CN1838950A - Methods for treating protein aggregation disorders - Google Patents

Abstract

The present invention is based, at least in part on the discovery of therapeutic agents capable of preventing, inhibiting or modulating abnormal processing, misfolding or aggregation of protein. The therapeutic agents of the invention may prevent, inhibit or modulate the formation of inclusions. The therapeutic agents of the invention may also be capable of facilitating clearance and/or blocking the cellular toxicity of inclusions to treat or ameliorate disorders characterized by protein aggregation. Compounds which bind to structural motifs commonly found in protein aggregates, such as ss-sheets, would represent strong candidates for such compounds and are therefore desirable.

Description

The method of treatment protein aggregation disorders

Related application

The application requires the U.S. Provisional Patent Application 60/480 of submission on June 23rd, 2003,918, the U.S. Provisional Application of submitting on October 17th, 2,003 60/512, the U. S. application 10/__ that on June 18th, 017 and 2004 submitted to, _ _ priority, the title of above-mentioned three applications is the method for protein aggregation disorders " treatment " (Methods for TreatingProtein Aggregation Disorders).

The application relates to the U.S. Provisional Patent Application 60/480 of submission on June 23rd, 2003,984, the U.S. Provisional Patent Application of submitting on October 17th, 2,003 60/512, the U. S. application 10/__ that on June 18th, 116 and 2004 submitted to, _ _ (file number NBI-152), title is " pharmaceutical preparation of amyloid inhibiting compounds " (PharmaceuticalFormulations of Amyloid-Inhibiting Compounds).

The application relates to the U.S. Provisional Application 60/482 of submission on June 23rd, 2003,214, the U.S. Provisional Application 60/436 of December in 2002 submission on the 24th, 379, title is " combination treatment of treatment Alzheimer " (Combination Therapy for the Treatment ofAlzheimer ' s Disease), the novel patent application 10/746 of U.S. utility of December in 2003 submission on the 24th, 138, the U. S. application 10/__ that International Patent Application PCT/CA2003/002011 (being labeled as NBI-154PC) and on June 18th, 2004 submit to, _ _, title is " in order to the treatment preparation of treatment amyloid-beta relevant disease " (Therapeutic Formulations forthe Treatment of Beta-Amyloid Related Diseases).

The application relates to the U.S. Provisional Patent Application 60/482 of submission on June 23rd, 2003,058, the U.S. Provisional Patent Application 60/512 that on October 17th, 2003 submitted to, 135, the title of two applications is " synthetic method of the chemical compound of preparation treatment amyloidosis " (Synthetic Process for Preparing Compounds for Treating Anzyloidosis), with the U. S. application 10/__ that submitted on June 18th, 2004, _ _ (file number NBI-156), title is " improved drug candidate and preparation method thereof " (Improved PharmaceuticalDrug Candidates and Method for Preparation Thereof).

The application also relates to the U.S. Provisional Patent Application 60/480 of submission on June 23rd, 2003,906, the U.S. Provisional Patent Application 60/512 that on October 17th, 2003 submitted to, 047, the U. S. application 10/__ that on June 18th, 2004 submitted to, _ _ (file number NBI-162A), the U. S. application 10/__ that on June 18th, 2004 submitted to, _ _ (file number NBI-162B), all application titles are " method and composition of treatment diseases associated with amyloid protein " (Methods and Compositions for Treating Amyloid-Related Diseases) more than.

The application also relates to the U.S. Provisional Patent Application series number 60/512 of submission on October 19th, 2003,018, the U.S. Provisional Patent Application series number 60/480, the U.S. Patent application 10/__ that on June 18th, 928 and 2004 submitted to, _ _ (file number NBI-163), all application titles are " method and composition of treatment amyloid and epilepsy generation relevant disease " (Methods and Compositions for Treating Amyloid-andEpileptogenesis-Associated Diseases) more than.

The application also relates to U.S. Patent application 08/463,548 (No. the 5th, 972,328, existing United States Patent (USP)) " method of treatment amyloidosis " (Method for Treating Amyloidosis).

More than each full content of these patent applications clearly be attached to herein by reference, unrestrictedly comprise description, claims and summary and any accompanying drawing, form or picture.

Background technology

Proteinic biological function depends on its three dimensional structure, and the latter is to a great extent by the decision of proteinic aminoacid sequence, but also affected by environment.In fact, proteinic conformation is being arranged the interaction of itself and other factor, and these factors can participate in regulating proteinic function.Polypeptide can not be taked and keeps its correct structure by correct protein folding, is the main threat of cellular function and existence.Therefore, the complicated accurate system that evolved out protects cell to avoid the adverse effect of misfolded proteins matter.

The first line of defence that prevents misfolded proteins matter is a molecular chaperones, and it can combine with the newborn polypeptide that comes out from ribosome, promotes the correct folding of polypeptide and prevents deleterious interaction.Molecular chaperones is also assisted impaired proteinic folding (Netzer and the Hartl.1998.Trends Biochem Sci 23:68) again in response to swashing effect and cell injury.However, still there is very most firm translated protein correctly not fold, produces a large amount of defective polypeptide (Schubert etc., 2000.Nature 404:770).These damaged protein are mainly by ubiquitin-proteasome system---and a kind of identification and the unnecessary proteinic multicomponent system of degrading are degraded.In some cases, the protein of misfolding can escape this quality control system.When the protein accumulation of these misfoldings arrived enough amounts, they had accumulative tendency, and can resist the proteolysis effect.Insoluble protein aggregate (or precipitating proteins) can be deposited in visible inclusion body of microscopically (also claiming occlusion body) or the albuminous plasue, it is characterized by can indicate disease usually, and contains disease specific protein.

When the proteolysis effect was impaired, proteasome and ubiquitin protein will gather, and form organized aggregation or aggregation.In a single day protein oligomer and bigger aggregation form, and will directly weaken important cell function, thereby have poisonous character (Wojcik and DeMartino.2003.Int J Biochem Cell Biol 35:579; Bence etc., 2001.Science 292:1552).In addition, ubiquitin-proteasome system that their gathering in aggregation or inclusion body can infringement usually be responsible for removing this harmful misfolded proteins matter (referring to Garcia-Mata etc., 2002.Traffic 3:388).Because molecular chaperones and ubiquitin dependence protein enzymolysis system are most important for the active adjusting of the elementary cell of cell division and apoptosis and so on, can increase the weight of the cytotoxicity that produces owing to gathering of protein aggregate to the obstruction of this system.But have data to show, the existence of inclusion body, aggregation or albuminous plasue is to the toxic reaction that sees protein sickness (proteopathy) dispensable (Klement etc., 1998.Cell 95:41).However, the existence of inclusion body, aggregation or albuminous plasue still characterizes the cell model of the human pathology of recovery and the fabulous cell marking of intravital mouse model.This labelling can be used as the detrimental protein that causes forming described inclusion body and assembles active indicant, in order to screen.

Therefore, unusual, the oligomerization of protein folding, assemble or be deposited in the pathophysiology of chronic progressive external degenerative disease of plurality of classes and can play important effect.

For example, there is the feature of many degenerative diseases to have inclusion body and albuminous plasue exactly.The limiting examples of this disease comprises following: parkinson (PD), diffusivity Lewy corpusculum dementia (DLBD), multiple system atrophy (MSA), dystrophia myotonica, dentate nucleus rubrum pallidum Louis body atrophy (DRPLA), the Fu Lidelixishi ataxia, fragile X syndrome, fragile X E mental retardation, Ma-Yue disease, spinal cord oblongata amyotrophy (also claiming Kennedy's disease), spinocebellar ataxia, Huntington's disease (HD), has neurofilament but the familial encephalopathia (FENIZB) of albumen inclusion body, Pick's disease, cortex basal nuclei degeneration (CBD), paralysis (PSP) on the carrying out property nuclear, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, amyotrophic lateral sclerosis (ALS), mongolism, age-related macular degeneration, cataract and Wilson's disease.In many cases, determined the gene mutation basis of the familial form of these diseases.But in most of the cases, first sexual activity of the conformation transition of promotion or initiation target protein is not known, but it finally causes proteinic abnormal processing, misfolding, oligomerization or gathering really, thereby causes cytotoxicity.As the part of cell detoxifcation, defensive strategy or the trial of the unusual unfolded protein of conduct degraded, this abnormal protein gathers in polytype cells inclusions or aggregation usually.Therefore, these inclusion bodys or aggregation have become one of the pathology sign of the degenerative disease of described plurality of classes.Up to now, also not at these treatment of diseases medicines and Therapeutic Method in full force and effect.

Summary of the invention

Wish to obtain to prevent, suppress or regulate proteinic abnormal processing, misfolding or gathering, thereby prevent primary cellular defect and dead therapeutic compound.These therapeutic compounds can be used for the treatment of the disease of mentioning in one joint of technical background above, can also be used for the treatment of hereinafter described which disease.For example, directly can suppress the formation of aggregation, aggregation or inclusion body in conjunction with target protein and the chemical compound that acts on the cascade of early protein oligomerization.Can also can effectively treat or improve the disease that protein aggregation causes in conjunction with aggregation and the blocking-up Cytotoxic chemical compound relevant with these aggregations.In conjunction with causing forming architectural feature common in the protein of this aggregation, as the chemical compound of beta sheet, fibril spline structure or hydrophobic domains, therefore the strong drug candidate of representing described treatment to use caters to the need.Expect this chemical compound by preventing the from the beginning formation of aggregation, can promote described abnormal protein and the removing of the protein aggregate that formed and/or suppress their toxicity.

The present invention at least on part based on to preventing, suppress or regulate the discovery of proteinic abnormal processing, misfolding or accumulative medicine.Medicine of the present invention can prevent, suppresses or regulate the formation of inclusion body.Medicine of the present invention can promote the removing of protein aggregate.Medicine of the present invention can also be blocked the cytotoxicity of inclusion body, thereby treatment or improvement are the disease of feature with the protein aggregation.Medicine of the present invention also can be used to prevent or treat the disease of protein conformation or protein aggregation.

In one embodiment of the invention, provide such chemical compound, it can be in conjunction with the target protein of the tendency with formation beta sheet structure, thereby prevents, suppresses or regulate described proteinic misfolding, conformation transition, abnormal processing or gathering.In another embodiment, chemical compound is in conjunction with the structural motif that sees protein aggregate usually, as beta sheet.

The screening technique that the present invention provides Profilin matter to assemble or treat the chemical compound of protein aggregation disorders on the other hand, described method comprise the chemical compound of screening energy conjugated protein, the sign that described proteinic gathering is a disease (for example synapse nucleoprotein of PD).

In another embodiment, provide such chemical compound, it can prevent described proteinic from combination, oligomerization or gathering, and the cytotoxicity relevant with these activities.

In another embodiment, the chemical compound of binding purpose target protein prevents that protein conformation from changing to beta sheet, and prevents that oligomer, aggregation or the fibril of Lock-in after described transformation from forming.

In another embodiment, provide such chemical compound, it prevents, suppresses or regulate the formation of such aggregation or inclusion body in cultured cell in vitro, and described aggregation or inclusion body show toxic protein oligomer, aggregation or fibriilar assembling.

In another embodiment, screening technique in order to the chemical compound of treatment or prevention protein aggregation disorders is provided, described method comprises chemical compound given just to take place the transgenic mice that the carrying out property degeneration of simulating human disease changes, and can prevent the chemical compound of degeneration variation that some or all are relevant with this disease usually with screening.In other embodiment, this method can comprise measures the effectiveness that test-compound promotes the removing of detrimental protein aggregation, perhaps measures the effectiveness that test-compound promotes the degraded of detrimental protein aggregation.

In one embodiment of the invention, provide the method for treatment or prevention protein aggregation disorders, described method comprises the individuality of a kind of The compounds of this invention being suffered from or easily suffering from this disease.In one embodiment, protein aggregation disorders is not amyloid disease (Amyloid Proteopathy).

In another embodiment of the invention, the pharmaceutical composition that contains chemical compound is provided, described pharmaceutical composition comprises the chemical compound and the medicine acceptable carrier of the treatment protein aggregation disorders of effective dose.In one embodiment, protein aggregation disorders is not an amyloid disease.

In one embodiment, provide the packaging compositions in order to the treatment protein aggregation disorders, described compositions comprises the explanation with the active chemical compound of targeted therapy and relevant use combination treatment protein aggregation disorders.

In another embodiment, provide the adjusting detrimental protein accumulative method, described method comprises the detrimental protein aggregation or has the protein that forms beta sheet structure tendency to contact with the The compounds of this invention of effective dose, it is adjusted that detrimental protein is assembled, and wherein said protein aggregation disorders is not an amyloid disease.

In another embodiment, provide the adjusting detrimental protein accumulative method, described method comprises the detrimental protein aggregation or has the protein that forms beta sheet structure tendency to contact with the The compounds of this invention of effective dose, make the accumulative removing of detrimental protein adjusted, assemble thereby regulate detrimental protein, wherein said protein aggregation disorders is not an amyloid disease.

In another embodiment, provide the adjusting detrimental protein accumulative method, described method comprises the detrimental protein aggregation or has the protein that forms beta sheet structure tendency to contact with the The compounds of this invention of effective dose, make detrimental protein aggregating cells toxicity adjusted, assemble thereby regulate detrimental protein, wherein said protein aggregation disorders is not an amyloid disease.

In one embodiment, provide the method for neurofibrillary tangles relevant with tau protein in treatment or the object of prevention, described method comprises the The compounds of this invention that gives effective dose, the neurofibrillary tangles relevant with tau protein obtained medical treatment or prevents.

In one embodiment, provide the method for the neurofibrillary tangles relevant with tau protein in the controlled plant, described method comprises the The compounds of this invention that gives effective dose, makes the neurofibrillary tangles relevant with tau protein adjusted.

In one embodiment, the method that contains the pulsating inclusion body of alpha-synapse nucleoprotein NAC in treatment or the object of prevention is provided, described method comprises the The compounds of this invention that gives effective dose, makes to contain the pulsating inclusion body of alpha-synapse nucleoprotein NAC and obtain medical treatment or prevent.

In one embodiment, provide the method that contains the pulsating inclusion body of alpha-synapse nucleoprotein NAC in the controlled plant, described method comprises the The compounds of this invention that gives effective dose, makes that to contain the pulsating inclusion body of alpha-synapse nucleoprotein NAC adjusted.

The accompanying drawing summary

Fig. 1---this figure (being produced by computer) shows and uses NAC peptide under the variable concentrations that thioflavine (sulfo-flavin) the T test described among the embodiment hereinafter carries out to be assembled into the situation of beta sheet.

The circular dichroism analysis of Fig. 2---the NAC peptide conformation described among the embodiment (producing) by computer.

Fig. 3---show the electron micrograph (producing) of the NAC fiber outward appearance of describing among the embodiment hereinafter by computer.

Fig. 4---show the heparin described among the embodiment hereinafter electron micrograph (producing) by computer to the fibroplastic influence of NAC.

Fig. 5-68---illustrate The compounds of this invention as herein described.Shown in application in chemical compound and the acceptable salt of medicine, prodrug (ester and the amide that comprise them), its pharmaceutical composition and the described hereinafter method thereof, comprise in the present invention as part of the present invention.

Detailed Description Of The Invention

The invention provides the method and the compound that can be used for preventing, treating or regulate protein aggregation disorders. For simplicity, below illustrate some definition of term mentioned in this article.

The biological function of protein depends on its three-dimensional structure, and the latter is determined by the amino acid sequence of protein to a great extent. When protein produces from ribosomes, and the beginning folding process is when forming correct three-dimensional structure, its hydrophobic domains is exposed, and this can cause occurring unsuccessful combination and detrimental protein is assembled (Wetzel.1994.Trends Biotechnol 12:193). " misfolded proteins matter " used herein refers to that its conformation not yet meets protein or the peptide of its correct three-dimensional structure, usually cause abnormal protein itself or with other protein or peptide assemble, oligomerization or fibrillatable (fibrillization). The activity that " conformation change " used herein instigates normal protein matter to stand to change, result of variations causes structural property to change. Protein misfolding or conformation change can take place in translation process or after translation. This activity can because of such as special sudden change (familial or special send out property), expansion polyglutamyl amine repetitive sequence, dna mutation or RNA modifies, the amino acid mistake is mixed or oligomeric protein in subunit do not wait synthetic or other protein modifications and (Wetzel.1994. Trends Biotechnol 12:193 takes place; Bonifacino etc., 1989.J Cell Biol 109:173; Hurle etc., 1994.Proc Natl Acad Sci USA, 91:5446; See table). Specifically, the shortage (or minimizing) of the shortage of natural binding partners (or minimizing) or specific chaperone (seeing lower) can cause usually and the misfolding of these protein or the interactional protein of the factor (directly or indirectly) in many subunits complex. These variations can take place in the posttranslational modification process of protein, such as the processing of paraprotein enzymolysis, the phosphorylation of target protein, methylate, acetylation, glycosylation or nitrosylation. This modification can be special sudden change or activates the result of specific cells biochemical route.

Following table is enumerated various types of protein post-translational modifications:

Sequence number	Protein post-translational modification
		1	PPoly (ADP-ribosyl) changes (Burkle, 2000)
2	Isoprenoid (Maltese, 1990)
		3	Enzymatic glycosylation (Guevara etc., 1998) (Berninsone ﹠ Hirschberg, 1998)
4	Acetylation (Ogryzko, 2001)

5	(Person etc., 2003) methylate
		6	S-nitrosoglutathione (Lane etc., 2001 of protein C ys residue; Gu etc., 2002))
7	Phosphorylation (Berninsone ﹠ Hirschberg, 1998) (Verkman ﹠ Mitra, 2000)
		8	List-ADP-ribosylation (Okazaki ﹠ Moss, 1999)
9	Palmitoylation (Beers ﹠ Fisher, 1992)
		10	The hydroxylating of prolyl residue (Rucker ﹠ Dubick, 1984)
11	The oxidative deamination of lysyl-residue (Rucker ﹠ Dubick, 1984)
		12	Cross-bond (Rucker ﹠ Dubick, 1984) with the polypeptide chain covalent bonding
13	Tyrosine sulphation (Huttner, 1988)
		14	The sulphation of glycan (Berninsone ﹠ Hirschberg, 1998)
15	The phosphorylation of glycan (Moses etc., 1997)
		16	Carboxy methylation (Eggo etc., 1983)
17	Iodate (Eggo etc., 1983)
		18	Tyrosine (Nath etc., 1981)
19	The side chain of the oxidation of amino acid side chain, especially cysteine, prolyl, arginyl, lysyl and histidyl-residue) (Nath etc., 1981)
		20	The deamination of asparaginyl-and glutaminyl residue (Nath etc., 1981)
21	The interpolation of metal ion (Waggoner etc., 2000)
		22	The S-glutathione of Cys (Dalle-Donne etc., 2003)
23	Proteolysis (Nakayama etc., 2001)
		24	The non-enzymatic reaction of carbohydrate and protein amino (Munch etc., 1998)
25	The carboxylated of glutamine residue (Ware etc., 1989)
		26	The hydroxylating of proline and lysine (Uzawa etc., 1998)
27	Carboxyl terminal amidatioon (Evans ﹠ Shine, 1991)
		28	Citrulling (Citrullination) (van Venrooij ﹠ Pruijn, 2000)
29	Carbamyl (Hasuike etc., 2002)

30	Sumoization (Freiman and Tjian 2003)

Beers，M.F.& Fisher，A.B.(1992).Am J Physiol 263，L151-60.

Berninsone，P.& Hirschberg，C.B.(1998)..Ann N Y Acad Sci 842，91-9.

Burkle，A.(2000).Ann NY Acad Sci 908，126-32.

Dalle-Donne，I.，Giustarini，D.，Rossi，R.，Colombo，R. & Milzani，A.(2003).Free Radic Biol Med 34，23-32.

Eggo，M.C.，Drucker，D.，Cheifetz，R.& Burrow，G.N.(1983).Can J Biochem Cell Biol 61，662-9.

Evans，H F.& Shine，J.(1991).Endocrinology 129，1682-4.

Freiman RN，Tjian R.(2003).Cell 112：11-7

Gu，Z.，Kaul，M.，Yan，B.，Kridel，S.J.，Cui，J.，Strongin，A.，Smith，J.W.，Liddington， R.C.& Lipton，S.A.(2002).Science 297，1186-90.

Guevara，J.，Espinosa，B.，Zenteno，E.，Vazguez，L.，Luna，J.，Perry，G.& Mena，R. (1998).J Neuropathol Exp Neurol 57，905-14.

Hasuike，Y.，Nakanishi，T.，Maeda，K.，Tanaka，T.，Inoue，T.& Takamitsu，Y.(2002). Nephron 91，228-34.

Huttner，W.B.(1988).Annu Rev Physiol 50，363-76.

Lane，P.，Hao，G.& Gross，S.S.(2001).Sci STKE 2001，RE1.

Maltes，W.A.(1990)..Faseb J 4，3319-28.

Moses，J.，Oldberg，A.，Cheng，F.& Fransson，L.A.(1997).Eur J Biochem 248，521-6.

Munch，G.，Schinzel，R.，Loske，C.，Wong，A.，Durany，N.，Li，J.J.，Vlassara，H.， Smith，M.A.，Perry，G.& Riederer，P.(1998).J Neural Transm 105，439-61.

Nakayama，K.I.，Hatakeyama，S.& Nakayama，K.(2001).Biochem Biophys ResCommun 282，853-60.

Nath，J.，Flavin，M.& Schiffmann，E.(1981).J Cell Biol 91，232-9.

Ogryzko，V.V.(2001).Cell Mol Life Sci 58，683-92.

Okazaki，I.J.& Moss，J.(1999).Annu Rev Nutr 19，485-509.

Person，M.D.，Monks，T.J.& Lau，S.S.(2003).Chem Res Toxicol 16，598-608.

Rucker，R.B.& Dubick，M.A.(1984).Environ Health Perspect 55，179-91.

Uzawa，K.，Marshall，M.K.，Katz，E.P.，Tanzawa，H.，Yeowell，H.N.& Yamauchi，M.(1998)..Biochem Biophys Res Commun 249，652-5.

van Venrooij，W.J.& Pruijn，G.J.(2000).Arthritis Res 2，249-51.

Verkman，A.S.& Mitra，A.K.(2000).Am J Physiol Renal Physiol 278，F13-28.

Waggoner，D.J.，Drisaldi，B.，Bartnikas，T.B.，Casareno，R.L.，Prohaska，J.R.，Gitlin，J.D.& Harris，D.A.(2000).J Biol Chem 275，7455-8.

Ware，J.，Diuguid，D.L.，Liebman，H.A.，Rabiet，M.J.，Kasper，C.K.，Furie，B.C.，Furie，B.& Stafford，D.W.(1989).J Biol Chem 264，11401-6.

The variation that occurs in the post translational modification may be special sudden change or the result who activates the specific cells biochemical route.Misfolding, oligomerization or assemble and also may be caused by the variation of cellular environment are as pH, temperature, ionic strength, redox environment or put on other stressors of particular organisms environment.For example, it is folding that pH and variations in temperature cause proteinic part to be separated, and energy of initiation alleviates the stress of primary cellular defect.Owing to inevitable a certain amount of misfolding occurs, cell several systems that evolved out with so that this misfolding reduces to minimum, and made before gathering and dispose misfolded proteins matter (Wickner etc., 1999.Science 286:1888).

The first line of defence that prevents misfolded proteins matter is a molecular chaperones." molecular chaperones " used herein or " chaperone " are meant with the newborn polypeptide that comes out from ribosome and combine, and promote the correct deleterious interactional molecule that folds and prevent.Chaperone is also assisted impaired proteinic folding (Netzer and the Hartl.1998.Trends Biochem Sci 23:68) again in response to swashing effect and cell injury.Chaperone combines and makes its stabilisation with the hydrophobic amino acid residue of exposure, by preventing incorrect intramolecularly and intermolecular interaction partially folded or that separate folding polypeptide, makes protein can take and keep correct folded state.In fact, numerous protein needs chaperone could correctly fold (Hartl.1996.Nature381:571).However, still there is very most new translated protein correctly not fold, produces a lot of defective polypeptide (Schubert etc., 2000.Nature 404:770).Of short duration or the long-term lacking of specific chaperone also can cause gathering of misfolded proteins matter.

These damaged protein are mainly by ubiquitin-proteasome system degraded." ubiquitin-proteasome system " used herein refers to the identification and the unnecessary proteinic multicomponent system of degrading." proteasome " used herein refers to many subunits complex of occurring in nucleus and kytoplasm.The degraded of proteasome mediation cytoplasmic protein, nucleoprotein (Hershko and Ciechanover.1998.Ann RevBiochem 67:425), secretory protein and transmembrane protein (Hirsch and Ploegh.2000.TrendsCell Biol 10:268).Ubiquitin-proteasome system also carries out the selectivity degraded to short-lived normal protein matter except that removing damaged protein, thereby helps the adjusting of numerous cellular activities.In some cases, misfolded proteins matter may escape design and be used for promoting the correct folding and proteinic ubiquitin of elimination defectiveness-proteasome monitoring system.When these misfolded proteins matter accumulate to enough amounts, have accumulative tendency, and the proteolysis effect is produced resistance." aggregation " used herein, " inclusion body ", " occlusion body ", " fibril " and " albuminous plasue " are meant the undesired combination of abnormal protein and gather, this paraprotein has resistance to proteolysis, can or can not combine with the molecule of proteasome system.In many cases, these aggregations may with specific marker, as cytoskeleton microtubule labelling Vimentin, 'beta '-tubulin and γ-tubulin co, and may be outside born of the same parents, in the born of the same parents or in the nuclear.

When the proteolysis effect was impaired, proteasome and ubiquitin protein can gather usually, and as the part of cell detoxifcation or defence policies, they can form organized bunch in inclusion body or albuminous plasue.When these bunches are transported to inclusion body specifically by the reverse transportation of dynein dependency on the microtubule, and when forming in the centrosome peripheral region, these aggregations (used herein) are called aggregation.The aggregation approach provides a kind of mechanism, makes that assembling albumen mass-energy forms the little aggregation of graininess (about 200nm), and the latter is by negative terminal dynein matter---and the process of dynein mediation is transported to MT organization center (MTOC) on microtubule (MT).In a single day independent granule has arrived MTOC, just by the single spheric aggregation (1-3 micron) that is generally around the integrated MTOC of being centered around of bag.Aggregation is active: they can raise multiple chaperone and proteasome, may be to assemble protein for assist process, and take on the Cytotoxic cytoprotective mechanism (Taylor etc., 2003.Hum Mol Genet12:749) that prevents.In addition, the formation of aggregation activates the autophagy purge mechanism that terminates in the lysosome degraded probably.Therefore, the aggregation approach can provide new system, is transported to lysosome from Cytoplasm and degrades will assemble protein.The protein oligomer or the aggregation (Bence etc. in characteristic of concentration aggregation (Wojcik and DeMartino.2003.Int J Biochem Cell Biol 35:579) and cell other places, 2001.Science 292:1552) in a single day form, can weaken the function and the toxigenicity of ubiquitin-proteasome system.(relevant summary referring to Garcia-Mata etc., 2002 Traffic3:388).Therefore, protein aggregation or sedimentaryly unusually in the pathophysiology of the chronic progressive external degenerative disease of plurality of classes, can play important effect.

In fact, existing studies show that, many degenerative diseases relevant with oligomerization, gathering or the fibrosis of range protein (relevant summary is referring to Kakizuka.1998.TIG 14:396).For example, many neurodegenerative diseases are that expansion CAG repetitive sequence by coding polyglutamyl amine section causes.As if self takes place the protein that contains expansion polyglutamyl amine repetitive sequence assembles, the result causes neuronal cell death or degeneration.The limiting examples of these diseases is as follows: spinal cord oblongata amyotrophy or title Kennedy disease are caused by the expansion polyglutamyl amine repetitive sequence in androgen receptor (AR) encoding gene; Huntington's disease (HD) is caused by the expansion polyglutamyl amine repetitive sequence in the Huntington protein gene; Spinocebellar ataxia 1 type (SCA1) is caused by the polyglutamyl amine repetitive sequence that increases in the ataxia protein-1 gene; Silk presses down the albumen disease, and the sudden change that is pressed down in albumen (serpin) gene by silk causes; Spinocebellar ataxia 2 types (SCA2) are caused by the polyglutamyl amine repetitive sequence that increases in the ataxia protein-3 gene; Ma-Yue disease (MJD or SCA3) is caused by the polyglutamyl amine repetitive sequence that increases in the ataxia protein-3 gene; Spinocebellar ataxia 6 types (SCA6) are caused by the polyglutamyl amine repetitive sequence that increases in the ataxia protein-6 gene; Spinocebellar ataxia 7 types (SCA7) are caused by the polyglutamyl amine repetitive sequence that increases in the ataxia protein-7 gene; Spinocebellar ataxia 17 types (SCA17) are caused by the polyglutamyl amine repetitive sequence that increases in the ataxia protein-17 gene; Dentate nucleus rubrum pallidum Louis body atrophy (DRPLA); Reach silk and press down the albumen disease, the sudden change that is pressed down in the protein gene by silk causes.Though each in these diseases may be caused that they all have a common feature by the sudden change of different proteins, promptly by assembling from combination.Prove that polyglutamyl amine protein can carry out the aggregation of being facilitated by lengthening polyglutamyl amine section, and cell death can be induced or increase to this gathering.The research of carrying out with transgenic mice shows that also polyglutamyl amine segment has toxicity, and it is neurodegenerative basic reason (Schilling etc., 1999.Hum Mol Genet 8:397 that prompting polyglutamyl amine is assembled; Reddy etc., 1998.Nat Gen20:198; DiFiglia etc., 1997.Science 277:1990; Yamamoto etc., 2000.Cell101:57).

