TW200848063A - Methods and compositions for the treatment of neurodegenerative disorders - Google Patents

Abstract

Provided are compositions, kits, and methods for treating, preventing, and ameliorating neurodegenerative disorders, e. g., Huntington's disease.

Description

200848063 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the treatment, prevention, and alleviation of neurodegenerative disorders such as Huntington's disease and its symptoms. [Prior Art] In general, the present invention relates to the treatment, prevention, and alleviation of neurodegenerative disorders such as Huntington's disease and its symptoms. Neurodegenerative disorders affect millions of individuals. One such disorder, polyglutainate expansi〇n disorder, is characterized by the presence of an expanded CAG repeat region in a gene coding sequence. Although in these disorders, the critical length of CAG expansion is measurable, longer repeat lengths generally result in an earlier onset of the disease. For utton chorea, the critical aG repeat length for disease onset is generally considered to be greater than 38 CAG, resulting in the formation of a polyglutathione domain proximal to the n-terminus of the Huntington protein. Huntington's disease (10), which affects at least nine known hereditary polyglutamines, affects men and women at the same frequency, with about 5-10 per 100:000. It can be determined by five characteristics · heritability; dance a disease '仃 or psychiatric interference; cognitive dysfunction (cancer); and late onset 'death 15 2 years after the onset of motor dysfunction. In most patients, the onset of this disease occurs between 3 and 5 years of life. HD is a species-chromosomal dominant hereditary disorder with a mutation in chromosome 4. This gene is encoded as - large protein, huntmgtin (ϋ ΐ t), and 呑 蛋白 暂 暂 暂 暂 暂 暂 暂 暂 暂 暂 暂 暂 要 要 要 要 要 要 要HD due to the huntingtiη

1084>9596-PF 5 200848063 The (htt)-based CAG repeats expansion, resulting in the appearance of a dilated polysitrite (p〇 1 y Q) region near the N-terminus of Htt. Although the disease progression of HD is accompanied by extensive loss of brain neurons, the earliest lesions are observed in striatums, especially moderately spine neurons, and are less in the cerebral cortex. The fundamental pathogenesis of HD has not been fully resolved. The main hypotheses include: excitotoxicity, granulocyte dysfunction, ubiquitin-mediated cleavage of proteolysis, protease-dependent accumulation of polyglutamine protein fragments, formation of cytosol and nuclear inclusions, Changes in gene expression, and neuronal cell degradation and death. Although the pattern of death in neuronal cells continues to be controversial, there is considerable evidence that apoptosis (ap〇pt〇sis) plays an important role. Although some patients have reduced chorea and psychotropic medications with known antipsychotics to address depression, obsessive-compulsive symptoms, or psychosis, there is currently no HD therapy. There are currently no effective therapies for preventing or slowing the progression of HD. Therefore, there is a need to develop effective new therapies to treat, prevent or reduce HD and other neurodegenerative disorders. SUMMARY OF THE INVENTION The present invention provides for the treatment, prevention, and the possible use of compositions, methods, and kits.

Compositions, methods and kits. The compositions described herein are useful for treating patients suffering from or suffering from polygluten. The combination of symptoms associated with neurodegenerative disorders described here, depression, compulsive behavior, psychosis

1084-9596-PF 6 200848063 , and the interference of behavior. Accordingly, the present invention provides a composition comprising: one or more diterpenoids, independently selected from the agents of Tables 13 and 11); and one or more of the second different agents' independently selected from Table 1 and 2 categories and pharmaceuticals. One or a plurality of agents of the table la and lb may be, for example, a paracyclic antidepressant, an ionophore antibiotic (i-antibiQtiGS), a cannabinoid receptor synergist two-channel blocker, an antihistamine, a selective serotonin. Resorption inhibitors (SSRIs), anticholinergics, PDE inhibitors, or estrogen modulators. In some embodiments, the first and second agents are selected from the list of Tables 3a and 3b. In the case where the first agent and the second agent are present, when administered to a patient, it is sufficient to treat, prevent or alleviate a neurodegenerative disorder, such as a disorder selected from the group consisting of: Amine dilatation disorders (eg HD, Dentatorubropallidoluysian atrophy, Kennedy's disease (also known as spinal medullary muscular atrophy), and spinocerebellar ataxia (eg type 1 and type 2) , type 3 (also known as Mach ado-Joseph disease), type 6, type 7 'and type 17 () type), other trinucleotide repeat expansion disorders (eg, fragile X-line incompatibility, fragile XE mental retardation, Fr i edreich's cerebellar ataxia Tiao, myotonic dystrophy, spinal cord cerebellar ataxia type 8, and vertebral cerebellar ataxia type 12), Alexandria, A1 per disease, Alzheimer's disease, amyotrophic lateral sclerosis , cerebellar ataxia telangiectasia, Batten's disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, cortical basal ganglia degeneration, creutzf eldt - Jakob

1084-9596-PF 7 200848063 Disease, ischemic stroke, celebral disease, dementia with Lewy bodies, multiple sclerosis, multiple systemic atrophy, Parkinson's disease, Pel izaeus_Merzbacher disease, Pick disease, primary lateral sclerosis , Refsum's disease, Sandhoff's disease, SchUder's disease, spinal cord injury, spinal muscular atrophy, Steele-Rlchards〇n - 〇lszewski disease, and spinal cord dorsalis). The composition can be formulated in any route of administration, for example, orally, systemically, intracranically, intrathecalally, or epidurally. / The present invention also provides a composition comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient consists of the following: :::: two forms of the agent: and - the second is different (four) , categories ... and 2, and pharmaceuticals. In some embodiments, the first and second medicaments are selected from the individual columns of Tables and 3b. Sexual Disability =: Lifting: A method for treating, preventing, or alleviating neurodegenerative injections, by using a single dose independently of the expression a. 1 — The above agents that prevent or alleviate this neurodegenerative disorder. In addition to the treatment, the present invention further provides a method for the treatment of sputum disorders, which is independently selected from Table 113 by means of an agent for preventing or alleviating a neurodegeneration: The different agents are independently selected from: different types of drugs, treatment, prevention or alleviation of the nerve retreat: sexual disorders: categories and medicaments, the amount is sufficient to treat the invention, and the method for the treatment of sexual disorders is From the treatment of a disease or a neurodegenerative agent, the agents are independently selected from ~ χ 1 less than 2 different t drugs ... & and any agent of 1b, which

1084-9596-PF 200848063 The first and second agents are administered simultaneously or administered in 28 days, and the amount of a leaf is used to treat, prevent or alleviate the neurodegenerative disorder. In a specific embodiment, the 2nd rate diterpene agent is selected from the list of Table 1. The first and the hour, 12 hours, 18 hours, 24 hours, 3 days, 7 days or 14 days are administered. 1 to:: In some cases, 'the method described here, for the patient to give one of the eclipse agents, such as the ring-shaped antidepressant, ionophore anti-sheng Xin ^ Qing ^ mail heart), cannabinoid receptor synergy Agent, channel resistance = n histamine, selective serotonin re-absorption of drugs, P ..., or estrogen regulation: neuronal mortality in patients (such as humans). This:,, the special method can include additional therapies. For example, if the patient is given an additional therapeutic agent, the treatment may include a lb of the drug or a plurality of agents and the additional treatment, which is sufficient for treatment and pre-treatment. The child is placed, and when the additional therapeutic agent is administered, for example, it can be selected from: =: degenerative from the appearance of the cockroach... species or a variety of Huajing 2: categories and medicaments. It can be administered simultaneously or at each other for one hour. 2 additional therapeutic agents, hour, hour, 18 hours, administered via any route. Within 7 days or 14 days, the present invention further provides a kit, a package of -1 and 1b; and instructions for the spleen - Loose agent, selected from the table la suffering from nerve withdrawal b 4 Finally, the agent for patients with or right (four) test ^. «(4)

1084-9596-PF 200848063 3, 4 or more types of white visitor, the agents of Tables 1a and 1b, but not necessarily pre-mixed in the same composition φ to include the additional agent or evening seed The instructions are instructed to be administered to the patient using 'or a fungic agent or the well-mixed composition. From the Ming and the other: supply-type kits, including: 2, 3, 4 or more choices, pharmaceuticals; and more than one type independently selected from Table 2. "These agents are not - must Premixed in the same composition. This kit may also include a reference to + % + heart instructions for the administration of such agents to patients with or at risk of deliberate neurodegenerative disorders. The kit 'includes: 2, 3, 4 or 4 or more of the agents selected for &lb; or 1 or more of the ethical agents independently selected from Table 2. The kit may further include instructions f for These agents are administered together to patients with or at risk of developing neurodegenerative disorders. Any of the two sets of agents described herein can be selected from the list of supplements. A method for identifying a combination that may be used for treatment, prevention, or a light-neuronal degenerative disorder, comprising the steps of: (4) providing - a cell comprising a gene encoding one of a polyglutamine repeat polypeptide to cause the The multi-peptide repeats the multi-peptide with wild-type polyglutamine, including the expanded polyglutamine repeat region; (8) the gene is expressed; (c) the cell is contacted with cells selected from Table 13 and "-, and a candidate compound" and (4) is determined by comparison with cells that are in contact with the agent but are not in contact with the candidate compound, The combination of the agent and the candidate compound reduces the nuclear staining of the p〇iyQ antibody, such as 1F8, in the nucleus

