, and spastic paraplegia is relevant with chaperone and/or the proteic functional impairment of three A, and spinocebellar ataxia is DRPLA or Ma-Yue disease.

Also preferred, be selected from Creutzfeldt-Jakob disease, Gerstmann-Str  ussler-Scheinker disease and mutation Creutzfeldt-Jakob disease with prion-related diseases and amyloid polyneuropathy is old amyloid polyneuropathy or SA.

More preferably, the disease of described central or peripheral nervous system or general organ is the parkinson disease that comprise familial or non-familial.Most preferably, the disease of described central or peripheral nervous system or general organ is an Alzheimer.

Preferably, with The compounds of this invention with the about 1g/kg experimenter's body weight of about 1mg-, the preferred about 200mg/kg experimenter's body weight of 1mg-, more preferably from about the about 100mg/kg experimenter's body weight of 10mg-, most preferably from about the dosage of the about 70mg/kg experimenter's body weight of 30mg-is to experimenter's administration.Administration can be by finishing such as following the whole bag of tricks: oral (oral administration pills, oral liquid or suspension), intravenous, intramuscular, intraperitoneal, Intradermal, percutaneous, subcutaneous, intranasal, Sublingual, rectal suppository or suction, wherein oral administration most preferably.The compounds of this invention at interval the multiple time carry out administration, for example once a day, twice of every day, weekly, January once or continue medication.

Preferably, The compounds of this invention and other therapeutic agent administering drug combinations, these therapeutic agents for example are beta-secretase inhibitors, inhibitors of gamma-secretase (APP-specificity or non-specific), ε-Secretase inhibitors (APP-specificity or non-specific), β-lamellar gathering/microfibre generation/ADDL generates other inhibitor of (for example Alzhemed), nmda antagonist (for example memantine), nonsteroidal anti-inflammatory compound (ibuprofen for example, celecoxib), antioxidant (for example vitamin E), hormone (for example estrogen), nutrient and food supplement (for example Semen Ginkgo); Acetylcholinesteraseinhibitors inhibitors (for example donezepil), muscarinic agonist (for example AF102B (cevimeline, EVOXAC), AF150 (S) and AF267B), psychosis (for example haloperidol, clozapine, olanzapine); Antidepressants comprise tricyclic antidepressants and serotonin reuptake inhibitor (for example Sertraline and citalopram Hbr), based on gene therapy and/or the medicine of just regulating neprilysin (enzyme of a kind of A of degraded β); Based on gene therapy and/or the medicine of just regulating insulin-degrading enzyme (enzyme of a kind of A of degraded β), vaccine, the immunization therapy of A β and antibody (for example ELAN AN-1792), statins and other anticholesteremic agent (for example lovastatin and simvastatin), stem cell and other therapeutic agent based on cell, proteic kinases (the CDK5 of phosphorylation TAU, GSK3 α, GSK3 β) inhibitor (for example lithium chloride), or kinases (the GSK3 α of adjusting A β generation, GSK3 β, the Rho/ROCK kinases) inhibitor (for example lithium chloride and ibuprofen).

We think that these other therapeutic agents work by different mechanism, and the present invention is had summation action/synergism.In addition, many other therapeutic agents may have based on the effect of mechanism and/or other side effect, and this meeting dose limitation or toleration at this moment can be individually dosed with them.

Because The compounds of this invention has discussed in detail hereinafter in vivo in conjunction with the ability of amyloid, so also being useful on, The compounds of this invention use following method to diagnose unusual folding or the protein that gathers and/or the existence of amyloid fibrils or amyloid among the experimenter, this method comprises: to described experimenter's administration radioactive compound or labelling the chemical compound that is allowing the material of emission detectable signal under described chemical compound and unusual folding or the protein that gathers and/or fibril or the bonded condition of amyloid of q.s, if the folding unusually or protein that gathers and/or fibril or amyloid exist; With detect from unusual folding or the protein that gathers and/or the radioactivity or the signal of fibril or the bonded chemical compound of amyloid, unusual folding or the protein that gathers and/or the existence of amyloid fibril or amyloid of diagnosis thus.

In addition, collect from the experimenter and to suspect and to contain unusual folding or the protein that gathers and/or the sample of amyloid fibrils or amyloid, and made described sample and radioactive compound or labelling and contact at the chemical compound that allows the material of emission detectable signal under described chemical compound and unusual folding or the protein that gathers and/or amyloid fibril or the bonded condition of amyloid, if protein and/or amyloid fibril or amyloid existence folding unusually or that gather; And detect subsequently from unusual folding or the protein that gathers and/or the radioactivity or the signal of fibril or the bonded chemical compound of amyloid, diagnose described experimenter unusual folding or the protein that gathers and/or the existence of amyloid fibril or amyloid thus.

Preferably, described detectable signal is fluorescence signal or enzyme-linked immunosorbent assay signal, and described sample is whole blood (comprising all cell component) or blood plasma.

Shown in hereinafter, in the transgene mouse model of Alzheimer, before obvious cognitive defect and amyloidotic neuropathy reason appear in " presymptomatic late period " stage, mice, give The compounds of this invention, can eliminate that IC A β gathers, brain amyloid plaque deposition and cognitive decline.In addition, even give these chemical compounds after cognitive defect and amyloid plaque europathology occurring, they also can reverse amyloid beta deposition and europathology effectively.Importantly, regulate the set of A beta monomers according to these chemical compounds and be neurovirulent oligomer and/or fibriilar ability, be guided out rational design by the mechanism of action of these chemical compounds.

Other advantage of The compounds of this invention comprises that they are transported to CNS by two kinds of known transporters and passive diffusion, thereby good CNS bioavailability is provided.The second, these chemical compounds are metabolised to glucose.The 3rd, as a class material, these chemical compounds have hypotoxicity spectrum usually, and for different purposes, in the past with in them some to human administration.

Embodiment 1-makes up the method for Alzheimers mouse model and administration The compounds of this invention

As described in people such as Janus (Nature 408:979-982 (2000)), the TgCRND8 mice is the strong catastrophic model of Alzheimer.They are expressing human amyloid precursor protein (APP695) transgenic under the regulation and control of the hamster,syrian of C3H/B6 outbreeding background and Protein virus promoter.People APP695 transgenic has two catastrophe points, and it causes the mankind to suffer from AD (K670N/M671L and V717F).From about 3 monthly ages, carrying out property space learning defective appears in the TgCRND8 mice, and follow brain A β content to raise and the outer amyloid plaque quantity increase of brain cell, these all similar (people such as C.Janus, Nature 408:979-982 (2000)) to situation about arriving seen in the human brain of suffering from AD.

With age and sex-matched TgCRND8 mice group and not genetically modified brood mice group (every group of n=35) or do not treat, or begin by following amount administration The compounds of this invention with 30mg/ days/Mus from about 6 all ages.When 4 monthly ages and 6 monthly ages, measure cognitive function, brain A β content, brain pathology and the survival rate of these mices subsequently.

The Prevention Research method

Mice-give test group TgCRND8 mouse feeding myo-inositol, table-inositol and Cocositol with the amount in 30mg/ Mus/sky.6 weeks during ages two groups enter research and analysis result during at 4 monthly ages and 6 monthly ages.Behavior in monitoring body weight, fur feature and the cage.The animal of all experimental evidence Canada committee is taken care of guide and carries out.

4 tests are carried out in performance testing-after the pre-training of non-space, mice was carried out the orientation discrimination training 5 days every day.Use medicine or genotype and training period to analyze behavioral data as the mixed model of the factor variance analysis (ANOVA) of replication factor.

Brain amyloid burden-taking-up brain and a brain hemisphere are fixed in 4% paraformaldehyde and along central sagittal plane (mid saggital plane) imbeds paraffin.In order to produce group system section at random uniformly, the whole hemisphere of crosscut is collected 5 μ m serial section.The section group of 50mm is used for analyzing (10-14 sheet/group) at interval.Carry out identifying speckle after the antigen retrieval with formic acid, and with it with former anti-amyloid beta antibodies (Dako M-0872), use secondary antigen (Dako StreptABCcomplex/horseradish kit) to hatch then.End-product carries out DAB through hematoxylin and can observe dying.Use the Leco IA-3001 image analysis software evaluation starch sample albuminous plasue that is connected with Hitachi KIP-MU ccd video camera with the Lycra microscope to bear.Analyze the blood vessel burden similarly, and use the detacher measurement to be attacked the diameter of blood vessel.

Blood plasma and brain A β content-in the sucrose buffer is brain hemisphere sample homogenization, and then or adding 0.4% diethylamine/100mM NaCl is used to dissolve A β content, or adding cold formic acid is used to separate total A β.After the neutralization, dilute sample also uses the test kit (BIOSOURCE International) that is purchased to analyze A β 40 and A β 42.Each hemisphere is analyzed three times, the record mean+SD.Carry out the plaque of protein point analysis to analyze the A beta substance in the enterprising enforcement of all parts with urea gel.The chemiluminescence (Amersham) of using 6E10 (BIOSOURCEInternational) and strengthening detects A β.

APP-in the analysis brain is with the homogenate in 20mM Tris pH7.4,0.25M sucrose, 1mM EDTA and 1mM EGTA and protease inhibitor mixed liquor of mouse brain hemisphere sample, mix and with 109 the 000Xg rotation with 0.4%DEA (diethylamine)/100mM NaCl.Use the analytically APPs content in the clear liquid of mAb 22C11 by Western blotting, use mAb C1/6.1 to analyze flaky precipitate to measure the APP whole protein.

Quantitatively gliosis-from the paraformaldehyde of treatment and control mice fix and refrigerated hemisphere on select evenly spaced five sagittal slices at random.To cut into slices with anti-Mus GFAP IgG2a (Dako; Dilution in 1: 50) comes immune labeled star-shaped glial cell and with anti-Mus CD68IgG2b (Dako; Dilution in 1: 50) comes immune labeled microgliacyte.Use is installed in Coolsnap digital camera (Photometrics, Tuscon, Arizona) the collection digital picture on the Zeiss Axioscope 2 Plus microscopes.Use Openlab 3.08 image softwares (Improvision, Lexington MA) analysis image.

The survival rate investigation-by Kaplan-Meier technology evaluation survival odds, computational analysis survival odds when death occurring, thus make its suitable small sample amount.Each treatment group uses 35 mices to be used for the viability analysis.Use Tarone-Ware to detect the comparison of putting down in writing between each treatment group.