Similarly, the frontotemporal dementia FTD related with chromosome 17 and the main pathology of parkinson's syndrome (FTDP17) are that tau protein is assembled into fibril (being called conjugate spirals fibril or PHF), and the latter forms neurofibrillary tangles (NFT).This neuropathological feature is the peculiar variation that definition is called the disease family of tau protein disease (tauopathies), and described tau protein disease comprises Alzheimer, the dementia pugilistica, mongolism, prion disease, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, argyrophilic grain dementia (Argyophilic graindementia), the degeneration of cortex basal nuclei, diffusivity neurofibrillary tangles companion calcification disease, frontotemporal dementia FTD/the parkinson's syndrome related with chromosome 17, Ha-Si disease, multiple system atrophy (MSA), C type Ni-Pi disease, Pick's disease, benumb on the carrying out property nuclear, subacute sclerosing panencephalitis and entanglement dominance (Tangle-predominant) Alzheimer (AD).

In frontotemporal dementia FTD (FTD), unusual assembling is to be caused by the post translational modification of full ripe tau protein, super phosphorylation.Protein modification can be caused by the upstream activity, for example induce by the excessive generation of A β peptide among the AD, perhaps the τ gene unconventionality montage activity that is caused by sudden change in the τ intron sequences is induced, and relevant with frontotemporal dementia FTD (Spillantini etc., 1998.Proc Natl Acad Sci USA 95:7737).The expression of the mutant form of τ in transgenic mice is enough to induce the formation with the similar neurofibrillary tangles of the sick peculiar neurofibrillary tangles of human tau protein, proves that abnormal τ is enough to induce the neural degeneration of some form.In the transgenic mice of the mutant form of expressing amyloid precursor protein (APP) gene and τ, the sudden change tau protein is collaborative with sudden change APP, produce its neuro pathology change with AD in observed more similar disease (relevant summary is referring to Lee etc., 2001.Science 293:1446; Gotz etc., 2001.Science 293:1491; Lewis etc., 2001.Science 293:1487).

A pathological characters of parkinson (PD) is to form the kytoplasm endosome that is called the Lewy corpusculum; These Lewy corpusculums also see dementia (DLBD) and the multiple system atrophy (MSA) with Lewy corpusculum.The main component of Lewy corpusculum is an alpha-synapse nucleoprotein.Therefore, alpha-synapse nucleoprotein becomes another example of its gathering and neural degeneration proteins associated matter.Show that alpha-synapse nucleoprotein gathering in the Lewy corpusculum is relevant with some autosomal dominants sudden change in the alpha-synapse nucleoprotein gene.These replacement sudden changes obviously help the conformation transition in the mature protein, cause protein to gather (Polymeropoulos etc., 1997.Science 276:2045 with pathology oligomer and fibriilar form; Kruger etc., 1998.Nat Genet18:106; Conway etc., 2000.Proc Natl Acad Sci USA 97:571).PD also with handkerchief gold protein gene in recessive mutation relevant (Kitada etc., 1998.Nature 392:605; Lucking etc., 2000.N Engl J Med 3421560; Ishikawa and Tsuji.1996.Neurology 47160), handkerchief gold albumen is as E2 dependency ubiquitin protein ligase, its activity is for predetermined proteinic ubiquitinization very important (Shimura etc., 2000.Nat Genet 25:302) by the proteasome degraded.Therefore, reduce or the sudden change of eliminating handkerchief gold protein function can cause gathering of original protein substrate for the degraded target or assembles.When lacking handkerchief gold protein active, handkerchief proteic binding partners of gold or substrate, as PaelR1, cdc-rel1, synphilin-1, alpha-synapse nucleoprotein, β-and γ-tubulin (the some of them pair cell is directly poisonous) (Petrucelli etc., 2002.Neuron 36:1007; Imai etc., 2001.Cell 105:891; Ren etc., 2003.J Neurosci 23:316) can gather and trigger cell infringement and dead (relevant summary is referring to Cookson.2003.Neuron 37:7).Another nearest report shows, being present in another kind and alpha-synapse nucleoprotein interacting proteins in the Lewy corpusculum---the dysregulation (sudden change) of synphilin-1 can cause some PD Sporadic cases (Marx etc., 2003.Hum Mol Genet 12:1223).Similarly, in amyotrophic lateral sclerosis (ALS), often can be observed the inclusion body that is called the hyalomitome inclusion body, known its contains the proteic precipitate of superoxide dismutase (SOD1) of sudden change.Have approximately 20% familial ALS case also with the SOD1 gene in sudden change relation (Rosen etc., 1993.Nature 362:59 are arranged; Orrell, 2000.Neuromuscular Disord 10:63).

Generally speaking, these observed results show that the dysregulation of the degradation pathway of proteasome ubiquitin mediation can cause misfolding and assemble proteinic gathering, and forms inclusion body, and this is the reason of cytotoxicity and degeneration.Electronic microscope photos shows that these protein contain graininess, filamentous and fibril shape structure usually.Though these structures are completely different, with observed amyloid structure similar in for example Alzheimer and prion disease.Insoluble " amyloid " aggregation with congo red staining after, under polarized light, demonstrate distinctive red-green birefringent phenomenon.Though gathering protein discussed above itself is not amyloid, they can form similar structure, comprise beta sheet lamella secondary structure.Hydrophobic region also is that gathering protein is distinctive.Therefore, though many gathering protein of finding in protein aggregation disorders itself are not amyloid, many architectural features of their total amyloids, i.e. beta sheet, fibril spline structure and/or hydrophobic domains.Because all aggregations all have common architectural feature, by the chemical compound that interaction combined or suppressed amyloid formation taking place, can effectively prevent or suppress to relate to the protein aggregation effect of protein aggregation disorders with these structural motifs (for example beta sheet).

Therefore, treat, regulate, prevent or suppress the screening of the accumulative chemical compound of detrimental protein, represented the reasonable and conventional method of treatment or prevention protein aggregation disorders.

In general, " protein aggregation disorders or protein aggregation albumen disease " comprise with object in detrimental protein assemble diseases associated, disease or the patient's condition." detrimental protein gathering " is that two or more allos or homologous protein or peptide bad and deleterious gathers, oligomerization, fibrosis or gathering.The detrimental protein aggregation can be deposited in inclusion body, occlusion body or the albuminous plasue, the feature of these inclusion bodys, occlusion body or albuminous plasue can be used as the sign of disease usually, and they contain disease specific protein, for example contain alpha-synapse nucleoprotein Lewy corpusculum in the parkinson.The detrimental protein aggregation is a three dimensional structure, can contain the misfolded proteins matter of for example being made up of beta sheet, fibril spline structure and/or height hydrophobic domains, and these misfolded proteins matter trend towards assembling, and pair cell has toxicity.In addition, though the detrimental protein aggregation does not contain the amyloid beta deposition thing, and because it does not meet the strict difinition of amyloid, be it under polarized light, can not demonstrate after with congo red staining distinctive red-green or apple green birefringent phenomenon, therefore also be not considered to relevant, but it still can be described to amyloid sample aggregation with amyloidosis." non-amyloid " detrimental protein aggregation used herein or " albumen disease " are meant the detrimental protein aggregation of not starch-containing sample proteinosis thing.The non-limiting kind of protein aggregation disorders or albumen disease comprises that protein conformation disease (Protein Conformational Disorders), alpha-synapse nucleoprotein disease (Alpha-Synucleinopathies), polyglutamyl amine disease, silk press down the albumen disease, tau protein is sick or other relevant diseases.The limiting examples of protein aggregation disorders comprises parkinson (PD), diffusivity Lewy corpusculum dementia (DLBD), multiple system atrophy (MSA), dystrophia myotonica, dentate nucleus rubrum pallidum Louis body atrophy (DRPLA), the Fu Lidelixishi ataxia, fragile X syndrome, fragile X E mental retardation, Ma-Yue disease (MJD or SCA3), spinal cord oblongata amyotrophy (also claiming Kennedy's disease), spinocebellar ataxia 1 type (SCA1), spinocebellar ataxia 2 types (SCA2), spinocebellar ataxia 6 types (SCA6), spinocebellar ataxia 7 types (SCA7), spinocebellar ataxia 17 types (SCA17), chronic hepatopathy, Huntington's disease (HD), has neurofilament but the familial encephalopathia (FENIZB) of albumen inclusion body, Pick's disease, cortex basal nuclei degeneration (CBD), paralysis (PSP) on the carrying out property nuclear, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, amyotrophic lateral sclerosis (ALS), cataract, silk presses down the albumen disease, hemolytic anemia, Cystic fibrosis, Wilson's disease, neurofibromatosis 2 types, the demyelinating peripheral neuropathy, retinitis pigmentosa, Marfan syndrome, edema due to disorder of QI, idiopathic pulmonary fibrosis, argyrophilic grain dementia, the degeneration of cortex basal nuclei, diffusivity neurofibrillary tangles companion calcification disease, frontotemporal dementia FTD/the parkinson's syndrome related with chromosome 17, Ha-Si disease, C type Ni-Pi disease or subacute sclerosing panencephalitis.

These kinds of Diseases and example further go through hereinafter.Should be appreciated that to the present invention includes the embodiment of assembling disease with protein proteins associated matter, described protein has can be by the architectural feature of The compounds of this invention selectivity targeting.The example of this architectural feature comprises beta sheet, fibril spline structure and/or hydrophobic domains.It is also understood that protein aggregation disorders of the present invention does not mean the method that comprises amyloid disease or amyloidosis or adjusting or suppress amyloid beta deposition.Instantiation vide infra.

The accumulative influence of detrimental protein is cumulative often, and the progressive loss of cell function finally causes cell death, the reason of multiple pathological condition that Here it is.

Amyloidosis

The pathology deposition of amyloid is the feature that is called one group of disease of amyloidosis, described disease comprises AA (reactivity) amyloidosis, the AL amyloidosis, senile SA, cerebral amyloidosis (comprising Alzheimer and cerebral blood vessel amyloidosis), dialysis dependency amyloidosis, type ii diabetes (" IAPP " causes by Diabetes-associated peptide) and other diseases, their feature all is to have the amyloid fibrils with common morphological properties, can be by specificity dyestuff (for example Congo red) dyeing, and the dyeing back under polarized light, have distinctive red-green birefringence outward appearance.Referring to for example WO 2003/017994A1.Their also total common superstructure feature and common X-ray diffraction phenomenon and infrared spectrums.Each all relevant short amyloidosis albumen with these diseases, though its aminoacid sequence is different, oneself forms oligomer and fibril in conjunction with character but all have similarly, and combines with various other compositions such as Dan Baijutang, amyloid P and/or complement component.And, though its aminoacid sequence of every kind of short amyloidosis albumen is different, all demonstrating the functional domain similarity, glycosaminoglycans (GAG) that can conjugated protein polysaccharide partly (is called the GAG binding site) and promotes the zone that beta sheet forms.Many short amyloidosis albumen are that the proteolysis cutting by precursor protein forms, described precursor protein is serum amyloid sample A albumen (" ApoSAA " for example, produce the AA peptide), transthyretin (being sometimes referred to as prealbumin), beta amyloid precursor protein (" β APP " produces A β peptide) and spread out from the peptide in monoclonal immunoglobulin κ or lambda light chain N-terminal zone.Referring to for example 2001.Physiological Reviews the 81st volume.

Diseases associated with amyloid protein may be confined to an organ, perhaps is diffused into several organs.The former is called " localized amyloidosis ", and the latter is called " SA ".

Some amyloid disease may be idiopathic, but this class disease of great majority is with the complication form appearance of existing disease.For example, primary amyloidosis can perhaps may occur after plasma cell dyscrasia or multiple myeloma without any other pathological symptom.

Usually find that secondary amyloidosis is relevant with chronic infection (as tuberculosis) or chronic inflammatory disease (as rheumatoid arthritis).Also visible familial form secondary amyloidosis in familial Mediterranean fever (FMF).As one of familial amyloidosis of other types, this familial form amyloidosis is genetic, sees specific crowd.In constitutional and secondary amyloidosis, deposit all can be found in several organs, therefore can think that they are systemic amyloidosis sample albumen diseases.

The SA of another kind of type sees the chronic hemodialysis patient.In these cases each all has different amyloidogenic proteins to participate in amyloid beta deposition.

" localized amyloidosis " is the amyloidosis that often influences single tract.Protein type in the also available deposit of different amyloidosis characterizes.For example, diseases such as neurodegenerative disease such as pruritus disease, bovine spongiform encephalitis, creutzfeldt-jakob disease can (be called PrP with the protease resistant form of prion protein among the central nervous system ^ScOr PrP27-30) outward appearance and gather situation and characterize.Similarly, another kind of neurodegenerative disease Alzheimer can characterize with neuritis's albuminous plasue and neurofibrillary tangles.In this case, albuminous plasue and blood vessel amyloid form by the deposition of fiber A amyloid beta.Other diseases gathers as the limitation of maturity-onset diabetes (type ii diabetes) available starches sample albumen in pancreas and to characterize.

Unless specify in addition, term used herein " amyloid-beta " or " amyloid beta " refer to amyloid beta protein matter or peptide, amyloid precursor protein or peptide, they intermediate, modify body and segment.Specifically, " A β " refers to that especially relevant with amyloid pathology peptide comprises A β by amyloid precursor protein (APP) gene outcome being carried out any peptide that proteolysis processing produces _1-39, A β _1-40, A β _1-41, A β _1-42With A β _1-43Term used herein " amyloid-beta ", " amyloid beta " and " A β " synonym.

Unless otherwise indicated, term " amyloid " refers to amyloidogenic proteins matter, peptide or their segment of solvable (for example for monomeric form or oligomer form) or soluble (for example have fibre structure or in amyloid plaque).

In one embodiment of the invention, protein aggregation disorders does not comprise amyloid disease.Term used herein " amyloid disease " refers to following disease (being the amyloidogenic proteins of being correlated with in the disease unquote): reactivity or secondary amyloidosis (AA); The special property sent out (constitutional) amyloidosis; Myeloma or the macroglobulinemia amyloidosis (amyloid κ light chain or amyloid lambda light chain) of being correlated with; Familial amyloid polyneuropathy (Hereditary amyloid polyneuropathy Portuguese type, Japanese type, Sweden's type) (ATTR); Familial amyloid sample cardiomyopathy [danish type] (ATTR); Independent cardiac amyloidosis (isolated cardiac amyloid) (ATTR); Systematicness amyloidosis of aging (ATTR); Thyroid medullary carcinoma (short calcitonin); Independent atrium amyloidosis (isolated atrial amyloid) (atrial natriuretic peptide); Familial amyloidosis [Finland's type] (gelsolin); Hereditary cerebral hemorrhage with amyloidosis [Iceland's type] (cysteine proteinase inhibitor C); Familial amyloid polyneuropathy [Iowa type] (AApoA-I); Mice quickens old and feeble (AApoA-II); The Fibrinogen amyloidosis of being correlated with; The lysozyme amyloidosis of being correlated with; The human prion disease; Transmissible spongiform encephalopathy; Pruritus disease (Protein virus or PrP); Creutzfeldt-jakob disease (PrP); GSS syndrome (PrP); Fatal familial insomnia (PrP); Bovine spongiform encephalitis (PrP); Alzheimer (A β); Cerebral amyloid angiopathy (A β); Hereditary cerebral hemorrhage (A β); Familial Mediterranean fever; Familial amyloid sample nephropathy companion's urticaria and deafness; Mu-Wei syndrome; The relevant amyloidosis (B2M) of dialysis; Type ii diabetes (IAPP); Mongolism (A β); Age relationship type degeneration of macula (A β); And inclusion body myositis (A β).Amyloid disease can be familial or idiopathic or sporadic or communicable, and is intended to comprise the form of ownership of above listed disease.Should be appreciated that term " amyloid disease " means the disease that comprises that JIUYUE disclosed WO 00/64420 on disclosed WO on the 19th November 2 in 96/28287,2000 in 1996 and on October 13rd, 1994 describe among the disclosed WO 94/22437.

The protein conformation disease

One group of disease that has nothing in common with each other is returned together called after protein conformation disease (PCD) (Carrell and Lomas.1997.Lancet 350:134; Kelly.1996.Curr Opin StructBiol 6:11; Thomas etc., 1995.Trends Biochem Sci 20:456; Soto.1999.JMol Med 77:412; Carrell and Gooptu.1998.Curr Opin Struct Biol 8:799).The limiting examples of this class disease comprises that silk presses down albumen disease, hemolytic anemia, Huntington's disease (HD), Cystic fibrosis, amyotrophic lateral sclerosis (ALS) and parkinson (PD).This class disease also comprises diseases associated with amyloid protein, for example Alzheimer (AD), Transmissible spongiform encephalopathy (TSE), type ii diabetes, the relevant amyloidosis of dialysis, Secondary cases (AA) amyloidosis, cerebral amyloid angiopathy, inclusion body myositis, mongolism and age relationship type degeneration of macula.PCD also comprises spinal cord oblongata amyotrophy (SBMA) or claims Kennedy's disease, Huntington's disease (HD), spinocebellar ataxia 1 type (SCA1); Spinocebellar ataxia 2 types (SCA2), Ma-Yue disease (MJD or SCA3), spinocebellar ataxia 6 types (SCA6), spinocebellar ataxia 7 types (SCA7), spinocebellar ataxia 17 types (SCA17), dentate nucleus rubrum pallidum Louis body atrophy (DRPLA), dystrophia myotonica, Pick's disease, cortex basal nuclei degeneration (CBD), paralysis (PSP) on the carrying out property nuclear, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, the Fu Lidelixishi ataxia, fragile X E brain development is slow, fragile X syndrome, Wilson's disease, chronic hepatopathy and cataract.

The defined feature of PCD is that the secondary or the tertiary structure of normal protein matter changes.The variation of protein conformation can be by obtaining toxicity or urging to give birth to disease (Thomas etc., 1995.Trends Biochem Sci20:456 by the mode that makes the proteinic biological function disappearance of natural folding; Carrell and Gooptu.1998.Curr Opin Struct Biol 8:799).In the middle of relating to the protein of PCD, do not have obvious sequence or structural homology, but these proteinic marked featurees are their inherent abilities (Carrell and Gooptu.1998.Curr Opin Struct Biol 8:799) of taking at least two kinds of differences to stablize conformation.In most of PCD, misfolded proteins matter is rich in beta sheet conformation (Soto.1999.J Mol Med 77:412; Carrell and Gooptu.1998.Curr Opin Struct Biol 8:799).Beta sheet is one of repetition secondary structure that generally occurs in the unfolded protein, and the alternately peptide folded chain that is connected by NH group and the hydrogen bond between the CO group by peptide bond constitutes.Hydrogen bond in the alpha-helix appears between same the intrachain group, and the hydrogen bond in the beta sheet appears between a chain and another chain.Because the second beta chain is from the zones of different of same protein or from different protein molecules, the formation of beta sheet is usually by proteinic oligomerization or gathering stabilisation.Really, in most of PCD, misfolded proteins matter takes place from combination, and is deposited in a plurality of organs with various types of aggregations or inclusion body form, causes tissue injury and organ dysfunction unusual (Kelly.1996 Curr Opin Struct Biol 6:11).In one embodiment of the invention, the protein conformation disease does not comprise amyloid disease.

The alpha-synapse nucleoprotein disease

In general, the alpha-synapse nucleoprotein disease comprises parkinson (PD) and other relevant diseases, comprises diffusivity Lewy corpusculum dementia (DLBD; Also claim Lewy corpusculum disease), Xi-De syndrome, nerve orthostatic hypotension, Xi-Mai-De syndrome, parkinson supraposition syndrome (Parkinson ' s plus syndrome) and multiple system atrophy (MSA; The syndromic four kinds of big brain degenerative diseases of Xi-De, nerve orthostatic hypotension and parkinson are added syndrome return together title).The common trait of this group disease is alpha-synapse nucleoprotein abnormal deposition in the Cytoplasm of neuron or neurogliocyte, forms the inclusion body that is called the Lewy corpusculum.

In parkinson and diffusivity Lewy corpusculum dementia, alpha-synapse nucleoprotein is the main component of Lewy corpusculum and underfed neural axon; Alpha-synapse nucleoprotein also gathers in the Cytoplasm of glial cell.In multiple system atrophy, alpha-synapse nucleoprotein forms Cytoplasm oligodendroglia inclusion body and neuron inclusion body, and they are signs of this disease.

Alpha-synapse nucleoprotein is to contain 140 amino acid whose protein.Its Unknown Function, but its demonstration has chaperone activity (Souza etc., 2000.FEBS Lett 474:116), and its play a role in the formation of regulating synaptic vesicle (Murphy etc., 2000.JNeurosci 29:3214) proposed.In addition, the alpha-synapse nucleoprotein demonstration can be in conjunction with tau protein (Jensen etc., 1999.J Biol Chem 274:25481) and microtubule-associated protein MAP-1B (Jensen etc., 2000.J Biol Chem 275:21500).

Alpha-synapse nucleoprotein gathering in the alpha-synapse nucleoprotein disease has common fibre structure, produce soluble and high-molecular weight aggregation external, but these accumulations have difference aspect the combining of alpha-synapse nucleoprotein and different proteins, but ubiquitin is an exception, and it is (relevant summary is referring to Ferrer.2001.Neurologia 16:163) that has with being combined in all alpha-synapse nucleoprotein inclusion bodys of alpha-synapse nucleoprotein.For example, find that the Lewy corpusculum contains 14-3-3 albumen among the MSA patient, the signal transduction pathway (Kawamoto etc., 2002.Ann Neurol 52:722) of its mediation several types; PD patient's Lewy corpusculum contains the synphilin-1 (Wakabayashi etc. relevant with alpha-synapse nucleoprotein, 2000.Ann Neurol47:521), and in DLBD patient's Lewy corpusculum, find cyclin-dependent kinase 5 (Cdk5) (Takahashi etc., 2000.Brain Res 862:253).

Constructed the transgenic mice of expressing alpha-synapse nucleoprotein mutant A30P and A53T.These mices demonstrate carrying out property of the motor function decline of early onset thereof.On the neuro pathology, the aixs cylinder of these animals demonstrates typical alpha-synapse nucleoprotein immunoreactivity Lewy corpusculum inclusion body (Putten etc., 2000.J Neurosci 20:6021; Sommer etc., 2000.ExpGerontol 35:1389; Kahle etc., 2002.J Clin Invest 110:1429; Kahle etc., 2001.Am J Pathol.159:2215; Gomez-Isla etc., 2003.Neurobiology Aging24:245-258; Lee etc., 2002.Proc Natl Acad Sci USA 99:8968).

Parkinson

Parkinson (PD) is slow carrying out property late onset neurodegenerative disease.It is characterized in that muscle rigidity, posture are unstable and tremble.

Relevant data has hinted several inherited genetic factorss in the PD cause of disease recently.Familial aggregation is done the research prompting, and late onset PD has significant inherited pathogenic factor (Payami etc., 2002.Arch Neurol 59:848).But the PD of mode of inheritance is caused by gene mutation.Up to now, relevant with the PD of familial form with several other locus (relevant summary is referring to Shastry.2000.Neuroscientist 6:234 to have shown four kinds of genes (alpha-synapse nucleoprotein, handkerchief gold albumen, COOH-terminal hydrolase-l 1 and DJ-1); Shasrty.2001.Neurosci Res 41:5; Cookson.2003.Neuron 37:7).Autosomal dominant PD causes by the sudden change of alpha-synapse nucleoprotein gene, and autosomal recessive PD is caused by the sudden change of handkerchief gold protein gene.

Several evidence promptings are arranged, and in the PD of all form known, it is neurodegenerative common mechanism that the detrimental protein in substantia nigra dopaminergic neuron is assembled.There are three kinds of its sudden change protein (alpha-synapse nucleoprotein, handkerchief gold albumen and COOH-terminal hydrolase-l 1) relevant also to be present in the Lewy corpusculum among sporadic PD (Mouradian.2002.Neurology 58:179) and the DLBL (Schlossmacher etc., 2002.Am J Pathol 160:1655) with the PD development.A parkinsonian pathological characteristics is to form the Cytoplasm inclusion body that is called the Lewy corpusculum; These inclusion bodys also see among DLBD and the MSA.The main component of Lewy corpusculum is an alpha-synapse nucleoprotein.Therefore, alpha-synapse nucleoprotein is its gathering another example with neural degeneration proteins associated matter.Shown that inner some the autosomal dominant sudden change of the gathering of alpha-synapse nucleoprotein in the Lewy corpusculum and alpha-synapse nucleoprotein gene is relevant.These replace the conformation transition that sudden change obviously helps mature protein inside, cause mature protein to assemble (Polymeropoulos etc., 1997.Science 276:2045 with the form of pathologic oligomer and protofibril; Kruger etc., 1998.Nat Genet 18:106; Conway etc., 2000.Proc Natl Acad SciUSA 97:571).PD also with recessive mutation relevant (Kitada etc., the 1998.Nature 392:605 of handkerchief gold protein gene; Lucking etc., 2000.N Engl J Med 342:1560; Ishikawa and Tsuji.1996.Neurology 47:160), described handkerchief gold albumen is as E2 dependency ubiquitin protein ligase, its activity is very important (Shimura etc., 2000.Nat Genet 25:302) for predetermined proteinic ubiquitinization of degrading by proteasome.Therefore, the forfeiture of handkerchief gold protein function can cause gathering of original protein substrate for the degraded target or assemble.When lacking handkerchief gold protein active, handkerchief proteic binding partners of gold or substrate, as PaelR1, cdc-rel1, synphilin-1, alpha-synapse nucleoprotein, α-and γ-tubulin (the some of them pair cell is directly poisonous) (Petrucelli etc., 2002.Neuron 36:1007; Imai etc., 2001.Cell 105:891; Ren etc., 2003.J Neurosci 23:316) can gather and trigger cell infringement and dead (relevant summary is referring to Cookson.2003.Neuron 37:7).Another nearest report shows, being present in another kind and alpha-synapse nucleoprotein interacting proteins in the Lewy corpusculum---the dysregulation (sudden change) of synphilin-1 can cause some PD Sporadic cases (Marx etc., 2003.Hum Mol Genet 12:1223).Generally speaking, these observed results show that the dysregulation of the degradation pathway of proteasome ubiquitin mediation can cause misfolding and assemble proteinic gathering, and forms inclusion body, and this is the reason of cytotoxicity and degeneration.

Importantly, alpha-synapse nucleoprotein accumulating in the presence of the dopamine in cultivating people's cell can optionally make the dopaminergic neuron degeneration, but non-dopamine neuron is not by degeneration, selective toxicity (the Xu etc. of this prompting alpha-synuclein aggregation, 2002.Nat Med, 8,600).Down the reorganization alpha-synapse nucleoprotein of long-time incubations can external formation aggregation and fibrils at 37 ℃, its form to from the isolating fibril of Lewy corpusculum similar (E1-Agnaf etc., 1998.FEBS Lett 440:67; Conway etc., 1998.Nat Med 4:1318).The overexpression of handkerchief gold albumen in the presence of proteasome inhibitor causes forming aggregation sample inclusion body (Junn etc., 2002.J Biol Chem 6:47870).In addition, the mice of expressing the sudden change of the known people's alpha-synapse nucleoprotein neural degeneration and the alpha-synapse nucleoprotein that demonstrate outbreak when growing up assembled (Lee etc., 2002.Proc Natl Acad Sci USA, 99,8968 in brain; Kahle etc., 2001.Am JPathol.159:2215; Kahle etc., 2002.J Clin Invest 110:1429; Gomez-Isla etc., 2003.Neurobiology Aging 24:245).

Nearest discovery proves also have the Lewy corpusculum to form in very most Alzheimer (AD) patient, with maximum (Hamilton.2000.Brain Pathol, 10:378 in the tonsil; Mukaetova-Ladinska etc., 2000.J Neuropathol Exp Neurol 59:408).What is interesting is that the non-amyloid composition of the high hydrophobicity of alpha-synapse nucleoprotein (NAC) district also is described to second multicomponent of amyloid plaque in AD patient's brain, is only second to A β.

Shown that alpha-synapse nucleoprotein can be at external formation fibril.In addition, it can and promote its gathering (Yoshimoto etc., 1995.Proc Natl Acad Sci USA 92:9141) in conjunction with A β.In fact, it is accredited as precursor (Ueda etc., the 1993.Proc Natl Acad Sci USA 90:11282 of non-amyloid beta (A β) component (NAD) of AD albuminous plasue at first; Iwai.2000.Biochem Biophys Acta 1502:95; Masliah etc., 1996.Am J Pathol148:201).NAC is the peptide of 35 amino acid longs, has the section of high hydrophobicity, and it external self aggregation can take place, and forms fibril.And these fibrils can cause effectively that A β fibril is at external formation (Han etc., 1995.Chem Biol.2:163-169; Iwai etc., 1995.Biochemistry 34:10139).Alpha-synapse nucleoprotein is actually by its NAC domain and keeps its fibril to generate character.Therefore, regulate the character of NAC or with the The compounds of this invention NAC that leads, may be the approach of effectively treating, form with sick proteins associated matter aggregation of alpha-synapse nucleoprotein and inclusion body suppressing, and be suppressed between the NAC of beta amyloid peptide and alpha-synapse nucleoprotein and form aggregation.

Polyglutamyl amine disease

Having shown several usually fatal adult onset diseases with the degeneration of carrying out property of nervous system is caused by the expansion of [CAG] n (polyglutamyl amine is polyQ in other words) section in the particular target albumen.Up to now, these diseases comprise dystrophia myotonica, dentate nucleus rubrum pallidum Louis body atrophy (DRPLA), Fu Lidelixishi ataxia, fragile X syndrome, fragile X E mental retardation, Ma-Yue disease, spinal cord oblongata amyotrophy (also claiming Kennedy's disease), spinocebellar ataxia and Huntington's disease (HD) (Kaneko etc., 1997.Proc NatlAcad Sci 94:10069; Zoghbi and Orr.2000.Ann Rev Neurosci, 23:217).