1084-9596-PF 10 200848063 Peripheral staining (e.g., as determined by immunocytochemistry (IC C) analysis) identifies a combination that may be useful for treating, preventing, or ameliorating a neurodegenerative disorder. The polyglutamine repeat polypeptide comprising an expanded polyglutamine repeat region can include, for example, full length Htt Q111 or other multipeptide variants associated with polyglutamine dilatation disorders. The method may use, for example, a mammalian cell, such as a mouse striate cell, such as a force Q111 cell derived from a knock-in mouse. Table la Pharmacy (negative staining around the cell 50 EC50 (juM) (negative staining around the cell 90 Imax (cell density inhibition? 0 EC50 (// M) (cell density inhibition 90 1-[2-(1Η-吲哚-3- Ethyl]-3-mercapto-1H-°Pilo_2, 5-di_97. 0°/〇4.61 99.00% 1.51 2-Amino-8-hydroxyquinoline 61.9% 26.01 58.70% 16.81 A -134974 (eg dihydrogenated hydrogen salt monohydrate) 32. 5% 14.20 40.30% 15.10 Acetopromazine (eg maleate) 49. 8% 23.89 32.10% 19.81 AG-879 87.4% 3.09 76. 23% 2.48 Ajmaline 52 4% 18.40 -16.60% N/A Akt inhibitor IV 52. 4% 1.52 64.25% 1.07 Alverine (eg citrate) 67. 9% 15.49 6. 62% N/A Ami odarone (eg hydrogen chloride) 37. 9% 24.38 -4.99% N/A Amlodipine (eg benzoate) 91.43⁄4 8.22 80.923⁄4 13.46 Amsacrine 93. 8% 4. 54 63.81% 0.04 Andrographis 96.3% 15.92 53.10% 7.46 Antazoline sulphate 28. 3% 26.34 -5.19% N/A Apomorph i ne (eg gasified hydrogen salt) 50. 7% 25.72 46. 27% 15.11 Astemizole 91.9% 5.92 100.28% 10.60 Auranofin 90. 0% 2.42 99.18% 1.12 Azelastine 32.1% 7.32 17.18% BAPTA-AM 91.6% 10.79 80.70% 6.24 Bay 11-7082 93.1% 5.39 97.80% 4. 80 Benztrop i ne (eg bismuth salt) 44.1% 18.70 -7. 27% N/A Bepridil 55. 7% 4.96 16.203⁄4 13.60 BML-248 68. 9% 4.44 -13.33% N/A BTCP (eg gasified argon salt) 49. 43⁄4 4.36 -5.32% N/A Calcimycin A23187 78.53⁄4 1.21 72.45% 0.77 Calmidazolium 95. 33⁄4 8.72 95.893⁄4 8.17 Capecitabine 56. 9% 20.06 1.053⁄4 N/A Carboxymethylene Norch1orpromaz i ne 54. 0% 12.14 2. 33% N/A Cepharanthine 97. 9% 10.67 96.81% 13.18 Cerivastatin (eg sodium salt) 30.1% 0.15 9 · 493⁄4 N/A CGP74514A 102.8% 19.61 101.23% 7. 60

1084-9596-PF 11 200848063 Pharmacy Inax (Cellular Peripheral Staining Inhibition » ECso ( " M) (Nuclear Peripheral Staining Inhibition 90 Iaax (Cell Density Inhibition %) ~98.33%8=8 Ε〇5〇( ^ Μ) (Cell Density inhibition 9〇Chelerythrine (eg gas salt) 94. 2% 1.56 1.52 Chiorhexidine 71.6% 4. 56 97. 88% 7. 39 Chlorhexidine (eg diacetate) 94. 4% 13. 56 74. 60% 4. 70 Chloroxine 43.1% 16.82 58. 91% 13.08 Chlortetracycline (eg gasified hydrogen salt) 75. 4% 21.89 30. 40% 14.50 clemastine (eg fumarate) 80. 7% 9.91 6. 70% 10.20 Clemizole (eg gasified argon salt) 44. 0% 7. 47% Ν/Α Clofoctol 83. 7% 17.83 47. 76% 27.08 Clomiphene (eg #595) 62. 5% 5.28 82. 00% 16.10 Cloperastine (eg hydrogen chloride) 53. 7% 7. 67 27.19% 21.95 Colchicine 60. 6% 0.47 66. 36% 0.38 Cycloheximide 89. 2% 0.12 75. 75% 0.53 Cyproheptad i ne (eg gasified hydrogen salt) 62. 2 % 14.00 -0. 06% Ν/Α Dactinomycin 54. 9% 0.02 17. 95% Desloratadine 103.0% 20.50 76. 70% Dexamethasone (eg B Salt) 57. 8% 17.90 11.70% Ν/Α Dibucaine (eg gasification hydrogen salt) 29. 53⁄4 25.52 -2. 58% Ν/Α Dichlorophen 50. 6% 25.49 8.16% Ν/Α Dicyclomine (eg hydrogen chloride) 55 4% 13.90 -4.10% Ν/Α diphenyleneiodonium (eg gas salt) 60. 2% 19.55 33. 46% 1.22 Doxorubicin (eg argon chloride salt) (formulated) 56. 33⁄4 0.38 29. 56% 0.04 Drofenine 59. 5% 25.33 -8. 69% Ν/Α Duloxetine 73. 0% 16.19 94.03% 28.86 Ethopropaz i ne (eg gasified hydrogen salt) 69. 5°/〇15.50 -17. 70% Ν/Α Flunarizine (eg gasification Hydrogen salt) 27. 3% 16.80 15.20% Fluvastatin 39.13⁄4 8.09 33. 60% 6.42 Gemcitabine (eg gasification hydrogen salt) 43. 8% 0.02 47. 30% 0.01 Hexachlorophene 79.1% 4. 23 -4 72% Ν/Α Homochlorcyclizine (eg dihydrogenated hydrogen salt) 99.1% 15.70 95. 00% 15.40 Maduramicin (eg ammonium salt) 75.5% 0.06 60. 00% 3.31 Mebhydroline 1,5-naphthalene (eg disulfonate) 32. 63⁄4 5.80 18. 09% 9.02 Mefloquine 97. 83⁄4 15.27 96. 53% 16.57 Menadiol (eg disodium disulfate trihydrate) 86 8% 11.91 100.47% 10.83 Metergoline 87. 8°/〇10.90 32. 00% 21.20 Methdilazine 35. 2% 6.54 -8.13% Ν/Α Methdilazine (eg hydrogen chloride) 31.2°/〇8.01 98. 56% 24.42 Methotrimeprazine ( For example, maleate) 52. 9°/〇22.77 -2. 01% Ν/Α Methyl benzimidate (eg gasification hydrogen salt) 40. 6°/〇3. 04% Ν/Α MG-132 93. 63⁄4 2.40 90. 50% 0.89 Mitoxantrone (eg gasification hydrogen salt) 56. 53⁄4 0.15 52. 80% 0.02 Narasin 84. 6« 0.07 73. 70% 9.59 Niclosamide 73. 9% 0.76 32. 50% 2.16 Nigericin 81.3% 0.005 4. 75% Ν/Α Nitazoxanide 94. 4% 7.12 -8. 89% Ν/Α