The prevention of the cognitive disappearance of embodiment 2-

Use the georeferencing memory models of Mo Lisi water maze, use the cognitive function of 5 days test example assessment TgCRND8 mices.(untreated with treatment, table-inositol or Cocositol) and genotype (TgCRND8 and non--Tg) as " between the experimenter " factor, use blended variance analysis (ANOVA) model analyze by the data that obtain with untreated TgCRND8 mice of treatment and by treatment with untreated non--data that mice obtains that Tg is brood are (for all combinations, n=10).Through the performance of the TgCRND8 mice of table-inositol or Cocositol treatment significantly than good (p＜0.02 of untreated TgCRND8 mice; Fig. 1 C and D).With treatment with untreated non--the brood mice of Tg compares, in first three day of training, the TgCRND8 mice that table-inositol is treated shows slower a little learning curve.But, after training 4 days, no statistical difference (Fig. 2 E) between the TgCRND8 mice of table-inositol treatment and the brood mice of its non--Tg.On the contrary, in all these days, indifference between the TgCRND8 mice of Cocositol treatment and the brood mice of non--Tg.Therefore, these two kinds of stereoisomers all suppress the development of cognitive defect, and in fact, and the cognitive disappearance of Cocositol prevention has reached a kind of like this degree of indifference between the TgCRND8 mice that makes the Cocositol treatment and the normal mouse.This improved performance is not owing to the nonspecific action to behavior system, motor system or consciousness system, because table-inositol and Cocositol treatment are to the not effect (Fig. 2 G and 2H) of performance of non--Tg mice.This improved performance neither be owing to nutrition or heat effect, because do not having difference aspect body weight, activity and the fur condition between treatment group and the not treatment group.In addition, with mannitol (a kind of sugar of similar molecular weight) treatment behavior is not acted on.The influence of sex not significantly (p=0.85) between any treatment group.

The minimizing of embodiment 3-brain A β burden and amyloidotic neuropathy reason

During 4 monthly ages, untreated TgCRND8 mice gives expression to a large amount of A β 40 and A β 42 (table 1) mice.When 4 monthly ages, as described in embodiment 1, (solvable and soluble storehouse has reduced 43 ± 2% to A β 40 content of table-inositol treatment group; P≤0.05) and A β 42 content (solvable storehouse has reduced 69%, p=0.005; Soluble storehouse has reduced 28%, p=0.02) has all reduced.But these improve not lasting, when 6 monthly ages brain A β content be elevated to do not treating the TgCRND8 mice in the similar content (table 1) observed.

On the contrary, when 4 monthly ages, total brain A β 40 of Cocositol treatment group 62% (p=0.0002) and total brain A β 42 22% (p=0.0096 that descended that descended; Table 1).When 6 monthly ages, to compare with untreated TgCRND8 mice, the Cocositol treatment causes A β 40 content to reduce by 32% (p=0.04) and A β 40 content have reduced by 20% (p=0.02).

Because detected A β lowering of concentration after the inositol treatment may be taken place to change and cause, so detected the A β-β content (table 1) in the blood plasma when 4 monthly ages and 6 monthly ages by the excessive inflow blood plasma of A β.The TgCRND8 mice had high plasma A β concentration and keep constant when 6 monthly age when 4 monthly ages, even when CNS speckle loading still rose at 6 monthly ages (table 1).Do not compare with treating the TgCRND8 mice, table-inositol or Cocositol are treated plasma A β content all without any effect (p=0.89).To this observation phenomenon the most economical explanation is that inositol has optionally changed the A betaization among the CNS, but to β-or gamma-secretase activity or A β be scavenged into the not influence of normal mechanism of blood plasma.But for two reasons, this observation phenomenon is significant.At first, in untreated patient AD, detect among blood plasma and the CSF A β content usually and reduce as clinical course progress (people such as Mayeux, Ann.Neurol 46,412,2001).Secondly, taken place the powerful antibody reaction and obviously the AN1792 immune Research patient of clinical response do not have plasma A β-β content people such as (, Neuron 38,547 2003) Hock of change.Therefore, these results show in order to obtain the unnecessary change plasma A of effective therapeutic outcome β content.

In order to confirm of expression or the proteolysis processing not influence of inositol stereoisomer, in inositol treatment and untreated TgCRND8 mouse brain, detected the content of APP whole protein, sAPP-α and various A beta substances to APP.Data consistent (people such as McLaurin with report before us, Nat.Med.8,1263,2002), A β 42, A β 40 and A β 38 are the main matter (Fig. 3 A) in the TgCRND8 mouse brain, and no matter whether treat, the CNS content of the CNS content of immaturity and sophisticated glycolysis APP (Fig. 3 B) and sAPP-α all is difficult to distinguish.Integrating, these results show-inositol and Cocositol plays directly for A β oligomerization and optionally effect, but inoperative to APP processing.

The change of A β-β peptide loading is accompanied by the remarkable reduction (table 1 of speckle burden; Fig. 2 A-2I).The TgCRND8 mice of table-inositol treatment is not compared with treating the TgCRND8 mice, at 4 monthly ages but not during 6 monthly ages, average speckle diameter occurs significantly descending (being respectively 95 ± 4.3 μ m ²Contrast 136 ± 15 μ m ², p=0.04; 370 ± 9 μ m ²Contrast 423 ± 22 μ m ², p=0.06).In a single day these results show that when moderate A β content, table-inositol prevents A β oligomerization, but higher A β concentration occurs, table-inositol then can not suppress microfibre and generate.When 4 monthly ages, the average speckle diameter of Cocositol treatment group is by 136 ± 15 μ m ²Reduce to 103 ± 4 μ m ²(p=0.01).When 6 monthly ages, the A β peptide content of Cocositol treatment TgCRND8 mice group reduces, and is attended by speckle quantity minimizing 20% (p=0.005), and brain area minimizing 35% (p=0.015) and the average speckle size that are covered by speckle reduce (339 ± 10 μ m ²Contrast 423 ± 21 μ m ², p=0.009).By every test, these results confirm that after the Cocositol treatment, the speckle burden has descended.

The treatment minimizing of table 1. inositol A β 40 and A β 42 content

A β 40 (brain ± standard error of mean that ng/gm is wet)		A β 42 (ng/gm wet brain ± standard error of mean)		Total A β	The speckle counting	Plaque area (μ m ²)	Total plaque area/total brain area (%)
A β 40 (brain ± standard error of mean that ng/gm is wet)		A β 42 (ng/gm wet brain ± standard error of mean)						Soluble	Insoluble	Soluble	Insoluble
4 months prevention contrast epi-cyclohexanehexol scyllitols prevention contrast in 6 months epi-cyclohexanehexol scyllitol	75±6 43±7 ^* 37±5 ^* 187±29 188±24 105±8 ^*	1163±9 615±32 437±80 3576±172 3668±149 2453±251 ^*	273±18 85±7 206±8 ^* 626±87 665±39 475±26 ^*					Soluble	Insoluble	Soluble	Insoluble	5658±248 4059±179 ^4409±135 ^ 15802±237 13943±277 12588±82	7169±284 4802±176 5089±173 20191±211 18464±229 15621±151	696±25 678±64 598±19 ^* 960±44 979±32 774±10 ^*	100766±7564 65042±5199 63847±2895 411288±11912 380456±13498 262379±5373	0.026±0.004 0.020±0.001 0.015±0.001 ^* 0.120±0.001 0.096±0.04 0.079±0.013
	75±6 43±7 ^* 37±5 ^* 187±29 188±24 105±8 ^*	1163±9 615±32 437±80 3576±172 3668±149 2453±251 ^*	273±18 85±7 206±8 ^* 626±87 665±39 475±26 ^*	Plasma A β level (pg/ml)									7169±284 4802±176 5089±173 20191±211 18464±229 15621±151	696±25 678±64 598±19 ^* 960±44 979±32 774±10 ^*
Prevention in 4 months			Prevention in 6 months
Prevention in 4 months			Prevention in 6 months					Synopsis-inositol Cocositol	1018±27 1082±164 952±49		915±59 952±56 905±55

Use the PLSD of Fisher to carry out variance analysis p＜0.001 He ^*P＜0.05

The minimizing of embodiment 4-neuroglia activity and inflammation

Astroglia and microglial reaction are europathology feature (Irizarry etc., J Neuropathol ExpNeurol.56,965,1997 that people AD and all amyloid mouse models all have; K.D.Bornemann etc., Ann NY Acad Sci.908,260,2000).Therefore, studied table-inositol and Cocositol astrocytosis and the outgrowth therapeutical effect of microglia (Fig. 3 A-3D) to the TgCRND8 mouse brain.A series of sagittal slices are come quantitatively with star-shaped glial cell label glial fibrillary acidic (GFAP) dyeing and with the percent of the brain area that astrocytosis was covered.The TgCRND8 mice has high basic astrocytosis (0.459 ± 0.048%) when 4 monthly ages, marginal increase (0.584 ± 0.089%) is arranged during to 6 monthly ages, and is not subject to plaque area (Fig. 2 A-2C).When 6 monthly ages, table-inositol is reduced to 0.388 ± 0.039% (p=0.04 with the proliferation response of astroglia; Fig. 2 D-F) on the other hand, Cocositol more effectively is reduced to 0.269 ± 0.028% (p=0.006 with the proliferation response of astroglia; Fig. 2 G-I).When with the age with sex-matchedly do not treat TgCRND8 mice (0.31 ± 0.01%; P＜0.001) when comparing, the TgCRND8 mice of Cocositol treatment has also weakened microglial activation (0.20 ± 0.008% brain area) significantly.But, confirmed that the microglia activation of the mice of table-inositol treatment when 6 monthly ages does not significantly reduce (0.248 ± 0.02%; P=NS).These data combine and show, Cocositol treatment minimizing A β among the CNS-inductive inflammatory reaction.

Embodiment 5-blood vessel amyloid loading

Alzheimer is characterised in that and has parenchyma and blood vessel amyloid beta deposition.In the TgCRND8 at 6 monthly ages mice, nearly 0.03% brain area and blood vessel are amyloid related.In the table-inositol treatment group at 6 monthly ages, do not observe the difference (Fig. 3 C) of blood vessel amyloid burden.On the contrary, the blood vessel amyloid of Cocositol treatment group burden has reduced (p=0.05) (Fig. 3 C) significantly, and amyloid beta deposition mainly is confined to less blood vessel, and diameter is less than 25m ²(56 ± 2% to 70 ± 8%, in the little blood vessel of untreated TgCRND8 mice).Compare with untreated mice, the average-size of the cerebrovascular speckle in the mice of Cocositol treatment obviously reduce (154 ± 16 to 363 ± 34, p=0.008; Fig. 3 D).