Prototype polyglutamyl amine disease---Huntington's disease (HD) is a kind of autosomal dominant neurodegenerative disease, is characterized as involuntary movement, cognitive competence decline and develops into dementia and emotional maladjustment.The feature of this disease is the selectivity loss of striatal neuron, causes (Shastry.1994.Nasir etc., 1996 by the expansion of polyglutamyl amine section in Huntington protein (HD) gene; Tobin and Singer.2000.Trends Cell Biol, 10,531).Mutein (subfragment that perhaps contains polyglutamyl amine) forms the ubiquitin aggregation in the neuron of patient or mouse model, in most of the cases form the ubiquitin aggregation in neuronal cell nuclear.

As if though cause the gene of polyQ disease irrelevant mutually on function, they all have such common trait, and the CAG trinucleotide repeats sequence is promptly all arranged in the coding region of each gene, it causes occurring polyglutamyl amine section in protein.In normal population, the length of polyQ is generally in the scope of 10-36 continuous glutamine residue.But in each of these patient's condition, the expansion of polyQ section exceeds normal range, causes occurring slowly the carrying out property neural degeneration of adult onset.Expand longly more, duration of seizure more early, the disease situation is also about serious.

The total probably common molecule pathogenesis that causes by the toxicity of expansion polyglutamyl amine section of these diseases.Now clear, expansion polyQ significantly increases the function of disease protein matter, and this function is toxic to neuron.Every kind of polyQ disease all has different neural degeneration feature modes, and therefore has different clinical manifestations.To the selectivity of different neuron colony in these diseases easily wound property also have little understanding, but its probably with the normal function of various diseases expression of gene pattern and disease gene product and interact relevant (Dragatsis etc., 2000.Nature Genet 26:300; Zuccato etc., 2001.Science 293:493).

Have recognized that expansion polyQ forms neuron intranuclear inclusion (Ross.1997.Neuron19:1147) in the animal model of polyQ disease neutralizes this patient's central nervous system.These inclusion bodys contain polyQ protein by insoluble gathering or contain the polyQ segment accumulation that produces that combines with other protein and form.Proposed to have the protein misfolding of long polyQ section and be gathered into antiparallel beta chain, be called " polar zipper " (Perutz.1994.Proc Natl Acad Sci USA, 91:5355).Accumulative threshold PolyQ length takes place in experimental system supported such argument with the dependency that causes the mankind to occur between the CAG repetitive sequence length of disease, promptly expand polyQ from conjunction with or to assemble be reason of its acquisition toxicity function.Though in some experimental systems, the toxicity of expansion polyQ is irrelevant with the formation of visible inclusion body, seemingly Cytotoxic invariant feature (the Sisodia.1998.Cell 95:1 of the formation of soluble molecular aggregates thing; Klement etc., 1998.Cell 95:41; Saudou etc., 1998.Cell 95:55; Muchowski etc., 2002.Proc Natl Acad Sci USA99:727).

The allelic transgenic mices of Huntington protein that expression has many cover expansion polyglutamyl amine sections show in early days hold (clasping) phenotype, motor coordination is impaired and hyperkinesia.These phenotypes are relevant with neuro pathology's phenomenon of cortex inclusion body, barrier film inclusion body, Hippocampus inclusion body, reactive gliosis, loss cell, general cerebral atrophy and cells inclusions, described phenomenon consistent (Schilling etc., 1999.Hum Mol Genet 8:397 with the variation that sees the Huntington's disease patient usually; Reddy etc., 1998.Nat Genet 20:198; DiFiglia, etc., 1997.Science 277:1990; Yamamoto etc., 2000.Cell 101:57).Constructed the similar animal model of other polyglutamyl amine diseases.

Silk presses down the albumen disease

Silk presses down that the albumen disease comprises that α (1)-antitrypsin (SERPINA1) lacks and having of characterizing recently pressed down the familial encephalopathia (FENIB) that neurofilament that albumen (SERPINI1) gene mutation produces presses down the albumen inclusion body by neurofilament.

Silk press down albumen in other words serpin be to be found in far-ranging species, comprise virus, plant and human protein superfamily.This family comprises many different members, as α 1-chymotrypsin inhibitor, C1 inhibitor, antithrombase and plasminogen activator inhibitor-1.Silk presses down albumen except playing a role in inflammation, complement, blood coagulation and fibrinolytic process, also participate in chromatin packaging, comprises that protein MENT and neurofilament press down albumen.It is included into silk and presses down superfamily protein, be based on to have and surpass 30% amino acid identity with α 1-trypsin, and based on three beta sheets (A-C) and the movable reactive conservative tertiary structure that encircles (it presents to target protease with peptide sequence as counterfeit substrate) that exposes.

This conformation is that the function of protease is necessary, but also makes their easy generations can cause the conformation transition of disease.Point mutation can destroy the stability of beta sheet A, allows another ring that presses down protein molecular mix.The insertion successively of reactive ring produces polymer chain, and it is retained in the cell subsequently, and constantly accumulation causes histologic lesion (Stein and Carrell.1995.NatStruct Biol 2:96).

This common mechanism has been suggested and has been used for explaining and presses down with silk that sudden change diseases associated phenotype changes among the superfamily protein member, and the result causes that these diseases that has nothing in common with each other are classified as silk and presses down albumen disease (the relevant summary referring to Lomas and Carrell.2002.Nat Rev Genet 3:759).

The tau protein disease

The principal character of sporadic neuro pathology's disease that kind is a lot of is thread tau protein inclusion body, it is similar to observed inclusion body in AD and Protein virus patient, this observed result impels research worker to propose, and tau protein is these reasons that are called the disease of tau protein disease jointly.This class disease comprises Alzheimer, the dementia pugilistica, mongolism, prion disease, cerebral amyloid angiopathy, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, argyrophilic grain dementia, the degeneration of cortex basal nuclei, diffusivity neurofibrillary tangles companion calcification disease, frontotemporal dementia FTD/the parkinson's syndrome related with chromosome 17, Ha-Si disease, multiple system atrophy (MSA), C type Ni-Pi disease, Pick's disease, benumb on the carrying out property nuclear, subacute sclerosing panencephalitis and entanglement dominance Alzheimer (AD) (Lee and Goedert.2001.Ann Rev Neurosci 24:1121).

Tau protein is the low-molecular-weight microtubule-associated protein, and content is abundant in central nervous system is unified peripheral nervous system.Multiple mutation in the τ encoding gene is relevant with parkinson's syndrome (FTDP-17) with frontotemporal dementia FTD, this finds proof forcefully, the tau protein of anomaly pattern can facilitate these diseases and other potential neurodegenerative diseases (Reed etc., 2001.Neurobiol22:89).In addition, paralysis and parkinsonian risk factor (Martin etc., 2001.J Am MedAssoc 286:2245 on the seemingly sporadic cortex basal nuclei of the polymorphism degeneration relevant, the carrying out property nuclear with the τ gene; Cole etc., 1999.Semin Neurol 19:407).The distinctive neurofibrillary tangles of AD (NFT) (referring to above) also is made up of aggregation in the born of the same parents of super phosphorylation microtubule tau protein.In fact, to promote that seemingly tau protein is assembled into after the translation of aggregation movable for super phosphorylation.

Though had nothing in common with each other by each brain region that influences in these diseases, as if but prompting on evidence has some common traits to come across in the All Ranges: the impaired montage of tau protein causes the unusual super phosphorylation of tau protein, tau protein generation fibrosis and tau protein finally to be deposited as aggregation (the relevant summary referring to Avila.2000.FEBS Lett 476:89; Taylor etc., 2002.Science, 296:1991).

The tau protein disease appears in the transgenic mice that expression carries the long isotype of tau protein of the sudden change that sees frontotemporal dementia FTD and parkinson's syndrome patient, it is characterized in that forming in the pro-brain neuron having a liking for the super phosphorylation τ inclusion body of Congo red.These inclusion bodys just occurred when 18 monthly ages.In human case, the τ inclusion body is made up of saltant and endogenous wild type tau protein, and destroys relevant with influenced neuronic flame-shaped conversion (flame-shaped transformations) with microtubule.In behavior, old transgenic saltant τ mice shows cognitive defect, particularly impaired (Lewis etc., 2000.Nat Genet 25:402 of association type memory; Gotz etc., 2001.J Biol Chem276:529; Tatebayashi etc., 2002.Proc Natl Acad Sci USA 99:13896; Gotz etc., 2001.Eur J Neurosci.13:2131; Tanemura etc., 2002.J Neurosci 22:133; Ishihara etc., 1999.Neuron 24:751; Spittaels etc., 1999.Am J Pathol155:2153; Probst etc., 2000.Acta Neuropathol 99:469).

The protein aggregation disorders that other are relevant

Amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is neuronic the carrying out property neurodegenerative disease that moves up and down.It is genetic that 10% ALS case is arranged approximately; Remaining case it is believed that (19:407), its neuropathological feature is motor neuron degeneration and damage and gliosis to the genus Sporadic cases for Cole etc., 1999.Semm Neurol.In the neuron of degeneration and neuroglia, find inclusion body in the born of the same parents (Rowland etc., 2001.N Eng J Med, 344:1688).In the middle of the heritability case, there is 20% case to cause approximately by the sudden change in superoxide dismutase 1 (SOD1) encoding gene.Recorded and narrated the different pathogenic SOD1 sudden change of kind more than 70.Neuron Lewy corpusculum sample hyalomitome inclusion body and spider cell hyalomitome inclusion body that the neuropathological feature of familial ALS is made up of saltant SOD1.Confirm that the pathogenic toxic of saltant SOD1 aggregation is such observed result, be that the disease mediated muroid model of saltant SOD1 has following feature: inclusion body in the tangible born of the same parents is arranged in the motor neuron, in some cases, inclusion body (Cleveland and Liu.2000.Nature Med 6:1320) in the tangible born of the same parents is arranged in the spider cell around the motor neuron.

Cataract

The proteic sudden change of alpha-crystal can cause cataract.Alpha-crystal albumen is the lenticular major protein composition of mammal eyes.They are to participate in the folding molecular chaperones of numerous protein, and known several families are present in the mammalian cell, comprise little heat shock protein (sHSP) family.The molecular weight of sHSP is about 15-30kDa.Think that alpha-crystal albumen suppresses the accumulative ability of detrimental protein of stress-induced by it, in keeping lenticular transparency, play crucial effect.Alpha-crystal albumen ' is held back ' in the high molecular complex by will not folding other lens crystallines and protein, prevents that them from assembling.But in aging course, the proteic chaperone function of alpha-crystal is impaired gradually, and light scattering aggregation or inclusion body are formed.At lenticular core, impaired protein does not obtain upgrading, therefore the proteic post translational modification of alpha-crystal is constantly gathered, this can further reduce the proteic chaperone function of alpha-crystal, thereby causes forming cataractous lens (relevant summary is referring to Horwitz.2003.ExpEye Res.76:145).

Wilson's disease

Wilson's disease is a kind of genetic diseases, it is characterized in that because copper hyposecretion from hepatocyte causes copper to gather in vivo.The location is accredited as the endosome in late period recently in the born of the same parents of Wilson's disease gene outcome ATP7B.ATP7B is that the film copper transport protein is white.Write down the various mutations among the Wilson's disease patient.Patient's clinical manifestation alters a great deal.The common ATP7B mutant His1069Gln of green fluorescent protein labelling expresses in Huh7 cell and HEK293 cell.This mutain is not positioned the endosome in late period, is degraded by the proteasome in the Cytoplasm.In addition, His1069Gln forms the aggregation of being made up of degradation product and intermediate filament (Harada etc., 2001.Gastroenterology 121:1264) in microtublue organizing center (MTOC).In addition, show that ubiquitin and heat shock protein hsp70 and hsp90 are positioned in the aggregation in Wilson's disease patient's the liver biopsy section (Riley.2003.Exp Mol Pathol74:168) altogether.(be positioned to examine other district based on the aggregation feature among the Wilson's disease patient, locate altogether with proteasome subunit, T-5398 and heat shock protein), proposed such suggestion, promptly Wilson's disease can be classified as a member (French.2001.Gastroenterology 121:1264) of protein conformation disease.

The compounds of this invention

The present invention relates to treatment or object of prevention (preferred mammal, more preferably human) in do not belong to the method for the protein aggregation disorders of amyloid disease (as defined herein), described method comprises and gives the chemical compound shown in object effective dose any following various, protein aggregation disorders is obtained medical treatment or prevents.In another embodiment, the present invention relates to prevention, inhibition, treatment or controlled plant (preferred mammal, more preferably human) in do not belong to the method for the protein aggregation disorders of amyloid disease (as defined herein), described method comprises the The compounds of this invention that gives the object effective dose, makes protein aggregation disorders obtain prevention, suppress, treat or regulate.

One group of example of The compounds of this invention is an alkyl sulfonic acid, and it has formula Q-[-Y ^--X ⁺] _nStructure, wherein Q is a carrier molecule; Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺X ⁺Be cation group, as atom or other parts of positively charged.The suitable carriers molecule comprises carbohydrate, polymer, peptide, peptide derivant, aliphatic group, alicyclic group, heterocyclic group, aromatic group or their combination.Carrier molecule can be substituted, and is for example replaced by one or more amino, nitro, halogen, sulfydryl or hydroxyl.Referring to No. the 5th, 840,294, WO96/28187, WO 01/85093 and United States Patent (USP).

One group of concrete The compounds of this invention has the following formula structure:

Wherein Y is that amino (has formula-NR ^aR ^bStructure) or sulfonic group (have formula-SO ₃ ^-X ⁺), n is the integer of 1-5, X is hydrogen or cation group (for example sodium).Some exemplary alkyl sulfonic acids comprise following:

In some cases, alkyl sulfonic acid is " micromolecule ", be that chemical compound itself is not genetic transcription or translation product (for example protein, RNA or DNA) and molecular weight low (for example less than about 2500), in other cases, The compounds of this invention can be a biologic, as antibody or immunogenic peptide.

Alkyl sulfonic acid can be by the method for illustrating in general reaction process, for example at United States Patent (USP) the 5th, 643, No. 562, the 5th, 972, No. 328, the 5th, 728, No. 375, the 5th, 840, No. 294, the 4th, 657, No. 704 and title are the method for illustrating in the U.S. Provisional Patent Application (attorney docket NBI-156-1, on June 23rd, 2003 submitted to) of " synthetic method of the chemical compound of preparation treatment amyloidosis " (" SYNTHETIC PROCESS FOR PREPARING COMPOUNDSFOR TREATING AMYLOIDOSIS "), use the raw material that obtains easily, reagent adopts conventional synthesis program to prepare.In these reactions, also might utilize the variation known but that this paper does not mention of itself behaving.Compound functions described herein and equivalent structures with identical general aspects, wherein one or more simple changes that substituent group is done can not have a negative impact to the fundamental property or the application of chemical compound, and such equivalent can prepare by several different methods well known in the art.

That term used herein " alkyl sulfonic acid " comprises replacement or unsubstituted alkyl sulfonic acid, and that replace or unsubstituted low alkyl group sulfonic acid.Amino-substituted compounds merits attention especially, so amino substituted alkyl sulfonic acid that the present invention relates to replace or unsubstituted and replacement or the unsubstituted amino low alkyl group sulfonic acid that replaces, the example is 3-amino-1-propane sulfonic acid.And, it shall yet further be noted that term used herein " alkyl sulfonic acid " is interpreted as and term " alkyl sulfonic acid " synonym.

That the present invention relates to replace or unsubstituted alkyl sulfonic acid, replacement or unsubstituted alkyl sulphuric acid, replacement or unsubstituted alkyl thiosulfonic acid, replacement or the unsubstituted alkyl thiosulfuric acid, perhaps their ester or amide comprise their drug acceptable salt.For example, the chemical compound that the present invention relates to for replace or unsubstituted alkyl sulfonic acid, perhaps its ester or amide comprise its drug acceptable salt.In another embodiment, the chemical compound that the present invention relates to is that replace or unsubstituted low alkyl group sulfonic acid, and perhaps its ester or amide comprise its drug acceptable salt.Similarly, the present invention includes such chemical compound, it is (amino replacement or unsubstituted) substituted alkyl sulfonic acid, and perhaps its ester or amide comprise its drug acceptable salt.In another embodiment, chemical compound is that (amino replacement or unsubstituted) replaces low alkyl group sulfonic acid, and perhaps its ester or amide comprise its drug acceptable salt.

" alkyl " used herein comprises the saturated hydrocarbons with one or more carbon atom, comprises the alkyl (for example cycloalkyl of alkyl replacement and the alkyl of cycloalkyl substituted) that straight chained alkyl (for example methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl etc.), cyclic alkyl (or title " cycloalkyl " or " alcyl " or " carbocylic radical ") (for example cyclopropyl, cyclopenta, cyclohexyl, suberyl, ring octyl group etc.), branched alkyl (isopropyl, the tert-butyl group, sec-butyl, isobutyl group etc.) and alkyl replace.Term " aliphatic group " comprises that what have 1 to 22 carbon atom usually is the organic moiety of feature with straight chain or side chain.In labyrinth, described chain can branch, bridging or crosslinked.Aliphatic group comprises alkyl, thiazolinyl and alkynyl.

Therefore, the present invention relates to replace or unsubstituted alkyl sulfonic acid, it is that replace or unsubstituted straight chained alkyl sulfonic acid, replacement or unsubstituted cycloalkyl sulfonic acid and that replace or unsubstituted branched alkyl sulfonic acid.

The structure of some The compounds of this invention comprises chiral carbon atom.Should be understood that the isomer (for example all enantiomers and diastereomer) that produces owing to this unsymmetry comprises within the scope of the invention, unless otherwise.That is to say that unless otherwise prescribed, (R)-or (S)-three-dimensional chemical configuration can be taked in any chiral carbon center.Can obtain the described isomer of substantially pure by classical isolation technics and synthetic by spatial chemistry control.In addition, The compounds of this invention can non-solvent compound form exists, and perhaps forms solvate with acceptable solvent such as water, THF, ethanol etc.For the purposes of the present invention, generally solvate form thereof is thought and be equal to non-solvent compound form.Polymer, one or more molecule of its inclusion compound and one or more molecule of drug solvent such as water, ethanol etc. that term " solvate " representative is such.

In certain embodiments, can have 30 or be less than 30 carbon atoms, for example C on the main chain of straight chain or branched alkyl ₁-C ₃₀Straight chain or C ₃-C ₃₀Side chain.In certain embodiments, can have 20 or be less than 20 carbon atoms, for example C on the main chain of straight chain or branched alkyl ₁-C ₂₀Straight chain or C ₃-C ₂₀Side chain, even can have 18 or be less than 18 carbon atoms.Equally, have 4-10 carbon atom in its ring structure of exemplary cycloalkyl, perhaps have 4-7 carbon atom in its ring structure.

Term " low alkyl group " refers to have in the chain alkyl of 1-6 carbon, perhaps has the cycloalkyl of 3-6 carbon in the ring structure.Unless the number of carbon has appointment in addition, " rudimentary " in " low alkyl group " refers to that described group partly has at least one and is less than about 8 carbon atoms.In certain embodiments, can have 6 or be less than 6 carbon atoms (C for example on the main chain of straight chain or side chain low alkyl group ₁-C ₆Straight chain or C ₃-C ₆Side chain), for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl and the tert-butyl group.Equally, can have 3-8 carbon atom in its ring structure of cycloalkyl, for example can have 5 or 6 carbon atoms in its ring structure." C ₁-C ₆Alkyl " in term " C ₁-C ₆" refer to that alkyl contains 1-6 carbon atom.

In addition, unless otherwise specified, the term alkyl comprises " unsubstituted alkyl " and " alkyl of replacement ", and the latter refers to that alkyl has the substituent group that replaces one or more hydrogen on one or more carbon of hydrocarbon main chain.This substituent group can comprise for example thiazolinyl; alkynyl; halogen; hydroxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkoxy-carbonyl oxy; aryloxy group; aryloxycarbonyl oxygen base; carboxyl; alkyl-carbonyl; aryl carbonyl; alkoxy carbonyl; amino carbonyl; alkyl amino-carbonyl; dialkyl amino carbonyl; alkyl thiocarbonyl; alkoxyl; phosphate; phosphonate group (phosphonato); phosphonous acid base (phosphinato); cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; carbamoyl and urea groups); imino group; sulfydryl; alkylthio group; arylthio; thiocarboxyl group; sulfate; the alkyl sulfinyl; sulfonic group (sulfonato); sulfonamides; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; alkylaryl or aromatic group (comprising heteroaryl).

The alkyl that " aryl alkyl " group is replaced by aryl (for example phenyl methyl (being benzyl)).The aryl (for example p-methylphenyl (being p-methylphenyl)) that " alkylaryl " part is replaced by alkyl.Term " n-alkyl " refers to straight chain (being non-branch) unsubstituted alkyl." alkylidene " is the bivalence analog of corresponding alkyl.Term " thiazolinyl " and " alkynyl " refer to be similar to alkyl but contain at least one carbon-to-carbon double bond respectively or triple-linked unsaturated aliphatic base.Suitable thiazolinyl and alkynyl comprise having 2 to about 12 carbon atoms, preferred 2 groups to about 6 carbon atoms.

Term " aromatic group " or " aryl " comprise unsaturated aromatics cyclic hydrocarbon and the unsaturated aromatic heterocycle that contains one or more ring.Aryl also can with aliphatic series ring or the heterocyclic fused or bridging of non-aromatic property, multi-ring to form (for example 1,2,3,4-tetralin)." arlydene " is the bivalence analog of corresponding aryl.Aryl can also encircle or heterocyclic fused or bridging multi-ring to form (for example 1,2,3,4-tetralin) with non-aromatic property aliphatic series.

Term " heterocyclic radical " comprises the closed-loop structure that is similar to carbocylic radical, and one or more atom in its medium ring is the element beyond the carbon, for example nitrogen, sulfur or oxygen.Heterocyclic radical can be saturated or unsaturated.In addition, heterocyclic radical (as pyrrole radicals, pyridine radicals, isoquinolyl, quinolyl, purine radicals and furyl) can have aromatics character, and in this case, they can be described as " heteroaryl " or " heteroaromatic group ".

Unless otherwise prescribed, aryl and heterocyclic radical (comprising heteroaryl) also can be substituted on its one or more composed atom.Heteroaromatic group and heterolipid family examples of groups can have 1-3 separate or condensed ring, and each ring is 3 yuan of extremely about 8 yuan of rings, has one or more N, O or S hetero atom.In general, term " hetero atom " comprises any element beyond de-carbon or the hydrogen, and preferred hetero atom example comprises nitrogen, oxygen, sulfur and phosphorus.Heterocyclic radical can be saturated or unsaturated or fragrant property.

Heterocyclic example includes but not limited to acridine; The azocine base; Benzimidazolyl; Benzofuranyl; Benzimidazole thiophanate is for furyl; Benzothienyl; Benzoxazolyl; Benzothiazolyl; The benzotriazole base; The benzo tetrazole radical; The benzoisoxazole base; The benzisothiazole base; The benzimidazoline base; Carbazyl; The 4aH-carbazyl; Carbolinyl; Chromanyl; Benzopyranyl; Cinnolinyl; Decahydroquinolyl; 2H, 6H-1,5,2-dithiazine base; Dihydrofuran is [2,3-b] oxolane also; Furyl; The furazan base; Imidazolidinyl; Imidazolinyl; Imidazole radicals; The 1H-indazolyl; Indolenyl; Indolinyl; The indolizine base; Indyl; The 3H-indyl; Isobenzofuran-base; The isochroman base; Iso indazolyl; Iso-dihydro-indole-group; Isoindolyl; Isoquinolyl; Isothiazolyl; Isoxazolyl; Methylenedioxyphenyl; Morpholinyl; The naphthyridine base; The octahydro isoquinolyl; The oxadiazole base; 1,2,3-oxadiazole base; 1,2,4-oxadiazole base; 1,2,5-oxadiazole base; 1,3,4-oxadiazole base; Oxazolidinyl; Oxazolyl; Oxazolidinyl; Pyrimidine radicals; Phenanthridinyl; The phenanthroline base; Phenazinyl; Phenothiazinyl; Fen Sai Evil base (phenoxathiinyl); Phenoxazine group; The 2 base; Piperazinyl; Piperidyl; Piperidone base; The 4-piperidone base; Piperonyl; Pteridyl; Purine radicals; Pyranose; Pyrazinyl; Pyrazolidinyl; Pyrazolinyl; Pyrazolyl; Pyridazinyl; Bi Ding Bing oxazolyl; The pyridine-imidazole base; The pyrido thiazolyl; Pyridine radicals; Pyridine radicals; Pyrimidine radicals; Pyrrolidinyl; Pyrrolinyl; The 2H-pyrrole radicals; Pyrrole radicals; Quinazolyl; Quinolyl; The 4H-quinolizinyl; Quinoxalinyl; Quininuclidinyl; Tetrahydrofuran base; Tetrahydro isoquinolyl; Tetrahydric quinoline group; Tetrazole radical; 6H-1,2,5-thiadiazine base; 1,2, the 3-thiadiazolyl group; 1,2, the 4-thiadiazolyl group; 1,2, the 5-thiadiazolyl group; 1,3, the 4-thiadiazolyl group; Thianthrene group; Thiazolyl; Thienyl; The thieno thiazolyl; Thiophene Bing oxazolyl; The Thienoimidazole base; Thienyl; Triazine radical; The 1,2,3-triazoles base; 1,2, the 4-triazolyl; The oso-triazole base; 1,3, the 4-triazolyl; And xanthyl.Preferred heterocycle includes but not limited to pyridine radicals; Furyl; Thienyl; Pyrrole radicals; Pyrazolyl; Pyrrolidinyl; Imidazole radicals; Indyl; Benzimidazolyl; The 1H-indazolyl; Oxazolidinyl; The benzotriazole base; The benzoisoxazole base; The hydroxyindole base; Benzoxazole quinoline base; With isatin acyl group (isatinoyl).Also comprise and contain for example above-mentioned heterocyclic fused ring compound and spiro-compound.

Common hydrocarbon aryl is the phenyl with a ring.Two cyclic hydrocarbon aryl comprise naphthyl, indenyl, benzo cyclo-octene base, benzocyclohepta thiazolinyl, pentalene base and azulene base, and their partial hydrogenation analog, as indanyl and tetralyl.Exemplary tricyctic hydrocarbon aryl comprises acenaphthenyl (acephthylenyl), fluorenyl, phenalenyl, phenanthryl and anthryl.

Aryl also comprises assorted monocyclic aryl, i.e. bicyclic heteroaryl is as thienyl, furyl, pyranose, pyrrole radicals, imidazole radicals, pyrazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals and pyridazinyl; And their oxidation analog, as pyriconyl, oxazole ketone group, pyrazoles ketone group, isoxazole ketone group and thiazole ketone group.Corresponding hydrogenation (being non-aromatics) heteromonocyclic group comprises pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl and piperidino, piperazinyl and morpholino and morpholinyl.

Aryl also comprises fused bicyclic heteroaryl, as indyl, isoindolyl, indolizine base, indazolyl, quinolyl, isoquinolyl, 2,3-phthalazinyl, quinoxalinyl, quinazolyl, cinnolinyl, benzopyranyl, different benzopyranyl, benzothienyl, benzimidazolyl, benzothiazolyl, purine radicals, quinolizinyl, isoquinolone base, quinolonyl, 1,5-phthalazinyl and pteridyl, and the partial hydrogenation analog, as chromanyl, isochroman base, indolinyl, iso-dihydro-indole-group and tetrahydro indole base.Aryl also comprises the fused tricyclic group, as Fen Sai Evil base, carbazyl, phenanthridinyl, acridine, perimidinyl (perimidinyl), phenanthroline base, phenazinyl, phenothiazinyl, phenoxazine group and dibenzofuran group.

Some typical aryl comprise 5 yuan and 6 yuan of monocyclic aryl replacement or unsubstituted.On the other hand, optional that replace certainly or unsubstituted phenyl, pyrrole radicals, furyl, thienyl, thiazolyl, isothiazolyl, imidazole radicals, triazolyl, tetrazole radical, pyrazolyl, oxazolyl, isoxazolyl, pyridine radicals, pyrazinyl, pyridazinyl and pyrimidine radicals of each Ar group.More example comprises phenyl replacement or unsubstituted, the 1-naphthyl, the 2-naphthyl, xenyl, the 1-pyrrole radicals, the 2-pyrrole radicals, the 3-pyrrole radicals, the 3-pyrazolyl, the 2-imidazole radicals, the 4-imidazole radicals, pyrazinyl, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, the 2-pyrimidine radicals, the 4-pyrimidine radicals, the 5-benzothiazolyl, purine radicals, the 2-benzimidazolyl, the 5-indyl, the 1-isoquinolyl, the 5-isoquinolyl, the 2-quinoxalinyl, the 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.

Term used herein " amine " or " amino " refer to formula-NR ^aR ^bThe part of shown unsubstituted or replacement, wherein R ^aAnd R ^bIndependently be hydrogen, alkyl, aryl or heterocyclic radical, perhaps R separately ^aAnd R ^bThe nitrogen-atoms that connects with them forms the annulus that has 3-8 atom in the ring.Therefore, term amino comprises the cyclic amino part, as piperidyl or pyrrolidinyl, unless otherwise prescribed.Therefore, term used herein " alkyl amino " refers to be connected with on it amino alkyl.Suitable alkyl amino comprises having 1 group to about 12 carbon atoms, for example has 1 to about 6 carbon atoms.Term amino comprises the wherein chemical compound or the part of nitrogen-atoms and at least one carbon atom or hetero atom covalent bonding.Term " dialkyl amido " comprises wherein nitrogen-atoms and at least two bonded groups of alkyl.Term " arylamino " and " ammonia diaryl base " comprise wherein nitrogen respectively with at least one or two bonded groups of aryl.Term " alkyl aryl amino " refers to and at least one alkyl and the bonded amino of at least one aryl.Term " alkyl amino alkyl " refers to the alkyl, thiazolinyl or the alkynyl that are replaced by alkyl amino.Term " amide " or " amino carbonyl " comprise chemical compound or the part that contains with the bonded nitrogen-atoms of carbon of carbonyl or thiocarbonyl.