1084-9596-PF 12 200848063 Pharmacy Iaax (nuclear periplasmic staining inhibition? 〇55. 53⁄4 EC50 (//M) (Nuclear peripheral staining inhibition 90 Iaax (cell density inhibition EC50 (M) (cell density inhibition!) 〇Oxiconazole (eg Acid salt) 22.50 37. 40% 23.60 Paramethadione 14.1°/〇6.80% N/A Perlapine 38. 2% 9.99 -6. 67% N/A PKR inhibitor 94.9% 7.41 95.90% 5.25 Propoxyphene (eg gasification Hydrogen salt) 21.93⁄4 17.23 -16.73% 19.40 Pyrithione zinc 62. 3% 1.31 76. 30% 3.30 Quinidine (eg glycolate) 35. 0% 23.60 -7. 95% N/A Raloxifene (eg hydrogen chloride) 63 5% 14.00 59. 70°/〇19.20 Salinomycin (eg sodium salt) 81.3% 0.23 18.48% 1.31 Sorafenib 71.0% 26.83 16.75% 19.37 Spiramycin 39. 3% 17. 58 -10.40% N/A Tamoxifen (eg citrate 88.13⁄4 11.20 3. 693⁄4 N/A Thiethyl perazine (eg maleate) 100.6% 16.76 96.20% 19.52 Thiram 36. 2% 7. 92 53. 70% 12.00 Toremifene (eg citrate) 70.2% 15.96 32.60% 26.24 Trihexyphenidyl (eg gasified hydrogen salt) 33.1% 21.80 -9. 49% N/AT Rimeprazine 58.1% 23.25 3. 98% N/A Tyrphostin 9 70. 3% 1.01 48.80% 2.51 Ursolic acid 94· 03⁄4 24.15 55.83% 20.91 Γ Valinomycin 93. 8°/〇1.65 25.20% N/A II Vanoxerine 78. 53⁄4 9.11 101.00% 26.50 Vinblastine (eg sulphate) 81.03⁄4 0.12 23.29% N/A Vincristine (eg sulphate) 35. 5% 0.03 28.10% 0.05 II Vindesine (eg sulphate) 32. 3% 0.07 17.643⁄4 0.39 13

1084-9596-PF 200848063 Table lb

Drug Ioax (negative staining around the cell w EC50 (/z M) (inhibition of nuclear staining around the cell 90 Iaax (% inhibition of cell density) EC50 (// M) (% inhibition of cell density) ACR16 56.4% 10.90 -9. 68% N/ A Adenosine 34. 0% 22.49 -4. 57% N/A Amitriptyline (eg gasified hydrogen salt) 43. 6°/〇28.00 -17. 60% N/A Amodiaquine 70.1°/〇15.80 73. 70% 19.40 Amoxapine 43. 6°/〇26.90 11.59% CGS 15943 37. 7% 12.34 11.88% N/A Chloroquine (eg, acid salt) 81.33⁄4 8.14 -5.11% N/A Ch 1 orpromaz i ne (eg gas Hydrogen salt) 90. 9% 12.91 86. 94% 11.64 Chlorprothixene (eg gasification hydrogen salt) 60. 3% 16.60 -16.50% 5.48 Clomipramine (eg hydrogen chloride) 58. 6% 11.80 26. 90% 16.00 Clozapine 48. 4% 15.76 -16.43% N/A Desipramine (eg hydrogen chloride) 37. 9% 15.24 -19.54% N/A Dimebon 21.0% 12.40 3. 34% N/A Fluoxetine (eg hydrogen chloride) 71.4% 10.33 104.14% 25.18 Fluphenazine (eg hydrogen chloride) 29.13⁄4 14.75 66. 46% 25.42 Fluvoxamine (eg maleate) 34. 7% 19.00 13. 60% 24.20 Haloperido l 30. 8% 23.49 9. 50% N/A HU-210 89.1% 12.30 99.20% 16.50 hydroxy ch 1 oroqu i ne (eg sulfate) 74. 9°/〇 14.10 -10.60% N/A IKK-2 inhibitor VIII 71.9% 21.80 92. 30% 13.40 IMD-0354 81. 2X 0.64 60. 67% 2.65 Maprotiline (eg gasified hydrogen salt) 64. 5% 17.50 88.06% N6-Benzy1adenosine 84.4% 15.41 76. 20% 10.16 Nabilone 97.1% 12.70 57. 70% N/A Norfluoxetine (eg gasification hydrogen salt) 36. 6% 5.27 -12.21% N/A Nortriptyline (eg gasification hydrogen salt) 60. 8% 11.00 24.10% 26.90 Paroxetine (eg hydrogenated hemihydrate) 47. 0% 11.31 64. 89% 27.02 Perphenazine 43. 83⁄4 8.95 -26.73% 14.06 Pimethixene 69. 9% 18.08 -8. 72% N/A Prochlorperazine (eg maleate) 51.8% 15.29 -17.02% 2.79 Promethazine (eg gasification hydrogen salt) 34. 6% 17. 80 -22. 70% N/A Protriptyline (eg gasification hydrogen salt) 31.5% 12.93 49. 983⁄4 25.68 SAHA (Suberoylanilide hydroxamic Acid) 56. 9% 3.33 60. 00% 0.47 Sertraline (eg gasification hydrogen salt) 55. 53⁄4 8.31 88. 20% 24.60 Tetrabenazine 32. 6% 7.96 56.11 % 22.85 Tetrahydrocannabinol 22. 3% 0.04 -3. 74% N/A Thioridazine (eg hydrogen chloride) 73. 5% 7. 78 98. 62% 14.37 1 WIN 55,212-2 76.1% 7. 45 -21.20% N/A 14

1084-9596-PF 200848063 Table 2 1 Illustrated agent anti-apoptotic agent (Ant i apoptot ic) minocycline (minocycline), trogl itazone, 11 pioglitazone, and Taurosodeoxycholic acid (an ti depressant) fluoxetine, sertraline argon, and nortriptyline antioxidants (ant i ox i dant) lipoic acid ), melatonin, BN 8251, 0PC-14117, and antipsychotic antipsychotic drug or psychotropic drug (Anti psychot ic/psychotropic), haloperidol, clozapine, Chlorpromazine, and olanzapine Bioenergetic Coenzyme Q10, Creatine, and Dichloroacetate COX Inhibitor/NSAID Fluorbiprofen, Naproxen Naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, n piroxicam, indomethacin (indomethacin), different cloth Ibuprofen, nabumetone, bilirubin salicylate, sodium salicylate, hydrazine, fenoprofen, ketoprofen, meclofenamate Sodium), meloxicam, oxaprozin, sulindac, tolmetin, rofecoxib, celecoxib, valdecoxib, and lumiracoxib dopamine antagonist olanzapine, quetiapine, and butylbenzene Terbenazine glutamate antagonists riluzole, remacemide, amantadine, memantine, ifendprodil, and eliprodil histone deacetylase inhibitors Agent/transcriptional regulators sodium butyrate, phenylbutyrate, suberoylanilide hydroxamic acid, and mithramycin heat shock protein regulators geldanamycin, celastrol, bimoclomol, and arimoclomol immunomodulator Copolymer 1 mood stabilizer chain, sodium valproate (valproate), and carbamazepine anti-psychotic drugs (Neuroleptic) dopamine receptor blockers (such as fluoride briquettes (hal Operidol), perphenazine, and presynaptic dopamine depleting agents (eg reserpine) protein agglutination inhibitor cystamine, and trehalose trehalose (Tranqui 1 izer) clonazepam, benzene And benzodiazepine (eg alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, diazepam, flunitrazepam, lorazepam, nitrazepam, oxazepam, temazepam or triazolam), paroxetine, venlafaxine, and beta-blocking Agents (eg acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, labetalol, metoprolol, nadolol, penbutolol, propranolol, sotalol and timolol) nutrients or tonics (GD), BDNF, CNTF, fetal streak cells, And other cells for colonization of other cannabinoids (eg, delta-9-tetrahydrocannabinol, tetrahydrocannabivarin, cannabidiol, cannabino, cannabidivarin, and cannabinolic acid), BCTC, chain, ethyl-EPA, free lipids Acids (e.g. palmitic acid, stearic acid, and arachidonic acid), rapamycin, KW60Q2, and botulinum toxin