Embodiment 6-survival rate is improved

The TgCRND8 mice is 50% the 175th day survival rate, brings up to 72% (every group of n=35, Cocositol than matched group p＜0.02, Figure 10 B) after Cocositol treatment.Use the myo-inositol treatment not influence total survival rate (Figure 10 A) significantly.Controlled trial has confirmed that the growth of the survival rate of the mice that Cocositol is treated is not is the indirect action that the heat intake increases.Thereby, with Cocositol wild-type mice to be treated, it is to not effect of behavior in survival rate or other parameter such as body weight, coat condition or the cage.In addition, in body weight, coat condition or the cage of the TgCRND8 mice that inositol is treated, there is not difference between behavior and the untreated TgCRND8 mice.Carry out similar test with mannose (a kind of monosaccharide of similar molecular weight), it is to the also not effect of survival rate of TgCRND8 mice.

The treatment and the reverse of embodiment 7-amyloid beta deposition

In sum, Prevention Research has confirmed that Cocositol can suppress the amyloid beta deposition of parenchyma and blood vessel, thereby has improved the survival rate and the cognitive function of the TgCRND8 mouse model of Alzheimer.But, most of Alzheimer people probably only when symptom occurring and A β oligomerization, deposition, toxicity and speckle form when in CNS, having reached high level and just seek treatment.Therefore the TgCRND8 mice with 5 monthly ages begins to carry out the test of leading property.Compare with people's brain of suffering from AD, these mices have tangible A β and speckle stockpiles.

The treatment research method

Mice-give test group TgCRND8 mouse feeding myo-inositol, table-inositol and Cocositol with the amount in 30mg/ Mus/sky.One group begins to enter research and analysis result when 6 monthly ages when 5 monthly ages.Behavior in monitoring body weight, fur feature and the cage.The animal of all experimental evidence Canada committee is taken care of guide and carries out.

The survival rate investigation-by Kaplan-Meier technology evaluation survival odds, computational analysis survival odds when death occurring, thus make its suitable small sample amount.Each treatment group uses 35 mices to be used for survival rate analysis.Use the comparison between each treatment group of Tarone-Ware check record.

Performance testing-reverse research-without pre-training allows mice enter to have the Mo Lisi water maze test of hiding platform.Mice is accepted 6 training and reach 3 days every day.At the 4th day, from the pond, take platform away, and every mice is accepted one time 30 seconds swimming detection tests.In the end one day, once point out test to animal, to estimate swimming ability, the visual field and common cognitive power.In prompting test, platform is placed on and the flag of having tested used different signal area and labelling.Allow animal with finding platform in 60 seconds.Do not find the animal of platform to be not used in the final analysis of spatial memory.Use medicine or genotype and training period to analyze behavioral data as the mixed model of the factor variance analysis (ANOVA) of replication factor.

A brain amyloid burden-taking-up brain and brain hemisphere is fixed in 4% paraformaldehyde and along central sagittal plane (mid saggital plane) imbeds paraffin.In order to produce the section at random uniformly of a group system, the whole hemisphere of crosscut is to collect 5 μ m serial section.The section group of interval 50mm is used for analyzing (10-14 sheet/group).Carry out identifying speckle after the antigen retrieval with formic acid, and with it with former anti-amyloid beta antibodies (Dako M-0872), use secondary antigen (Dako StreptABCcomplex/horseradish kit) to hatch then.End-product carries out DAB through hematoxylin and can observe dying.Use the amount of load of the Leco IA-3001 image analysis software evaluation starch sample albuminous plasue that is connected with Hitachi KIP-MU ccd video camera with the Lycra microscope.

Blood plasma and brain A β content-in the sucrose buffer is brain hemisphere sample homogenization, and then or adding 0.4% diethylamine/100mM NaCl is used to dissolve A β content, or adding cold formic acid is used to separate total A β.After neutralization, dilute sample also uses the test kit (BIOSOURCE International) that is purchased to analyze A β 40 and A β 42.Each hemisphere is analyzed three times, record meansigma methods ± standard error of mean.

Result and significance-participation reverses the external sign that all animals of studying all survive and do not demonstrate worry or poisoning.Use the georeferencing memory models of Mo Lisi water maze, use the cognitive function (Fig. 4-8) of 3 days test example assessment TgCRND8 mices.(use myo-inositol, table-inositol or Cocositol with treatment, treatment) and genotype (TgCRND8 with non--Tg) as " between the experimenter " factor, the mixed model of user's difference analysis (ANOVA) analyze by the data that obtain with untreated TgCRND8 mice of treatment and by treat with untreated non--data (all combination n=10) of mice acquisition that Tg is brood.Compare with the brood mice of wild type, the ability of TgCRND8 mice obviously weakens (Fig. 4).On the contrary, in all these days, indifference (p=0.38 between the TgCRND8 mice of Cocositol treatment and the brood mice of non--Tg; Fig. 5).Compare the almost obviously different (p=0.07 of the TgCRND8 mice of table-inositol treatment with the brood mice of non--Tg of treatment; Fig. 6).Similarly, the also obviously different (p=0.05 of TgCRND8 mice of myo-inositol treatment with the brood mice of non--Tg of treatment; Fig. 7).This water maze test is during the learning period between the relatively treatment group, all mice behaviors similar (Fig. 8).On the contrary, indifference (Fig. 8) between Cocositol group and the non--Tg compatriot mice.Therefore, in fact, Cocositol reverses cognitive disappearance and has reached a kind of like this degree of indifference between the TgCRND8 mice that makes the Cocositol treatment and the normal mouse.This improved performance is not owing to the nonspecific action to behavior system, motor system or consciousness system, because table-inositol and Cocositol treatment are to the not effect of performance of non--Tg mice.This improved performance neither be owing to nutrition or heat effect, because do not have difference aspect body weight, activity and the fur condition between treatment and not treatment group.

Whether relevant with the minimizing of A β load for the cognition of determining to improve with the speckle amount of stockpiling, cerebral tissue has been carried out obduction.The corresponding change (Fig. 9 and table 2) of speckle amount of stockpiling and A β load has been followed in cognitive variation.The myo-inositol treatment is to speckle amount of stockpiling or the not influence (Fig. 9 and table 2) of A β load.The TgCRND8 mice of table-inositol treatment is compared with untreated TgCRND8 mice, and average speckle diameter does not reduce (Fig. 9) significantly, but A β load obviously reduces (table 2).These results show, when moderate A β content, table-inositol prevents A β oligomerization, but in case higher A β concentration occurs, table-inositol then can not suppress the microfibre generation fully.The speckle amount of stockpiling of Cocositol treatment group and A β load obviously reduce.By every test, these results confirm that the speckle amount of stockpiling has descended after the Cocositol treatment.These results are comparable to 6 months preventative research effect in effect aspect big or small, and have further supported the potentiality of Cocositol.

Because detected A β lowering of concentration after the inositol treatment may change take place owing to the excessive inflow blood plasma of A β, so we has detected the A β content (table 2) in the blood plasma.The TgCRND8 mice has high plasma A β concentration when 6 monthly ages.Compare with untreated TgCRND8 mice, myo-inositol, table-inositol or Cocositol are treated plasma A β content all without any effect (p=0.89).To this observation phenomenon the most economical explanation is that inositol has optionally changed the A betaization among the CNS, but to β-or gamma-secretase activity or A β be eliminated the not effect of normal mechanism that enters blood plasma.But for two reasons, this observation phenomenon is significant.At first, in untreated patient AD, detect A β content among blood plasma and the CSF usually and reduce progress as clinical course.Secondly, the plasma A β content that in the AN1792 immune Research patient that powerful antibody reaction and obvious clinical response take place, does not have change.Therefore, these results further show in order to obtain the unnecessary change plasma A of effective therapeutic outcome β content.

In sum, these data have disclosed in the transgene mouse model of Alzheimer, before significantly cognitive disappearance and amyloidotic neuropathy reason appearred in " presymptomatic late period " stage, mice, the Cocositol of selection can eliminate that IC A β gathers, brain amyloid plaque deposition and cognitive decline.In addition, even give Cocositol after cognitive disappearance and amyloid plaque europathology occurring, these chemical compounds also can reverse amyloid beta deposition, europathology and cognitive disappearance effectively.Therefore, these results show that Cocositol is effective in prevent disease with treating in the disease of having diagnosed patient's existence of suffering from AD.

Table 2. inositol is handled the level that has reduced A β 40 and A β 42

A β 40 (brain ± standard error of mean that ng/gm is wet)		A β 42 (brain ± standard error of mean that ng/gm is wet)		Total A β	The speckle counting	Plaque area (μ m ²)	Total plaque area/total brain area (%)
A β 40 (brain ± standard error of mean that ng/gm is wet)		A β 42 (brain ± standard error of mean that ng/gm is wet)						Soluble	Insoluble	Soluble	Insoluble
4 months prevention contrast myo-inositol epi-cyclohexanehexol scyllitols prevention contrast in 6 months myo-inositol epi-cyclohexanehexol scyllitol treatment contrast in 1 month myo-inositol epi-cyclohexanehexol scyllitol	75±6 42±6 43±7 ^* 37±5 ^* 187±29 221±19 188±24 105±8 ^* 207±16 194±12 264±11 178±11	1163±9 485±143 615±32 437±80 3576±172 3436±189 3668±149 2453±251 ^* 4965±457 4187±226 3637±113 3527±241	273±18 174±9 85±7 206±8 ^* 626±87 543±71 665±39 475±26 ^* 426±14 487±25 540±14 374±23					Soluble	Insoluble	Soluble	Insoluble	5658±248 4268±308 4059±179 ^* 4409±135 ^* 15802±237 13289±535 13943±277 12588±82 14503±1071 15622±675 12830±330 11115±647	7169±284 4969±434 4802±176 5089±173 20191±211 17489±354 18464±229 15621±151 20101±854 20490±526 17271±415 15194±579	696±25 649±50 678±64 598±19 ^* 960±44 927±78 979±32 774±10 ^* 1441±29 1324±69 1342±114 1260±27 ^*	100766±7564 91902±7453 65042±5199 63847±2895 411288±11912 400013±19638 380456±13498 262379±5373 486002±16156 469968±35664 459706±49966 420027±14986 ^*	0.026±0.004 0.023±0.004 0.020±0.001 0.015±0.001 ^* 0.120±0.001 0.100±0.005 0.096±0.04 0.079±0.013 0.159±0.014 0.153±0.088 0.134±0.017 0.119±0.010 ^*
				Plasma A β level (pg/ml)
Prevention in 4 months			Prevention in 6 months									Treatment in 1 month
Prevention in 4 months			Prevention in 6 months		Contrast myo-inositol table-inositol Cocositol	1018±27 942±30 1082±164 952±49			915±59 969±67 952±56 905±55		2287±151 2110±174 2158±157 1980±146

Use the PLSD of Fisher to carry out variance analysis p＜0.001 He ^*P＜0.05; IP=is in progress.