Term " alkylthio group " refers to have the alkyl that is connected with sulfydryl.Suitable alkylthio group comprises having 1 to about 12 carbon atoms, preferred 1 group to about 6 carbon atoms.

Term used herein " alkyl carboxyl " refers to have the alkyl that is connected with carboxyl.

Term used herein " alkoxyl " refers to have the alkyl that is connected with oxygen atom.Representational alkoxyl comprises having 1 to about 12 carbon atoms, preferred 1 alkoxyl to about 6 carbon atoms, for example methoxyl group, ethyoxyl, propoxyl group, tert-butoxy etc.The example of alkoxyl comprises methoxyl group, ethyoxyl, isopropoxy, propoxyl group, butoxy and amoxy.Alkoxyl can be replaced by for example following group: thiazolinyl; alkynyl; halogen; hydroxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkoxy-carbonyl oxy; aryloxycarbonyl oxygen base; carboxyl; alkyl-carbonyl; aryl carbonyl; alkoxy carbonyl; amino carbonyl; alkyl amino-carbonyl; dialkyl amino carbonyl; alkyl thiocarbonyl; alkoxyl; phosphate; phosphonate group; the phosphonous acid base; cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; carbamoyl and urea groups); imino group; sulfydryl; alkylthio group; arylthio; thiocarboxyl group; sulfate; the alkyl sulfinyl; sulfonic group; sulfamoyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; alkylaryl or aromatics or heteroaromatic moiety.The example of the alkoxyl that halogen replaces includes but not limited to fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, chlorine methoxyl group, dichloro methoxyl group, trichlorine methoxyl group etc., and the perhalogeno alkoxyl.

Term " acyl amino " comprises wherein amino part and the bonded part of acyl group.For example, acyl amino comprises alkyl-carbonyl-amino, aryl-amino-carbonyl, carbamoyl and urea groups.

Term " alkoxyalkyl ", " alkyl amino alkyl " and " thio alkoxy alkyl " comprise the abovementioned alkyl that further comprises oxygen, nitrogen or the sulphur atom of one or more carbon on the replacement hydrocarbon main chain.

Term " carbonyl " or " carboxyl " comprise and contain carbon compound or the part that is connected with oxygen atom by two keys.The example that contains the part of carbonyl comprises aldehyde, ketone, carboxylic acid, amide, ester, acid anhydride etc.

Term " ether " or " ether " comprise chemical compound or the part that contains with two bonded oxygen of carbon atom.For example, the group of ether group or ether comprises " alkoxyalkyl ", and it refers to alkyl, thiazolinyl or alkynyl that alkoxy replaces.

" sulfonic acid " or " sulfonate " group be with carbon atom bonded-SO ₃H or-SO ₃ ^-X ⁺Group, wherein X ⁺It is cationic counter ion group.Similarly, " sulfonic acid " chemical compound have with carbon atom bonded-SO ₃H or-SO ₃ ^-X ⁺Group, wherein X ⁺It is cation group." sulfate " used herein be with carbon atom bonded-OSO ₃H or-OSO ₃ ^-X ⁺Group, " sulphuric acid " chemical compound have with carbon atom bonded-OSO ₃H or-OSO ₃ ^-X ⁺Group, wherein X ⁺It is cation group.According to the present invention, suitable cation group can be a hydrogen atom.In some cases, in fact cation group can be another group on the therapeutic compound of positively charged under physiological pH, for example amino.

Need " counter ion " to keep electric neutrality, it is that medicine is acceptable in the present composition.The chemical compound that contains with the covalently bound cation group of anionic group can be described as " inner salt ".The example of anionic property counter ion comprises halogenide, the trifluoromethanesulfonic acid root, sulfate radical, nitrate anion, hydroxyl, carbonate, bicarbonate radical, acetate, phosphate radical, oxalate, the cyanogen root, the alkyl carboxylic acid root, N-hydroxy-succinamide, the N-hydroxybenzotriazole, the alcohol anion, sulfo-alcohol anion, alkylsulfonyloxy, the haloalkyl sulfonyloxy, aryl-sulfonyl oxygen, bisulfate ion, oxalate, pentanoate, the oleic acid root, the Petiolus Trachycarpi acid group, stearate radical, laurate, borate, benzoate anion, lactate, citrate, maleate, fumaric acid radical, amber acid radical, tartrate anion, the naphthoic acid root, methanesulfonate, glucoheptose acid group or lactose acid group.The chemical compound that contains with the covalently bound cation group of anionic group can be described as " inner salt ".

Term " nitro " refers to-NO ₂Term " halogen " or " halo " refer to-F ,-Cl ,-Br or-I; Term " sulfo-" or " sulfydryl " refer to SH; Term " hydroxyl " refers to-OH.

Carbonyl (for example benzoyl) that term " acyl group " refers to the carbonyl (being formoxyl) that is connected with hydrogen by its carbon atom, the carbonyl (for example acetyl group) that is connected with aliphatic group, be connected with aromatic group etc.Term " substituted acyl " comprises the acyl group that one or more hydrogen atom on one or more carbon atom is replaced by for example following group: alkyl; alkynyl; halogen; hydroxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkoxy-carbonyl oxy; aryloxycarbonyl oxygen base; carboxyl; alkyl-carbonyl; aryl carbonyl; alkoxy carbonyl; amino carbonyl; alkyl amino-carbonyl; dialkyl amino carbonyl; alkyl thiocarbonyl; alkoxyl; phosphate; phosphonate group; the phosphonous acid base; cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; carbamoyl and urea groups); imino group; sulfydryl; alkylthio group; arylthio; thiocarboxyl group; sulfate; the alkyl sulfinyl; sulfonic group; sulfamoyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; alkylaryl or aromatics or heteroaromatic moiety.

Unless otherwise specified, the chemical part of The compounds of this invention comprises that gene discussed above can be " substituted or unsubstituted ".In some embodiments, term " replacement " refers to that described part has the non-hydrogen substituent group (promptly in most of the cases, replacing hydrogen) that places on this part, and this makes this molecular energy carry out its predetermined function.Described substituent example comprises and is selected from following part: straight chain or branched alkyl (C for example ₁-C ₅), cycloalkyl (C for example ₃-C ₈), amino (comprising-NH ₂) ,-SO ₃H ,-OSO ₃H ,-CN ,-NO ₂, halogen (for example-F ,-Cl ,-Br or-I) ,-CH ₂OCH ₃,-OCH ₃,-SH ,-SCH ₃,-OH and-CO ₂H.Described substituent example comprises and is selected from following part: straight chain or branched alkyl (preferred C ₁-C ₅), cycloalkyl (preferred C ₃-C ₈), alkoxyl (preferred C ₁-C ₆), alkylthio (preferred C ₁-C ₆), thiazolinyl (preferred C ₂-C ₆), alkynyl (preferred C ₂-C ₆), heterocyclic radical, carbocylic radical, aryl (for example phenyl), aryloxy group (for example phenoxy group), aralkyl (for example benzyl), aryloxy alkyl (for example phenoxyalkyl), aryl acetylamino (arylacetamidoyl), alkylaryl, heteroarylalkyl, alkyl-carbonyl and aryl carbonyl or other this class acyl groups, heteroaryl carbonyl and heteroaryl, and (CR ' R ") _0-3NR ' R " (for example-NH ₂), (CR ' R ") _0-3CN (for example-CN) ,-NO ₂, halogen (for example-F ,-Cl ,-Br or-I), (CR ' R ") _0-3(halogen) ₃(for example-CF ₃), (CR ' R ") _0-3CH (halogen) ₂, (CR ' R ") _0-3CH ₂(halogen), and (CR ' R ") _0-3CONR ' R ", (CR ' R ") _0-3(CNH) NR ' R ", (CR ' R ") _0-3S (O) _1-2NR ' R ", (CR ' R ") _0-3CHO, (CR ' R ") _0-3O (CR ' R ") _0-3H, (CR ' R ") _0-3S (O) _0-3R ' (for example-SO ₃H), (CR ' R ") _0-3O (CR ' R ") _0-3H (for example-CH ₂OCH ₃With-OCH ₃), (CR ' R ") _0-3S (CR ' R ") _0-3H (for example-SH and-SCH ₃), (CR ' R ") _0-3OH (for example-OH), (CR ' R ") _0-3COR ', (CR ' R ") _0-3(phenyl replacement or unsubstituted), and (CR ' R ") _0-3(C ₃-C ₈Cycloalkyl), (CR ' R ") _0-3CO ₂R ' (for example-CO ₂H) and (CR ' R ") _0-3OR ' group, wherein R ' and R " independently be hydrogen, C separately ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl or aryl; Or the side chain of any natural amino acid.

In another embodiment, substituent group can be selected from straight chain or branched alkyl (preferred C ₁-C ₅), cycloalkyl (preferred C ₃-C ₈), alkoxyl (preferred C ₁-C ₆), alkylthio (preferred C ₁-C ₆), thiazolinyl (preferred C ₂-C ₆), alkynyl (preferred C ₂-C ₆), heterocyclic radical, carbocylic radical, aryl (for example phenyl), aryloxy group (for example phenoxy group), aralkyl (for example benzyl), aryloxy alkyl (for example phenoxyalkyl), aryl acetylamino, alkylaryl, heteroarylalkyl, alkyl-carbonyl and aryl carbonyl or other this class acyl groups, heteroaryl carbonyl and heteroaryl, (CR ' R ") _0-10NR ' R " (for example-NH ₂), (CR ' R ") _0-10CN (for example-CN) ,-NO ₂, halogen (for example F, Cl, Br or I), (CR ' R ") _0-10(halogen) ₃(for example-CF ₃), (CR ' R ") _0-10CH (halogen) ₂, (CR ' R ") _0-10CH ₂(halogen), and (CR ' R ") _0-10CONR ' R ", (CR ' R ") _0-10(CNH) NR ' R ", (CR ' R ") _0-10S (O) _1-2NR ' R ", (CR ' R ") _0-10CHO, (CR ' R ") _0-10O (CR ' R ") _0-10H, (CR ' R ") _0-10S (O) _0-3R ' (for example-SO ₃H), (CR ' R ") _0-10O (CR ' R ") _0-10H (for example-CH ₂OCH ₃With-OCH ₃), (CR ' R ") _0-10S (CR ' R ") _0-3H (for example-SH and-SCH ₃), (CR ' R ") _0-10OH (for example-OH), (CR ' R ") _0-10COR ', (CR ' R ") _0-10(phenyl replacement or unsubstituted), and (CR ' R ") _0-10(C ₃-C ₈Cycloalkyl), (CR ' R ") _0-10CO ₂R ' (for example-CO ₂H) or (CR ' R ") _0-10OR ' group, or the side chain of any natural amino acid; Wherein R ' and R " independently be hydrogen, C separately ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl or aryl, perhaps R ' and R " become together benzal or-(CH ₂) ₂O (CH ₂) ₂-group.

Should be understood that, " replacement " or " being substituted " implies collateral condition, be described replacement according to being substituted atom and substituently allowing that quantivalence carries out, and described replacement causes occurring stable chemical compound, and for example described chemical compound can not change by reaction is spontaneous such as rearrangement, cyclisation, elimination etc.Term used herein " replacement " means and comprises all permissible organic compound substituent groups.Broadly, permissible substituent group comprise acyclic and cyclic, contain side chain and organic compound substituent group unbranched, isocyclic and heterocyclic, aromatics and non-aromatics.Permissible substituent group can be one or more.

Should be understood that, " replacement " or " being substituted " implies collateral condition, be described replacement according to being substituted atom and substituently allowing that quantivalence carries out, and described replacement causes occurring stable chemical compound, and for example described chemical compound can not change by reaction is spontaneous such as rearrangement, cyclisation, elimination etc.Term used herein " replacement " means and comprises all permissible organic compound substituent groups.Broadly, permissible substituent group comprise acyclic and cyclic, contain side chain and organic compound substituent group unbranched, isocyclic and heterocyclic, aromatics and non-aromatics.For suitable organic compound, permissible substituent group can be one or more, and can be identical or different.

In some embodiments, " substituent group " can be selected from for example halogen, trifluoromethyl, nitro, cyano group, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkyl-carbonyl oxygen base, aryl carbonyl oxygen base, C ₁-C ₆Alkoxy-carbonyl oxy, aryloxycarbonyl oxygen base, C ₁-C ₆Alkyl-carbonyl, C ₁-C ₆Alkoxy carbonyl, C ₁-C ₆Alkoxyl, C ₁-C ₆Alkylthio group, arylthio, heterocyclic radical, aralkyl and aryl (comprising heteroaryl).

The examples of compounds that more can be used as The compounds of this invention is included in title and is " method and composition for the treatment of diseases associated with amyloid protein " " METHODS andCOMPOSITIONS FOR TREA TING AMYLOID-RELA TED DISEASES " (attorney docket NBI-162-1; Submitted on June 23rd, 2003) and the U.S. Provisional Patent Application of " method and composition for the treatment of amyloid and epilepsy generation relevant disease " " METHODSANDCOMPOSITIONS FOR THE TREA TMENT OFAMYLOID-ANDEPILEPTOGENESIS-ASSOCIATED DISEASES " (attorney docket NBI-163-1, submission on June 23rd, 2003) in the compound described.

In one embodiment, the present invention relates to the compositions that contains chemical compound shown in the formula I-A or its drug acceptable salt at least on part:

Wherein:

R ¹Be replace or unsubstituted cycloalkyl, aryl, cycloalkyl aryl, bicyclo-or three rings, bicyclo-or three ring condensed ring groups or that replace or unsubstituted C ₂-C ₁₀Alkyl;

R ²Be selected from hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl;

Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺

X ⁺Be hydrogen, cation group or one-tenth ester group (promptly as in the prodrug, it locates to have description at this paper);

L ¹And L ²Independently be that replace or unsubstituted C separately ₁-C ₅Alkyl or do not exist,

Condition is to work as R ¹When being alkyl, L ¹Do not exist.

In another embodiment, the present invention relates to the compositions that contains chemical compound shown in the formula II-A or its drug acceptable salt at least on part:

Wherein:

R ¹Be replace or unsubstituted ring, bicyclo-, three ring or benzheterocycle group or replacement or unsubstituted C ₂-C ₁₀Alkyl;

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl, benzimidazolyl, perhaps with R ¹Be connected to form heterocycle;

Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺

X ⁺Be hydrogen, cation group or one-tenth ester moiety;

M is 0 or 1;

N is 1,2,3 or 4;

L is that replace or unsubstituted C ₁-C ₃Alkyl or do not exist,

Condition is to work as R ¹When being alkyl, L does not exist.

In another embodiment, the present invention relates to the compositions that contains chemical compound shown in formula III-A or its drug acceptable salt and ester at least on part:

Wherein:

A is nitrogen or oxygen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

R ³, R ^3a, R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aIndependently be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, cyano group, halogen, amino, tetrazole radical separately, perhaps two R groups on the Lin Jin annular atoms form two keys with annular atoms, and condition is R ³, R ^3a, R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aOne of be the part shown in the formula III a-A:

Wherein:

M is 0,1,2,3 or 4;

R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Independently be selected from hydrogen, halogen, hydroxyl, alkyl, alkoxyl, haloalkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, cyano group, thiazolyl, triazolyl, imidazole radicals, tetrazole radical, benzothiazolyl and benzimidazolyl;

Condition is that this chemical compound is not 3-(4-phenyl-1,2,3,6-tetrahydrochysene-1-pyridine radicals)-1-propane sulfonic acid.

In another embodiment, the present invention relates to the compositions that contains chemical compound shown in the formula IV-A and drug acceptable salt and ester at least on part:

Wherein:

A is nitrogen or oxygen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aIndependently be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, cyano group, halogen, amino, tetrazole radical separately, R ⁴And R ⁵The annular atoms that connects with them forms two key, perhaps R ⁶And R ⁷The annular atoms that connects with them forms two keys;

M is 0,1,2,3 or 4;

R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Independently be selected from hydrogen, halogen, hydroxyl, alkyl, alkoxyl, haloalkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, cyano group, thiazolyl, triazolyl, imidazole radicals, tetrazole radical, benzothiazolyl and benzimidazolyl.

In another embodiment, the present invention includes the compositions that contains chemical compound shown in the formula V-A and drug acceptable salt and prodrug:

Wherein:

A is nitrogen or oxygen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

Aa is natural or the alpha-non-natural amino acid residue;

M is 0,1,2 or 3;

R ¹⁴Be hydrogen or protecting group;

R ¹⁵Be hydrogen, alkyl or aryl.

In another embodiment, the present invention includes the compositions that contains chemical compound shown in the formula VI-A or its drug acceptable salt:

Wherein:

N is 1,2,3,4,5,6,7,8,9 or 10;

A is oxygen or nitrogen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

R ¹⁹Be hydrogen, alkyl or aryl;

Y ¹Be oxygen, sulfur or nitrogen;

Y ²Be carbon, nitrogen or oxygen;

R ²⁰Be hydrogen, alkyl, amino, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl;

R ²¹Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl, benzimidazolyl, if perhaps Y ²Be oxygen, R then ²¹Do not exist;

R ²²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl, benzimidazolyl; If perhaps Y ¹Be nitrogen, R then ²²Be hydrogen, hydroxyl, alkoxyl or aryloxy group; If perhaps Y ¹Be oxygen or sulfur, then R ²²Do not exist; If perhaps Y ¹Be nitrogen, R then ²²And R ²¹Can be joined together to form annulus.

In another embodiment, the present invention includes the compositions that contains chemical compound shown in the formula VII-A and its drug acceptable salt:

Wherein:

N is 2,3 or 4;

A is oxygen or nitrogen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

G is direct key or oxygen, nitrogen or sulfur;

Z is 0,1,2,3,4 or 5;

M is 0 or 1;

R ²⁴Be selected from hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, aroyl, alkyl-carbonyl, aminoalkyl carbonyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl;

Each R ²⁵Independently be selected from hydrogen, halogen, cyano group, hydroxyl, alkoxyl, sulfydryl, amino, nitro, alkyl, aryl, carbocylic radical or heterocyclic radical.

Additional compounds comprises for example chemical compound and drug acceptable salt thereof, ester and prodrug shown in the formula I-B:

Wherein:

X is oxygen or nitrogen;

Z is C=O, S (O) ₂Perhaps P (O) OR ⁷

M and n independently are 0,1,2,3,4,5,6,7,8,9 or 10 separately;

R ¹And R ⁷Independently be separately hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, with X form natural or alpha-non-natural amino acid residue part or-(CH ₂) _p-Y;

Y is hydrogen or the heterocyclic moiety that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl;

P is 0,1,2,3 or 4;

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl;

R ³Be hydrogen, amino, cyano group, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, replacement or unsubstituted aryl, heteroaryl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl;

In going back an embodiment, m is 0,1 or 2.Going back in the embodiment again, n is 0,1 or 2.Going back in the embodiment R again ³Be aryl, for example heteroaryl or phenyl.In a further embodiment, Z is S (O) ₂

In another embodiment, The compounds of this invention is chemical compound shown in the formula II-B and drug acceptable salt, ester and prodrug:

Wherein:

Each R ⁴Independently be selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkyl, aryl, carbocylic radical or heterocyclic radical;

J be do not exist, oxygen, nitrogen, sulfur or bivalence bonding part, include but not limited to low-grade alkylidene, alkylidene oxygen base, alkylidene amino, alkylidene sulfenyl, alkylidene oxygen base alkyl, alkylidene amino alkyl, alkylidene alkylthio, thiazolinyl, thiazolinyl oxygen base, alkenyl amino or thiazolinyl sulfenyl;

Q is 1,2,3,4 or 5.

In going back another embodiment, The compounds of this invention is chemical compound shown in formula III-B and drug acceptable salt, ester and prodrug:

Wherein:

X is oxygen or nitrogen;

M and n independently are 0,1,2,3,4,5,6,7,8,9 or 10 separately;

Q is 1,2,3,4 or 5;

R ¹Be hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or with X form natural or alpha-non-natural amino acid residue part or-(CH ₂) _p-Y;

Y is hydrogen or the heterocyclic moiety that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl;

P is 0,1,2,3 or 4;

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl;

R ⁵Be selected from hydrogen, halogen, amino, nitro, hydroxyl, carbonyl, sulfydryl, carboxyl, alkyl, alkoxyl, alkoxy carbonyl, acyl group, alkyl amino, acyl amino;

Q is the integer that is selected from 1-5;

J be do not exist, oxygen, nitrogen, sulfur or bivalence bonding part, include but not limited to low-grade alkylidene, alkylidene oxygen base, alkylidene amino, alkylidene sulfenyl, alkylidene oxygen base alkyl, alkylidene amino alkyl, alkylidene alkylthio, thiazolinyl, thiazolinyl oxygen base, alkenyl amino or thiazolinyl sulfenyl.

In another embodiment, The compounds of this invention is;

In going back an embodiment, m is 0.

In another embodiment, the present invention relates to chemical compound shown in the formula V-B:

Wherein:

R ⁶Be that replace or unsubstituted heterocyclic moiety.

In going back an embodiment, m is 0 or 1.In another embodiment, n is 0 or 1.In going back another embodiment, R ⁶Be thiazolyl, oxazolyl, pyrazolyl, indyl, pyridine radicals, thiazinyl, thienyl, benzothienyl, glyoxalidine base, dihydro-thiazolyl, oxazolidinyl, thiazolidinyl, tetrahydro-pyrimidine base, Huo person's oxazinyl.In going back another embodiment, Z is S (O) ₂

The invention still further relates to chemical compound shown in the formula I-C (referring to WO 00/64,420):

R wherein ¹And R ²Independently be separately hydrogen atom or replacement or unsubstituted aliphatic group or aryl; Z and Q independently are carbonyl (C=O), thiocarbonyl (C=S), sulfonyl (SO separately ₂) or sulfoxide (S=O) group; K and m are 0 or 1, and condition is when k is 1, R ¹Not hydrogen atom, when m is 1, R ²It or not hydrogen atom.In one embodiment, at least one k or m must equal 1.Variable p and s independently are the positive integer through selecting separately, make at the bio distribution of the therapeutic compound of predetermined target site not interruptedly, keep the activity of therapeutic compound simultaneously again.T is linking group (as an alkylidene), and Y is formula SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺Shown in group; X wherein ⁺It is cation group; And the drug acceptable salt and the prodrug of this chemical compound.

In another embodiment of chemical compound shown in the formula I-C, R ¹Be alkyl, thiazolinyl or mono-cyclic aromatic group, wherein said alkyl can be replaced by hydroxyl; R ²Be alkyl, thiazolinyl, hydroxy alkyl, monocyclic aryl or hydrogen atom, perhaps R ¹And R ²The nitrogen that connects with their forms the heterocyclic radical of condensed ring structure; K and m are 0, and p and s are 1; T is an alkylidene; Y is SO ₃X, X are cation groups; And the acceptable salt of medicine and the prodrug of this chemical compound.

In another embodiment of chemical compound shown in the formula I-C, R ¹Be alkyl, thiazolinyl or aryl; R ²Be hydrogen atom, alkyl or aryl, perhaps R ¹And R ²Form the heterocyclic radical of condensed ring structure together; Z and Q independently are carbonyl (C=O), thiocarbonyl (C=S), sulfonyl (SO separately ₂) or sulfoxide (S=O) group; K is 1, and m is 0 or 1, and condition is when k is 1, R ¹Not hydrogen atom, when m is 1, R ²It or not hydrogen atom; P and s each naturally 1; T is an alkylidene; Y is SO ₃X, X are cation groups; And the drug acceptable salt of this chemical compound.

On the other hand, the R of chemical compound shown in the formula I-C ¹And R ²Can be alkyl, thiazolinyl or monocyclic aryl, perhaps R ¹And R ²The nitrogen that can connect with them is the heterocyclic radical of condensed ring structure; K and m are 0, and p and s are 1; T is an alkylidene; Y is SO ₃X, X are cation groups; And the drug acceptable salt and the prodrug of this chemical compound.

In another embodiment of chemical compound shown in the formula I-C, R ¹Be alkyl, thiazolinyl or monocyclic aryl, wherein said alkyl can be replaced by hydroxyl; R ²Be alkyl, thiazolinyl, monocyclic aryl or hydrogen atom, wherein said alkyl can be replaced by hydroxyl; Perhaps R ¹And R ²The nitrogen that connects with their forms the heterocyclic radical of condensed ring structure; K and m are 0, and p and s are 1; T is an alkylidene; Y is SO ₃X, X are cation groups; And the drug acceptable salt and the prodrug of this chemical compound.

In a further embodiment, the present invention relates to formula I-D chemical compound:

Wherein:

R ¹Be replace or unsubstituted cycloalkyl, heterocyclic radical, aryl, cycloalkyl aryl, bicyclo-or three rings, bicyclo-or three ring condensed ring group or replacement or unsubstituted C ₂-C ₁₀Alkyl;

R ²Be selected from hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl;

Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺

X ⁺Be hydrogen, cation group or one-tenth ester group;

L ¹And L ²Each that replace naturally or unsubstituted C ₁-C ₅Alkyl or do not exist, the perhaps acceptable salt of the medicine of this chemical compound, condition is to work as R ¹When being alkyl, L ¹Do not exist.

In a further embodiment, the present invention relates to formula II-D chemical compound:

Wherein:

R ¹Be replace or unsubstituted ring, bicyclo-, three ring or benzheterocycle base or replacement or unsubstituted C ₂-C ₁₀Alkyl;

R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl, benzimidazolyl or and R ¹Be connected to form heterocycle;

Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺

X ⁺Be hydrogen, cation group or one-tenth ester moiety;

M is 0 or 1;

N is 1,2,3 or 4;

L is that replace or unsubstituted C ₁-C ₃Alkyl or do not exist, the perhaps drug acceptable salt of this chemical compound, condition is to work as R ¹When being alkyl, L does not exist.

In going back an embodiment, R ²Be hydrogen.In going back another embodiment, R ¹Be straight chained alkyl, for example ethyl, n-pentyl, n-heptyl or n-octyl.In another embodiment, R ¹It is the tert-butyl group.In another optional embodiment, R ¹Be C ₇-C ₁₀Bicyclic alkyl or tricyclic alkyl, for example three ring [3.3.1.0 ^3,7] decyl (or claim adamantyl), bicyclo-[2.1.2] heptyl or indyl.In another embodiment, R ¹It is tetralyl.

In one embodiment, L ²Be-(CH ₂) ₃-.In another embodiment, L ²Be-(CH ₂) ₄-or-(CH ₂) ₅-.In going back an embodiment, L ²Be-(CH ₂) ₂-.In a further embodiment, L ²Be the alkyl that replaces, for example-CH ₂-(CHOH)-CH ₂-.

In another embodiment, L ¹Be CH ₂CH ₂Perhaps do not exist.

In going back an embodiment, R ¹Be branched alkyl, the tert-butyl group for example.In another embodiment, R ¹It is adamantyl.In another embodiment, R ¹Be cyclic alkyl, for example cyclopropyl, cyclohexyl, suberyl, ring octyl group etc.Cycloalkyl moiety can further be replaced by other alkyl or other groups that for example can allow molecule carry out its predetermined function.In another embodiment, R ¹By the alkyl of propargyl part (for example HC ≡ C-) replacement.In another embodiment, R ¹By the cyclohexyl of one or more methyl or propargyl replacement.

In other embodiments, L ¹Be C ₁-C ₂The alkyl linking group (for example-CH (CH ₃)-or-(CH ₂) ₂-).In going back an embodiment, R ¹It is phenyl.In certain embodiments, R ¹Replaced by methoxyl group.In other embodiments, L ¹Be C ₃, for example-(CH ₂) ₃-or C (CH ₃) ₂-.In certain embodiments, L ¹For example alkoxy, carboxyl (COOH), benzyl, acylamino-(C=O-NH-) or ester group (C=O-C-O) replace.In certain embodiments, ester group is methyl ester, ethyl ester, propyl ester, butyl ester, cyclohexyl or benzyl ester.In other embodiments, ester group can be the propylene ester.In other embodiments, L ¹By carboxyl substituted.In going back an embodiment, R ¹Substituted acylamino-replaces, and wherein said acylamino-is by alkyl, and for example methyl, ethyl, propyl group, butyl, amyl group or hexyl replace.In another embodiment, alkyl R ¹Quilt-C=O-NH-OH, C=O-NH ₂Perhaps acylamino-replaces.In certain embodiments, for example methyl, ethyl, propyl group, butyl, amyl group, hexyl, cyclohexyl, benzyl or aryl replace acylamino-by alkyl.In another embodiment, acylamino-quilt-CH (CH ₂) ₂Group replaces.R ¹Itself can be replaced by phenyl, perhaps can be side chain or straight chained alkyl.In certain embodiments, R ¹Also can partly be replaced by thioether.The example of thioether comprises S-Me, S-Et etc.In certain embodiments, alkyl R ¹Part is partly replaced by aryl or thioether part and acylamino-simultaneously.In other embodiments, alkyl R ¹Part can be replaced by thioether and carboxy moiety simultaneously.In other embodiments, alkyl R ¹Group is replaced by hydroxyl.R ¹Group, for example alkyl R ¹Group also can be replaced by thioether and hydroxyl simultaneously.In other embodiments, R ¹Group, for example alkyl R ¹Group is replaced by cyano group.Comprise-CN R partly ¹Examples of groups comprises-C (CH ₃) ₂CN, cyclohexyl of being replaced by one or more cyano group etc.