1084-9596-PF 15 200848063 Table 3a Combined HSA Volume Synergy Score (Synergy Score) Bepridil x Metergoline 5. 47 0.81 Metergoline x Tyrphostin 9 4.49 0.97 Gas 喧 硫酸 sulfate x Maduramicin ammonium salt 4.49 0.93 Bepridil x Dactinomycin 4.32 1.81 Chlorine Hexachlorophene 4.06 1.40 Cyproheptadine gasification hydrogen x hexaphene 4. 02 0.98 gas lindane sulphate x Nitazoxanide 3.83 0.73 Benztropine bismuth salt X hexaphene 3. 70 0.79 gas Clemastine fumarate X hexaphene 3. 65 0.74 Cyproheptadine gas hydrazine x Chlorprothixene gasification hydrogen 3.65 0.74 hexafluorophene X hydroxyquinoline sulphate 3. 65 0.54 Chlorprothixene Hydrogen chloride x Tyrphostin 9 3 65 0.80 Bepridil x sertraline hydrogenated hydrogen 3.60 0.20 Benztropine oxime acid salt X Tyrphostin 9 3.52 0.84 tamoxifen citrate X Tyrphostin 9 3.50 0.75 clemastine fumarate X Nitazoxanide 3.48 0.56 Chlorprothixene gas b hydrogen x Metergoline 3.46 0.51 six gas xenon Vanoxerine 3.41 0.52 six gas xenon Thioridazine hydrogen chloride 3.38 0.95 Nitazoxanide x Tyrphostin 9 3.37 0.55 sertraline gasified argon x Thioridazine gasification hydrogen 3.37 0.47 gas 嗤 硫酸 sulfate x Tetrahydrocannabinol 3.37 0.99 hexaphene fen X sertraline hydrogen chloride 3.36 0.75 Alverine citrate X Nitazoxanide 3. 35 0·81 Thioridazine Hydrogen Chloride x Vanoxerine 3.31 0.30 I Metergoline x Nitazoxanide 3.24 0.65 Dicyclomine Hydrogen Chloride x Nitazoxanide 3. 20 0.53 Gas Masking Fumarate x Sertraline Hydrogenated Hydrogen 3.16 0.74 Gas Sulfate Sulfate X Nitazoxanide 3.11 0.38 Alverine Citric Acid Salt X Dicyclomine Hydrogenated Hydrogen 3.11 0.82 Metergoline x Niclosamide 3.10 0.50 Metergoline x Vanoxerine 3. 08 0.48 Gas masted fumarate x Vanoxerine 3.08 0.42 hexaphene x Tyrphostin 9 3.07 0.31 gas masted fumarate x Tyrphostin 9 2.98 0.32 Chlorprothixene gas nitrogen x Nitazoxanide 2. 98 0.77 Bepridil x WIN 55,212-2 2. 97 0.35 hexaphene x tamoxifen citrate 2. 95 0.58 Ajmaline X hexaphene 2.92 0.75 Dactinomycin x Liuqifen 2. 92 1.14 Paroxetine Hydrogenated Hydrogen Hemihydrate X Sertraline Gasified Argon 2.91 0.68 Chlorprothixene Hydrogen Chloride X Maduramicin Salt 2.86 0.62 Benztropine Vermiculite X Nitazoxanide 2.81 0.56

1084-9596-PF 16 200848063 Combined HSA Volume Synergic Score (Synergy Score) Meridian Sulfate X Vanoxerine 2. 81 0.39 Nabilone X Thioridazine Hydrogenated Hydrogen 2.79 0.29 Hexaphene x Oxiconazole nitrate 2.77 0.72 Alverine Citrate x Liuqifen 2.76 0.89 gas masted fumarate x Thioridazine hydrogenated hydrogen 2. 76 0.15 Maduramicin salt X Tyrphostin 9 2. 76 0.22 Bepridil x Thioridazine hydrogen chloride 2.75 0.46 Chlorprothixene hydrogenated gas x hexafen 2.72 0.60 Met ergo Line x Thioridazine Hydrogenated hydrogen 2.71 0.38 Chlorprothixene Hydrogenated hydrogen x Nigericin 2. 66 0.65 Dicyclomine Hydrogenated hydrogen x Tyrphostin 9 2.60 0.66 Chlorprothixene Hydrogen chloride x IMD-0354 2.60 0.09 Hydroxylquinone sulfate x Tyrphostin 9 2.60 0.32 Acid salt x Nigericin 2.59 0.97 Cyproheptadine hydrogen chloride x sertraline hydrogen chloride 2.58 0.22 gas hydrazine salt X Maduramicin salt 2.56 0.72 Dicyclomine hydrogen sulfide X Nigericin 2. 54 0.66 Ethopropazine hydrogen chloride X hexaphene 2. 53 0.47 Cyproheptadine gasification Hydrogen x Tyrphostin 9 2.47 0.49 Nitazoxanide x Oxiconazol e nitrate 2.45 0.13 hexafluorophene x mD-0354 2.44 0.26 Dicyclomine hydrogenated gas x hexafluorocarbon 2.43 0.71 gas masted fumarate x IMD-0354 2.41 0.27 Benztropine oxime acid salt x Metergoline 2.39 0.37 Nitazoxanide x Thioridazine gas Nitrogen 2.39 0.07 Alverine Citrate x Sertraline Hydrogenated Hydrogen 2. 37 0.08 Hexafen X Maduramicin Salt 2.36 0.30 Cyproheptadine Hydrogenated Hydrogen X Maduramicin Ammonium Salt 2.33 0.29 Sertraline Hydrogenated Hydrogen X Tamoxifen Lemon Acid salt 2.32 0.18 gas masted fumarate X Niclosamide 2.29 0.27 Benztropine oxime acid salt X Niclosamide 2. 28 0.49 Dimebon x Niclosamide 2. 27 0.57 hexafluorophene x Nigericin 2.24 0.36 Benztropine methic acid salt x Bepridil 2.23 0.44 Ajmaline x Tyrphostin 9 2.23 0.40 Nitazoxanide x Vanoxerine 2.21 0.16 Bepridil x tamoxifen citrate 2. 18 0.51 Bepridil x hexaphene 2. 17 0.11 Niclosamide x Quinidine Glycolate 2.16 0.51 Sertraline hydrogenated hydrogen x Tyrphostin 9 2. 15 0.30 Dicyclomine Hydrogenated Hydrogen x Trihexyphenidyl Hydrogenated Hydrogen 2. 13 1.02 Quinidine Glycolate x Vanoxerine 2. 13 0.60 Bepridil x Vanoxerine 2.13 0.14 Ethopropazine Nitrogen x Trihexyphenidyl Nitrogen 2. 12 0.47 Bepridil x Chlorprothixene Hydrogen chloride 2. 12 0.20 17

1084-9596-PF 200848063 Combined HSA volume synergy score (Synergy Score) Benztropine alpha phoxate x Ethopropazine Hydrogenated hydrogen 2.10 0.47 gas masted fumarate x Nabilone 2.10 0.65 Alverine citrate x Nigericin 2.09 0.40 Chlortetracycline Hydrogenated hydrogen x hexachlorophene 2.08 0.19 hexaphene X Met ergo line 2.07 0.31 hexaphene x Nitazoxanide 2.07 0.56 Cyproheptadine gasification hydrogen x gas 啥 硫酸 sulfate 2. 05 0.39 Alverine citrate X Tyrphostin 9 2. 04 0. 64 Liuqifen X Paroxetine Hydrogenated Hydrogen Hemihydrate 2. 04 0.15 Ethopropazine Hydrogenated Hydrogen X via Chloroquinone Sulfate 2. 04 0.22 Bepridil X IMD-0354 2. 02 0.59 Dicyclomine Hydrogenated Hydrogen X Thioridazine Hydrogen 2.00 0.34 Mercuryline Sulfate X Niclosamide 1.99 0.15 Maduramicin Salt x Nitazoxanide 1.99 0.11 Tyrphostin 9 x Vanoxerine 1.99 0.18 Cyproheptadine Gasification A x Nitazoxanide 1.96 0.38 Ethopropazine Hydrogen Chloride x Tyrphostin 9 1.95 0.48 Met ergo line x Paroxetine Gasification Hydrogen Hemihydrate 1.93 0.22 Nitazoxanide x Sertraline Hydrogenated Hydrogen 1.92 0.26 Benztropine Rhein X Vanoxerine 1.92 0.62 Benztropine acid salt X gas masted fumarate 1.91 0.59 Benztropine mesylate X tamoxifen citrate 1.90 0.17 Ethopropazine Hydrogenated hydrogen x Nabi lone 1.89 0.83 Alverine lemon Acid salt x Benztropine methacrylate 1.89 0.20 Chlorprothixene Hydrogenated hydrogen x Nabi lone 1.84 0.55 hexafluorophene x Quinidine glycolate 1.79 0.39 Nabilone x Nitazoxanide 1.77 0.32 Alverine citrate x Quinidine glycolate 1.77 0.18 Nitazoxanide x Nigericin 1.76 0.13 Bepridil x Quinidine Glycolate 1.75 0.28 Paroxetine Hydrogen Chloride Hemihydrate x Tyrphostin 9 1.73 0.21 Tricarboline Sulfate X Nigericin 1.69 0.65 IMD-0354 X Vanoxerine 1.69 0.15 Nitazoxanide x Trihexyphenidyl Hydrogenated Hydrogen 1.68 0.70 Alverine Citric Acid Salt x Vanoxerine 1.65 0.27 clastastine fumarate x tamoxifen citrate 1.64 0.35 Bepridil X clumastine fumarate 1.57 0.26 Bepridil x Ethopropazine Hydrogen chloride 1.57 0.32 Ethopropazine Hydrogenated hydrogen x Thioridazine hydrochloride 1.53 0.39 Fluvastatin x Tyrphosti n 9 1.50 0.57 sertraline hydrogenation x Vanoxerine 1.49 0.15 Chlorprothixene hydrochloride x Vanoxerine 1.48 0.27 Alverine citrate x gas leaching sulphate 1.47 0.17 Bepridil x Nitazoxanide 1.44 0.21 Chlorprothixene hydrochloride x Quinidine Glycolate 1.44 0.43