Treatment researchs in two months of embodiment 8-Cocositol

In order to determine the more long-acting scope of Cocositol treatment disease, to the TgCRND8 at 5 monthly ages mouse feeding Cocositol or do not treat and reach 2 months (every group of n=10).With three days Mo Lisi water maze tests 7 months big are compared through the TgCRND8 mice of Cocositol treatment and the brood mice of non--Tg of untreated TgCRND8 mice and treatment.Use medicine and genotype to analyze behavioral data as the mixed model of the factor variance analysis (ANOVA) of experimenter's internal variable as variable between the experimenter and training period.Find out between the brood mice of non--Tg of 2 months TgCRND8 mice of Cocositol treatment and Cocositol treatment, do not having difference (Figure 12 B) by Cocositol treatment 1 month (Figure 12 A).For cognitive power and the pathology that will improve connect, A β 40 and A β 42 content (table 3) in the brain have been analyzed.After the Cocositol treatment, insoluble A β 40 and A β 42 content have all descended 20%.These results confirm that Cocositol acts on during disease progression lasting.

The content of the treatment reduction of table 3 inositol A β 40 and A β 42

Brain A β 40 (brain ± standard error of mean that ng/gm is wet)		Brain A β 42 (brain ± standard error of mean that ng/gm is wet)		Plasma A β content (pg/ml)
				Plasma A β content (pg/ml)		Soluble	Insoluble	Soluble	Insoluble	Aβ40	Aβ42
2 months treatment contrast Cocositol	487±14 395±60	6924±287 5703±612 ^*	764±51 688±28	25827±1238 20818±1404 ^*	5212±219 4507±207	Soluble	Insoluble	Soluble	Insoluble	Aβ40	Aβ42	3455±331 3035±236

Use the PLSD of Fisher to carry out variance analysis, ^*P＜0.05.

Embodiment 9-dosage is to the effect of the TgCRND8 mice pathological examination of suffering from disease

Dosage with 10mg/Kg, 30mg/Kg and 100mg/Kg is treated 5 months big TgCRND8 mices of Cocositol feeding soluble in water once a day or not.Treat and put to death animal after one month and analyze pathological examination.A β analysis on Content in the brain of all groups has been confirmed to compare with untreated TgCRND8 mice, and all identical degree of all drug doses ground is imitated and has been reduced soluble A β 42 content (decline 20%, F _3,15=3.1, p=0.07; Figure 13 A).Single dosage analytical proof 10mg/Kg and 30mg/Kg dosage group be different from significantly and do not treat matched group (being respectively p=0.03 and p=0.02).Selected dosage does not have significant difference (F each other _2,11=0.6, p=0.57; Figure 13 A).Feeding dosage is for insoluble A β 42 (F _3,15=0.69, p=0.58; Figure 13 B) or soluble and insoluble A β 40 (be respectively F _3,15=0.04, p=0.99 and F _3,15=0.36, p=0.79; Figure 14 A and 14B) have no significant effect.

Whether also can effectively prevent and further develop and/or part reverses established AD-sample phenotype in order to assess different-inositol, Cai begin treatment TgCRND8 mice when being deferred to for 5 monthly ages.TgCRND8 mice group and the brood mice of non--transgenic are organized or treated 28 days with different-inositol, or do not treat.In these trials, the dosage of chemical compound carries out with the neuro chemistry assessment employing mode identical with above-mentioned therapeutic test with oral administration and behavior.

The TgCRND8 mice group of different-inositol treatment at 6 monthly ages is than the untreated TgCRND8 mice (F that puts up a good show significantly _1,13=0.45, p=0.05; Data do not provide).The cognitive performance of the TgCRND8 mice of the different-inositol treatment at 6 monthly ages also is different from the brood mice of non--transgenic significantly.This beneficial effect of inositol treatment is not owing to the nonspecific action to behavior system, motor system or consciousness system, because the cognitive performance that inositol is treated non--Tg mice does not act on (F _1,12=0.98; P=0.49).Treatment and the brain A β content of untreated TgCRND8 mice are analyzed, whether changed relevant (table 4) with A β with the behavior of determining to improve.Different-inositol treatment has reduced soluble A β 42 (descending 20%, p＜0.05), and it is similar that this effect and Cocositol are observed.Different-inositol does not change insoluble A β 42 or A β 40 (solvable and soluble storehouse) significantly.A kind of possible explanation that A β 42 reduces is the removing of periphery A β 42, causes the increase of plasma A β 42 subsequently.In different-inositol treatment back blood plasma in A β 42 content and the untreated TgCRND8 blood plasma content do not have difference (table 5).Consistent with other inositol stereoisomer, the influence of different-inositol treatment that these results have proved that plasma A β content is not subjected to.

Table 4. is different-inositol treatment reduction A β 42 content

Brain A β 40 (brain ± standard error of mean that ng/gm is wet)		Brain A β 42 (brain ± standard error of mean that ng/gm is wet)		Plasma A β content (pg/ml)
					Soluble	Insoluble	Soluble	Insoluble
1 month different-inositol of treatment contrast	252±48 281±21	4105±851 3787±342	666±39 547±47 ^*		Soluble	Insoluble	Soluble	Insoluble	16448±2120 16336±910	2359±147 2458±95

Use Fisher ' s PLSD to carry out variance analysis, ^*P＜0.05.

Table 5 haemobiochemistry-Cocositol dose study

	Untreated n=4	100mg/Kg n＝4	30mg/Kg n＝3	10mg/Kg n＝5	Reference levels (Vita-Tech ﹠ CCAC)
	Untreated n=4	100mg/Kg n＝4	30mg/Kg n＝3	10mg/Kg n＝5	Reference levels (Vita-Tech ﹠ CCAC)	Biochemistry gross protein albumin globulin bilirubin ALP ALT glucose urea creatinine haemolysis jaundice piarhemia	46 ± 2g/L, 35 ± 0g/L, 12 ± 1g/L, 2.4 ± 1umol/L, 81 ± 10U/L, 42 ± 4U/L, 11 ± 2mmol/L, 9 ± 3mmol/L, 36 ± 5umol/L is normal normal	49 ± 2 31 ± 1 19 ± 2 1.9 ± 0 76 ± 11 38 ± 4 11 ± 2 7.4 ± 1 31 ± 4 is normal normal	50 ± 2.6 33 ± 2 17 ± 1 2.0 ± 1 81 ± 10 42 ± 4 12 ± 29 ± 3 35 ± 5 is normal normal	50 ± 3 33 ± 4 17 ± 2 1.9 ± 0.6 73 ± 22 51 ± 20 7 ± 2 10 ± 2 40 ± 5 is normal normal	35-72 25-48 18-82 2-15 28-94 28-184 9.7-18.6 12.1-20.6 26-88

The treatment of embodiment 11-inositol does not influence hematochemistry

In order to get rid of any illeffects of inositol treatment, after 1 month blood has been carried out analyzing (table 5 and 6) at Cocositol and different-inositol treatment to hematochemistry and organ dysfunction.Between the treatment group or and untreated TgCRND8 mice between, gross protein, albumin, globulin, bilirubin, alkaline phosphatase, glucose, carbamide and creatinine all do not have notable difference.All content all dropped in the normal range of being measured by non--transgenic wild-type mice.Except haemolysis, also have jaundice and lipidemia also all normal.These results suggest are different-and inositol and Cocositol do not demonstrate deleterious effects to hematochemistry and organ dysfunction.

The treatment research of table 6 haemobiochemistry-1 month

	Untreated n=4	Different-inositol n=4	Reference levels (Vita-Tech ﹠ CCAC)
	Untreated n=4	Different-inositol n=4	Reference levels (Vita-Tech ﹠ CCAC)	Biochemistry gross protein albumin globulin bilirubin ALP ALT glucose urea creatinine haemolysis jaundice piarhemia	46 ± 2g/L, 35 ± 0g/L, 12 ± 1g/L, 2.4 ± 1umol/L, 81 ± 10U/L, 42 ± 4U/L, 11 ± 2mmol/L, 9 ± 3mmol/L, 36 ± 5umol/L is normal normal	48 ± 2 32 ± 2 17 ± 3 2.9 ± 3 95 ± 16 44 ± 4 10 ± 3 18.6 ± 13 69 ± 64 is normal normal	35-72 25-48 18-82 2-15 28-94 28-184 9.7-18.6 12.1-20.6 26-88

Embodiment 12-is at the double transgenic mouse model of Cocositol to Alzheimer The pathological effect of prevention AD-sample among PS1 * APP

Tg PS1 * APP mice is the reinforcement model of Alzheimer, and it expresses the mutant human PS1 transgenic of two familial form sudden changes of coding (M146L and L286V) and the people APP transgenic of coding Indiana and Sweden's familial sudden change.Through 30-45 days ages, these animals were developed the expression and the amyloid beta deposition of strong brain A β level.In preventive trial, begin to treat TgPS1 * APP mice from wean, and when 2 monthly ages, estimate neuro pathology's effect (Figure 16 and 17) with Cocositol.Compare with untreated TgPS1 * APP mice, TgPS1 * APP the mice of Cocositol treatment demonstrates significant minimizing (brain area %=0.157 ± 0.007 ratio=.065 ± 0.016 that speckle covers, p＜0.001 in all tests of speckle burden when 2 monthly ages; Average speckle size=177 ± 8 μ m ²Than 149 ± 5 μ m ², p＜0.05; Speckle counting 3054 ± 324 to 1514 ± 510, p＜0.01; Figure 17).These results show that Cocositol has prevented amyloid beta deposition in two strong Alzheimer models.