In other embodiments, alkyl R ¹Group is replaced by aryl.Aryl can for example be the phenyl that replaces.The phenyl that replaces can be by one or more for example substituent group replacement of hydroxyl, cyano group and alkoxyl.In other embodiments, alkyl R ¹Group is replaced by benzyl tetrazole radical or replacement or unsubstituted.

In going back an embodiment, L ¹Be-C (CH ₃) ₂-(CH ₂)-.In another embodiment, L ¹Be-(C (CH ₃) ₂-CHOH-.In another embodiment, L ¹Be-(C (CH ₃) ₂CH (OMe)-.In another embodiment, R ¹Be that replace or unsubstituted phenyl.In going back an embodiment, R ¹It is the phenyl of para-orientation.Substituent example includes but not limited to fluorine, chlorine, bromine, iodine, methyl, the tert-butyl group, alkoxyl, methoxyl group etc.In other embodiments, R ¹Be substituted in a position.Substituent example comprises methoxyl group, chlorine, methyl, the tert-butyl group, fluorine, alkyl, alkoxyl, iodine, trifluoroalkyl, methoxyl group etc.In another embodiment, L ¹It is the phenyl that is replaced by similar substituent group at the ortho position.In another embodiment, L ¹Comprise cycloalkyl moiety, for example cyclopenta.In another embodiment, L ¹Comprise alkylidene and optional substituted aryl, substituent group and above-mentioned substituent group are similar.

In certain embodiments, R ¹Be cyclopropyl or cyclohexyl.In certain embodiments, cyclopropyl or cyclohexyl are replaced by ether or alkyl.In some other embodiment, ether is the benzyl oxide group.

In another embodiment, R wherein ¹Be alkyl, it is replaced by the group of for example phenyl or hydroxyl.

In another embodiment, the present invention relates to chemical compound shown in formula III-D and drug acceptable salt thereof and ester:

Wherein:

A is nitrogen or oxygen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

R ³, R ^3a, R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aIndependently be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, cyano group, halogen, amino, tetrazole radical separately, perhaps two R groups on the adjacent loops atom form two keys with annular atoms, and condition is R ³, R ^3a, R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aOne of be the part shown in the formula III a-D:

Wherein:

M is 0,1,2,3 or 4;

R ^A, R ^B, R ^C, R ^DAnd R ^EIndependently be selected from hydrogen, halogen, hydroxyl, alkyl, alkoxyl, haloalkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, cyano group, thiazolyl, triazolyl, imidazole radicals, tetrazole radical, benzothiazolyl and benzimidazolyl; Condition is that this chemical compound is not 3-(4-phenyl-1,2,3,6-tetrahydrochysene-1-pyridine radicals)-1-propane sulfonic acid.In going back an embodiment, n is 2,3 or 4.

In another embodiment, R ¹¹It is salt-forming cation.The example of salt-forming cation comprises drug acceptable salt described herein and lithium, sodium, potassium, magnesium, calcium, barium, zinc, ferrum and ammonium.In another embodiment, R ¹¹Be into ester group.Become ester group comprise when in conjunction with the time can form the group of ester.That this examples of groups comprises replacement or unsubstituted alkyl, aryl, thiazolinyl, alkynyl or cycloalkyl.In another embodiment, A is an oxygen.

In another embodiment, R ³And R ⁴The carbon atom that connects with them forms two keys.In another embodiment, R ^A, R ^B, R ^C, R ^DAnd R ^EEach is hydrogen naturally.R ^A, R ^B, R ^DAnd R ^EEach is hydrogen naturally, R ^CBe halogen, as fluorine, chlorine, iodine or bromine.

In another embodiment, R ³Perhaps R ^5aIt is the part shown in the formula III a-D.

In another embodiment, R ⁴, R ⁵, R ⁶And R ⁷Each is hydrogen naturally.In going back an embodiment, R ^4a, R ^5a, R ^6aAnd R ^7aEach is hydrogen naturally.

In another embodiment, R ^3aBe hydroxyl, cyano group, acyl group or hydroxyl.

In going back an embodiment, R ¹¹With A be natural together or alpha-non-natural amino acid residue or its drug acceptable salt or ester.The example of amino acid residue comprises phenylalanine and leucic ester and salt.

In another embodiment, m is 0,1 or 3.

In another embodiment, the present invention relates to chemical compound shown in the formula IV-D and drug acceptable salt and ester:

Wherein:

A is nitrogen or oxygen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aIndependently be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, cyano group, halogen, amino, tetrazole radical separately, R ⁴And R ⁵The annular atoms that connects with them forms two key, perhaps R ⁶And R ⁷The annular atoms that connects with them forms two keys;

M is 0,1,2,3 or 4;

R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Independently be selected from hydrogen, halogen, hydroxyl, alkyl, alkoxyl, haloalkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, cyano group, thiazolyl, triazolyl, imidazole radicals, tetrazole radical, benzothiazolyl and benzimidazolyl.

In another embodiment, R ¹¹It is salt-forming cation.The example of salt-forming cation comprises drug acceptable salt described herein and lithium, sodium, potassium, magnesium, calcium, barium, zinc, ferrum and ammonium.In another embodiment, R ¹¹Be into ester group.Become ester group comprise when in conjunction with the time can form the group of ester.That this examples of groups comprises replacement or unsubstituted alkyl, aryl, thiazolinyl, alkynyl or cycloalkyl.In another embodiment, A is an oxygen.

In another embodiment, m is 0 or 1.In going back an embodiment, n is 2,3 or 4.In going back an embodiment, R ⁴, R ⁵, R ⁶And R ⁷Each is hydrogen naturally.R ^4a, R ^5a, R ^6aAnd R ^7aAlso can be hydrogen.R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Example comprise hydrogen.In other embodiments, R ⁸, R ⁹, R ¹¹And R ¹²Each is hydrogen naturally, R ¹⁰Be halogen (for example fluorine, chlorine, bromine or iodine), nitro or alkyl (for example methyl, ethyl, butyl).

In another embodiment, A-R ¹¹Can be amino acid residue, the residue of phenylalanine for example.In another embodiment, R ⁹, R ¹⁰, R ¹¹And R ¹²Each is hydrogen naturally, R ⁸Not being hydrogen, for example is halogen, for example fluorine, chlorine, bromine or iodine.

In another embodiment, the present invention relates to chemical compound shown in the formula V-D and drug acceptable salt and prodrug:

Wherein:

A is nitrogen or oxygen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

Aa is natural or the alpha-non-natural amino acid residue;

M is 0,1,2 or 3;

R ¹⁴Be hydrogen or protecting group;

R ¹⁵Be hydrogen, alkyl or aryl.

In another embodiment, R ¹¹It is salt-forming cation.The example of salt-forming cation comprises drug acceptable salt described herein and lithium, sodium, potassium, magnesium, calcium, barium, zinc, ferrum and ammonium.In another embodiment, R ¹¹Be into ester group.Become ester group comprise when in conjunction with the time can form the group of ester.That this examples of groups comprises replacement or unsubstituted alkyl, aryl, thiazolinyl, alkynyl or cycloalkyl.In another embodiment, A is an oxygen.

In one embodiment, n is 2,3 or 4.In certain embodiments, m is 0.In certain embodiments, A-R ¹¹Be natural amino acid residue or its salt or ester.The example of amino acid residue includes but not limited to acceptable salt of leucine or phenylalanine residue and medicine thereof and ester.The example of possible ester comprises methyl ester, ethyl ester and the tert-butyl ester.

In another embodiment, m is 1.The aa example comprises natural and the alpha-non-natural amino acid residue, as phenylalanine, glycine and leucine.

In another embodiment, (aa) _mIt is the phe-phe residue; And drug acceptable salt or suitable protecting group.

In certain embodiments, R ¹⁵Be the alkyl of hydrogen or replacement, for example aryl alkyl.

Term " alpha-non-natural amino acid " refers to any derivant of natural amino acid, comprises D type and α-and beta-aminoacid-derivatives.Notice that some is classified as the aminoacid of alpha-non-natural amino acid in this article, for example hydroxyproline can be found in some organism or the specified protein at occurring in nature.The aminoacid with many different protecting groups that is adapted at directly using in the solid phase synthesis of peptide can obtain by commercially available approach.Except that 20 kinds of modal natural amino acids, can use the following example (being common abbreviation in the bracket) of alpha-non-natural amino acid and amino acid derivativges by the present invention: Beta-alanine (β-ALA), γ-An Jidingsuan (GABA), 2-aminobutyric acid (2-Abu), α, β-dihydro-2-aminobutyric acid (8-AU), 1-amino-cyclopropane-1-formic acid (ACPC), aminoisobutyric acid (Aib), 2-amino-thiazolyl-quinoline-4-formic acid, 5-aminovaleric acid (5-Ava), 6-aminocaprolc acid (6-Ahx), 8-aminocaprylic acid (8-Aoc), the amino hendecanoic acid (11-Aun) of 11-, 12 amino dodecanoic acid (12-Ado), 2-amino benzoic Acid (2-Abz), 3-amino benzoic Acid (3-Abz), 4-amino benzoic Acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (Statine, Sta), amino oxygen guanidine-acetic acid (Aoa), 2-amino-naphthane-2-formic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), p-aminophenyl alanine (4-NH ₂-Phe), biphenyl alanine (Bip), to bromophenyl alanine (4-Br-Phe), Chloro-O-Phenyl alanine] (2-Cl-Phe), a chlorophenyl alanine (3-Cl-Phe), DL-3-alanine (4-Cl-Phe), m-chloro tyrosine (3-Cl-Tyr), to benzyl acyl group phenylalanine (Bpa), tert-butyl group glycine (TLG), Cyclohexylalanine (Cha), Cyclohexylglycine (Chg), 2; 3-diaminopropionic acid (Dpr), 2; 4-DAB (Dbu), 3; 4-Dichlorobenzene base alanine (3,4-Cl ₂-Phe), 3, and 4-difluorophenyl alanine (3,4-F ₂-Phe), iodogorgoic acid (3,5-I ₂-Tyr), adjacent fluorophenylalanine (2-F-Phe), between fluorophenylalanine (3-F-Phe), to fluorophenylalanine (4-F-Phe), between fluorine tyrosine (3-F-Tyr), homoserine (Hse), high phenylalanine (Hfe), high tyrosine (Htyr), 5-hydroxyryptophan (5-OH-Trp), hydroxyproline (Hyp), to iodophenyl alanine (4-I-Phe), Iotyrosine I 131 (3-I-Tyr), indoline-2-formic acid (Idc), different piperidine carboxylic acid (Inp), between methyl-tyrosine (3-Me-Tyr), 1-naphthyl alanine (1-Nal), 2-naphthyl alanine (2-Nal), p-nitrophenyl alanine (4-NO ₂-Phe), 3-nitrotyrosine (3-NO ₂-Tyr), nor-leucine (Nle), norvaline (Nva), ornithine (Orn), adjacent phosphotyrosine (H ₂PO ₃-Tyr), octahydro indole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenyl group alanine (F ₅-Phe), phenylglycine (Phg), pipecolinic acid (Pip), PGIY (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-formic acid (Tic) and Thiazolidine-4-formic acid (Thioproline, Th).In addition, also can use N-alkylation aminoacid, and have the aminoacid (amine wherein is by acidylate or alkylation) that contains amine side chain (as Lys and Orn).

In another embodiment, the present invention relates to chemical compound shown in the formula VI-D or its drug acceptable salt at least on part:

Wherein:

N is 1,2,3,4,5,6,7,8,9 or 10;

A is oxygen or nitrogen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

R ¹⁹Be hydrogen, alkyl or aryl;

Y ¹Be oxygen, sulfur or nitrogen;

Y ²Be carbon, nitrogen or oxygen;

R ²⁰Be hydrogen, alkyl, amino, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl;

R ²¹Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl, benzimidazolyl, if perhaps Y ²Be oxygen, R then ²¹Do not exist;

R ²²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl, benzimidazolyl; If perhaps Y ¹Be nitrogen, R ²²Be hydrogen, hydroxyl, alkoxyl or aryloxy group; If perhaps Y ¹Be oxygen or sulfur, R ²²Do not exist; If perhaps Y ¹Be nitrogen, R ²²And R ²¹Can be joined together to form annulus;

R ²³Be hydrogen, alkyl, amino, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl, if perhaps Y ²Be nitrogen or oxygen, then R ²³Do not exist.

In another embodiment, R ¹¹It is salt-forming cation.The example of salt-forming cation comprises drug acceptable salt described herein and lithium, sodium, potassium, magnesium, calcium, barium, zinc, ferrum and ammonium.In going back an embodiment, described salt is sodium salt.In going back an embodiment, A is an oxygen.

In another embodiment, Y ¹Be oxygen or sulfur, R ²²Do not exist.

In another embodiment, Y ¹Be oxygen, R ²¹Do not exist.R ²⁰Example comprise benzyl, aryl (for example phenyl), alkyl, cycloalkyl (for example adamantyl) etc.In other embodiments, Y ²Be nitrogen, R ²¹Be hydrogen.In other embodiments, R ²¹It is benzyl.In going back an embodiment, R ²⁰And R ²¹Be joined together to form pyridine ring.In another embodiment, Y ¹Be sulfur.

In another embodiment, the present invention relates to chemical compound and drug acceptable salt thereof shown in the formula VII-D at least on part:

Wherein:

N is 2,3 or 4;

A is oxygen or nitrogen;

R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester;

Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl;

X is 0,1,2,3 or 4;

G is direct key or oxygen, nitrogen or sulfur;

Z is 0,1,2,3,4 or 5;

M is 0 or 1;

R ²⁴Be selected from hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, aroyl, alkyl-carbonyl, aminoalkyl carbonyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl;

Each R ²⁵Independently be selected from hydrogen, halogen, cyano group, hydroxyl, alkoxyl, sulfydryl, amino, nitro, alkyl, aryl, carbocylic radical or heterocyclic radical.

In one embodiment, R ¹¹Be hydrogen.In another embodiment, A is an oxygen.For example, n can be 3, and m can be 1.In other embodiments, R ²⁴Be hydrogen or benzyl.

In certain embodiments, z is 0,2 or 3.In other embodiments, R ²⁵Be hydroxyl or alkoxyl, for example methoxyl group, ethyoxyl etc.In certain embodiments, two or more R ²⁵Substituent group can be joined together to form condensed ring (for example forming the methylenedioxyphenyl part).

The present invention relates to the salt form and the acid/alkali form of The compounds of this invention.For example, the present invention not only relates to herein the concrete salt form of the chemical compound of representing with salt, and the present invention also comprises the acceptable salt of other drug and the acid and/or the alkali form of described chemical compound.The invention still further relates to the salt form of chemical compound shown in this paper.

The exemplary compounds of any formula (for example formula I-D to VII-D) that Exemplary The compounds of this invention also shows in this paper accompanying drawing. this paper enumerates and concrete group thereof and subset belong to a part of the present invention; Be the U.S. Patent application of " Methods andCompositions for Treating Amyloid Related Diseases " " method and composition for the treatment of diseases associated with amyloid protein " (attorney docket NBI-162A and NBI-162B) and the title submitted on June 18th, 2004 provides for the U.S. Patent application of " Methods andCompositions for the Treatment of Amyloid-and Epileptogenesis-Associated Diseases " " method and composition for the treatment of amyloid and epilepsy generation relevant disease " (attorney docket NBI-163) by two titles submitting on June 18th, 2004, described patent application clearly is attached to herein by reference.

In one embodiment, the present invention does not relate to the chemical compound of describing among WO 00/64420, WO 97/023458 and the WO 96/28187.In one embodiment, the present invention does not relate to the disease described in these three patents of compounds for treating of describing among WO 00/64420, WO 97/023458 and the WO 96/28187 or the method for the patient's condition used.In going back an embodiment, the chemical compound that the present invention relates to describe among WO 00/64420, WO 97/023458 and the WO 96/28187 is used for the method for method described in the application, and the method for describing in the present patent application is not described in WO 00/64420, WO 97/023458 and WO 96/28187.In addition, WO 00/64420, WO 97/023458 and WO 96/28187 by reference integral body be attached to herein.

In general, The compounds of this invention can be by in general reaction process, and the method for illustrating in the reaction process of describing hereinafter for example perhaps by the improving one's methods of described method, uses the raw material, reagent and the conventional synthesis program that obtain easily to prepare.In these reactions, also might utilize the variation known but that this paper does not mention of itself behaving.Compound functions described herein and equivalent structures with identical general aspects, wherein substituent one or more simple changes can not have a negative impact to the fundamental property or the effectiveness of chemical compound.Can easily prepare The compounds of this invention according to synthesis flow described herein and scheme (it is illustrated) in specific procedure provided herein.But, those of skill in the art will recognize that and also can use other route of synthesis that can produce The compounds of this invention, following content just by way of example mode provide, be not limitation of the present invention.Referring to for example " the Comprehensive Organic Transformations " of R.Larock work, VCH Publishers (1989).Also to further recognize, can adopt the various standard protections and the deprotection strategy (referring to " the Protective Groups in Organic Synthesis " of for example Greene and Wuts work) of this area.Those skilled in the relevant art will appreciate that, the selection of any concrete protecting group (for example amine and carboxyl-protecting group) must be decided by the stability of protected part in reaction condition subsequently, and they will appreciate that suitable selection result.Following example in a large amount of Chemistry Literatures further illustrates " the Chemistryof the amino Acids " of those skilled in the art's knowledge: J.P.Greenstein and M.Winitz work, John Wiley ﹠amp; Sons, Inc., New York (1961); " the Comprehensive Organic Transformations " of R.Larock work, VCHPublishers (1989); T.D.Ocain etc., J.Med.Chem.31,2193-99 (1988); E.M.Gordon etc., J.Med.Chem.31,2199-10 (1988); " the Practice of Peptide Synthesis " of M.Bodansky and A.Bodanszky work, Springer-Verlag, NewYork (1984); " Protective Groups in OrganicSynthesis " (1991) of T.Greene and P.Wuts work; " the AsymmetricSynthesis:Construction of Chiral Molecules Using amino Acids " of G.M.Coppola and H.F.Schuster work, JohnWiley ﹠amp; Sons, Inc., New York (1987); " the The ChemicalSynthesis of Peptides " of J.Jones work, Oxford University Press, New York (1991); And " the Introduction of Peptide Chemistry " of P.D.Bailey work, John Wiley ﹠amp; Sons, Inc., New York (1992).

Chemical constitution is herein drawn according to usual standard well known in the art.Therefore, when as if certain atom such as carbon atom painted to such an extent that have not enough quantivalence, suppose that so this quantivalence is satisfied by hydrogen atom, although this hydrogen atom needn't clearly be drawn.The structure of chemical compounds more of the present invention comprises chiral carbon atom.Should be understood that the isomer (for example all enantiomers and diastereomer) that produces owing to this unsymmetry comprises within the scope of the invention, unless otherwise.That is to say that unless otherwise prescribed, (R)-or (S)-three-dimensional chemical configuration can be taked in any chiral carbon center.Can obtain the described isomer of substantially pure by classical isolation technics and synthetic by spatial chemistry control.In addition, under suitable situation, alkene can comprise E-or Z-geometry.In addition, The compounds of this invention can non-solvent compound form exists, and exists as the solvate form thereof with acceptable solvent such as water, THF, ethanol etc.For purpose of the present invention, generally solvate form thereof is thought to be equal to the non-solvent compound.

Should be understood that, any application of compound that application is described described in this paper or " related application " joint falls within the scope of the present invention, mean by the present invention and contain, at least clearly be attached to herein for these purposes, and clearly be attached to herein for every other purpose.

In one embodiment, protein aggregation disorders can be a Pick's disease, the degeneration of cortex basal nuclei, benumb on the carrying out property nuclear, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, parkinson (PD), Huntington's disease (HD), dystrophia myotonica, the Louis body atrophy of dentate nucleus rubrum pallidum, the Fu Lidelixishi ataxia, fragile X syndrome, fragile X E brain development is slow, spinal cord oblongata muscular atrophy, Wilson's disease, and spinocebellar ataxia 1 type (SCA1), spinocebellar ataxia 2 types (SCA2), Ma-Yue disease (MJD or SCA3), spinocebellar ataxia 6 types (SCA6), spinocebellar ataxia 7 types (SCA7), spinocebellar ataxia 17 types (SCA17), chronic hepatopathy, cataract, silk presses down the albumen disease, hemolytic anemia, Cystic fibrosis, neurofibromatosis 2 types, the demyelinating peripheral neuropathy, retinitis pigmentosa, Marfan syndrome, edema due to disorder of QI, idiopathic pulmonary fibrosis, argyrophilic grain dementia, the degeneration of cortex basal nuclei, diffusivity neurofibrillary tangles companion calcification disease, frontotemporal dementia FTD/the parkinson's syndrome related with chromosome 17, Ha-Si disease, C type Ni-Pi disease or subacute sclerosing panencephalitis.

In one embodiment, protein aggregation disorders is the alpha-synapse nucleoprotein disease.In preferred embodiments, protein aggregation disorders is parkinson, Xi-De syndrome, nerve orthostatic hypotension, Xi-Mai-De syndrome or parkinson supraposition syndrome.

In another embodiment, protein aggregation disorders is the tau protein disease, and condition is that described tau protein disease is not Alzheimer, prion disease or cerebral amyloid angiopathy.

In preferred embodiments, the tau protein disease is to benumb or subacute sclerosing panencephalitis on amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, argyrophilic grain dementia, DLBD, the degeneration of cortex basal nuclei, diffusivity neurofibrillary tangles companion calcification disease, the frontotemporal dementia FTD/parkinson's syndrome related with chromosome 17, Ha-Si disease, multiple system atrophy, C type Ni-Pi disease, Pick's disease, the carrying out property nuclear.

The present invention relates to treat, prevent or regulate the protein aggregation disorders that do not belong to amyloid disease or the method for protein sickness.One aspect of the present invention relates to be treated, prevents or regulate because the protein aggregation disorders that familial sudden change causes in the gene order or the method for protein sickness, for example following non-limiting disease example: familial parkinson (wherein for example alpha-synapse nucleoprotein, handkerchief gold albumen and COOH-terminal hydrolase-l 1 can form harmful protein aggregate); Dystrophia myotonica (for example wherein forming the detrimental protein aggregation of dystrophia myotonica protein kinase (DMPK)); Dentate nucleus rubrum pallidum Louis body atrophy (DRPLA) (detrimental protein that the DRPLA gene for example wherein occurs is assembled); Fu Lidelixishi ataxia (for example wherein forming the detrimental protein aggregation of ataxia albumen (FRDA) gene that not helps); Sudden change in the androgen receptor (AR) (wherein for example forming the detrimental protein aggregation in the spinal cord oblongata muscular atrophy) (also claiming Kennedy's disease); Spinocebellar ataxia is caused by the sudden change in the SCA1 gene for example; Huntington's disease (HD) causes by suddenling change in Huntington protein that for example causes forming harmful protein aggregate or IT 15 genes; The disease of similar Huntington's disease is caused by the sudden change that for example connects in protein-3 (JPH3/HDL2) or the TBP gene; Familial encephalopathia companion neurofilament presses down albumen inclusion body (FENIB), is pressed down to suddenly change in the protein gene by the neurofilament that for example causes forming harmful protein aggregate and causes; Perhaps amyotrophic lateral sclerosis (ALS) wherein for example causes forming in the SOD1 gene that is harmful to protein aggregate and suddenlys change; Wherein said disease is not an amyloid disease.

In one embodiment of the invention, the detrimental protein aggregation gather or oligomerization may be relevant with spy's property the sent out sudden change in the gene order, perhaps sporadic generation, as in following non-limiting disease example: amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, wherein tau protein is assembled, and forms harmful protein aggregate.One aspect of the present invention relates to treatment, the special protein aggregation disorders of property generation or the method for protein sickness sent out of prevention or adjusting, described disease for example below: parkinson (PD), diffusivity Lewy corpusculum dementia (DLBD), multiple system atrophy (MSA), dystrophia myotonica, dentate nucleus rubrum pallidum Louis body atrophy (DRPLA), the Fu Lidelixishi ataxia, fragile X syndrome, fragile X E brain development is slow, Ma-Yue disease, spinal cord oblongata muscular atrophy (also claiming Kennedy's disease), spinocebellar ataxia, Huntington's disease (HD), familial encephalopathia companion neurofilament presses down albumen inclusion body (FENIB), Pick's disease, cortex basal nuclei degeneration (CBD), paralysis (PSP) on the carrying out property nuclear, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, amyotrophic lateral sclerosis (ALS), cataract or Wilson's disease, wherein said disease are not amyloid diseases.

The invention still further relates to the method for regulating the detrimental protein aggregation, condition is that the amyloid disease of described protein aggregate and this paper definition is irrelevant, described method comprises the detrimental protein aggregation is contacted with the The compounds of this invention of effective dose, and the detrimental protein aggregation is regulated.

In one embodiment of the invention, the detrimental protein aggregation is relevant with the misfolding of mature protein.

In another embodiment, the detrimental protein aggregation is the outer aggregations of born of the same parents.

In another embodiment, the detrimental protein aggregation is an aggregation in the born of the same parents.

In another embodiment, the detrimental protein aggregation is the kytoplasm aggregation.

In one embodiment, the detrimental protein aggregation is the nuclear aggregation.

In another embodiment, the detrimental protein aggregation is an aggregation in the film.

In another embodiment, the detrimental protein aggregation is relevant with aggregation.

In another embodiment, the detrimental protein aggregation is relevant with proteinic incorrect degraded.

In another embodiment, the detrimental protein aggregation is in endoplasmic reticulum.

In one embodiment, the detrimental protein aggregation is in Golgi body reverse side network.

In one embodiment, the detrimental protein aggregation is relevant with the misfolded proteins matter of escaping ubiquitin-proteasome system.

In another embodiment, by improving the degraded of detrimental protein aggregation, make described protein aggregate adjusted.

In another embodiment, the detrimental protein aggregation is suppressed.

In another embodiment,, make described protein aggregate adjusted by increasing the clearance rate of detrimental protein aggregation.

In another embodiment, the detrimental protein aggregation is relevant with following situation: incorrect posttranscriptional modification, incorrect post translational modification, escape ubiquitin-proteasome system (this causes forming inclusion body, aggregation, aggregation, protein precipitation, soluble aggregation) or above every any combination owing to for example lacking mature protein misfolding, proteinic incorrect degraded, the protein that suitable chaperone causes.

In another embodiment, the detrimental protein aggregation is relevant with fibril, beta sheet or hydrophobic domains.

" treatment " used herein certain object comprises and therapeutic compound is applied to or gives object, perhaps therapeutic compound is applied to or gives the cell or the tissue of object, described object suffers from disease or disease, has the symptom of disease or disease or the disease of taking a disease is arranged or the danger of disease (easily being attacked by a disease in other words or disease), its objective is treatment, cures, alleviates, removes, changes, corrects, improves, improves or influence the danger (perhaps susceptibility) of symptom or the disease or the disease of disease or disease, disease or disease.

Term " object " comprises the live organism that protein aggregation disorders wherein can take place.The example of object comprises the mankind, monkey, cattle, sheep, goat, Canis familiaris L., cat, mice, rat and their genetically modified organism.Can use known program, accumulative dosage of detrimental protein and interval in the effectively controlled plant that further describes by this paper give object to be treated with the present composition.Therapeutic compound realizes that therapeutic effect required " effective dose " can change according to following factor: the sedimentary proteinic amount in clinical site in the object, the age of object, sex and body weight, and the accumulative ability of the detrimental protein in the therapeutic compound controlled plant.Can adjust dosage regimen, so that best therapeutic response to be provided.For example, but give several divided doses every day, the emergency of perhaps looking treatment reduces dosage in proportion.

In certain embodiments of the invention, object need be accepted the treatment of the inventive method, selects treatment according to this needs.Need the well known in the art of treatment to liking, comprise and identify to suffer from protein aggregation disorders diseases associated or disease, have the symptom of described disease or disease or the danger of suffering from described disease or disease is arranged, and will benefit from the object of treatment (for example treating, cure, prevent, alleviate, remove, change, correct, improve, improve or influence the danger of symptom or the disease or the disease of disease or disease, disease or disease) according to diagnosis (as medical diagnosis) expection.

Term " adjusting " means to be contained prevention or stops the gathering of detrimental protein or gather, suppress or the further gathering that just develops detrimental protein in the protein aggregation disorders object of (protein aggregate for example having occurred) and reduce, reverse or promote to remove detrimental protein aggregation in the object that is just developing protein aggregation disorders of slowing down.The accumulative adjusting situation of detrimental protein by with treatment target not relatively, perhaps by be subjected to relatively to come to determine before the treatment target treatment, perhaps for example determine by measurable improvement situation clinically, as in patient's case of suffering from parkinson for example or synucleinopathies, stabilisation that described improvement situation is a cognitive function or cognitive function further go down prevents (promptly prevent, slow down or stop disease progression).Term " adjusting " means to be contained the accumulative inhibition of detrimental protein (as giving a definition) and promotes two aspects.Therefore, term " adjusting " means contains 1) detrimental protein assembles or the prevention gathered or stop, just developing the further accumulative inhibition of detrimental protein in the protein aggregation disorders object of (protein aggregate for example having occurred) or slow down and just developing accumulative minimizing of detrimental protein or reverse in the object of protein aggregation disorders, and 2) promote detrimental protein and assemble, for example improve in the body or accumulative speed of external detrimental protein or quantity.Promote the animal model that the accumulative chemical compound of detrimental protein can be used for protein aggregation disorders, for example can be used for making the detrimental protein in the animal to assemble and can occur within a short period of time, perhaps being used in increases the detrimental protein gathering in seclected time.The accumulative chemical compound of enhancement detrimental protein can be used for suppressing the screening test of the accumulative chemical compound of detrimental protein in the body, for example in the accumulative animal model of detrimental protein, test cell line and in vitro tests.This chemical compound can for example be used to provide faster or more sensitive screening compound test.In some cases, also can promote the accumulative chemical compound of detrimental protein, for example to promote the accumulative deposition of detrimental protein for therapeutic purposes.The accumulative adjusting situation of detrimental protein by with treatment target not relatively, perhaps by be subjected to relatively to come to determine before the treatment target treatment.