1084-9596-PF 18 200848063 Combined HSA Volume Synergy Score IMD-0354 x Maduramicin Recorded Salt 1.43 T〇6 Metergoline x Sertraline Hydrogen Chloride 1.41 0.26 Gastrope Leachate x Cyproheptadine hydrochloride 1.33 0.76 IMD-0354 x Metergoline 1.23 0.14 Tamoxifen citrate x Thioridazine hydrochloride 1.07 0.12 Chiorprothixene hydrochloride x Prochlorperazine Maleate 4.83 2. 04 Methotrimeprazine Maleate x Paroxetine Hydrogen Hydrochloride Hemihydrate 4. 03 1.44 Perphenazine x Thioridazine hydrochloride 3.70 1.09 Chiorprothixene hydrochloride x Maprotiline hydrochloride 2.86 2.29 Metergoline x Promethazine hydrochloride 2.75 0.61 Clomipramine hydrochloride x Mercury Sulfate 2.71 1.37 Chiorprothixene hydrochloride x Trimeprazine 2.63 0.74 Nortriptyline Hydrogenated Hydrogen x Thioridazine hydrochloride 2. 45 1.35 Maprotiline hydrochloride x Paroxetine Hydrogenated Hydrogen Hemihydrate 2. 39 1.23 Metergoline x Nortriptyline Hydrogenated Hydrogen 2.38 1.64 Paroxetine Hydrogen Hydrochloride Half Water Compound X Perphenazine 2. 33 1.16 Chiorprothixene hydrochloride x Flunarizine hydrochloride 2.31 0.66 Amiodarone hydrochloride x Meridian sulfate 1.18 1.12 Perphenazine x sertraline gasification 2.02 1.12 Paroxetine hydrogen chloride hemihydrate x Pimethixene 2.01 0.81 Promethazine hydrochloride x Thioridazine Hydrochloride 1.99 0.31 clomiphene citrate x sertraline hydrogenated hydrogen 1.88 0.42 hydroxy gas sulfonate sulfate X Trimeprazine 1.87 0.58 Flunarizine hydrochloride x Metergoline 1.76 0.58 hydroxyquinoline sulfate x nortriptyline ( Nortriptyline) Hydrogen Chloride 1.69 1.28 Paroxetine Hydrogenated Hydrogen Hemihydrate X Thioridazine hydrochloride 1.63 0.42 IMD-0354 x Trihexyphenidyl hydrochloride 3.12 0.84 Nigericin x Vanoxerine 2. 83 0.20 Trihexyphenidyl hydrochloride x Vanoxerine 2.60 0.67 Thioridazine hydrochloride x Trihexyphenidyl hydrochloride 2. 52 0.30 Sting fumarate x Quinidine glycolate 2.50 0.74 Bepridil x Dicyclomine hydrochloride 2.30 0.27 Paroxetine hydrogen chloride hemihydrate x hemo Fen citrate 2.12 0.10 gas mascot fumarate X Trihexyphenidyl hydrochloride 2.10 0.66 Thioridazine hydrochloride x Nigericin 1.94 0.07 Nitazoxanide x tamoxifen citrate 1.86 0.43 Oxiconazole nitrate x Tyrphostin 9 1.78 0.46 Tyrphostin 9 x Nigericin 1.63 0.25 gas Maastin fumarate x Metergoline 1.63 0.07 Cyproheptadine hydrochloride x Metergoline 1.62 0.26 Quinidine glycolate x sertraline hydrogenated hydrogen 1.58 0.31 Nitazoxanide xparoxetine hydrogenated hemihydrate 1.56 0.08 _ 19

1084-9596-PF 200848063 Table 3b Combined HSA Volume Synergy Score 1 (flucyetine) Hydrogenated hydrogen X toremifene citrate 5.16 1.14 Ί Amiodarone hydrochloride X toremifene Citrate 2.85 0.78 Clomi SKclomiphene) Citrate X Sertraline Hydrogenated Hydrogen 2. 74 1.04 Fluoxetine Hydrogenated Hydrogen X Tamoxifen Citrate 2.41 0.71 Chlorprothixene hydrochloride X Nortriptyline (nortriptyline) gasification hydrogen 2. 34 0. 62 paroxetine hydrogen chloride x toremifene citrate 2.29 0.49 Thioridazine hydrochloride X toremifene citrate 2.15 0.64 || Chlorporthixene hydrochloride X Paroxetine hydrogenated hydrogen 2.15 0.53 Duloxetine X toremifene citrate 2.11 0.44 fluoxetine hydrogen chloride X sertraline hydrogenated hydrogen 1.93 0.47 fluvoxamine maleate X Thioridazine hydrochloride 1.90 0.39 fluoxetine gasification Hydrogen x N-desmethyltamoxifen 1.88 0.55 Nortriptyline Hydrogenated hydrogen X Tamoxifen citrate 1.71 0.49 Duloxetine x Thioridazine hydrochloride 1 .71 0.30 Chlorporthixene hydrochloride x Duloxetine 1.70 0.28 Defertalin gasified argon x toremifene citrate 1.69 0.66 clomiphene citrate X Duloxetine 1.68 0.57 Amiodarone hydrochloride X sertraline gas Hydrogen 1.67 0.54 Chlorporthixene hydrochloride X Fluvoxamine maleate 1.67 0.47 Chlorporthixene hydrochloride X Fluoride; Dihydrogenated hydrogen 1.65 0.29 | Fluvoxamine maleate X N-desmethyl tamoxifen 1.54 0.46 By "effective amount" is meant a compound, alone or in combination with other therapeutic therapies, in a clinically relevant manner, in need of treatment, prevention or alleviation of a neurodegenerative disorder, such as HD. The effective amount of active compound for the therapeutic treatment of neurodegenerative disorders depends on the mode of administration, the age of the patient and general health. Ultimately, the prescriber will determine the appropriate amount and dose therapy. In addition, an effective amount, which may be the amount of the compound in the combination, is safe and effective for treating a patient suffering from a neurodegenerative disorder such as HD, each agent being determined and approved by the competent authority alone (eg, US food and medicine) Authority). "Candidate compound" means a chemical that can be naturally occurring or human 20

1084-9596-PF 200848063 Made. Candidate compounds can include, for example, peptides, polypeptides, synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components and derivatives thereof. The compounds useful in the present invention are in any of their pharmaceutically acceptable forms, including: isomers, such as diastereomers and mirror image isomers ( Enanti〇mer), salt, ester, sulphate and its polymorph (p〇lym〇rph), as well as the (exo) racemic mixture of the compounds described herein and the pure isoform Structure. The δ species may also be isotopically calibrated compounds. Useful isotopes' include: hydrogen, carbon, nitrogen, oxygen, structure, fluorine, and chlorine (eg, 2{1, %, 13c, -C-SN-8〇.^〇.3^32p^5s^8FA36ci)〇 ^^#^ Preparation of Compounds can be synthesized by substituting a non-isotopic calibration reagent using an easily available isotope calibration reagent. "Expanded polyglutamine repeat region" means a poly-glutamine repeating peptide, wherein the number of glutamine residues is greater than the number of glutamine residues in the corresponding wild-type polypeptide. The compound of the expanded polyglutamine repeat region, such as the full length HttQlll, includes a region of ln glutamine residues. The expanded polyglutamine repeat region comprises more than, for example, 5, 15, 15, 20, 25, 30, 35, 4, 45, 5, 55, Mm, 80, 85, 9G, 95 or even Just a glutamine residue. Or the expanded polyglutamine repeat region 'comprises more than, for example, 1, 2, 3, 4, 5, 10, 15, 20, 25 compared to the number of glutamine residues in the corresponding wild-type polypeptide. , 3〇, 35, 40, 45, 50, 55, 6〇, 65, 70, 75, 80, 85,