The heat that embodiment 13-increases is taken in the influence to the TgCRND8 mice

For the heat of getting rid of increase is taken in or the contribution of nonspecific action, with the monosaccharide-mannitol treatment TgCRND8 mice of similar molecular weight.When 6 monthly ages, the TgCRND8 mice of mannitol treatment and untreated TgCRND8 mice do not have difference (Figure 11 A), and with the brood mice of non--Tg of mannitol treatment between significantly different (Figure 11 B) are arranged.Mannitol is to not effect of the behavior of non--Tg mice, be because the brood mice of non--Tg of mannitol treatment and untreated non--the Tg mice do not have difference.These results relevant with pathological study show that mannitol does not change the speckle load (Figure 11 C) of TgCRND8 mice.Detection to survival rate has simultaneously proved the survival rate not effect (Figure 11 D) of mannitol to the TgCRND8 mice.

Though invention has been described with its concrete embodiment, to those skilled in the art, numerous other changes and improvements and other purposes are conspicuous.Therefore, the present invention is not limited to the concrete disclosed content of this paper, only is subject to appended claims.

Claims

Treatment or prevention experimenter with protein folding or gather disorder or amyloid forms, deposits, gathers or retain the method for relevant central or peripheral nervous system or general organ disease, it comprises the chemical compound with following structure to the medical effective dose of described experimenter's administration:

Wherein, each R ₁, R _{1 '}, R ₂, R _{2 '}, R ₃, R _{3 '}, R ₄, R _{4 '}, R ₅, R _{5 '}, R ₆And R _{6 '}Be independently selected from following group:

(a) hydrogen atom;

(b) NHR ₇, wherein said R ₇Be selected from hydrogen; C ₂-C ₁₀Acyl group and C ₁-C ₁₀Alkyl;

(c) NR ₈R ₉, wherein said R ₈Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl, and described R ₉Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl;

(d) OR ₁₀, wherein said R ₁₀Be selected from no group, hydrogen, C ₂-C ₁₀Acyl group, C ₁-C ₁₀Alkyl and SO ₃H;

(e) C ₅-C ₇Glycosyl;

(f) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OH, NH ₂, SH, OSO ₃H and OPO ₃H ₂

(g) SR ₁₁, R wherein ₁₁Be selected from hydrogen, C ₁-C ₁₀Alkyl and O ₃H;

(h) randomly be selected from hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁The C that replaces of substituent group ₁-C ₁₀Alkyl; With

(i) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁,

Condition is that this chemical compound is not a myo-inositol.
2. the process of claim 1 wherein that described chemical compound is 1,2,3,4,5, the 6-cyclohexanhexanol.
3. the method for claim 2, that wherein said chemical compound is selected from is suitable-, table-, different-, sticking-, new-, shark-, D-chirality-and L-chirality-inositol.
4. the process of claim 1 wherein that described chemical compound is 1,2,3,4, the 5-quercitol.
5. the method for claim 4, wherein said chemical compound be selected from table-, vibo-, shark-, different-, Ta Luo-, gala-, suitable-, sticking-, new-, the quercitol of former-quercitol and enantiomer thereof.
6. the process of claim 1 wherein that described chemical compound is selected from the chemical compound of the enantiomer of the enantiomer of the stereoisomer of the stereoisomer of cyclohexanetetraol, phloroglucite, cyclohexanetetraol, phloroglucite, cyclohexanetetraol and phloroglucite.
7. the process of claim 1 wherein that described chemical compound is penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
8. the method for claim 7, wherein said chemical compound is the inosose chemical compound that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
9. the process of claim 1 wherein that described chemical compound is trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
10. the method for claim 9, wherein said chemical compound is (-)-1-deoxidation-Cocositol single ketones.
11. the process of claim 1 wherein that described chemical compound is penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
12. the method for claim 11, wherein said chemical compound are the inosose chemical compounds that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
13. the process of claim 1 wherein that described chemical compound is trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
14. the method for claim 13, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
15. the process of claim 1 wherein that described chemical compound is O-monomethyl-cyclohexanhexanol or its stereoisomer or enantiomer.
16. the method for claim 15, wherein said chemical compound are selected from D-pinitol, L-bornesitol and D-bornesitol.
17. the process of claim 1 wherein described chemical compound be selected from an amino quercitol (inosamine), diaminourea cyclohexanetetraol (inositol diamidogen), diaminourea phloroglucite, its stereoisomer and enantiomer thereof, with and officinal salt.
18. the method for claim 17, wherein said chemical compound be selected from L-new-inosamine, DL-table-inosamine-2, streptamine and deoxystreptamine.
19. the process of claim 1 wherein that described chemical compound is single sulfydryl-quercitol or its stereoisomer or enantiomer.
20. the method for claim 19, wherein said chemical compound are L-1-deoxidation-1-sulfydryl-8-O-methyl-chirality-inositols.
21. the process of claim 1 wherein that described chemical compound is a Cocositol.
22. the process of claim 1 wherein that described chemical compound is different-inositol.
23. the process of claim 1 wherein that the disease of described central or peripheral nervous system or general organ causes protein, protein fragments and the peptide form precipitation with beta-pleated sheet and/or fibril and/or aggregation.
24. the method for claim 23, the disease of wherein said central or peripheral nervous system or general organ is selected from: Alzheimer, senilism and old and feeble formation; Amyloid blood vessel disease; Mild cognitive goes down; The dementia relevant with Alzheimer; The tauo disease; The alpha-synapse nucleoprotein disease; Parkinson; Amyotrophic lateral sclerosis; Motor neuron; Spastic paraplegia; The Heng Yandun disease; Spinocebellar ataxia; Friedreich ataxia; With in the cell and/or the relevant neurodegenerative disease of gathering of neuron internal protein and polyglutamic amide, poly-alanine or other repeat body of causing by three in the corresponding gene or the unitary pathology expansion of tetranucleotide; Cerebrovascular disease; Mongolism; The head trauma that gathers with amyloid beta after the wound; With prion-related diseases; Familial Britain dementia; Familial Denmark dementia; Presenile dementia with spasmodic ataxia; Britain's type cerebral amyloid angiopathy; Presenile dementia with spasmodic ataxia; The danish type cerebral amyloid angiopathy; Has neurofilament but the familial encephalopathia (FENIB) of albumen inclusion body; Amyloid polyneuropathy; The inclusion body myositis that causes by amyloid beta; The familial amyloidosis Finnish type; The SA relevant with multiple myeloma; Familial Mediterranean fever; Chronic infection and inflammation; And with the relevant type ii diabetes of Diabetes-associated peptide (IAPP).
25. the method for claim 24, the disease of wherein said central or peripheral nervous system or general organ is an Alzheimer.
26. the method for claim 24, the wherein said dementia relevant with Alzheimer is vascular or Alzheimer.
27. the method for claim 24, wherein said tau disease is selected from the argentaffine grannles dementia, the cortex substrate is degenerated, the dementia pugilistica, dispersivity neurofibrillary tangle with calcification, frontotemporal dementia with parkinson's syndrome, with prion-related diseases, Hallervorden Spatz, myotonic dystrophy, C type Niemann-Pick disease, non-Guam motor neuron with neurofibrillary tangle, Pick disease, Ba Jinsen syndrome after the encephalitis, the prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear plasy, subacute sclerosing panencephalitis and only entanglement type dementia.
28. the method for claim 24, wherein said alpha-synapse nucleoprotein disease are selected from the dementia with Louis corpusculum, the multiple system atrophy with neurogliocyte matter inclusions, shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, have neural degeneration, heterosmia and amyotrophic lateral sclerosis that I type brain ferrum gathers.
29. the method for claim 24, the disease of wherein said central or peripheral nervous system or general organ is parkinson disease.
30. the method for claim 29, wherein said parkinson disease are familials.
31. the method for claim 29, wherein said parkinson disease are non-familials.
32. the method for claim 24, wherein said motor neuron and neurofilament filamentous or aggregation and/or superoxide dismutase albumen are relevant.
33. the method for claim 24, wherein said spastic paraplegia is relevant with chaperone and/or the proteic functional impairment of three A.
34. the method for claim 24, wherein said spinocebellar ataxia are DRPLA or Ma-Yue disease.
35. the method for claim 24, wherein said and prion-related diseases is selected from Creutzfeldt-Jakob disease, Gerstmann-Str  ussler-Scheinker disease and mutation Creutzfeldt-Jakob disease.
36. the method for claim 24, wherein said amyloid polyneuropathy are old amyloid polyneuropathy or SA.
37. the process of claim 1 wherein the described chemical compound of dosed administration with the about 1g/kg experimenter's body weight of about 1mg-.
38. the method for claim 37 is wherein with the described chemical compound of dosed administration of the about 200mg/kg experimenter's body weight of about 1mg-.
39. the method for claim 37 is wherein with the described chemical compound of dosed administration of the about 100mg/kg experimenter's body weight of about 10mg-.
40. the method for claim 37 is wherein with the described chemical compound of dosed administration of the about 70mg/kg experimenter's body weight of about 30mg-.
41. one kind prevention experimenter abnormal protein is folding, abnormal protein gathers, amyloid forms, deposit, gather or retain or the interactional method of amyloid lipid, it comprises the chemical compound that is selected from following structure to the medical effective dose of described experimenter's administration:

Wherein, each R ₁, R _{1 '}, R ₂, R _{2 '}, R ₃, R _{3 '}, R ₄, R _{4 '}, R ₅, R _{5 '}, R ₆And R _{6 '}Be independently selected from following group:

(a) hydrogen atom;

(b) NHR ₇, wherein said R ₇Be selected from hydrogen; C ₂-C ₁₀Acyl group and C ₁-C ₁₀Alkyl;

(c) NR ₈R ₉, wherein said R ₈Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl, and described R ₉Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl;

(d) OR ₁₀, wherein said R ₁₀Be selected from no group, hydrogen, C ₂-C ₁₀Acyl group, C ₁-C ₁₀Alkyl and SO ₃H;

(e) C ₅-C ₇Glycosyl;

(f) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OH, NH ₂, SH, OSO ₃H and OPO ₃H ₂

(g) SR ₁₁, R wherein ₁₁Be selected from hydrogen, C ₁-C ₁₀Alkyl and O ₃H;

(h) randomly be selected from hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁The C that replaces of substituent group ₁-C ₁₀Alkyl; With