Detrimental protein accumulative " inhibition " comprises the prevention that aggregation forms or stops, suffering from the inhibition of amyloid further precipitation in the amyloidosis object of (protein aggregate for example having occurred) or slow down and reduce or reverse protein aggregation disorders or deposit in the object that just develops protein aggregation disorders.The accumulative inhibition situation of detrimental protein by with treatment target not relatively, perhaps by be subjected to relatively to come to determine before the treatment target treatment, perhaps for example determine by measurable improvement situation clinically, as in patient's case of suffering from parkinson for example or synucleinopathies, stabilisation that described improvement situation is a cognitive function or cognitive function further go down prevents (promptly prevent, slow down or stop disease progression).

The present invention further provides the method for regulating the cytotoxicity relevant with the detrimental protein aggregation (preferably neurotoxicity), described method comprises the detrimental protein aggregation is contacted with the The compounds of this invention of effective dose, makes cytotoxicity be regulated.In a preferred embodiment, cytotoxicity is relevant with inclusion body.In another preferred embodiment, cytotoxicity is regulated in neuronal cell or glial cell.

The present invention also provides treatment or object of prevention (preferred mammal, more preferably human) in the method for the neurofibrillary tangles relevant with tau protein, described method comprises the The compounds of this invention that gives the object effective dose, the neurofibrillary tangles relevant with tau protein obtained medical treatment or prevents.In another embodiment, the present invention relates to controlled plant (preferred mammal, more preferably human) in the method for the neurofibrillary tangles relevant with tau protein, described method comprises the The compounds of this invention that gives the object effective dose, and the neurofibrillary tangles relevant with tau protein regulated.

The invention provides treatment or object of prevention (preferred mammal, more preferably human) in contain the method for the pulsating inclusion body of alpha-synapse nucleoprotein NAC, described method comprises the The compounds of this invention that gives the object effective dose, makes to contain the pulsating inclusion body of alpha-synapse nucleoprotein NAC and obtain medical treatment or prevent.In another embodiment, the present invention relates to controlled plant (preferred mammal, more preferably human) in contain the method for the pulsating inclusion body of alpha-synapse nucleoprotein NAC, described method comprises the The compounds of this invention that gives the object effective dose, makes to contain the pulsating inclusion body of alpha-synapse nucleoprotein NAC and regulated.

In another embodiment, the detrimental protein aggregation is relevant with one of following protein or segment: alpha-synapse nucleoprotein, tau protein, NAC, Huntington protein, DRPLA, neurolemmal cell tumor albumen, cytokeratin, myelin protein 22, rhodopsin, atrophy albumen-1, fibrillin-1, ataxia albumen-1, ataxia albumen-2, ataxia protein-3, ataxia albumen-6, ataxia protein-17, androgen receptor, surfactant protein-C or alpha1-antitrypsin.

The compounds of this invention treatability or prophylactically give, with treatment and following situation diseases associated: the accumulative formation of detrimental protein, detrimental protein aggregation develop into aggregation or the detrimental protein aggregation is deposited as inclusion body such as Lewy corpusculum.The compounds of this invention can be before the protein that forms aggregation be forgiven protein aggregate or protein when becoming an aggregation part in conjunction with this protein, perhaps can be in conjunction with aggregation itself.The compounds of this invention also can prevent that its conformation from becoming the form that can form harmful aggregation in conjunction with the protein of native form.The compounds of this invention can adopt following any mechanism (be intended to describe in this mechanism of enumerating, rather than limit) to work, to improve the process of protein aggregation disorders: the formation or the deposition velocity of the detrimental protein aggregation that slows down; Alleviate the deposition degree of detrimental protein aggregation; Suppress, reduce or prevent the fibriilar formation of detrimental protein aggregation; Neural degeneration or the cytotoxicity that causes assembled in inhibition by detrimental protein; The inflammation that inhibition is caused by the detrimental protein aggregation; Perhaps promote the removing of detrimental protein aggregation from brain.

The compounds of this invention can use separately, perhaps unites use with second kind of chemical compound.Described chemical compound can be any chemical compound or the material useful to object known in this field.Described second kind of chemical compound can be any chemical compound that can treat, prevent or alleviate the symptom of protein aggregation disorders (for example parkinson) known in this field.In addition, described second kind of chemical compound can be any chemical compound useful to object when giving with the The compounds of this invention combination, for example neuroprotective chemical compound.Second kind of chemical compound of term " combination gives " comprises following implication: give The compounds of this invention and second kind of chemical compound jointly; At first give The compounds of this invention, give second kind of chemical compound then; At first give second kind of chemical compound, give The compounds of this invention then.

The compounds of this invention enters (after penetrating blood brain barrier) behind the brain, perhaps from the peripheral part effect, can effectively control the deposition of detrimental protein aggregation.When chemical compound is done the time spent from peripheral part, its can Change Example such as brain and blood plasma between the alpha-synapse nucleoprotein balance, discharge from brain thereby help alpha-synapse nucleoprotein.Alpha-synapse nucleoprotein is discharged increase from brain, can cause alpha-synapse nucleoprotein concentration reduction in the brain, therefore helps reducing the deposition of alpha-synapse nucleoprotein in aggregation or Lewy corpusculum.Perhaps, the chemical compound that is penetrated in the brain can for example by it being maintained non-fibers form or promoting it to remove, be controlled deposition by directly acting on the brain alpha-synapse nucleoprotein from brain.

Object and patient colony

Term " object " is as described herein, comprises the live organism that amyloidosis wherein can take place or suffer from protein aggregation disorders easily.The example of object comprises the mankind, chicken, duck, Beijing duck, goose, monkey, cattle, rabbit, sheep, goat, Canis familiaris L., cat, mice, rat and their genetically modified organism.Can use known method, detrimental protein is assembled or aggregation causes toxic dosage and interval in the effective controlled plant that further describes by this paper, gives object to be treated with the present composition.Therapeutic compound realizes that the required effective dose of therapeutic effect can change according to following factor: the amount of the sedimentary detrimental protein aggregation in clinical site in the object, object age, sex and body weight, and the accumulative ability of detrimental protein in the therapeutic compound controlled plant.Can adjust dosage regimen, so that best therapeutic response to be provided.For example, but give several divided doses every day, the emergency of perhaps looking treatment reduces dosage in proportion.

In illustrative aspects of the present invention, to liking the people.For example, to as if people more than 30 years old, the people more than 40 years old, the people more than 50 years old, the people more than 60 years old, the people more than 70 years old, the people more than 80 years old, people, people more than 90 years old or the people more than 95 years old more than 85 years old.Object can be the woman, comprises woman after the menopause that can just accept hormone (estrogen) alternative medicine.Object also can be the man.In another embodiment, object is lower than 40 years old.

Object can be the people that the danger of suffering from protein aggregation disorders is arranged, and for example the age is more than 40 years old or the people who tends to suffer from protein aggregation disorders.The protein aggregation disorders predisposing factor of confirming in scientific literature or proposing comprises: make object tend to suffer from the genotype of protein aggregation disorders; Make object tend to suffer from the environmental factors of protein aggregation disorders; Make object tend to suffer from the virus or the bacterial factor infection history of past illness of protein aggregation disorders; And make object tend to blood vessel factor of suffering from protein aggregation disorders etc.Object also can have the risk factor of one or more cardiovascular disease (coronary atherosclerosis, angina pectoris and myocardial infarction) or cerebrovascular disease (the outer arteriosclerosis of intracranial or cranium, apoplexy, faintness and of short duration ischemic episode), as hypercholesterolemia, hypertension, diabetes, smoking, coronary artery disease, cerebrovascular disease and cardiovascular disease family history or history of past illness.Hypercholesterolemia is normally defined total cholesterol density of serum greater than about 5.2mmol/L (about 200mg/dL).

The inventive method can be used for following one or more aspect: prevention protein aggregation disorders, the generation of treatment protein aggregation disorders, the symptom of improving protein aggregation disorders or adjusting detrimental protein aggregation.In one embodiment, the people has the family history of protein aggregation disorders or dementia.

In another embodiment, people's age is about 40 years old at least.In another embodiment, people's age is about 60 years old at least.In another embodiment, people's age is about 70 years old at least.In another embodiment, people's age is about 80 years old at least.In another embodiment, people's age is about 85 years old at least.In one embodiment, people's age is between about 60 years old to about 100 years old.

In going back an embodiment, diagnostic brain image technology display object has ill danger, and described technology is for example measured the technology of cerebral activity, albuminous plasue deposition (for example detrimental protein gathering) or brain atrophy.

In going back an embodiment, cognitive test display object has ill danger, for example clinical dementia classification of described test (" CDR ") or simple intelligent status checkout (" MMSE ").The contrast in the past that object is suitable with age and education background is compared, score subaverage in the understanding test.And object can show with the score of participating in identical or similar cognitive test in the past and compared, and score descends.

When determining CDR, with reference to each of following six kinds of cognitions and behavior kind object is assessed usually and graded: memory, orientation force, judgement and problem-solving ability, social communication, family and hobby, and personal nursing.Described assessment can comprise the information in the past that object provides, and perhaps preferably includes to be familiar with this object witness really.With reference to above-mentioned each object assessed and graded, determine rating result (0,0.5,1.0,2.0 or 3.0) substantially.Can think normal for 0 grade.1.0 can thinking, level is equivalent to slight dementia.CDR is that 0.5 grade object has following feature: slight persistence is forgetful, past event is partly recalled and " optimum " is forgetful.In one embodiment, object through assess its CDR grading more than 0 grade, about more than 0.5 grade, about more than 1.0 grades, about more than 1.5 grades, about more than 2.0 grades, about more than 2.5 grades or be about 3.0 grades.

Another kind of test be Folstein at " Mini-mental state.A practical method forgrading the cognitive state of patients for the clinician. " J.Psychiatr.Res.12:189-198, the simple intelligent status checkout of describing in 1975 (MMSE).Whether the MMSE assessment exists overall intellectual deterioration.Also can be referring to Folstein " Differential diagnosis ofdementia.The clinical process. " Psychiatr Clin North Am.20:45-57,1997.MMSE is a kind of means of assessing dementia onset and overall intellectual deterioration existence.MMSE marks by the 0-30 branch.MMSE does not resemble and assesses the basic cognitive potentiality for example so-called IQ test.On the contrary, its test is intellectual skill.The people of " normally " mental capacity must be divided into " 30 minutes " (still, MMSE must be divided into 30 minutes people score also may be far below " normally " in IQ test) in the MMSE objective examination.Referring to for example Kaufer, J.Neuropsychiatry Clin.Neurosci.10:55-63,1998; Becke, Alzheimer DisAssoc Disord.12:54-57,1998; Ellis, Arch.Neurol.55:360-365,1998; Magni, Int.Psychogeriatr.8:127-134,1996; Monsch, Acta Neurol.Scand.92:145-150,1995.In one embodiment, object has at least a score to be lower than 30 fens in the MMSE test.In another embodiment, the object score is lower than about 28 minutes, is lower than about 26 minutes, is lower than about 24 minutes, is lower than about 22 minutes, is lower than about 20 minutes, is lower than about 18 minutes, is lower than about 16 minutes, is lower than about 14 minutes, is lower than about 12 minutes, is lower than about 10 minutes, is lower than about 8 minutes, is lower than about 6 minutes, is lower than about 4 minutes, is lower than about 2 minutes or is lower than about 1 minute.

In another embodiment, object does not show the protein aggregation disorders symptom.In another embodiment, to as if the age at least at 40 years old and do not show the people of protein aggregation disorders symptom.In another embodiment, to as if the age at least at 40 years old and show the people of one or more protein aggregation disorders symptoms.

The inventive method can be used as Therapeutic Method, is used to suffer from the object of protein aggregation disorders, and perhaps the inventive method can be used as prevention method, is used to have the object of suffering from protein aggregation disorders or dementia tendency (for example genome undergo mutation object).

Should be understood that by any numerical value provided herein and scope (for example aspect object crowd age, dosage and the blood levels), all numerical value and scope that these numerical value and scope are contained are forgiven within the scope of the invention anyplace.And all numerical value between these numerical value and the scope also can be the upper limit or the lower limits of scope.

Pharmaceutical preparation

In another embodiment, the present invention relates to be used for the treatment of the pharmaceutical composition that comprises chemical compound shown in any formula of this paper of protein aggregation disorders, and the method for preparing this pharmaceutical composition.

In general, The compounds of this invention can be by the method that illustrates in general reaction process, the method of illustrating in patent that this paper mentions and patent application for example perhaps by the improving one's methods of described method, uses the raw material, reagent and the conventional synthetic method that obtain easily to prepare.In these reactions, also might utilize the variation known but that this paper does not mention of itself behaving.Comprise compound functions described herein and equivalent structures with identical general aspects, wherein substituent one or more simple changes can not have a negative impact to the fundamental property or the effectiveness of chemical compound yet.

Medicine of the present invention can provide with the solution form that is dissolved in appropriate solvent or with solvent-free form (for example lyophilizing).In another aspect of this invention, the medicine and the buffer that are used to carry out the inventive method can be packaged into medicine box, the optional container that comprises.Medicine box can be used for carry out commerce according to method described herein, can comprise the operation instructions of the inventive method.The medicine box complementary element can comprise acid, alkali, buffer agent, inorganic salt, solvent, antioxidant, antiseptic or metal-chelator.The medicine box complementary element is with the form of pure compositions, perhaps exists with the aqueous solution that mixes one or more medicine box complementary elements or the form of organic solution.The optional buffer that further comprises of any or all medicine box complementary elements.

Term " container " comprises any storage that is used to load the treatment preparation.For example, in one embodiment, container is the packing material that comprises preparation.In another embodiment, container is not the packing material that comprises preparation, that is to say, container is the storage of box or bottle and so on for example, and it comprises the operation instructions of packaged preparation or unpackaged preparation and preparation.In addition, packing technique is known in the art.Should be understood that the operation instructions of treatment preparation can comprise on the packing material for the treatment of preparation, like this, the functional relationship of description and packaging product strengthens.

The treatment chemical compound also can be outer by gastrointestinal tract, administration in the intraperitoneal, spinal column or in the brain.Dispersant can prepare at glycerol, liquid macrogol and their mixture and in oil.Under common storage and service condition, these preparations can comprise antiseptic, to prevent microbial growth.

For giving therapeutic compound by the approach beyond the gastrointestinal tract external administration, have the necessary usefulness combined thing of certain material bag or with the chemical compound co-administered, to prevent the chemical compound inactivation.For example, can for example in liposome or the diluent, give object in appropriate carriers with therapeutic compound.The medicine acceptable diluent comprises saline and aqueous buffer solutions.Liposome comprises W/O/W CGF emulsion and conventional liposome (Strejan etc., (1984) J.Neuroimmunol.7:27).

The pharmaceutical composition that is fit to the injection use comprises sterile aqueous solutions (when energy is water-soluble) or dispersant, and is used for preparing the sterilized powder of sterile injectable solution agent or dispersant temporarily.In all cases, compositions must be aseptic, and flowability must reach the degree that is easy to inject.Compositions must be stablized under preparation and storage requirement, must prevent for example contamination of antibacterial and fungus of microorganism during preservation.

Carrier can be solvent or disperse medium, and it comprises for example water, ethanol, polyhydric alcohol (for example glycerol, propylene glycol and liquid macrogol etc.), their suitable mixture and vegetable oil.Can be for example by using coating such as lecithin, pass through the required granular size (under the dispersant situation) of maintenance and, keeping suitable flowability by using surfactant.Can pass through various antibacterial agents and antifungal, for example parabens, methaform, phenol, ascorbic acid, thimerosal etc. prevent action of microorganisms.Under many circumstances, in compositions, can comprise isotonic agent, for example saccharide, sodium chloride or polyhydric alcohol such as mannitol and Sorbitol.The prolongation of Injectable composition absorbs can be by adding the chemical compound that postpones absorption in compositions, for example aluminum monostearate or gelatin are realized.

The sterile injectable solution agent can be prepared as follows: the combination (on demand) with the above a kind of composition enumerated or multiple composition of the therapeutic compound of aequum is incorporated in the appropriate solvent, carries out filtration sterilization then.Usually, be prepared as follows dispersant: with therapeutic compound be incorporated into contain basic disperse medium and above-mentioned enumerate other must the sterile carrier of composition in.In the situation of the sterilized powder that is used for preparing sterile injectable solution, preparation method is solution for vacuum drying and the lyophilization with aseptic filtration in advance, produces the powder of active component (being therapeutic compound) and any required complementary element.

Therapeutic compound can for example pass through oral administration with inert diluent or absorbable edible carrier.Therapeutic compound and other composition also can be packed in duricrust or the soft shell gelatin capsules, can be pressed into tablet, perhaps can directly be incorporated in patient's the food.Oral administration when treatment, therapeutic compound can with mixed with excipients, and use can digest forms such as tablet, buccal tablets, tablet, capsule, elixir, suspending agent, syrup, wafer.Therapeutic compound percentage composition in compositions and preparation certainly changes.Therapeutic compound content in the useful composition in this treatment is the amount that can obtain suitable dose.

With dosage unit form preparation parenteral compositions advantageous particularly, to make things convenient for administration and dosage homogeneous.Dosage unit form used herein refers to be suitable as the discontinuous unit of physics that dosage unit gives patient to be treated; Each unit comprises the therapeutic compound of the scheduled volume that will produce required therapeutic effect as calculated and essential pharmaceutical carrier.The specification of dosage unit form of the present invention is subject to and directly depends on the unique property of (a) therapeutic compound and the concrete therapeutic effect that will obtain and (b) this area inherent limitation of using the amyloid beta deposition of this therapeutic compound treatment target.

Therefore, the present invention includes the pharmaceutical preparation of the various described medication medication of this paper that comprises in the drug acceptable carrier (comprising its drug acceptable salt), for spraying, oral and parenteral.Equally, the present invention includes medicine and salt thereof, it can be resumed into medicine and can accept preparation by lyophilizing, for example by intravenous, intramuscular or subcutaneous injection administration.Administering mode also can be intradermal administration or transdermal administration.

According to the present invention, various described chemical compound of this paper and drug acceptable salt thereof can the oral or inhalations of solid form, perhaps can solution, suspending agent or Emulsion form intramuscular or intravenous administration.In addition, medicine or its salt also can liposome suspending agent form by suction, intravenous or intramuscular administration.

The pharmaceutical preparation that is suitable as the aerosol inhalation also is provided.This preparation comprises the solution or the suspension of any formula compound or its salt of required this paper, perhaps a large amount of solids of described compound or its salt.Required preparation can be packed in the loculus to atomize.Can realize atomizing by compressed air or by ultrasonic energy, form a large amount of drop that comprises medicine or its salt or solids.The particle size of drop or solids should be about 0.5 to about 5 microns scope.Can handle solid chemical compound or its salt of any formula described herein by any suitable method well known in the art (for example passing through micronization), obtain solid particle.The size of solids or drop may be for example about 1 to about 2 microns.For this reason, available commercial aerosol apparatus achieves this end.

The pharmaceutical preparation that is suitable as aerosol drug delivery can be liquid form, and preparation may comprise the water solublity that is dissolved in carrier (comprising water) any formula chemical compound described herein or its salt.Can have surfactant in the preparation, when preparation was sprayed, it can fully reduce the surface tension of preparation, so that the drop that forms is in required magnitude range.

Oral composition also comprises liquid solution agent, Emulsion, suspending agent etc.The drug acceptable carrier that is applicable to this compositions of preparation is being known in the art.The typical carriers composition that is used for syrup, elixir, Emulsion and suspending agent comprises ethanol, glycerol, propylene glycol, Polyethylene Glycol, liquid sugar, sorbose alcohol and water.For the suspending agent preparation, typical suspending agent comprises methylcellulose, sodium carboxymethyl cellulose, tragacanth and sodium alginate; Typical wetting agent comprises lecithin and polysorbate80; Typical preservatives comprises methyl hydroxybenzoate and sodium benzoate.The per os fluid composition also can comprise one or more above disclosed compositions, as sweeting agent, correctives and coloring agent.

Pharmaceutical composition also can adopt pH or time dependence coating usually with conventional method coating, and target compound perhaps discharges in the different time in the contiguous release in the gastrointestinal tract topical application position of expectation like this, to prolong the effect of expectation.This dosage form generally includes but is not limited to one or more acetic acid-O-phthalic acid cellulose, phthalic acid polyvinylacetate, Hydroxypropyl Methylcellulose Phathalate, ethyl cellulose, wax and Lac.

Other compositions that the whole body that can be used for realizing drug target is passed medicine comprises Sublingual, oral cavity and nasal cavity dosage form.This compositions comprises one or more solubility implants usually, as sucrose, Sorbitol and mannitol; And binding agent, as Radix Acaciae senegalis, microcrystalline Cellulose, carboxymethyl cellulose and hydroxypropyl emthylcellulose.Also can comprise above disclosed fluidizer, lubricant, sweeting agent, coloring agent, antioxidant and correctives.

The present composition also can the topical administration object, for example by directly compositions being smeared or interspersed among the epidermis or the epithelial tissue administration of object, perhaps by " patch " transdermal administration.This compositions comprises for example lotion, unguentum, solution, gel and solid formulation.These topical compositions can comprise the The compounds of this invention of effective dose, be at least usually about 0.1%, perhaps even be about 1% to about 5%.The carrier that is applicable to topical is retained on the skin with the form of continuous rete usually, can keep out because of coming off of perspiring or soak and cause.Usually, carrier is Organic substance in essence, can disperse therein or the dissolution treatment chemical compound.Carrier can comprise the acceptable softening agent of medicine, emulsifying agent, thickening agent, solvent etc.

Active medicine is to be enough to suppress the accumulative treatment effective dose of detrimental protein administration in the object.With respect to treatment target not, " treatment effectively " dosage suppresses detrimental protein and assembles and for example reach at least about 20%, perhaps at least about 40%, perhaps even at least about 60%, perhaps at least about 80%.Under for example parkinsonian's situation, " treatment effectively " dosage can make the stable or prevention cognitive function of cognitive function further descend (promptly prevent, slow down or stop the progress of disease).Therefore the present invention provides curative drug." therapeutic agent " or " medicine " refers to specified disease or disease among people who lives or the non-human animal are had the chemical compound of property improved or preventative beneficial effect.

The toxicity of this medicine and therapeutic efficiency can be measured in cell culture or laboratory animal by the method for pharmacy of standard, for example measure LD50 (50% colony's fatal dose) and ED50 (50% mass treatment effective dose).Dosage ratio between toxic action and the therapeutical effect is a therapeutic index, can be expressed as the LD50/ED50 ratio, and the general therapeutic index is big more then effective more.Though can use the medicine of toxic side effect, should be noted that design can make the transmission system at this drug targeting damaged tissues position, minimizing, thereby reduce side effect to the potential damage of damaged cell not.

It should be understood that proper dosage depends on the factor in a lot of ordinary skill doctors, veterinary or the researcher ken.Micromolecular dosage can change according to for example following factor: the object for the treatment of or the characteristic of sample, size and situation, and the route of administration of compositions (if applicable), also have the medical practitioner to expect the effect that micromolecule should have nucleic acid of the present invention or polypeptide.Exemplary dose comprises the micromolecule milligram number of every kilogram of object or sample weight or micrograms (for example, every kilogram of about 1 microgram to every kilogram about 500 milligrams, every kilogram about 100 micrograms to every kilogram of about 5 milligrams or every kilogram of about 1 microgram to every kilogram of about 50 micrograms).Being appreciated that in addition that suitable dosage depends on waits regulate to express or active effect.This suitable dosage can use test method as herein described to measure.When these micromolecular one or more being given animal (for example people), during with adjusting polypeptide of the present invention or expression of nucleic acids or activity, doctor, veterinary or researcher can for example be opened relatively low dosage when beginning, increase dosage subsequently, until obtaining suitable reaction.In addition, it is also understood that, the concrete dosage level that gives any concrete animal target may depend on multiple factor, comprises age, body weight, general health situation, sex and diet, administration time, route of administration, the excretion rate of activity, the object of used particular compound, any drug regimen, expression or active degree to be regulated.

Can in animal model system, assess the accumulative ability of chemical compound Profilin matter, this measurable inhibition effect to protein aggregation in the human diseases, described animal model is the transgenic mice of expressing human alpha-synapse nucleoprotein for example, perhaps can predict other relevant animal models of protein aggregation, those models for example as herein described.Similarly, chemical compound prevention or the ability that reduces cognitive impairment in the model system can be shown in the effect among the mankind in advance.Perhaps, can assemble the ability that the ability that forms is assessed chemical compound, for example use fibril as described herein to form and analyze, comprise that ThT, CD or EM analyze by vitro detection chemical compound Profilin matter.

Blood brain barrier

Can prepare medicine of the present invention, to guarantee its correct distribution in vivo.For example, blood brain barrier (BBB) repels many highly hydrophilic medicines.For guaranteeing that more hydrophilic medicine of the present invention can pass BBB, these medicines for example can be formulated in the liposome.The relevant method for preparing liposome is referring to United States Patent (USP) for example the 4th, 522, No. 811, the 5th, 374, No. 548 and the 5th, 399, No. 331.Liposome can comprise one or more can by optionally the transhipment enter the part (" targeting moiety ") of specific cells or organ, thereby target administration (referring to for example V.V.Ranade (1989) J.Clin.Pharmacol.29:685) is provided.

Exemplary targeting moiety comprises that folic acid or biotin are (referring to the United States Patent (USP) the 5th of for example Low etc., 416, No. 016), mannoside (Umezawa etc. (1988) Biochem.Biophys.Res.Commun.153:1038), antibody (P.G.Bloeman etc. (1995) FEBS Lett.357:140; M.Owais etc. (1995) Antimicrob.Agents Chemother.39:180), surfactant protein matter A receptor (Briscoe etc. (1995) Am.J Physio.1233:134), gp120 (Schreier etc. (1994) J Biol.Chem.269:9090); Simultaneously referring to K.Keinanen; M.L.Laukkanen (1994) FEBS Lett.346:123; J.J.Killion; I.J.Fidler (1994) Immunomethods 4:273.In one embodiment, curative drug of the present invention is formulated in the liposome; It can comprise targeting moiety.

For guaranteeing that medicine of the present invention passes BBB, can be with medicine and the coupling of BBB transport vehicle (summary of relevant BBB transport vehicle and mechanism referring to Bickel etc., Adv.Drug DeliveryReviews, the 46th volume, 247-279 page or leaf, 2001).Exemplary transport vehicle comprises cationization albumin or anti-TfR OX26 monoclonal antibody; These albumen mediate by absorption respectively or receptor-mediated transcytosis passes BBB.

The example that receptor-mediated movement system targeting is imported other BBB transport vehicle of brain comprises for example insulin, insulin like growth factor (IGF-I, IGF-II), Angiotensin II, atrium and the factors such as brain natriuretic factor(peptide) (ANP, BNP), interleukin I (IL-1) and transferrins.The monoclonal antibody of the bind receptor of these factors also can be used as the BBB transport vehicle.The BBB transport vehicle of the transcytosis mechanism of targeting absorption mediation comprises cationic moiety, for example cationization LDL, with the link coupled albumin of polylysine or horseradish peroxidase, cationization albumin or cationization immunoglobulin.Little alkaline oligopeptide such as dynorphin analog E-2078 and ACTH analog ebiratide (ebiratide) also can pass brain by the transcytosis of absorption mediation, and they are potential transport vehicle.

Other BBB transport vehicle targeted system is with nutrient transport system guiding brain.The example of this BBB transport vehicle comprises hexose part (for example glucose), monocarboxylic acid (for example lactic acid), neutral amino acid (for example phenylalanine), amine (for example choline), basic amino acid (for example arginine), nucleoside (for example adenosine), purine base (for example adenine) and thyroxin (for example Lithyronine (triiodothyridine)).The antibody of the proteic ectodomain of nutrient transport also can be used as transport vehicle.Other possible carrier comprises Angiotensin II and ANP, and it may participate in regulating the BBB permeability.

In some cases, transhipment enters after the brain, and the key that connects therapeutic compound and transport vehicle can split, with the delivery of biologically active chemical compound.Exemplary connecting key comprises disulfide bond, ester bond, thioether bond, amido link, sour labile bond and Schiff's base key.Also can use the avidin/biotin linking group, wherein Avidin and BBB drug delivery carrier covalent coupling.Avidin itself can be a drug delivery carrier.

Prodrug

The present invention also relates to the prodrug of various medicine described herein.Prodrug is the medicine that can change into activity form in vivo (referring to for example R.B.Silverman, 1992, " The OrganicChemistry of Drug Design and Drug Action, " Academic Press, the 8th chapter).Prodrug can be used to change the bio distribution (medicine that for example allows to enter the mmp reaction site usually enters) or the pharmacokinetics of particular compound.For example, hydroxy-acid group can be for example with methyl or ethyl esterification, to produce ester.When giving object with ester, ester shows anionic group by enzyme or non-enzyme, reduction, oxidation or hydrolytic rupture.Anionic group can show part (for example acyloxy methyl ester) esterification of intermediate compound in the time of can be with cracking, intermediate compound decomposes the generation reactive compound subsequently.Prodrug moiety also can be metabolized to carboxylic acid by esterase or by other mechanism in vivo.