90, 95 or even more than 100 glutamine residues. 1084-9596-PF 21 200848063 “High dose” means the standard recommendation of a given route of administration above a given compound for any human disease or condition (eg, at least 10%, 20%) , 50%, job, 2〇〇% or even job). example. For example, one of the high doses for the prevention or slowing of the rate of neurodegeneration or death associated with neurodegenerative disorders and formulated for intravenous administration may be different from the high dose for the same pharmaceutical formulation for oral administration. A low dose '' means at least 5% lower than the recommended minimum dose for a particular compound to treat any human condition in a given path (eg, at least 1 (U, 20%, 50%, 80%, 90%, or even 95%) "Neurodegenerative disorder," means any disease or disorder associated with deterioration of cells or tissues of the nervous system. Exemplary neurodegenerative disorders are polystamine dysfunction disorders (eg HD, dentate red nucleus pallidus) Atrophy = (Dentatorubropallidoluysian atrophy), Kennedy's disease (also known as spinal medullary muscular atrophy), and spinocerebellar ataxia (eg type 1, type 2, type 3 (also known as Machado-Joseph disease), beta Type, type 7, and type 17)), other trinucleotide repeat dilatation disorders (eg, fragile sputum syndrome, fragile sputum mental retardation, Friedreich's cerebellar ataxia, myotonic dystrophy, spinal cord cerebral Ataxia type 8, and spinocerebellar ataxia type 12), Alexandria, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, cerebellar ataxia telangiectasia, Ba Teng disease (also known as

Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease,

Cockayne syndrome, cortical basal ganglia degeneration, Creutzf eldt — Jak〇b disease, ischemic stroke, celebral disease, dementia with Lewy bodies, multiple sclerosis,

1084-9596-PF 22 200848063 Multiple systemic atrophy, Parkinson's disease, PeHzaeus-Merzbacher disease, Pick disease, Primary lateral sclerosis, Refsum's disease, Sandhoff's disease, Schilder's disease, Spinal cord injury, Spinal muscular atrophy, Steele-Richardson-01szewski disease, and spinal cord dorsal is "patient" refers to any animal, such as a mammal (eg, human). Other animals that can be treated using the methods, compositions, and kits of the invention include: horses, dogs, cats, pigs, goats, rabbits, hamsters, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and bird. Patients who are to be treated for neurodegenerative disorders such as HD have been diagnosed with this condition by a medical practitioner. Diagnosis can be performed by any suitable method, such as those described herein. Patients who wish to prevent the development of neurodegenerative disorders may or may not receive such a diagnosis. Those skilled in the art will understand that a standard test may be performed when a person has a high risk due to the presence of more than one risk factor, such as age, family history of neurodegenerative disorders, and a psychological or psychiatric profile. Or has been identified without testing. "Domino-recitin repeats multi-peptide, meaning any multi-peptide that contains at least 5 consecutive glutamine residues. The illustrated polyglutamine repeats multi-peptide, which is an obstacle to expansion with polyglutamine (eg HD, Dentatorubropallidoluysian atrophy, Kennedy's disease (also known as spinal medullary muscular atrophy), and spinocerebellar ataxia (eg type 1, type 2, type 3 (also Called Machado-Joseph disease), type 6, 7

Type, and type 1 7)) related. For example, associated with a fairy, the polypeptide is repeated for a poly glutamine. 1084-9596-PF 23 200848063 Used in combination with peptides and peptides, and refers to any chain of more than two natural or unnatural amino acids, whether or not post-translationally modified (eg, glycosylated or phosphorylated) ), which constitutes all or part of a naturally occurring or non-naturally occurring multi-peptide or peptide as described herein. As described herein, a native amino acid is a naturally occurring alpha-amino acid having an L-configuration, such as is typically found in natural proteins. An unnatural amino acid refers to an amino acid that does not normally occur in a protein, such as an epimer having a natural alpha-amino acid having an L-configuration, ie, having a non-natural d configuration. An amino acid; or a (D,L)-isomeric mixture thereof; or a homologue of such an amino acid, such as a non-amino acid, an α-disubstituted amino acid or an α-amino acid Wherein the amino acid side chain is shortened by hydrazine or 2 methylene groups, or is extended to up to 10 carbon atoms, for example, an α-amino alkanoic acid having 5 to fluorene carbon atoms is unsubstituted or in the straight chain Substituting aromatic (α-aryl or α-aryl lower alkyl) 'for example substituted phenylalanine or phenylglycine. Wang Yi I* biotechnology refers to all nondermal, nondermal, and especially topical and transdermal routes. Treating, preventing or ameliorating neurodegenerative disorders means reducing the condition before or after the onset. The degree of such reduction or prevention is measured according to any standard technique, relative to an equal untreated control group, at least , m , 20% , 30% , 40% , 50% , 60% , 70% , 80% , 90% , 95% or 100% 总 a general description of the compounds described herein, in a specific class of substituents The atomic number of 5 L is usually given a range, for example, a pyridyl group or a Ci-Ce alkyl group containing 1 to 6 carbon atoms. This range is intended to be included herein.

1084-9596-PF 24 200848063 A group with an integer number of atoms in the range. For example, c y , ^ For example, an alkyl group ϊ to β carbon atoms 'includes Cl, C2, C3, C4, C=i; ® Γ Γ k and c6. The Ci-Cu heteroalkyl group includes, for example, in addition to one or more kinds of hetero atoms, including T T丨匕祜1 to i 2 carbon atoms. Other atomic numbers and other atom types can be represented in a similar manner. The term "alkyl" and radical "alk_", as used herein, includes both straight and branched chains, and cyclic groups, ie, cycloalkyl. The cyclic group may be monocyclic or polycyclic, and In some embodiments, it contains from 3 to 6 ring carbon atoms. Examples of the oxime group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Ci-C6 alkyl" means a branched or unbranched fe group having 1 to 6 carbon atoms. The Ci-C6 alkyl group may be substituted or unsubstituted. The exemplified substituents include alkoxy groups. , aryloxy, thiol, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoroalkyl, amine, aminoalkyl, disubstituted amine, quaternary amine, hydroxy Alkyl, carboxyalkyl and carboxyl. Cl-c6 alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl , 2 butyl, 3 butyl and cyclobutyl. "C2-C6 alkenyl" means a branched or unbranched hydrocarbon group containing one or more double bonds and 2 to 6 carbon atoms. C2-C6 alkenyl Optionally, a monocyclic or polycyclic ring may be included, wherein each ring is desirably having a 3 to 6 membered ring. The C2-C6 alkenyl group may be substituted or unsubstituted. The exemplified substituents include alkoxy groups, aromatic groups. Oxygen, thiol, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoroalkyl, amine, aminoalkyl, disubstituted amine, quaternary amine, hydroxyalkyl , slow base burning and Wei The C2-C6 alkenyl group includes, but is not limited to, vinyl, allyl, 2-cyclopropyl-1-vinyl, propylene, butenyl, 1084-9596-PF 25 200848063 2-butyl Base, 3-butenyl group, 2-methyl-1 -propenyl group, and 2-mercapto-2-propane group

"C 2 - C 6 block: ', stand, A think', containing more than one key and 2 to 6 carbon j-knife or non-branched hydrocarbon groups. C2-C6 alkynyl may optionally include a single %以上% or 参裱', wherein each ring is desirably having a 5 or 6 membered ring. The alkynyl group may be substituted or unsubstituted. The exemplified substituents include alkoxy, aryloxy, sulfhydryl, and Thio group, arylthio group, dentate, mercapto group, fluorine group, perfluoroalkyl group, amine group, amino group, amine group, quaternary amine group, thiol group, thiol group and The aryl group. The CrC6 alkynyl group includes, but is not limited to, a B-group, a propyl group, a 3-butynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, and a C2-C6 heterocyclic group, Means a stable 5 to 7 membered monocyclic ring or a 7 to 14 membered double soil heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic) and includes 2 to 6 carbon atoms and 2, 3 or 4 heteroatoms independently selected from N, hydrazine and S, and including any bicyclic group, wherein any of the heterocyclic rings defined above is fused to a -benzene ring. The heterocyclyl group may be substituted or unsubstituted The exemplified substituents include alkoxy groups and aromatic groups. Base, sulfhydryl group, sulfur-sulfur group, arylthio group, hydroxyl element, mercapto group, fluoroalkyl group, all-gas alkyl group, amine group, amine group, disubstituted amine group, quaternary amine group, (four) a base, (d) a thiol group and a ruthenium group. The nitrogen and sulfur heteroatoms can be optionally oxidized. The heterocyclic ring can be covalently attached via any hetero atom or carbon atom, resulting in stable formation, for example, a di- ortho-position ring can be Linked to any ring carbon atom position or nitrogen atom. The nitrogen atom in the hetero ring can be arbitrarily quaternized. In some embodiments, when the total number of s and deuterium atoms in the heterocycle exceeds 丨, then the heteroatoms are not Adjacent. 2 ring package