(i) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁,

Condition is that this chemical compound is not a myo-inositol.
42. the method for claim 41, wherein said chemical compound is 1,2,3,4,5, the 6-cyclohexanhexanol.
That 43. the method for claim 42, wherein said chemical compound are selected from is suitable-, table-, different-, sticking-, new-, shark-, D-chirality-and L-chirality-inositol.
44. the method for claim 41, wherein said chemical compound is 1,2,3,4, the 5-quercitol.
45. the method for claim 44, wherein said chemical compound be selected from table-, vib0-, shark-, different-, Ta Luo-, gala-, suitable-, sticking-, new-, the quercitol of former-quercitol and enantiomer thereof.
46. the method for claim 41, wherein said chemical compound are selected from the stereoisomer of cyclohexanetetraol, phloroglucite, cyclohexanetetraol, the stereoisomer of phloroglucite, the enantiomer of cyclohexanetetraol and the enantiomer of phloroglucite.
47. the method for claim 41, wherein said chemical compound are penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
48. the method for claim 47, wherein said chemical compound are the inososes that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
49. the method for claim 41, wherein said chemical compound are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
50. the method for claim 49, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
51. the method for claim 41, wherein said chemical compound are penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
52. the method for claim 51, wherein said chemical compound are the inososes that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
53. the method for claim 41, wherein said chemical compound are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
54. the method for claim 53, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
55. the method for claim 41, wherein said chemical compound are O-monomethyl-cyclohexanhexanol or its stereoisomer or enantiomer.
56. the method for claim 55, wherein said chemical compound are selected from D-pinitol, L-bornesitol and D-bornesitol.
57. the method for claim 41, wherein said chemical compound are selected from an amino quercitol (inosamine), diaminourea cyclohexanetetraol (inositol diamidogen), diaminourea phloroglucite, its stereoisomer and enantiomer and its officinal salt.
58. the method for claim 57, wherein said chemical compound be selected from L-new-inosamine, DL-table-inosamine-2, streptamine and deoxystreptamine.
59. the method for claim 41, wherein said chemical compound are single sulfydryl-quercitol or its stereoisomer or enantiomer.
60. the method for claim 59, wherein said chemical compound are 1L-1-deoxidation-1-sulfydryl-8-O-methyl-chirality-inositols.
61. the method for claim 41, wherein said chemical compound is a Cocositol.
62. the method for claim 41, wherein said chemical compound are different-inositols.
63. the method for claim 41, the disease of wherein said central or peripheral nervous system or general organ cause protein, protein fragments and the peptide form precipitation with beta-pleated sheet and/or fibril and/or aggregation.
64. the method for claim 63, the disease of wherein said central or peripheral nervous system or general organ is selected from: Alzheimer, senilism and old and feeble formation; Amyloid blood vessel disease; Mild cognitive goes down; The dementia relevant with Alzheimer; The tau disease; Alpha-synapse albumen disease; Parkinson disease; Amyotrophic lateral sclerosis; Motor neuron; Spastic paraplegia; The Heng Yandun disease; Spinocebellar ataxia; Friedreich ataxia; With in the cell and/or the relevant neurodegenerative disease of gathering of neuron internal protein and polyglutamic amide, poly-alanine or other repeat body of causing by three in the corresponding gene or the unitary pathology expansion of tetranucleotide; Cerebrovascular disease; Mongolism; The head trauma that gathers with amyloid beta after the wound; With prion-related diseases; Familial Britain dementia; Familial Denmark dementia; Presenile dementia with spasmodic ataxia; Britain's type cerebral amyloid angiopathy; Presenile dementia with spasmodic ataxia; The danish type cerebral amyloid angiopathy; Has neurofilament but the familial encephalopathia (FENIB) of albumen inclusion body; Amyloid polyneuropathy; The inclusion body myositis that causes by amyloid beta; The familial amyloidosis Finnish type; The SA relevant with multiple myeloma; Familial Mediterranean fever; Chronic infection and inflammation; And with the relevant type ii diabetes of Diabetes-associated peptide (IAPP).
65. the method for claim 64, the disease of wherein said central or peripheral nervous system or general organ is an Alzheimer.
66. the method for claim 64, the wherein said dementia relevant with Alzheimer is vascular or Alzheimer.
67. the method for claim 64, wherein said tau disease is selected from the argentaffine grannles dementia, the cortex substrate is degenerated, the dementia pugilistica, dispersivity neurofibrillary tangle with calcification, frontotemporal dementia with parkinson's syndrome, with prion-related diseases, Hallervorden Spatz, myotonia atrophica, C type Niemann-Pick disease, non-Guam motor neuron with neurofibrillary tangle, Pick disease, Ba Jinsen syndrome after the encephalitis, the prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear plasy, subacute sclerosing panencephalitis, only entanglement type dementia.
68. the method for claim 64, wherein said alpha-synapse albumen disease are selected from the dementia with Louis corpusculum, the multiple system atrophy with neurogliocyte matter inclusions, shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, have neural degeneration, heterosmia and amyotrophic lateral sclerosis that I type brain ferrum gathers.
69. the method for claim 24, the disease of wherein said central or peripheral nervous system or general organ is parkinson disease.
70. the method for claim 69, wherein said parkinson disease are familials.
71. the method for claim 69, wherein said parkinson disease are non-familials.
72. the method for claim 64, wherein said motor neuron and neurofilament filamentous or aggregation and/or superoxide dismutase albumen are relevant.
73. the method for claim 64, wherein said spastic paraplegia is relevant with chaperone and/or the proteic functional impairment of three A.
74. the method for claim 64, wherein said spinocebellar ataxia are DRPLA or Ma-Yue disease.
75. the method for claim 64, wherein said and prion-related diseases is selected from Creutzfeldt-Jakob disease, Gerstmann-Str  ussler-Scheinker disease and mutation Creutzfeldt-Jakob disease.
76. the method for claim 64, wherein said amyloid polyneuropathy are old amyloid polyneuropathy or SA.
77. the method for claim 41 is wherein with the described chemical compound of dosed administration of the about 1g/kg experimenter's body weight of about 1mg-.
78. the method for claim 77 is wherein with the described chemical compound of dosed administration of the about 200mg/kg experimenter's body weight of about 1mg-.
79. the method for claim 77 is wherein with the described chemical compound of dosed administration of the about 100mg/kg experimenter's body weight of about 10mg-.
80. the method for claim 77 is wherein with the described chemical compound of dosed administration of the about 70mg/kg experimenter's body weight of about 30mg-.
81. amyloid fibril or an amyloid dissolving or a disruptive method that makes the protein dissociation of experimenter's abnormal accumulation and/or make pre-formation or pre-deposition, it comprises the chemical compound that is selected from following structure to described experimenter's administration medicine effective dose:

Wherein, each R ₁, R _{1 '}, R ₂, R _{2 '}, R ₃, R _{3 '}, R ₄, R _{4 '}, R ₅, R _{5 '}, R ₆And R _{6 '}Be independently selected from following group:

(a) hydrogen atom;

(b) NHR ₇, wherein said R ₇Be selected from hydrogen; C ₂-C ₁₀Acyl group and C ₁-C ₁₀Alkyl;

(c) NR ₈R ₉, wherein said R ₈Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl, and described R ₉Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl;

(d) OR ₁₀, wherein said R ₁₀Be selected from no group, hydrogen, C ₂-C ₁₀Acyl group, C ₁-C ₁₀Alkyl and SO ₃H;

(e) C ₅-C ₇Glycosyl;

(f) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OH, NH ₂, SH, OSO ₃H and OPO ₃H ₂

(g) SR ₁₁, R wherein ₁₁Be selected from hydrogen, C ₁-C ₁₀Alkyl and O ₃H;

(h) randomly be selected from hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁The C that replaces of substituent group ₁-C ₁₀Alkyl; With