The example of prodrug and application thereof is (referring to (1977) " Pharmaceutical Salts " such as for example Berge, J Pharm.Sci.66:1-19) well known in the art.Prodrug can separate and in-situ preparing during purification in that medicine is last, perhaps reacts and prepares by independent purifying compounds and suitable derivatization chemical compound with free acid form.Carboxylic acid can be converted into ester through Ethanol Treatment when catalyst exists.

The example of the carboxylic acid prodrug moiety of cleavable comprises replacement or unsubstituted, band side chain or unbranched low alkyl group ester moiety (ethyl ester for example, propyl ester, butyl ester, pentyl ester, the ring pentyl ester, own ester, cyclohexyl), the low-grade alkenyl ester, two elementary alkyl amido lower alkyl esters (for example dimethylaminoethyl), the acylamino-lower alkyl esters, acyloxy lower alkyl esters (for example new pentane acyloxy methyl ester), aryl ester (phenyl ester), aryl lower alkyl ester (for example benzyl ester), replace (for example by methyl, halogen or methoxyl group replace) aryl and aryl lower alkyl ester, amide, the low alkyl group amide, two low alkyl group amide and hydroxy amides.

The acceptable salt of medicine

Some embodiment of medicine of the present invention can comprise basic functionality, as amino or alkyl amino, and therefore can form the acceptable salt of medicine with the acceptable acid of medicine.Term " the acceptable salt of medicine " refers to the nontoxic relatively inorganic or organic acid addition salt of medicine of the present invention in this sense.These salt can separate and in-situ preparing during purification in that medicine of the present invention is last, and are perhaps independent with the purification The compounds of this invention of free alkali form and suitable organic or inorganic acid reaction, and separate formed salt.

Representational salt comprises halogen acid salt (comprising hydrobromate and hydrogen chlorate), sulfate, disulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluene fulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, gluceptate, Lactobionate, 2-isethionate and lauryl sulfonate etc.(referring to (1977) " Pharmaceutical Salts " such as for example Berge, J Pharm.Sci.66,1-19).

In other cases, medicine of the present invention can comprise one or more acidic functionality, and therefore can form the acceptable salt of medicine with the acceptable alkali of medicine.Term " drug acceptable salt " is at the nontoxic relatively inorganic and organic base addition salts of these situation middle fingers medicine of the present invention.

These salt can separate and in-situ preparing during purification in that medicine of the present invention is last equally, perhaps separately with the purifying compounds of the sour form of freedom and suitable alkali reaction, as hydroxide, carbonate or the bicarbonate of the acceptable metal cation of medicine, the acceptable organic primary amine of ammonia or medicine, secondary amine or tertiary amine.The salt of representational alkali-metal salt or alkaline-earth metal comprises lithium salts, sodium salt, potassium salt, calcium salt, magnesium salt and aluminum salt etc.The representative organic amine that can be used for forming base addition salts comprises ethamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine etc.

Embodiment

The present invention is further elaborated by following examples, and these embodiment should not be understood that further restriction of the present invention.

Those skilled in the art only adopt routine test, just will appreciate that or can determine the multiple equivalent of concrete grammar described herein, embodiment, claim and embodiment.These equivalents are considered to belong within the scope of the present invention, and are contained by claims of the present invention.The content of all lists of references of quoting everywhere in the present specification, granted patent and publication application is attached to herein by reference.

Embodiment 1: relevant with protein aggregation disorders in order to detect

The test of detrimental protein aggregation

In order to detect harmful test of gathering relevant detrimental protein aggregation with NAC

The preparation of NAC peptide

Discuss as this paper, acronym NAC refers to the non-amyloid component of the amyloid plaque found in AD patient, specifically, refer to 35 amino acid peptides corresponding to the 61-95 residue of alpha-synapse nucleoprotein.The NAC peptide is at Protein Technologies, and is synthetic by Fmoc tert-butyl group chemistry method on the peptide synthesizer of Inc., purity＞98%.The content of peptide is defined as 71.6% through amino acid analysis.

The prepared product of NAC may contain aggregation substance.For removing these aggregations and make peptide monomerization, according to the article of Walsh and Colleagues (J Biol Chem.1997 August 29; 272 (35): 22364-72) reorganization acquires down depolymerization/filter method.This method comprises peptide carries out supersound process 1,1,1,3,3 in the 3-hexafluoroisopropanol (HFIP), to dismiss any structure that may exist.Remove by filter any big aggregation that may remain in the solution with the 20nm filter subsequently, and standby-80 ℃ of following preservations.

The preparation of chemical compound

At TBSA buffer (Tris 0.02M, NaCl 0.15M, NaN ₃0.005%, pH 7.4) in preparation 2mM solution and be stored in 4 ℃.During test, mixture TBSAE buffer (Tris 0.02M, NaCl 0.15M, NaN ₃0.005%, EDTA 100 μ M, pH 7.4) be diluted to required concentration, and merge with the NAC peptide.

Fibril generates test

Utilize fibril to generate test and identify that test-compound suppresses the ability that NAC is assembled into fiber.At N ₂Evaporation is removed after the HFIP under the atmosphere, add in the microtest plate reader at Perkin-Elmer HTS 7000, under 37 ℃ with 20 μ M NAC peptides at test buffer (0.02MTris, 0.15M NaCl, 0.005% NaN ₃, 100 μ M EDTA) and middle incubation, every vibration in 20 minutes 1 minute.Can be by the existence of three kinds of distinct methods monitoring fibers.

Following test following carrying out in transparent polystyrene 96 hole microtest plates: with the 200 μ M test-compounds of the 40 μ M NAC peptides of 125 μ L and 125 μ L at 0.02M Tris, 0.15M NaCl, 0.005% NaN ₃, merge among the 100 μ M pH 7.4.Microtest plate placed 37 ℃ of following incubations of Perkin-Elmer HTS 7000 microtest plate readers after sealing with sheet plastic, every vibration in 20 minutes 1 minute.

Thioflavine T is analyzed.For carrying out this test, 5 μ M thioflavine Ts are joined in the above-mentioned NAC assembled condition.In process of the test, with Perkin-Elmer HTS microtest plate reader excite 430/measured first order fluorescence every 20 minutes under 485 emissions.As shown in Figure 1, can come the existence of detection fibers by the enhancing of fluorescence.This test can be identified the enhanced chemical compound of fluorescence in the time of suppressing incubation.

Nephelometric analysis.Perhaps, can be by reading absorbance at the 40nm place, with the turbidity of monitoring solution, analyze the NAC peptide with test-compound incubation under suitable assembled condition, described turbidity also is the sign that aggregation forms.

Circular dichroism (CD) is analyzed.The circular dichroism spectroscopy check and analysis of in the assembling process of NAC peptide it being carried out show, NAC did not exist under the test-compound after the about 15-20 of incubation hour, from random-coil conformation to beta sheet/corner conformation transition.This test can be identified and can prevent that NAC from taking the chemical compound of beta sheet/β-corner conformation when incubation.Appropriate time point in the incubation process will be tried solution and be transferred to 0.1-cm optical path length quartz cuvette, carry out the scanning of CD spectroscopy with Jasco J-715 spectropolarimeter between 190 to 260nm down at 37 ℃, and resolution is 0.1nm, and bandwidth is 1nm.Independent NAC finds to have taked beta sheet/corner conformation in the back that is incubated overnight.Some contains the sample of test-compound according to observing the NAC that still keeps the random coil form, and some is just carrying out conformation transition, but does not change into beta sheet/β-corner conformation as yet.

Electronic Speculum (EM) is analyzed.Time point carrying out CD scanning pipettes 3 μ l aliquots from sample, its point is dripped to Formvar carry on the net, uses 4% uranyl acetate negative staining then.25, the 000X amplification is observed down and is carried net, whether has fibril and amorphous aggregation to check with JOEL 2000 transmission electron microscopes.This test can be used to confirm identifying that through ThT and CD no fiber exists in the presence of the chemical compound that can suppress the NAC assembling.Obtain final result by the meansigma methods of getting 10 complete sections.

Embodiment 2: the thioflavine T test is in the application of determining to separate in the NAC formation beta sheet

The test of having carried out shows that thioflavine T (ThT) can be used for using in the high flux work and confirmation work of NAC peptide.The fluorescence signal that the indication beta sheet forms began to occur (Fig. 1) in 10 hours at incubation.Fluorescence signal intensity is directly related with NAC concentration in the solution, reaches maximum when 30 μ MNAC.(in 96 orifice plates) observe T _1/2(for obtaining to equal the required time of half signal of gained peak signal) is～15 hours similar ThT collection of illustrative plates.

The circular dichroism analysis and the electronic microscope photos of embodiment 3:NAC peptide conformation

The circular dichroism analysis (Fig. 2) that NAC peptide incubation carried out its conformation after 10-72 hour shows, is minima at the 227nm place, and this makes the people associate observed result in being rich in the zone of alpha-helix.NAC is behind incubation in the presence of the heparin, and its CD spectrum is presented at the 218nm place and is evident as minima, and this is the feature of beta sheet conformation.Electronic microscope photos (Fig. 3) has monitored the NAC fiber and has occurred.The existence of heparin obviously promotes conformation transition, and helps promoting the high beta sheet content (Fig. 2) of aggregation/fibril formation.This result shows that glucosaminoglycan participates in oligomerization/fibril forming process of NAC really, confirms to use the GAG simulated compound as preventing that this method of means that NAC oligomerization and poisonous aggregation form from being effective.EM analyzes and has supported this observed result, as if promptly the NAC peptide forms fiber (Fig. 4) longer and that tangle more in the presence of heparin.

Following form has been summed up the CD result of the test of a plurality of chemical compounds.

The CD analysis result of test-compound

As NAC during with the test-compound incubation, the CD analysis and observation arrives, and it shows different conformations: the NAC that " random coil " expression is observed in the sample still keeps its original random-coil conformation, show with NAC altogether the chemical compound of incubation have activity; " beta sheet " or " beta sheet/β-corner " expression chemical compound can not prevent that random coil from changing to beta sheet; " transition " expression is observed NAC and is in from random coil to the beta sheet transforming process, shows the chemical compound conformational change process that can slow down, and therefore demonstrates activity.For repeatedly chemical compound of test, if its prevent 50% or more tests in to the transformation of beta sheet/β-corner, this chemical compound has been classified as activity.

Electronic microscope photos: CD analyzes the fibril generation test of carrying out and also carries out the EM analysis.Visual examination electron micrograph, and following score.Briefly, carry net from 300 orders and choose 10 representational frames and analyze, the microphotograph of not having the chemical compound that is put to the test (100% fiber) with having only NAC is relatively given and is divided, and score is represented the fibre weight that forms in the sample.According to this analysis result, score by the staging of 0%-100% fiber: (-) expression is observed and is less than about 25% fiber; The fiber of (+) expression about 25%; The fiber of (++) about 50%; The fiber of (+++) about 75%; The fiber of (++ ++) 100%.(AA) amorphous aggregation is observed in expression.Following table provides the EM analysis result of sample.

The EM analysis result

Embodiment 4: the chemical compound of prevention protein aggregation disorders can screen in cell model

The various cell culture object models that form in order to the monitoring aggregation relevant have been put down in writing with protein accumulation.In addition, oligomerization and gathering can take place in this protein, and induce toxicity in these culture cells.For the parkinson disease model, the overexpression of various synapse nucleoprotein mutants can be induced the formation of aggregation in following several cell lines: SH-SY5Y cell (Kanda etc., 2000.Neurosci 97:279), BE (2)-M17 neuroblast oncocyte, HEK293 (Ko etc., 2000.JNeurochem 75:2546), NT-2, SK-N-MC cell line (Lee etc., 2001.J Neurochem 76:998) and BE-M17 neuroblast oncocyte (Ostrerova-Golts etc., 2000.J Neurosci 20:6048).

Set up similar model, to form as the Huntington protein research aggregation that participates in the Huntington's disease development by other protein; Sudden change Huntington protein gene (Wu etc., 2002.JBC 277:44208 in PC-12 cell line; Igarashi etc., 2003.Mol Neurosci14:565) (Carmichael etc., 2002.Neurosci Lett 330:270-274 or in Cos-7; Yang etc., 2002.Hum Mol Gen 11:2905) expression causes occurring aggregation.

Target can be assembled protein (for example synapse nucleoprotein or Huntington protein) and carry out immunity location altogether, easily realize the detection of aggregation or inclusion body with various cytoskeletal proteins such as 'beta '-tubulin, γ-tubulin or Vimentin.The cell distribution of inclusion body can also be further determined in the eliminating of other labellings (as the alpha-Mannosidase II of Golgi body).(Shimohata etc., 2002 that DPRLA and neurolemmal cell tumor albumen are confirmed as preamble; Gautreau etc., 2003; Ginseng sees the above table), other labellings such as ubiquitin can be used for being characterized in the other aggregation that is accumulated into aggregation of distinguishing of nuclear of microtublue organizing center (MTOC) (MTOC).Other aggregations or inclusion body also can be in Cytoplasm in (Lewy corpusculum, Mallory body) or the nucleus (Huntington protein, ataxia albumen) find.

Though these big aggregations can be by the microscopic analysis visual detection, they itself may not have toxicity, and their existence may be not sufficient to induce toxicity.But their existence shows gathering of abnormal protein conformation and assembling intermediate, and both have shown inducing cytotoxic the back.

Up-to-date evidence has been unequivocally established and has contained the toxic action of androgen-receptor of expanding polyglutamyl amine section (causing spinal cord oblongata muscular atrophy).After AR mutant (AR-112Q) transfection with 112 repetitive glutamine sequences, all cells all shows the distinctive Cytoplasm inclusion body of aggregation, and shows significant cell death (Taylor etc., 2003.Hum Mol Genet 12:749).Importantly, the formation that suppresses aggregation with nocodazole can cause cell death to increase in the dose dependent mode, has given prominence to aggregation and has avoided importance in the toxic action of oligomer/aggregation at the protection cell.

The cell that has aggregation to gather can carry out extracorporeal treatment with the patent chemical compound, the formation of available several different methods monitoring toxicity aggregation.After the cell of his-and-hers watches mutant tat protein was handled, available fluorescent labeling was carried out quantitatively aggregation or inclusion body by microtechnique, and the viability of cell is tested or monitored with MTT or WST-1 staining to available above-mentioned viability.(Abee and Matsuke.2000.Neurosc Res 38:3256; Berridge etc., 1996.Biochemica 4:11).The available survival test based on FACS of cell death amount carries out quantitatively (Taylor etc., 2003.Hum Mol Genet 12:749).

By cell breakage and centrifugalize aggregation or aggregation, further characterize with quantitative.

Embodiment 5: the method for separating the aggregation relevant with protein aggregation disorders

Because aggregation comprises the nearly nuclear medicated cap of Vimentin, as Cystic fibrosis being striden the (Wanker etc. that film instrumentality (CFTR) is confirmed, 1999.Methods in Enzymology309:375), can improve technology (Starger and the Goldman of Starger, 1977.Proc NatlAcad Sci USA 74:2422), so that the separation from aggregation is optimized to the isolated protein aggregation.Briefly, cell is cultured to 85% and is paved with degree in the 100-mm plate, before separating, handles 12 hours with 10mg/ml ALLN.Cell washed twice in the PBS (6mM potassium-sodium phosphates buffer, 170mM NaCl, 3mM KCl) is scraped and is got and with 2,500g collected 3 minutes.The washed cell of each 100-mm plate is suspended among the 1ml PBS again, and, shows that up to the bright field micrography most of cell is broken by No. 25 pins three to four times.By in PBS, suspending again and with 2, described material is washed in 000g sedimentation three times.Check the gained material by fluorescence microscopy, confirm to contain the existence that GFP separates aggregation.With 2,000g collects cell grade part of being rich in aggregation of gained for the last time, and is suspended in again among the PBS/1% BSA of 200ml.This can be used as the raw material of Immunoelectron microtechnique.Also (Johnston etc. can followingly be described, 1998.JCB 143:1883), by carrying out quantitative ELISA after the protein denaturation, perhaps carry out Dot blot behind the centrifugalize aggregation and filter the delay test, the formation of these protein aggregates is done further quantitatively.

Embodiment 6: Dot blot filters and is detained test

The cell of expressing mutain is washed in freezing phosphate-buffered saline (PBS), scrape and get, and centrifugation (2000g, 10 minutes, under 4 ℃).Cell contains lysis buffer [the 50mM Tris-HCl (pH 8.8) of protease inhibitor PMSF (2mM), leupeptin (10 μ g/ml), pepstatin (10 μ g/ml), aprotinin (1 μ g/ml) and protease inhibitor (50 μ g/ml) at 500 μ L, 100mM NaCl, 5mM MgCl ₂, 0.5% (w/v) Nonidet P-40 (NP-40), 1mM EDTA] in cracking on ice 30 minutes.By under 4 ℃ in microcentrifuge centrifugal 5 minutes, remove insoluble material with 14000rpm.The precipitate that will contain insoluble material is suspended in 100 μ l DNA enzyme buffer liquid [20mM Tris-HCl (pH 8.0), 15mMMgCl again ₂] in, add DNA enzyme I (Boehringer Mannheim), to final concentration be 0.5mg/ml, then 37 ℃ of following incubations 1 hour.As standard, measure protein concentration after the DNA enzyme is handled with BSA by dotMetric test (Geno technology).By adjusting the gained mixture with 20mM EDTA, 2% (w/v) SDS and 50mM DTT, heated 5 minutes down at 98 ℃ then, stop incubation reaction.

The filtration test (Johnson etc., 1995.J Mol Recog 8:125) that contains the Huntington protein aggregation of polyglutamyl amine in order to detection has been described.Prepare degeneration and reductive protein example as mentioned above, to be equivalent to the 50-250ng fusion rotein of transfectional cell or the aliquot of 5-30 μ g extraction albumen (precipitation level part) is diluted among the 200 μ l 2%SDS, and in BRL Dot blot defecator, filter cellulose acetate membrane (the Sehleicher and Schuell used the 2%SDS pre-equilibration, Keene, NH, pore size 0.2 μ m).Filter membrane is with 200 μ l0.1%SDS washed twice, then with TBS (100mM Tris-HCI, pH 7.4, the 150mM NaCl) sealing that contains 3% defatted milk powder, then with anti-HD1 antibody (1: 1000) incubation.Filter membrane washs in TBS for several times, and then and the second anti-rabbit antibody of puting together with horseradish peroxidase (Sigma, 1: 5000) incubation together, (enhanced chemiluminescence Amersham) detects then to carry out ECL.(Rochester, NY) carry out quantitatively immunoblotting allowing to for several times by X-OMAT film or Lumi-Imager (Boehringer Mannheim) exposure to Kodak for the development trace.

For detecting and quantitatively containing polyglutamyl amine aggregation, used biotin/Streptavidin-AP detection system by what the GST-x fusion rotein of Protease Treatment produced.After the filtration, with cellulose acetate membrane with 1% (w/v) BSA incubation 1 hour under the room temperature in TBS, vibration gently in reciprocal shaker.Then with filter membrane and the Streptavidin-alkali phosphatase (Promega that was diluted among the TBS that contains 1%BSA with 1: 1000, Madison, WI) incubation 30 minutes together, with the TBS washing that contains 0.1% (v/v) Tween 20 three times, reuse TBS washing three times, at last with 1 of fluorescence alkaline phosphatase substrate AttoPhos or chlorine replacement, 2-dioxetane chemical luminous substrate CDPStar (Boehringer Mannheim) is together at 100mM Tris-HCl, pH 9.0,100mM NaCl and 1mM MgCl ₂Middle incubation 3 minutes.With Boehringer Lumi-Imager F1 system and LumiAnalyst software (BoehringerMannheim) fluorescence and chemiluminescence signal are carried out imaging and quantitative.

Embodiment 7: the test of filter trap

The test of filter trap is used for detecting the existence of aggregation in the freezing brain sample in simple experiment.Can improve this method, in order to detect various types of protein aggregates.Freezing mice half brain and freezing people's brain fragment are weighed, contain 1 * protease inhibitor cocktail (Cat.#P8340, Sigma, St.Louis, homogenate in phosphate-buffered saline MO) (pH 7.4) with polytron at 10 times of volumes then.Homogenate under 4 ℃ in microcentrifuge with 3, centrifugal 5 minutes of 000rpm.Get the supernatant aliquot, (Pierce Chemical Co., Rockford IL) measure protein concentration by the BCA method.Aliquot cold storage is standby in-70 ℃.Thaw earlier before the sample filtering, be diluted to the final volume of 200 μ l then with PBS, contain 1%SDS (Fig. 2 exception, wherein final SDS concentration changes) between 0.1-5%.(CA) making gained solution filter pore size is cellulose acetate membrane (OE66, the Schleicher ﹠amp of 0.2-μ m for Bio-Rad Laboratories, Hercules to use 96 hole Dot blot equipment then; Schuell, Keene, NH).Before the filtration, filter membrane immerses earlier and contains among the PBS of 1%SDS.Filter trace with 500 μ LPBS (pH, 7.4) washed twice.According to the program that is used for immunoblotting (Xu etc., 2002Alzheimer Dis Assoc Disord 16:191), detect the protein of membrane retention by immunostaining.

Be the protein that analysis and filter is held back, cut the target trace, in 40 μ L 1x SDS sample loading buffers (Laemmli, 1970), boiled 10 minutes, acutely mix then by (by the whirlpool agitator).On the SDS/ polyacrylamide gel, trace is to nitrocellulose filter (BA-S85, Schleicher ﹠amp then with sample (20 μ L) application of sample; Schuell, Keene, NH) on.(Jankowsky etc., 2001) as previously mentioned, (Boston MA) detects immobilized protein for NEN Life Science Products, Inc. to use mAb 6E10 and ECL.

Embodiment 8: relevant with protein aggregation disorders in order to detect

The method of multiple detrimental protein aggregation

Following table has been summarized detailed introduction in order to detect inclusion body or the method for aggregation and the list of references of technology relevant with various diseases.Should be noted that technology described herein can be used for implementing method described herein by those of ordinary skills.

The protein of being studied	The aggregation detection technique	Indication	Inclusion body type and location	List of references
					Handkerchief gold albumen alpha-synapse nucleoprotein synphilin-1	1-locatees 2-microtubule inhibitor/protease inhibitor altogether by immunofluorescence and handkerchief gold albumen/γ-tubulin (MOTC labelling)	Parkinson	Lewy corpuscle matter	Junn etc., 2002. JBC 277,47870-47877
DRPLA albumen	1-locatees 2-microtubule inhibitor/protease inhibitor altogether by immunofluorescence and 'beta '-tubulin/γ-tubulin/Vimentin	The Louis body atrophy of dentate nucleus rubrum pallidum	Other and the nuclear inclusion body of aggregation nuclear	Shimohata etc., 2002., Neurosci. Lett.323,215-218
					Huntington protein	Locate altogether by immunofluorescence and γ-tubulin/Vimentin	Huntington's disease	Intranuclear inclusion and malnutrition neural axon or neuropilem kytoplasm aggregation	Waelter etc., 2001.Mol.Biol Cell 12,1393-1407
Cystic fibrosis is striden film instrumentality (CFTR)	1-locatees 2-protease inhibitor 3-electron microscopic examination 4-subcellular fractionation altogether by immunofluorescence and Vimentin/γ-tubulin and separates with aggregation	Cystic fibrosis	The aggregation Cytoplasm	Johnston et al， 1998，JCB 143，1883-1898
					Alpha-synapse nucleoprotein	Locate altogether by immunofluorescence and γ-tubulin	Parkinson	Lewy corpuscle matter	McNaught et al 2003.Eur.J. Neurosci.16， 2136-2148
Neurolemmal cell tumor albumen	1-locatees the pulse code/immunoprecipitation of 2-nocodazole 3-EM 4-component altogether by immunofluorescence and γ-tubulin	Neurofibroma	2 types	The aggregation Cytoplasm						2003.JBC such as Gautreau 278,6235-6242
					Cytokeratin	Locate altogether by immunofluorescence and ubiquitin/proteasome subunit P25	Alcoholic hepatitis, non-alcoholic stellato-hepatitis, chronic cholestasis, copper poisoning, drug intoxication, and liver cell tumor	Mallory body	French et al， 2001.Exp.Mol. Pathol.71，241- 246

Embodiment 9: SCREENED COMPOUND in the transgene mouse model of protein aggregation disorders

Following table provides the example of being set up in order to the transgenic mice pedigree of simulating human protein sickness.

Designed in order to the construction of expressing various muteins and be introduced in the transgenic mice, assembled disease or protein sickness with the simulation range protein.These expression of gene cause taking place various neuro pathologys' variations and behavior changes, and these variations meet the human disorders relevant with mutant gene.

For example, express the transgenic mice generation tau protein disease of appropriate level's the long isotype of tau protein (carrying the sudden change that sees volume temporal lobe type dementia and Parkinsonian), it is characterized in that occurring having a liking for the super phosphorylation τ inclusion body of Congo red in the pro-brain neuron.These inclusion bodys began to occur when 18 monthly ages.In the mankind, the τ inclusion body is made of jointly saltant tau protein and endogenous wild type tau protein, and destroys relevant with the flame-shaped conversion with influenced neuronic microtubule.In behavior, old Tg τ R406W mice shows cognitive defect, particularly association type memory impaired (seeing table).

The example of the human diseases model that another kind of success is made is the transgene mouse model of expressing alpha-synapse nucleoprotein sudden change A30P and A53T.These mices show carrying out property of the motor function decline of early onset thereof.On the neuro pathology, these mices demonstrate typical alpha-synapse nucleoprotein immunoreactivity Lewy corpusculum inclusion (seeing table) in neural axon.

Various Huntington protein allele are incorporated in the mice.The allelic transgenic mices of Huntington protein that expression has many cover expansion polyglutamyl amine sections show hold phenotype in early days, damage and hyperkinesia are coordinated in muscular movement.This disease is relevant with neuro pathology's phenomenon of cortex inclusion body, barrier film inclusion body, Hippocampus inclusion body, reactive gliosis, loss cell, general cerebral atrophy and cells inclusions, described phenomenon consistent with the variation that sees the Huntington's disease patient usually (seeing table).

Therefore, this application of showing the transgene mouse model of the simulation various mankind non-amyloid disease phenotype, for test can be in conjunction with target protein, prevent protein assembling, oligomerization, gathering or promote the therapeutic efficiency of the chemical compound that protein is removed that animal model is provided.