1084-9596-PF 26 200848063 Includes but are not limited to: 1H-carbazole, 2-pyrrolidone, 2H, 6H-1,5,2-dithiacarbyl, 2H-fluorenyl, 3H-fluorenyl , 4-acridinone, 4aH-isoxazole, 4H 0 gu  Qin, 1, 2, 5-113⁄4 σ 秦 基, σ 丫 、, π 丫 octinyl, benzyl bromide Benzo, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzethyl, benzathionyl, benzaltrisyl, benzethirazolyl, benzyl isoxazole, Benzylisothiazolyl, benzimidazolone, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromany, chromenyl, cinnol inyl, decahydroquinolyl, 2H,6H-1,5,2- 'di-π-s-decyl, dihydroindeno[2,3-b]tetrahydrofuran, n-folyl, acetoin-imidazol idiny 1 ), imidazolinyl, succinyl, iH-called | Sitting group, indoleny 1, porphyrin, pyridazinyl, fluorenyl, isobenzofuranyl, isopropenyl, isoxazolyl, isoindolyl, isoindole Basis, isoindole, heterosexual base, and different. Ruthenyl, morphinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl 1,2, 5-oxadiazolyl, 1,3,4-oxadidecyl, σ. Sitting on the base, ° sulphate, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsaziny 1, phenaziny 1, phenazine嗟 恶 恶 恶 phen (phenoxathiinyl), phenoxazinyl, phthalazinyl, foxazinyl. Gualouding base, 嗓11 basal, piperidonyl, 4-17 melon ketone group, biting base, σ 呤 呤, 旅 基 base, u 嗓 base, σ 峻 峻 咬 base, 吼唆琳基,° ratio σ sit base, tower 17 Qin base, ϋ 咬 bite and 嗤 嗤 嗤 吼 吼 吼 吼 吼 吼 嗤 嗤 嗤 嗤 嗤 嗤 嗤 吼 吼 吼 吼喧 喧, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, 1084-9596-PF 27 200848063 quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxaline , acridine, porphyrin, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, thiadiazinyl, 1,2,3-thiadiazolyl, 1,2, 4 -thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazole Base, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-diazolyl, 1,3,4- Dimercapto, xanthenyl) In some embodiments, a 5- to 10-membered heterocyclic ring includes, but is not limited to, a pyridyl group, a pyrimidinyl group, a tripodyl group, a decyl group, a thienyl group, a thiazolyl group, a pyrrolyl group, a pyrazolyl group. , imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, fluorenyl, benzimidazyl, 1-oxazolyl, oxazolidinyl, isoxazole Pyridyl, benzotriazolyl, benzylisoxazolyl, hydroxyindenyl, benzoic Oxazolinyl, porphyrinyl and isoquinolinyl. In some embodiments, a 5- to 6-membered heterocyclic ring includes, but is not limited to, an acridinyl group, a pyrimidinyl group, a triazinyl group, a furyl group, a thienyl group, a sigma group, a sigma-based group, a guar group, a fox sigma. Fixed base, ^ than sulfhydryl, taste σ sitting base. The scorpion sits on the base, the sigh base and the four sigma base. "Aryl" means an aromatic group having a ring system with a carbon atom (for example, a phenyl group) conjugated to a redundant electron. The aryl group has 6 to 2 carbon atoms. The aryl group may be optionally selected. The nature includes a monocyclic, bicyclic or cyclized ring wherein each ring is preferably a 5 or 6 membered ring. The aryl group may be substituted or unsubstituted. The exemplified substituents include alkyl, hydroxy, alkoxy, Aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxy, hydroxyalkyl, carboxyalkyl, amine, aminoalkyl, monosubstituted amine, disubstituted amine And a quaternary amine group. 1084-9596-PF 28 200848063 "C?-M alkaryl" means an aryl group (eg, benzyl, phenethyl or 3,4-dibenzene) Ethyl) substituted alkyl having 7 ^ , (to U carbon atoms. "Cm. alkane heterocyclyl" means having from 3 to 10 carbons in addition to one or more heteroatoms substituted by an alkyl group a heterocyclic group of an atom, (for example, 3-furylmethyl, 2-furylmethyl, 3-tetrahydrofuranylmethyl or 2-tetrahydrofurylmethyl). "Ch heteroalkyl" means Branch or An alkyl, alkenyl or alkynyl group having from 1 to 7 carbon atoms, in addition to the heteroatoms of the following N, 0, S and P groups, independently of the branch, 2, 3 or 4 Heteroalkyl, including but not limited to tertiary amines, secondary amines, ethers, thioethers, decylamines, thioguanamines, carbamates, carbamides, hydrazones, imines, phosphorus doubles Esters, phosphoramidates, sulfonamides and disulfides. Heteroalkyl groups may optionally include monocyclic, bicyclic or sulphonic rings, wherein each ring is desirably a 3 to 6 membered ring. It may be substituted or unsubstituted. The exemplified substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, _, hydroxy, fluoroalkyl, perfluoroalkyl, amine, Aminoalkyl, disubstituted amine 'quaternary amine', carbyl, hydroxyalkyl, carboxyalkyl and carboxyl groups.

Examples of the Ci - 7 miscellaneous group include, but are not limited to, methoxymethyl and ethoxyethyl. "Halogen" means bromine, chlorine, iodine or fluorine. "Fluoroalkyl" means an alkyl group substituted with fluorine. "Perfluoroalkyl" means an alkyl group consisting solely of carbon and fluorine atoms. "Carboxyl group" means a chemical structure having the formula -(R)-COOH, which

1084-9596-PF 29 200848063 wherein R is selected from Cm alkyl, o-alkenyl, C27 alkynyl, heterocyclyl, C^2 aryl, anthracene-!4 alkaryl, alkynyl and Ci_? heteroalkyl. ''Hydroxyalkyl" means a chemical structure having the formula -(R)-〇H, wherein R is selected from c"alkyl, alkenyl, I. alkynyl, CM heterocyclyl, aryl, C7-14 alkaryl group, C3-1G alkylene group and Ch heteroalkyl group.

Alkoxy means a chemical substituent of the formula _ 0R wherein R is selected from C" alkyl, Cw alkenyl, cardinyl alkynyl, 6 heterocyclyl, Q decaaryl, OM pyraryl, C3, Alkylheterocyclyl or anthracenealkyl. Aryloxy means a chemical substituent of the formula -0R wherein R is a Ce^aryl group. _ 6'12 "Alkylthio" refers to a chemical substituent of the formula -SR, wherein R is selected from the group consisting of Ch alkyl, C" alkenyl, c" alkynyl, C2 6 heterocyclyl, aryl, C^ 4 an aryl group, a C3-H alkane heterocyclic group and a Ci 7 heteroalkyl group. "Arylthio" refers to a chemical substituent of the formula _SR wherein R is a Ce12 aryl group. _ "Quaternary amine group, refers to a chemical substituent of the formula -(R)-N(R, )(R,,)(R,,,), wherein R, R, R, and R, , independently, is a decyl, alkenyl, alkynyl or aryl group. R 彳 is an alkyl group having a quaternary amine nitrogen atom as a substituent and other moieties. The four carbon atoms and/or aryl groups of the alkyl group, such as the nitrogen atomic band and other features and advantages of the invention, will be apparent from the following detailed description.

1084-9596-PF 30 200848063 The compounds provided by the present invention, when used alone or in combination, are effective in treating, preventing or ameliorating neurodegenerative disorders. The compositions, methods and kits described herein may be useful for treating patients at risk of developing or suffering from polystamine dilating disorders such as HD. Therefore, for patients who have been diagnosed with or suffering from neurodegenerative disorders, j, 2, 3 or 4 or more of the agents independently selected from Tables 1 a and 1 b are administered. Optionally, analogs of such agents can be employed. In the case of polyglutamine dilatation disorders, for example, this rate can prevent or slow the rate of neurological deterioration or death. The ability of the agent to prevent or slow the rate of neurological deterioration or death can be attributed, for example, to its ability to inhibit mutant polyglutamine proteins, such as Htt, which cause disease. Optionally, the patient can also receive other treatments. In a specific embodiment, the patient to be treated is administered two independent agents selected from Tables 1a and 1b, and within 28 days of each other, the total amount is sufficient to prevent, or alleviate, the neurodegenerative disorder. . These pharmacies hope that within 14 days ♦ they will be better placed within 7 days of each other, and even better if they are within 24 J, the Japanese Guardian, or even at the same time. One of the two agents can be administered in a low dose, as needed. Diagnosis of Neurodegenerative Disorders The methods and compositions described herein are useful for treating any condition that has been diagnosed as having or suffering from a neurodegenerative disorder such as HD. This diagnosis may or may not be accepted in patients who wish to prevent the development of neurodegenerative disorders. People in this technical field will know what to expect! Individuals are at high risk due to the presence of more than one risk factor. They may have implemented standard tests or have not tested