(i) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁,

Condition is that this chemical compound is not a myo-inositol.
82. the method for claim 81, wherein said chemical compound is 1,2,3,4,5, the 6-cyclohexanhexanol.
That 83. the method for claim 82, wherein said chemical compound are selected from is suitable-, table-, different-, sticking-, new-, shark-, D-chirality-and L-chirality-inositol.
84. the method for claim 81, wherein said chemical compound is 1,2,3,4, the 5-quercitol.
85. the method for claim 84, wherein said chemical compound be selected from table-, vibo-, shark-, different-, Ta Luo-, gala-, suitable-, sticking-, new-, the quercitol of former-quercitol and enantiomer thereof.
86. the method for claim 81, wherein said chemical compound are selected from the stereoisomer of cyclohexanetetraol, phloroglucite, cyclohexanetetraol, the stereoisomer of phloroglucite, the enantiomer of cyclohexanetetraol and the enantiomer of phloroglucite.
87. the method for claim 81, wherein said chemical compound are penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
88. the method for claim 87, wherein said chemical compound be selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-) inosose of inosose.
89. the method for claim 81, wherein said chemical compound are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
90. the method for claim 89, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
91. the method for claim 81, wherein said chemical compound are penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
92. the method for claim 91, wherein said chemical compound are the inososes that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
93. the method for claim 81, wherein said chemical compound are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
94. the method for claim 93, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
95. the method for claim 81, wherein said chemical compound are O-monomethyl-cyclohexanhexanol or its stereoisomer or enantiomer.
96. the method for claim 95, wherein said chemical compound are selected from D-pinitol, L-bornesitol and D-bornesitol.
97. the method for claim 81, wherein said chemical compound are selected from an amino quercitol (inosamine), diaminourea cyclohexanetetraol (inositol diamidogen), diaminourea phloroglucite, its stereoisomer and enantiomer and its officinal salt.
98. the method for claim 97, wherein said chemical compound be selected from L-new-inosamine, DL-table-inosamine-2, streptamine and deoxystreptamine.
99. the method for claim 81, wherein said chemical compound are single sulfydryl-quercitol or its stereoisomer or enantiomer.
100. the method for claim 99, wherein said chemical compound are 1L-1-deoxidation-1-sulfydryl-8-O-methyl-chirality-inositols.
101. the method for claim 81, wherein said chemical compound is a Cocositol.
102. the method for claim 81, wherein said chemical compound are different-inositols.
103. the method for claim 81, the disease of wherein said central or peripheral nervous system or general organ cause protein, protein fragments and the peptide form precipitation with beta-pleated sheet and/or fibril and/or aggregation.
104. the method for claim 103, the disease of wherein said central or peripheral nervous system or general organ is selected from: Alzheimer, senilism and old and feeble formation; Amyloid blood vessel disease; Mild cognitive goes down; The dementia relevant with Alzheimer; The tau disease; Alpha-synapse albumen disease; Parkinson disease; Amyotrophic lateral sclerosis; Motor neuron; Spastic paraplegia; The Heng Yandun disease; Spinocebellar ataxia; Friedreich ataxia; With in the cell and/or the relevant neurodegenerative disease of gathering of neuron internal protein and polyglutamic amide, poly-alanine or other repeat body of causing by three in the corresponding gene or the unitary pathology expansion of tetranucleotide; Cerebrovascular disease; Mongolism; The head trauma that gathers with amyloid beta after the wound; With prion-related diseases; Familial Britain crust is slow-witted; Familial Denmark dementia; Presenile dementia with spasmodic ataxia; Britain's type cerebral amyloid angiopathy; Presenile dementia with spasmodic ataxia; The danish type cerebral amyloid angiopathy; Has neurofilament but the familial encephalopathia (FENIB) of albumen inclusion body; Amyloid polyneuropathy; The inclusion body myositis that causes by amyloid beta; The familial amyloidosis Finnish type; The SA relevant with multiple myeloma; Familial Mediterranean fever; Chronic infection and inflammation; And with the relevant type ii diabetes of Diabetes-associated peptide (IAPP).
105. the method for claim 104, the disease of wherein said central or peripheral nervous system or general organ is an Alzheimer.
106. the method for claim 104, the wherein said dementia relevant with Alzheimer is vascular or Alzheimer.
107. the method for claim 104, wherein said tau disease is selected from the argentaffine grannles dementia, the cortex substrate degeneration, the dementia pugilistica, dispersivity neurofibrillary tangle with calcification, frontotemporal dementia with parkinson's syndrome, with prion-related diseases, Hallervorden Spatz, myotonia atrophica, C type Niemann-Pick disease, non-Guam motor neuron with neurofibrillary tangle, Pick disease, Ba Jinsen syndrome after the encephalitis, the prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear plasy, subacute sclerosing panencephalitis, only entanglement type dementia.
108. the method for claim 104, wherein said alpha-synapse albumen disease are selected from the dementia with the multiwalled corps ronds of centration, the multiple system atrophy with neurogliocyte matter inclusions, shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, have neural degeneration, heterosmia and amyotrophic lateral sclerosis that I type brain ferrum gathers.
109. the method for claim 84, the disease of wherein said central or peripheral nervous system or general organ is parkinson disease.
110. the method for claim 109, wherein said parkinson disease are familials.
111. the method for claim 109, wherein said parkinson disease are non-familials.
112. the method for claim 104, wherein said motor neuron and neurofilament filamentous or aggregation and/or superoxide dismutase albumen are relevant.
113. the method for claim 104, wherein said spastic paraplegia is relevant with chaperone and/or the proteic functional impairment of three A.
114. the method for claim 104, wherein said spinocebellar ataxia are DRPLA or Ma-Yue disease.
115. the method for claim 104, wherein said and prion-related diseases is selected from Creutzfeldt-Jakob disease, Gerstmann-Str  ussler-Scheinker disease and mutation Creutzfeldt-Jakob disease.
116. the method for claim 104, wherein said amyloid polyneuropathy are old amyloid polyneuropathy or SA.
117. the method for claim 81 is wherein with the described chemical compound of dosed administration of the about 1g/kg experimenter's body weight of about 1mg-.
118. the method for claim 117 is wherein with the described chemical compound of dosed administration of the about 200mg/kg experimenter's body weight of about 1mg-.
119. the method for claim 117 is wherein with the described chemical compound of dosed administration of the about 100mg/kg experimenter's body weight of about 10mg-.
120. the method for claim 117 is wherein with the described chemical compound of dosed administration of the about 70mg/kg experimenter's body weight of about 30mg-.
121. a method of diagnosing the unusual folding or protein that gathers of experimenter and/or amyloid fibril or amyloid to exist, it comprises:

(a) to described experimenter's administration radioactive compound or labelling q.s and chemical compound that allowing the material of emission detectable signal under described chemical compound and unusual folding or the protein that gathers and/or fibril or the bonded condition of amyloid, if the folding unusually or protein that gathers and/or fibril or amyloid exist; With

(b) detect from unusual folding or the protein that gathers and/or the radioactivity or the signal of fibril or the bonded chemical compound of amyloid, diagnose in described experimenter unusual folding or the protein that gathers and/or the existence of amyloid fibril or amyloid thus, wherein said chemical compound has following structure:

Wherein, each R ₁, R _{1 '}, R ₂, R _{2 '}, R ₃, R _{3 '}, R ₄, R _{4 '}, R ₅, R _{5 '}, R ₆And R _{6 '}Be independently selected from following group:

(a) hydrogen atom;

(b) NHR ₇, wherein said R ₇Be selected from hydrogen; C ₂-C ₁₀Acyl group and C ₁-C ₁₀Alkyl;

(c) NR ₈R ₉, wherein said R ₈Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl, and described R ₉Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl;

(d) OR ₁₀, wherein said R ₁₀Be selected from no group, hydrogen, C ₂-C ₁₀Acyl group, C ₁-C ₁₀Alkyl and SO ₃H;

(e) C ₅-C ₇Glycosyl;

(f) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OH, NH ₂, SH, OSO ₃H and OPO ₃H ₂

(g) SR ₁₁, R wherein ₁₁Be selected from hydrogen, C ₁-C ₁₀Alkyl and O ₃H;

(h) optional hydrogen, the OR of being selected from ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁The C that replaces of substituent group ₁-C ₁₀Alkyl; With

(i) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁,

Condition is that this chemical compound is not a myo-inositol.
122. the method for claim 121, wherein said chemical compound is 1,2,3,4,5, the 6-cyclohexanhexanol.
That 123. the method for claim 122, wherein said chemical compound are selected from is suitable-, table-, different-, sticking-, new-, shark-, D-chirality-and L-chirality-inositol.
124. the method for claim 121, wherein said chemical compound is 1,2,3,4, the 5-quercitol.
125. the method for claim 124, wherein said chemical compound be selected from table-, vibo-, shark-, different-, Ta Luo-, gala-, suitable-, sticking-, new-, the quercitol of former-quercitol and enantiomer thereof.
126. the method for claim 121, wherein said chemical compound are selected from the stereoisomer of cyclohexanetetraol, phloroglucite, cyclohexanetetraol, the stereoisomer of phloroglucite, the enantiomer of cyclohexanetetraol and the enantiomer of phloroglucite.
127. the method for claim 121, wherein said chemical compound are penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
128. the method for claim 127, wherein said chemical compound are the inososes that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
129. the method for claim 121, wherein said chemical compound are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
130. the method for claim 129, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
131. the method for claim 121, wherein said chemical compound are penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
132. the method for claim 131, wherein said chemical compound are the inososes that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
133. the method for claim 121, wherein said chemical compound are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
134. the method for claim 133, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
135. the method for claim 121, wherein said chemical compound are O-monomethyl-cyclohexanhexanol or its stereoisomer or enantiomer.
136. the method for claim 135, wherein said chemical compound are selected from D-pinitol, L-bornesitol and D-bornesitol.
137. the method for claim 121, wherein said chemical compound are selected from an amino quercitol (inosamine), diaminourea cyclohexanetetraol (inositol diamidogen), diaminourea phloroglucite, its stereoisomer and enantiomer and its officinal salt.
138. the method for claim 137, wherein said chemical compound be selected from L-new-inosamine, DL-table-inosamine-2, streptamine and deoxystreptamine.
139. the method for claim 121, wherein said chemical compound are single sulfydryl-quercitol or its stereoisomer or enantiomer.
140. the method for claim 139, wherein said chemical compound are 1L-1-deoxidation-1-sulfydryl-8-O-methyl-chirality-inositols.
141. the method for claim 121, wherein said chemical compound is a Cocositol.
142. the method for claim 121, wherein said chemical compound are different-inositols.
143. the method for claim 121, the disease of wherein said central or peripheral nervous system or general organ cause protein, protein fragments and the peptide form precipitation with beta-pleated sheet and/or fibril and/or aggregation.
144. the method for claim 143, the disease of wherein said central or peripheral nervous system or general organ is selected from: Alzheimer, senilism and old and feeble formation; Amyloid blood vessel disease; Mild cognitive goes down; The dementia relevant with Alzheimer; The tau disease; Alpha-synapse albumen disease; Parkinson disease; Amyotrophic lateral sclerosis; Motor neuron; Spastic paraplegia; The Heng Yandun disease; Spinocebellar ataxia; Friedreich ataxia; With in the cell and/or the relevant neurodegenerative disease of gathering of neuron internal protein and polyglutamic amide, poly-alanine or other repeat body of causing by three in the corresponding gene or the unitary pathology expansion of tetranucleotide; Cerebrovascular disease; Mongolism; The head trauma that gathers with amyloid beta after the wound; With prion-related diseases; Familial Britain dementia; Familial Denmark dementia; Presenile dementia with spasmodic ataxia; Britain's type cerebral amyloid angiopathy; Presenile dementia with spasmodic ataxia; The danish type cerebral amyloid angiopathy; Has neurofilament but the familial encephalopathia (FENIB) of albumen inclusion body; Amyloid polyneuropathy; The inclusion body myositis that causes by amyloid beta; The familial amyloidosis Finnish type; The SA relevant with multiple myeloma; Familial Mediterranean fever; Chronic infection and inflammation; And with the relevant type ii diabetes of Diabetes-associated peptide (IAPP).
145. the method for claim 144, the disease of wherein said central or peripheral nervous system or general organ is an Alzheimer.
146. the method for claim 144, the wherein said dementia relevant with Alzheimer is vascular or Alzheimer.
147. the method for claim 144, wherein said tau disease is selected from the argentaffine grannles dementia, the cortex substrate degeneration, the dementia pugilistica, dispersivity neurofibrillary tangle with calcification, frontotemporal dementia with parkinson's syndrome, with prion-related diseases, Hallervorden Spatz, myotonia atrophica, C type Niemann-Pick disease, non-Guam motor neuron with neurofibrillary tangle, Pick disease, Ba Jinsen syndrome after the encephalitis, the prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear plasy, subacute sclerosing panencephalitis, only entanglement type dementia.
148. the method for claim 144, wherein said alpha-synapse albumen disease are selected from the dementia with Louis corpusculum, the multiple system atrophy with neurogliocyte matter inclusions, shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, have neural degeneration, heterosmia and amyotrophic lateral sclerosis that I type brain ferrum gathers.
149. the method for claim 144, the disease of wherein said central or peripheral nervous system or general organ is parkinson disease.
150. the method for claim 149, wherein said parkinson disease are familials.
151. the method for claim 149, wherein said parkinson disease are non-familials.
152. the method for claim 144, wherein said motor neuron is relevant with neurofilament and/or superoxide dismutase albumen thread or the gathering shape.
153. the method for claim 144, wherein said spastic paraplegia is relevant with chaperone and/or the proteic functional impairment of three A.
154. the method for claim 144, wherein said spinocebellar ataxia are DRPLA or Ma-Yue disease.
155. the method for claim 144, wherein said and prion-related diseases is selected from Creutzfeldt-Jakob disease, Gerstmann-Str  ussler-Scheinker disease and mutation Creutzfeldt-Jakob disease.
156. the method for claim 144, wherein said amyloid polyneuropathy are old amyloid polyneuropathy or SA.
157. the method for claim 121 is wherein with the described chemical compound of dosed administration of the about 1g/kg experimenter's body weight of about 1mg-.
158. the method for claim 157 is wherein with the described chemical compound of dosed administration of the about 200mg/kg experimenter's body weight of about 1mg-.
159. the method for claim 121, wherein said detectable signal is a fluorescence signal.
160. the method for claim 121, wherein said detectable signal is a radiated signal.
161. a method of diagnosing the unusual folding or protein that gathers of experimenter and/or amyloid fibril or amyloid to exist, it comprises: (a) collect from described experimenter's sample; (b) made described sample and radioactive compound or labelling and contacted, if protein and/or amyloid fibril or amyloid existence folding unusually or that gather at the chemical compound that allows the material of emission detectable signal under described chemical compound and unusual folding or the protein that gathers and/or amyloid fibril or the bonded condition of amyloid; (c) detect from unusual folding or the protein that gathers and/or the radioactivity or the signal of fibril or the bonded chemical compound of amyloid, diagnose described experimenter unusual folding or the protein that gathers and/or the existence of amyloid fibril or amyloid thus, wherein said chemical compound has following structure:

Wherein, each R ₁, R _{1 '}, R ₂, R _{2 '}, R ₃, R _{3 '}, R ₄, R _{4 '}, R ₅, R _{5 '}, R ₆And R _{6 '}Be independently selected from following group:

(a) hydrogen atom;

(b) NHR ₇, wherein said R ₇Be selected from hydrogen; C ₂-C ₁₀Acyl group and C ₁-C ₁₀Alkyl;

(c) NR ₈R ₉, wherein said R ₈Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl, and described R ₉Be C ₂-C ₁₀Acyl group or C ₁-C ₁₀Alkyl;

(d) OR ₁₀, wherein said R ₁₀Be selected from no group, hydrogen, C ₂-C ₁₀Acyl group, C ₁-C ₁₀Alkyl and SO ₃H;

(e) C ₅-C ₇Glycosyl;

(f) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OH, NH ₂, SH, OSO ₃H and OPO ₃H ₂

(g) SR ₁₁, R wherein ₁₁Be selected from hydrogen, C ₁-C ₁₀Alkyl and O ₃H;

(h) randomly be selected from hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁The C that replaces of substituent group ₁-C ₁₀Alkyl; With

(i) C ₃-C ₈Cycloalkyl, it randomly is selected from following substituent group and is replaced: hydrogen, OR ₁₀, NHR ₇, NR ₈R ₉And SR ₁₁,

Condition is that this chemical compound is not a myo-inositol.
162. the method for claim 161, wherein said chemical compound is 1,2,3,4,5, the 6-cyclohexanhexanol.
That 163. the method for claim 162, wherein said chemical compound are selected from is suitable-, table-, different-, sticking-, new-, shark-, D-chirality-and L-chirality-inositol.
164. the method for claim 161, wherein said chemical compound is 1,2,3,4, the 5-quercitol.
165. the method for claim 164, wherein said chemical compound be selected from table-, vibo-, shark-, different-, Ta Luo-, gala-, suitable-, sticking-, new-, former-quercitol and enantiomer thereof.
166. the method for claim 161, wherein said chemical compound are selected from the stereoisomer of cyclohexanetetraol, phloroglucite, cyclohexanetetraol, the stereoisomer of phloroglucite, the enantiomer of cyclohexanetetraol and the enantiomer of phloroglucite.
167. the method for claim 161, wherein said chemical compound are penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
168. the method for claim 167, wherein said chemical compound are the inososes that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
169. the method for claim 161, wherein said chemical compound are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
170. the method for claim 169, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
171. the method for claim 161, wherein said chemical compound are penta hydroxy group Ketohexamethylene or its stereoisomer or enantiomer.
172. the method for claim 171, wherein said chemical compound are the inososes that is selected from Cocositol single ketones, L-chirality-inosose-1 and L-table-inosose.
173. the method for claim 161, wherein said chemical compound are trihydroxy Ketohexamethylene or its stereoisomer or enantiomer.
174. the method for claim 163, wherein said chemical compound are (-)-1-deoxidation-Cocositol single ketones.
175. the method for claim 161, wherein said chemical compound are O-monomethyl-cyclohexanhexanol or its stereoisomer or enantiomer.
176. the method for claim 175, wherein said chemical compound are selected from D-pinitol, L-bornesitol and D-bornesitol.
177. the method for claim 161, wherein said chemical compound are selected from an amino quercitol (inosamine), diaminourea cyclohexanetetraol (inositol diamidogen), diaminourea phloroglucite, its stereoisomer and enantiomer and its officinal salt.
178. the method for claim 177, wherein said chemical compound be selected from L-new-inosamine, DL-table-inosamine-2, streptamine and deoxystreptamine.
179. the method for claim 161, wherein said chemical compound are single sulfydryl-quercitol or its stereoisomer or enantiomer.
180. the method for claim 179, wherein said chemical compound are 1L-1-deoxidation-1-sulfydryl-8-O-methyl-chirality-inositols.
181. the method for claim 161, wherein said chemical compound is a Cocositol.
182. the method for claim 161, wherein said chemical compound are different-inositols.
183. the method for claim 161, the disease of wherein said central or peripheral nervous system or general organ cause protein, protein fragments and the peptide form precipitation with beta-pleated sheet and/or fibril and/or aggregation.
184. the method for claim 183, the disease of wherein said central or peripheral nervous system or general organ is selected from: Alzheimer, senilism and old and feeble formation; Amyloid blood vessel disease; Mild cognitive goes down; The dementia relevant with Alzheimer; The tau disease; Alpha-synapse albumen disease; Parkinson disease; Amyotrophic lateral sclerosis; Motor neuron; Spastic paraplegia; The Heng Yandun disease; Spinocebellar ataxia; Friedreich ataxia; With in the cell and/or neuron internal protein and polyglutamic amide, the relevant neurodegenerative disease of gathering of poly-alanine or other repeat body of causing by three in the corresponding gene or the unitary pathology expansion of tetranucleotide; Cerebrovascular disease; Mongolism; The head trauma that gathers with amyloid beta after the wound; With prion-related diseases; Familial Britain dementia; Familial Denmark dementia; Presenile dementia with spasmodic ataxia; Britain's type cerebral amyloid angiopathy; Presenile dementia with spasmodic ataxia; The danish type cerebral amyloid angiopathy; Has neurofilament but the familial encephalopathia (FENIB) of albumen inclusion body; Amyloid polyneuropathy; The inclusion body myositis that causes by amyloid beta; The familial amyloidosis Finnish type; The SA relevant with multiple myeloma; Familial Mediterranean fever; Chronic infection and inflammation; And with the relevant type ii diabetes of Diabetes-associated peptide (IAPP).
185. the method for claim 184, the disease of wherein said central or peripheral nervous system or general organ is an Alzheimer.
186. the method for claim 184, the wherein said dementia relevant with Alzheimer is vascular or Alzheimer.
187. the method for claim 184, wherein said tau disease is selected from the argentaffine grannles dementia, the cortex substrate degeneration, the dementia pugilistica, dispersivity neurofibrillary tangle with calcification, frontotemporal dementia with parkinson's syndrome, with prion-related diseases, Hallervorden Spatz, myotonia atrophica, C type Niemann-Pick disease, non-Guam motor neuron with neurofibrillary tangle, Pick disease, Ba Jinsen syndrome after the encephalitis, the prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear plasy, subacute sclerosing panencephalitis, only entanglement type dementia.
188. the method for claim 184, wherein said alpha-synapse albumen disease are selected from the dementia with the multiwalled corps ronds of centration, the multiple system atrophy with neurogliocyte matter inclusions, shy-Drager syndrome, striatonigral degeneration, olivopontocerebellar atrophy, have neural degeneration, heterosmia and amyotrophic lateral sclerosis that I type brain ferrum gathers.
189. the method for claim 184, the disease of wherein said central or peripheral nervous system or general organ is parkinson disease.
190. the method for claim 189, wherein said parkinson disease are familials.
191. the method for claim 189, wherein said parkinson disease are non-familials.
192. the method for claim 184, wherein said motor neuron and neurofilament filamentous or aggregation and/or superoxide dismutase albumen are relevant.
193. the method for claim 184, wherein said spastic paraplegia is relevant with chaperone and/or the proteic functional impairment of three A.
194. the method for claim 184, wherein said spinocebellar ataxia are DRPLA or Ma-Yue disease.
195. the method for claim 184, wherein said and prion-related diseases is selected from Creutzfeldt-Jakob disease, Gerstmann-Str  ussler-Scheinker disease and mutation Creutzfeldt-Jakob disease.
196. the method for claim 184, wherein said amyloid polyneuropathy are old amyloid polyneuropathy or SA.
197. the method for claim 161, wherein said detectable signal is a fluorescence signal.
198. the method for claim 161, wherein said detectable signal is a radiated signal.
199. the method for claim 161, wherein said detectable signal are the enzyme-linked immunosorbent assay signals.
200. the method for claim 161, wherein said sample is a whole blood.
201. the method for claim 161, wherein said sample is a blood plasma.