The transgenic models of human tau protein disease

Sudden change/gene	Transgenic/promoter	Genetic background	The behavior phenotype	The neurological feature	Quoted passage
						τ P301L	τ with 4 repetitive sequences, exons 10, but exon 2 and 3 disappearance and P301L sudden change/PrP promoteres	C57BL6 DBA/2 SW	Early stage and serious muscular movement and behavioral deficiency	The fibril gliosis appears in anterior angle, axonal degeneration, neuron infringement	2000.Nat Genet 25:402-5. such as Lewis J
τ P301L	τ 40 isotypes with 4 repetitive sequences, exon 2 and 3 and P301L sudden change/Thy12 promoter	B6D2F1, C57BL/6	The Wallerian degeneration sign, the nerve amyotrophy, muscle weakness.	Reactive neurosome of many τ and dendron; A large amount of pathology increases aixs cylinder, has the reactive spheroid of neurofilament and τ	2001.J Biol Chem.276:529-34. such as Gotz J
						τ R406W	τ/α CaMk-II the promoter of band R406W sudden change	B6SJL/F1 C57BL/6J	The association type memory is impaired.Unusual prepulse suppresses and the forced swimming experiment.	Soluble tau protein gathers.The super phosphorylation τ inclusion body of Congo red appears having a liking in the preceding brain neuron.	2002. Proc Natl Acad Sci USA.99:13896-901. such as Tatebayashi Y
τ G272V	The τ 40/ prion protein promoter of band G272V sudden change	B6D2F1 C57BL/6	Impassivity is learned defective	Fibril appears in the oligodendrocyte, band phosphorus-τ phosphorylation.The positive fibril inclusion body of ThioS is arranged in spinal cord oligodendrocyte and motor neuron	2001.Eur J Neurosci. 13:2131-40 such as Gotz J
						τ V337M	τ/PDGF-b promoter of band V337M, the Thy12 promoter	B6SJL	High degree of motion power.Overhead+word maze test is significantly different with the terrified result of the test of condition	Erose neuron has immunoreactivity to τ in the Hippocampus, and contains the conjugate spirals fibril.The atrophic cell death.	2002 J Neurosci. 22:133-41 such as Tanemura K
τ 3-repetitive sequence	τ with 3 repetitive sequences ,/prion protein promoter,	B6D2/F1	The muscular movement of carrying out property is unable, and harmony is impaired	Insoluble τ gathers, degree of depth astrocytosis and axonal degeneration.	1999 Neuron 24:751-62 such as Ishibara T
						τ 4-repetitive sequence	τ with 4 repetitive sequences ,/mice thy-1 promoter	FVB/N	Muscular movement and anaesthesia.	Axonal degeneration, astrocytosis and gather the protein ubiquitinization	1999 Am J Pathol. 155.2153-65 such as Spittaels K
τ 4-repetitive sequence ALZ17	τ/mice Thy.-1.2 promoter with 4 repetitive sequences	B6D2/F1 x B6D2/F1 C57BL/6	Muscular movement and reflection lack.	The obvious body of the super phosphorylation τ-tangible aixs cylinder disease of dendron dyeing companion	2000 Acta Neuropathol. 99:469-81 such as Probst A

The transgenic models of human Huntington's disease

Sudden change/gene	Transgenic/promoter	Genetic background	The behavior phenotype	The neurological feature	Quoted passage
						N171HD	The cDNA of the terminal segment of N-(171 aminoacid) of coding Huntington protein is with 82,44 or 18 glutamine/prion protein promoter	C3H C57BL/ 6	Dystropy only appears at 82Q.Present coordinate to lose, tremble, hypokinesia and abnormal gait.Hold in early days and coordinate impaired with muscular movement.Early dead.	Inclusion body appears in striatum, cortex, Hippocampus, tonsil and the cerebellum.Htt albumen diffusivity nuclear accumulation.Striatal cell loss and comprehensive brain atrophy.	1999. Human Molecular Genetics such as Schilling G
HD	HD genophore 16,48 or Q89 repetitive glutamine sequence CMV promoter	FVB/N	Pitch of the laps (circling), the hyperactive phenotype of holding in early days appear in 89Q and the 48Q mice	Inclusion body and gliosis appear in striatum, cerebral cortex, thalamus, the Hippocampus.The striatal cell loss.	1998. Nature Gen. 20:198-202 such as Reddy PH
						HD	HD gene extron 1-3 band 89Q repeat segment	FVB/N	Long-time hyperkinesia and holding in early days.	Inclusion body spreads all over brain.
HD	HD genophore 100Q, 48Q or 18Q repetitive sequence/NSE promoter	SJL C57BL/ 6	Phenotype is held in the demonstration of hyperkinesia 100Q mice in early days and muscular movement is coordinated impaired	Underfed neural axon appears in neuron intranuclear inclusion and cortex and the striatum.Loss cell and cerebral atrophy.	1997 Science 277:1990-1993. such as DiFiglia
						Condition HD mutant	The condition expression of sudden change Huntington protein band 94Q (tet-off, CamKII α-tTA)	CBA C57BL/ 6	Late onset is trembled and abnormal gait.Hold in early days and coordinate impaired with muscular movement	Inclusion body appears in striatum, barrier film, cortex, the Hippocampus.Reactive astrocyte.The comprehensive brain atrophy of carrying out property	2002. Cell 101:57-66 such as Yamamoto

Human parkinsonian transgenic models

Sudden change/gene	Transgenic/promoter	Genetic background	The behavior phenotype	The neurological feature	Quoted passage
						Alpha-synapse nucleoprotein	Alpha-synapse nucleoprotein band A53T/Thy1 gene promoter	C57BL/6	Carrying out property muscular movement function is impaired in early days	Spider cell gliosis and microgliacyte activation.The dyeing of diffusivity perikaryon alpha-synapse nucleoprotein.By the strong dyeing of Campbell-Switzer pyridine silver, show that the Lewy sample changes	The 2000 Exp Gerontol. 35:1389-403 such as 2000.J Neurosci 20:6021-9. Sommer B such as Putten H
Alpha-synapse nucleoprotein A30P	Alpha-synapse nucleoprotein-band A30P/Thy1 promoter	C57BL/6	No muscular movement is unusual	α-Syn positive neurons aixs cylinder shows the little body characteristics of Lewy, sends from neuron cell body	2002 J Clin. Invest 110:1429-1439 such as Kahle PJ
						Alpha-synapse nucleoprotein	The wt alpha-synapse nucleoprotein	C57BL/6	No record	Abnormal T g α-Syn positive neurons aixs cylinder is the feature of Lewy corpusculum disease,	2001.Am J Pathol. 159:2215-25. such as Kahle
Alpha-synapse nucleoprotein A30P or A53T	Alpha-synapse nucleoprotein A30P or A53T	Tg5093	Carrying out property movement disorders companion is stiff, myodystonia, gait is impaired and tremble	Can not identify discrete Lewy corpusculum sample alpha-synapse nucleoprotein inclusion body.The nigrostriatum dopaminergic system does not have specificity and degenerates.	Neurobiolog y of Aging 24 245-258 such as Gomez-Isla
						Alpha-synapse nucleoprotein	Alpha-synapse nucleoprotein. A30P or A53T	C3H/HeJx C57BL6/J	The carrying out property of outbreak neurodegenerative disease companion of growing up motor function is unusual	Neuron is unusual in perikaryon and the neural axon, comprises that the pathology of α-Syn and ubiquitin gathers	Lee etc., 2002 Proc Natl Acad Sci USA. 99:8968-73
The APP+ alpha-synapse nucleoprotein	Pedigree D heterozygosis α-SYN mice and the hybridization of pedigree J9 heterozygosis hAPP mice				2001.Proc Nat Acad Sci USA 98:12245-50 such as Masliah E

Embodiment 11: the mass spectrography evaluation is in conjunction with the chemical compound of NAC peptide

The compounds of this invention is estimated in conjunction with the ability of NAC peptide in aqueous solution.Binding ability is relevant with the intensity of passing through the observed peptide of Electrospray Mass Spectrometry-compound complex peak.Prepare all aqueous solutions with Millipore distillation deionized water.The Beckman Φ 36pH instrumentation that Corning Semi-Micro Combination pH electrode is equipped with in employing is decided pH value.

At first analyze the NAC (MW 3260.6Da) of 20 μ M at pH 7.40 ,+2 ,+3 and+4 observe common sodium bunch (sodium cluster), respectively in m/z 1335.5,1116.7 and 843.4.Best awl voltage is defined as 20V.

Mass spectral analysis---carry out mass spectral analysis with the Waters ZQ4000 mass spectrograph that Waters 2795 sample managing softwares are housed.Carry out date processing and analysis with MassLynx 4.0 (preceding version is MassLynx 3.5).Test-compound is mixed in water-bearing media (6.6%EtOH) with the ratio of 5: 1 (20 μ M NAC:100 μ M test-compounds or 40 μ M NAC:200 μ M test-compounds) with the depolymerization peptide.With 0.1%NaOH (3-5 μ L) pH of gained mixture is transferred to 7.4 (± 0.2).Regularly prepare the NAC peptide solution of 20 μ M or 40 μ M by same way as, with comparing.Following acquisition mass spectrum: by directly inculcating with the flow velocity of 25 μ l/min solution is introduced electrospray ionization source, and scan from 100-2100Da in the cation mode with syringe pump.Be 0.9 second the sweep time of each scanning, and the delay between the scanning is 0.1 second, and be 5 minutes the running time of each sample.All mass spectrums are the summation of 300 scannings.Desolvation and electrospray ionization source temperature are 70 ℃, and awl voltage and capillary voltage remain on 20V and 3.2kV respectively.

Measure each test-compound in conjunction with the gross area under the NAC-compound complex peak divided by not in conjunction with the quotient of gross area gained under the NAC peak.The results are summarized in the following table.

NAC peptide binding data

^*++ +=is strong; When summary is combined into 120% or when higher

++=medium; When total binding is between 120% and 70%

+=a little less than; When total binding is between 70% and 30%

Not-=do not have; When total binding is between 30% and 0%

Claims (54)

1. the method for protein aggregation disorders in treatment or the object of prevention, described method comprises

Give the described chemical compound of suffering from the object effective dose of protein aggregation disorders, make described protein aggregation disorders in the described object obtain medical treatment or prevent, wherein said chemical compound has one of following formula:

Q-[-Y ^--X ⁺] _n

Wherein Q is a carrier molecule; Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺X ⁺Be cation group, as atom or other parts of positively charged; The suitable carriers molecule comprises carbohydrate, polymer, peptide, peptide derivant, aliphatic group, alicyclic group, heterocyclic group, aromatic group or their combination; Perhaps

Wherein Y is amino or sulfonic group, and n is the integer of 1-5, and X is hydrogen or cation group; Perhaps

R wherein ¹Be replace or unsubstituted cycloalkyl, aryl, cycloalkyl aryl, bicyclo-or three rings, bicyclo-or three ring condensed ring group or replacement or unsubstituted C ₂-C ₁₀Alkyl; R ²Be selected from hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl; Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺X ⁺Be hydrogen, cation group or one-tenth ester group (be the one-tenth ester group in the prodrug, it locates to have description at this paper); L ¹And L ²Independently be that replace or unsubstituted C separately ₁-C ₅Alkyl or do not exist, or the acceptable salt of the medicine of described chemical compound, condition is to work as R ¹When being alkyl, L ¹Do not exist; Perhaps

R wherein ¹Be replace or unsubstituted ring, bicyclo-, three ring or benzheterocycle group or replacement or unsubstituted C ₂-C ₁₀Alkyl; R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl, benzimidazolyl, perhaps with R ¹Be connected to form heterocycle; Y is SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺X ⁺Be hydrogen, cation group or one-tenth ester moiety; M is 0 or 1; N is 1,2,3 or 4; L is that replace or unsubstituted C ₁-C ₃Alkyl or do not exist, condition is to work as R ¹When being alkyl, L ¹Do not exist; Perhaps

Wherein A is nitrogen or oxygen; R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester; Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl; X is 0,1,2,3 or 4; N is 0,1,2,3,4,5,6,7,8,9 or 10; R ³, R ^3a, R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aIndependently be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, cyano group, halogen, amino, tetrazole radical separately, perhaps two R groups on the adjacent loops atom form two keys with annular atoms, and condition is R ³, R ^3a, R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aOne of be part shown in the formula III a-A:

Wherein m is 0,1,2,3 or 4; R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Independently be selected from hydrogen, halogen, hydroxyl, alkyl, alkoxyl, haloalkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, cyano group, thiazolyl, triazolyl, imidazole radicals, tetrazole radical, benzothiazolyl and benzimidazolyl; And the drug acceptable salt and the ester of described chemical compound, condition is that described chemical compound is not 3-(4-phenyl-1,2,3,6-tetrahydrochysene-1-pyridine radicals)-1-propane sulfonic acid; Perhaps

Wherein A is nitrogen or oxygen; R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester; Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl; X is 0,1,2,3 or 4; N is 0,1,2,3,4,5,6,7,8,9 or 10; R ⁴, R ^4a, R ⁵, R ^5a, R ⁶, R ^6a, R ⁷And R ^7aIndependently be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl, cyano group, halogen, amino, tetrazole radical separately, R ⁴And R ⁵The annular atoms that connects with them forms two key, perhaps R ⁶And R ⁷The annular atoms that connects with them forms two keys; M is 0,1,2,3 or 4; R ⁸, R ⁹, R ¹⁰, R ¹¹And R ¹²Independently be selected from hydrogen, halogen, hydroxyl, alkyl, alkoxyl, haloalkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, cyano group, thiazolyl, triazolyl, imidazole radicals, tetrazole radical, benzothiazolyl and benzimidazolyl; Perhaps

Wherein A is nitrogen or oxygen; R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester; Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl; X is 0,1,2,3 or 4; N is 0,1,2,3,4,5,6,7,8,9 or 10; Aa is natural or the alpha-non-natural amino acid residue; M is 0,1,2 or 3;

R ¹⁴Be hydrogen or protecting group; R ¹⁵Be hydrogen, alkyl or aryl; Perhaps

Wherein n is 1,2,3,4,5,6,7,8,9 or 10; A is oxygen or nitrogen; R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester; Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl; X is 0,1,2,3 or 4; R ¹⁹Be hydrogen, alkyl or aryl; Y ¹Be oxygen, sulfur or nitrogen; Y ²Be carbon, nitrogen or oxygen; R ²⁰Be hydrogen, alkyl, amino, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl; R ²¹Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl, benzimidazolyl, if perhaps Y ²Be oxygen, R then ²¹Do not exist; R ²²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl, benzimidazolyl; If perhaps Y ¹Be nitrogen, R then ²²Be hydrogen, hydroxyl, alkoxyl or aryloxy group; If perhaps Y ¹Be oxygen or sulfur, then R ²²Do not exist; If perhaps Y ¹Be nitrogen, R then ²²And R ²¹Can be joined together to form annulus; Perhaps

Wherein n is 2,3 or 4; A is oxygen or nitrogen; R ¹¹Be hydrogen, salt-forming cation, one-tenth ester group ,-(CH ₂) _x-Q, perhaps when A is nitrogen, A and R ¹¹Can be natural together or alpha-non-natural amino acid residue or its salt or ester; Q is hydrogen, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl or benzimidazolyl; X is 0,1,2,3 or 4; G is direct key or oxygen, nitrogen or sulfur; Z is 0,1,2,3,4 or 5; M is 0 or 1; R ²⁴Be selected from hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, aroyl, alkyl-carbonyl, aminoalkyl carbonyl, cycloalkyl, aryl, aryl alkyl, thiazolyl, triazolyl, imidazole radicals, benzothiazolyl and benzimidazolyl; Each R ²⁵Independently be selected from hydrogen, halogen, cyano group, hydroxyl, alkoxyl, sulfydryl, amino, nitro, alkyl, aryl, carbocylic radical or heterocyclic radical;

And wherein said protein aggregation disorders is not an amyloid disease.

2. the method for protein aggregation disorders in treatment or the object of prevention, described method comprises

Give the described chemical compound of suffering from the object effective dose of protein aggregation disorders, make described protein aggregation disorders in the described object obtain medical treatment or prevent, wherein said chemical compound has one of following formula:

Wherein X is oxygen or nitrogen; Z is C=O, S (O) ₂Perhaps P (O) OR ⁷M and n independently are 0,1,2,3,4,5,6,7,8,9 or 10 separately; R ¹And R ⁷Independently be separately hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, with X form natural or alpha-non-natural amino acid residue part or-(CH ₂) _p-Y; Y is hydrogen or the heterocyclic moiety that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl; P is 0,1,2,3 or 4; R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl; R ³Be hydrogen, amino, cyano group, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, replacement or unsubstituted aryl, heteroaryl, thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl or benzimidazolyl; Perhaps

Each R wherein ⁴Independently be selected from hydrogen, halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkyl, aryl, carbocylic radical or heterocyclic radical; J be do not exist, oxygen, nitrogen, sulfur or bivalence bonding part, include but not limited to low-grade alkylidene, alkylidene oxygen base, alkylidene amino, alkylidene sulfenyl, alkylidene oxygen base alkyl, alkylidene amino alkyl, alkylidene sulfenyl alkyl, thiazolinyl, thiazolinyl oxygen base, alkenyl amino or thiazolinyl sulfenyl; Q is 1,2,3,4 or 5; Perhaps

Perhaps

Wherein X is oxygen or nitrogen; M and n independently are 0,1,2,3,4,5,6,7,8,9 or 10 separately; Q is 1,2,3,4 or 5; R ¹Be hydrogen, metal ion, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl or with X form natural or alpha-non-natural amino acid residue part or-(CH ₂) _p-Y; Y is hydrogen or the heterocyclic moiety that is selected from thiazolyl, triazolyl, tetrazole radical, imidazole radicals, benzothiazolyl and benzimidazolyl; P is 0,1,2,3 or 4; R ²Be hydrogen, alkyl, mercaptoalkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, alkyl-carbonyl, aryl carbonyl or alkoxy carbonyl; R ⁵Be selected from hydrogen, halogen, amino, nitro, hydroxyl, carbonyl, sulfydryl, carboxyl, alkyl, alkoxyl, alkoxy carbonyl, acyl group, alkyl amino, acyl amino; Q is the integer that is selected from 1-5; J be do not exist, oxygen, nitrogen, sulfur or bivalence bonding part, include but not limited to low-grade alkylidene, alkylidene oxygen base, alkylidene amino, alkylidene sulfenyl, alkylidene oxygen base alkyl, alkylidene amino alkyl, alkylidene sulfenyl alkyl, thiazolinyl, thiazolinyl oxygen base, alkenyl amino or thiazolinyl sulfenyl; Perhaps

R wherein ⁶Be that replace or unsubstituted heterocyclic moiety;

Wherein remaining substituent group definition is the same; And

Wherein said protein aggregation disorders is not an amyloid disease.

3. the method for protein aggregation disorders in treatment or the object of prevention, described method comprises

Give the described chemical compound of suffering from the object effective dose of protein aggregation disorders, make described protein aggregation disorders in the described object obtain medical treatment or prevent, wherein said chemical compound has one of following formula:

R wherein ¹And R ²Independently be separately hydrogen atom or replacement or unsubstituted aliphatic group or aryl; Z and Q independently are carbonyl (C=O), thiocarbonyl (C=S), sulfonyl (SO separately ₂) or sulfoxide (S=O) group; K and m are 0 or 1, and condition is when k is 1, R ¹Not hydrogen atom, when m is 1, R ²It or not hydrogen atom; T is linking group (as an alkylidene), and Y is formula SO ₃ ^-X ⁺, OSO ₃ ^-X ⁺Perhaps SSO ₃ ^-X ⁺Gene; X wherein ⁺It is cation group; Perhaps

R wherein ¹Be alkyl, thiazolinyl or mono-cyclic aromatic group, wherein said alkyl can be replaced by hydroxyl; R ²Be alkyl, thiazolinyl, hydroxy alkyl, mono-cyclic aromatic group or hydrogen atom, perhaps R ¹And R ²The nitrogen that connects with their forms the heterocyclic radical of condensed ring structure; K and m are 0, and p and s are 1; T is an alkylidene; Y is SO ₃X, X are cation groups; Perhaps

R wherein ¹Be alkyl, thiazolinyl or aromatic group; R ²Be hydrogen atom, alkyl or aromatic group, perhaps R ¹And R ²Form the heterocyclic radical of condensed ring structure together; Z and Q independently are carbonyl (C=O), thiocarbonyl (C=S), sulfonyl (SO separately ₂) or sulfoxide (S=O) group; K is 1, and m is 0 or 1, and condition is when k is 1, R ¹Not hydrogen atom, when m is 1, R ²It or not hydrogen atom; P and s each naturally 1; T is an alkylidene; Y is SO ₃X, X are cation groups; Perhaps

R wherein ¹And R ²Be alkyl, thiazolinyl or mono-cyclic aromatic group, perhaps R ¹And R ²The nitrogen that connects with their forms the heterocyclic radical of condensed ring structure; K and m are 0, and p and s are 1; T is an alkylidene; Y is SO ₃X, X are cation groups; Perhaps

R wherein ¹Be alkyl, thiazolinyl or mono-cyclic aromatic group, wherein said alkyl can be replaced by hydroxyl; R ²Be alkyl, thiazolinyl, mono-cyclic aromatic group or hydrogen atom, wherein said alkyl can be replaced by hydroxyl; Perhaps R ¹And R ²The nitrogen that connects with their forms the heterocyclic radical of condensed ring structure; K and m are 0, and p and s are 1; T is an alkylidene; Y is SO ₃X, X are cation groups;

And the drug acceptable salt and the prodrug of described chemical compound,

Wherein said protein aggregation disorders is not an amyloid disease.

4. the method for the protein aggregation disorders in the controlled plant, described method comprises

Give each the chemical compound of claim 1-3 of the described object effective dose of suffering from protein aggregation disorders, make that the described protein aggregation disorders in the described object is adjusted, wherein said protein aggregation disorders is not an amyloid disease.

5. regulate the accumulative method of detrimental protein for one kind, described method comprises

Each the chemical compound of claim 1-3 of detrimental protein aggregation and effective dose is contacted, and it is adjusted to make described detrimental protein assemble, and wherein said detrimental protein aggregation and amyloid disease have nothing to do.

6. regulate Cytotoxic method for one kind, described method comprises

Each the chemical compound of claim 1-3 of the cell that has harmful protein aggregate and effective dose is contacted, make that described cytotoxicity is adjusted, wherein said detrimental protein aggregation and amyloid disease have nothing to do.

7. each method of claim 1-4, wherein said to as if mammal.

8. the method for claim 7, wherein said mammal are human.

9. each method of claim 1-4, wherein said protein aggregation disorders is selected from Pick's disease, the degeneration of cortex basal nuclei, benumb on the carrying out property nuclear, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, parkinson (PD), Huntington's disease (HD), dystrophia myotonica, the Louis body atrophy of dentate nucleus rubrum pallidum, the Fu Lidelixishi ataxia, fragile X syndrome, fragile X E brain development is slow, spinal cord oblongata muscular atrophy, Wilson's disease, and spinocebellar ataxia 1 type (SCA1), spinocebellar ataxia 2 types (SCA2), Ma-Yue disease (MJD or SCA3), spinocebellar ataxia 6 types (SCA6), spinocebellar ataxia 7 types (SCA7), spinocebellar ataxia 17 types (SCA17), chronic hepatopathy, cataract, silk presses down the albumen disease, hemolytic anemia, Cystic fibrosis, neurofibromatosis 2 types, the demyelinating peripheral neuropathy, retinitis pigmentosa, Marfan syndrome, edema due to disorder of QI, idiopathic pulmonary fibrosis, argyrophilic grain dementia, the degeneration of cortex basal nuclei, diffusivity neurofibrillary tangles companion calcification disease, frontotemporal dementia FTD/the parkinson's syndrome related with chromosome 17, Ha-Si disease, C type Ni-Pi disease and subacute sclerosing panencephalitis.

10. each method of claim 1-4, wherein said protein aggregation disorders is a familial disease.

11. each method of claim 1-4, wherein said protein aggregation disorders is an idiopathic disease.

12. each method of claim 1-4, wherein said protein aggregation disorders is the alpha-synapse nucleoprotein disease.

13. each method of claim 1-4, wherein said protein aggregation disorders is the tau protein disease, and condition is that described tau protein disease is not Alzheimer, prion disease or cerebral amyloid angiopathy.

14. the method for claim 13, wherein said tau protein disease are selected from amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, argyrophilic grain dementia, the degeneration of cortex basal nuclei, diffusivity neurofibrillary tangles companion calcification disease, the frontotemporal dementia FTD/parkinson's syndrome related with chromosome 17, Ha-Si disease, multiple system atrophy, C type Ni-Pi disease, Pick's disease, the carrying out property nuclear and benumb and subacute sclerosing panencephalitis.

15. the method for claim 12, wherein said alpha-synapse nucleoprotein disease are parkinson, Xi-De syndrome, nerve orthostatic hypotension, Xi-Mai-De syndrome and parkinson supraposition syndrome.

16. the method for claim 6, wherein said cytotoxicity relates to neurotoxicity.

17. the method for claim 6, wherein said cytotoxicity is relevant with inclusion body.

18. the method for the neurofibrillary tangles relevant with tau protein in treatment or the object of prevention, described method comprises

Give each the chemical compound of claim 1-3 of described object effective dose with neurofibrillary tangles relevant, make the neurofibrillary tangles relevant described in the described object obtain medical treatment or prevent with tau protein with tau protein.

19. the method for the neurofibrillary tangles relevant with tau protein in the controlled plant, described method comprises

Give each the chemical compound of claim 1-3 of the described object effective dose of suffering from the neurofibrillary tangles relevant, make that the neurofibrillary tangles relevant with tau protein described in the described object is adjusted with tau protein.

20. contain the method for the pulsating inclusion body of alpha-synapse nucleoprotein NAC in treatment or the object of prevention, described method comprises

Give described claim 1-3 with the object effective dose that contains the pulsating inclusion body of alpha-synapse nucleoprotein NAC each chemical compound, make that containing the pulsating inclusion body of alpha-synapse nucleoprotein NAC described in the described object obtains medical treatment or prevent.

21. contain the method for the pulsating inclusion body of alpha-synapse nucleoprotein NAC in the controlled plant, described method comprises

Give described claim 1-3 with the object effective dose that contains the pulsating inclusion body of alpha-synapse nucleoprotein NAC each chemical compound, make that to contain the pulsating inclusion body of alpha-synapse nucleoprotein NAC described in the described object adjusted.

22. effectively suppressing detrimental protein, each method of claim 5 or 52-56, wherein said effective dose assemble.

23. the method for claim 6, wherein said effective dose effectively suppresses cytotoxicity.

24. further comprising described chemical compound and medicine acceptable carrier united, each method of claim 1-6,18-21 or 26-27, wherein said method give.

25. regulate the accumulative method of detrimental protein for one kind, described method comprises makes protein aggregate contact with chemical compound, makes that described detrimental protein gathering is adjusted, wherein said chemical compound is each a chemical compound of claim 1-3.

26. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is the outer aggregations of born of the same parents.

27. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is aggregations in the born of the same parents.

28. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is the kytoplasm aggregation.

29. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is the nuclear aggregation.

30. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is an aggregation in the film.

31. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is in endoplasmic reticulum.

32. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is in Golgi body reverse side network.

33. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is relevant with aggregation.

34. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is relevant with the misfolding of mature protein.

35. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is relevant with proteinic incorrect degraded.

36. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is relevant with the misfolded proteins matter of escaping ubiquitin-proteasome system.

37. assembling, claim 5,6 or each method of 50-54, wherein said detrimental protein is suppressed.

38. claim 5,6 or each method of 50-54, wherein by improving the degraded of described protein aggregate, it is adjusted that described detrimental protein is assembled.

39. claim 5,6 or each method of 50-54, wherein by increasing the clearance rate of described protein aggregate, it is adjusted that described detrimental protein is assembled.

40. claim 5,6 or each method of 50-54, wherein said detrimental protein gathering is relevant with fibril, beta sheet or hydrophobic domains.

41. a pharmaceutical composition, described compositions comprise each the chemical compound and the medicine acceptable carrier of claim 1-3 of effective dose, wherein said effective dose can effectively be treated protein aggregation disorders.

42. the pharmaceutical composition of claim 41, wherein said protein aggregation disorders is selected from Pick's disease, the degeneration of cortex basal nuclei, benumb on the carrying out property nuclear, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, parkinson (PD), Huntington's disease (HD), dystrophia myotonica, the Louis body atrophy of dentate nucleus rubrum pallidum, the Fu Lidelixishi ataxia, fragile X syndrome, fragile X E brain development is slow, spinal cord oblongata muscular atrophy, Wilson's disease, and spinocebellar ataxia 1 type (SCA1) gene, spinocebellar ataxia 2 types (SCA2), Ma-Yue disease (MJD or SCA3), spinocebellar ataxia 6 types (SCA6), spinocebellar ataxia 7 types (SCA7), spinocebellar ataxia 17 types (SCA17), chronic hepatopathy, cataract, silk presses down the albumen disease, hemolytic anemia and Cystic fibrosis, Pick's disease, the degeneration of cortex basal nuclei, benumb on the carrying out property nuclear, amyotrophic lateral sclerosis/parkinson's syndrome-chronic brain syndrome, parkinson (PD), Huntington's disease (HD), dystrophia myotonica, the Louis body atrophy of dentate nucleus rubrum pallidum, the Fu Lidelixishi ataxia, fragile X syndrome, fragile X E brain development is slow, Ma-Yue disease, spinal cord oblongata muscular atrophy, Wilson's disease, spinocebellar ataxia and cataract.

43. packaging compositions, described compositions is with having the active The compounds of this invention treatment of targeted therapy protein aggregation disorders, and described compositions comprises the explanation that has the active The compounds of this invention of described targeted therapy and treat described protein aggregation disorders about the described The compounds of this invention of use.

44. a method of identifying candidate compound, described chemical compound can be used for treatment or prevention protein aggregation disorders, described method comprises:

A) test-compound is given the protein aggregation disorders mouse model;

B) determine that carrying out property degeneration relevant with described protein aggregation disorders in described test-compound prevention, adjusting, reduction or inhibition and the described mouse model changes the effectiveness of development;

C) determine that described selection chemical compound is the candidate compound in order to treatment or prevention protein aggregation disorders.

45. claim 5,6 or each method of 50-54, wherein said detrimental protein aggregation is with at least a to be selected from following protein relevant: alpha-synapse nucleoprotein, tau protein, NAC, Huntington protein, DRPLA, neurolemmal cell tumor albumen, cytokeratin, myelin protein 22, rhodopsin, atrophy albumen-1, fibrillin-1, ataxia albumen-1, ataxia albumen-2, the ataxia protein-3, ataxia albumen-6, the ataxia protein-7, the ataxia protein-17, androgen receptor, surfactant protein-C and alpha1-antitrypsin.

46. a method of identifying candidate compound, described chemical compound can be used for prevention, regulate, reduce or suppress the detrimental protein aggregation, described method comprises:

A) at external contact detrimental protein aggregation;

B) determine that described test-compound prevents, regulates, reduces or suppress the effectiveness of detrimental protein aggregation;

C) determine that described selection chemical compound is the candidate compound in order to treatment or prevention protein aggregation disorders.

47. the method for claim 6, wherein said cell are neuronal cell or neurogliocyte.

48. further comprising, the method for claim 44, described method determine that described test-compound promotes the effectiveness that described detrimental protein aggregation is removed.

49. further comprising, the method for claim 44, described method determine that described test-compound promotes the effectiveness of described detrimental protein aggregation degraded.

50. regulate the accumulative method of detrimental protein for one kind, described method comprises

Each the chemical compound of claim 1-3 of detrimental protein aggregation and effective dose is contacted, make that the accumulative removing of described detrimental protein is adjusted, assemble thereby regulate detrimental protein, wherein said detrimental protein aggregation and amyloid disease are irrelevant.

51. regulate the accumulative method of detrimental protein for one kind, described method comprises

Each the chemical compound of claim 1-3 of detrimental protein aggregation and effective dose is contacted, make that described detrimental protein aggregating cells toxicity is adjusted, assemble thereby regulate detrimental protein, wherein said detrimental protein aggregation and amyloid disease are irrelevant.

52. regulate the accumulative method of detrimental protein for one kind, described method comprises

Each the chemical compound of claim 1-3 of the protein that forms beta sheet structure tendency and effective dose is contacted, make that described detrimental protein gathering is adjusted, wherein said protein aggregation disorders is not an amyloid disease.

53. regulate the accumulative method of detrimental protein for one kind, described method comprises

Each the chemical compound of claim 1-3 of the protein that forms beta sheet structure tendency and effective dose is contacted, make that the accumulative removing of described detrimental protein is adjusted, assemble thereby regulate detrimental protein, wherein said protein aggregation disorders is not an amyloid disease.

54. regulate the accumulative method of detrimental protein for one kind, described method comprises

Each the chemical compound of claim 1-3 of the protein that forms beta sheet structure tendency and effective dose is contacted, make that described detrimental protein aggregating cells toxicity is adjusted, assemble thereby regulate detrimental protein, wherein said protein aggregation disorders is not an amyloid disease.

Images