1084-9596-PF 31 200848063 Under identification. God, ,,: Degenerative disorders such as the diagnosis of HD can be performed using any of the technical fields known in the art, such as those described herein. Methods for diagnosing such F-guides are described, for example, in U.S. Patent No. 6, Shima 6, Milk, et al., 6, 21 0, 97. HD can be diagnosed and monitored by the method of careful application: such as genetic testing (for example, h 11 field epithelial 4, gene sequencing and testing for the presence of expanded CAG repeat regions); ^ r subtests, such as testing limb movements, reflexes, eye movements, hearing 戎 俭 / / / ^ ^ 次 及 及 and / or performing brain imaging examination; assessing family history of disease; or performing psychology or psychiatry Interview. Behaviors that can lead to the diagnosis of symptoms or changes in HD, including, for example, aggressiveness, altered sexual orientation, anxiety, apathy, fantasies, denials, depression, depression, depression, hallucinations, irritability, mania, duplication, and lack of perception. If a genetic test is carried out and the number of CAGs in the huji c QO soil is higher than the critical number, for example 38, the patient can be diagnosed as having or having a coffee repeat number, usually with a sputum. ^ ", , the early onset of the disease. For example, for any of the glutamate dilatation disorders, a similar diagnostic method can be used. In addition, transport, psychiatry and / or behavioral disorders can be used. Other neurodegenerative therapeutic agents for the treatment of patients with or with neurodegenerative effects can be administered with 3 or more independent choices from Yufeng! η 1 The agent, 俾治痕, , , a and 1 b any ', σ treatment, prevention or alleviation of this obstacle. In the case of ribs', for example, a drug d T sperm is prevented or reduced

1084-9596-PF 32 200848063 Less Htt aggregation, while inhibiting mutant Ht compounds listed in Tables U and lb into disease activity. Any of the methods, kits and sets described herein are used herein for the purposes of this analog. Treatments used in the methods described herein (4), including Shenhuan anti-renal; 5 specific effective agricultural depression agents, lonophore antibiotics, large " arboreal synergists, channels Blockers, antihistamines, selective serotonin reuptake inhibitors ("SSRIs"), anticholinergic agents, PDE inhibitors, and estrogen regulation are described in detail. Elbow and juice ginseng antidepressants Antidepressants (TCAS) generally act by inhibiting the recovery of neurotransmitters such as norepinephrine, dopamine or serotonin from nerve cells. They may be used to treat neurodegenerative disorders. Suitable for methods, kits, as described herein. And TCA of the composition, including: for example, oxazepine (am〇xapine), amitriptyline, BTCP hydrogen chloride, clomipramine (eg, imipramine gasification hydrogen), desica Desipramine, dothiepin, doxepin, duloxetine, fiuoxetine hydrogen chloride, fluvoxamine maleate, 7-hydroxy oxapine, 8 - hydroxy oxapine, 8-hydroxyl Loxapine, imipramine, lof epramine, loxapine (eg loxapine succinic acid _, loxapine hydrogen chloride), maprotin (maprotiline) hydrogen chloride, norf luoxetine, nortripty Forest (nortripty 1 ine) (eg, formazan 1084-9596-PF 33 200848063 forest gasification hydrogen), paroxetine hydrogen chloride, protriptyl ine, sertraline hydrogen chloride, trimipramine. Nortriptyline (Nortriptyline) The following structure is used for the forest:

Exemplary analogs of nortriptyline are: amitriptyline, mosoxapine, butriptyline, clomipramine dothiepin, doxepin, desipramine ), 8-hydroxy oxapine, 7-hydroxy oxapine, 8-pyralfloxacin, imipramine, iprind〇ie, lof epramine, loxapine (l〇xapine), loxapine Succinate, loxapine gas, mapr〇tiline, mianserin, octripty1ine, opipramol, oxaprot i1i ne, protriptyl ine, trimipramine, and pharmaceutically acceptable salts thereof (described in, for example, US patents) Nos. 4, 933, 438 and 4, 931, 435), which are parasitic antidepressants or act by blocking the transport of neuroepinephrine. Analogs of nortriptyline are also described in U.S. Patent Application Publication No. 2〇〇5-〇〇8〇265. Ion-loaded antibiotics (i〇noph〇re antibi〇tics)

1084-9596-PF 34 200848063 The ionophore destroys the transmembrane ion concentration gradient, which is necessary for proper functioning and survival of the cells, and therefore has antibiotic properties. Ionophore antibiotics can be used to treat neurodegenerative disorders. Iophore antibiotics suitable for use in the methods, kits and compositions described herein, including, for example, a 1 b〇rixin, antibiotic A204, antibiotic χ2〇6, antibiotic A32887, antibiotic X-14766A, beauvericin, calcimycine (also known as A23187), calixarene, CCCP, chlorogenic acid, compound 47, 224, compound 51, 532, crown ether, dianemycin, dinactin, 2, 4-dinitrophenol, N,N-dioctylfluorenyl (also Known as proton ionophore, etheromycin, FCCP, gramicidin A, grisorixin, ionomycin (i〇n omyc in), isolasalocid A, K41, lasal〇cid (A, B, C, D and E factor 'individual or various combinations thereof', i〇nomyCin, laidlomycin, lenoremycin, lysocellin, maduramicin (eg maduramicin ammonium), monactin, monensin, mutalomycin, narasin, nigericin, nonactin (also known as ammonium ionophore l), 4-nonadecylpyridine (also known as proton ionophore II), salinomycin, semduramicin, septamycin, tetranactin, tetronasin, tr Inactin, and valinomycin. maduramicin maduramycin has the following structure: 1084-9596-PF 35 200848063

The maduramycin analogs include other polyether antibiotics as referred to above. Cannabinoid is a synergistic agent of Cannabin〇id Agonist, including a substance group structurally related to THC or 5, a cannabinoid receptor (present in cannabis s sativa i/) such as diterpene C21 The substance group of the compound). Cannabinoid receptor synergists can be used to treat neurodegenerative disorders. Cannabinoid receptor synergists suitable for use in the methods, kits and compositions described herein, including, for example, CP-55940, HU210, SR141716, SR144528, WIN55, 212-2, JWH-133, nabilone, levonantradol, marinol, Sativex, tetrahydrocannabinol (THC) and its analogues. WIN 55, 212 - 2 WIN 55,212-2 has the following structure:

1084-9596-PF 36 200848063 WIN 55, an analog of 212-2, comprising a CB1 receptor ligand and a modulator, comprising: SR 141716A; US Patent No. 6,825,209 (II) and (in); U.S. Patent No. 5,596,106 (I) and (II); and U.S. Patent No. 6,509,367 (I). Channel Blockers Channel blockers are compounds of ions to complex organic molecules that block the passage of ions through the ion channel. Channel blockers can be used to treat neurodegenerative disorders. Channel blockers suitable for use in the methods, kits and compositions described herein include, for example, calcium channel blockers and sodium channel blockers. Calcium channel blockers include, for example, dihydropyridines (e.g., aml〇dipine (e.g., amlodipine besylate); felodipine; lacidipine; lercanidipine ( Lercanidipine); nicardipine; nifedipine; nimodipine; nis〇idipine; and nitrendipine; benzyl amide (eg gaii) 〇pamii and verapamil); benzothiazepines (eg diltiazem); and other agents, such as BAPTA-AM; bepridil; magnesium; and menthol; and prasedion (paramethadi〇ne). Sodium channel blockers, including, for example, dibucaine (eg, dibucaine hydrogen chloride); disopryamide; dyclonine (eg, drokonin hydrogenation); flecainide; lidocaine (iid〇caine); mexiletine ); moricizine; phenytoin; procainamide; propafenone; qunibin (eg quinidine glucose);

1084-9596-PF 200848063 and tocainide 0 may be useful for miscellaneous men's < external cervical channel blockers, including, for example, levetiracetam.

Bepridi1

Bepridi 1 has the following structure:

The structural analog of Bepridil' is described in formula (I) and compounds (1)-(6) of U.S. Patent No. 3,962,238, and formula (I) of re3〇577. Antihistamines Antihistamines are compounds that block the action of histamine. Antihistamines can be used to treat neurodegenerative disorders. Category of antihistamines, including: (1) ethanolamines (such as bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, diphenylpyraline, and doxylamine); (2) Ethylenediamines (eg, pheniramine, pyrilamine, tripelennamine, and triprolidine); (3) phenotypes of sputum (eg, diehazine, ethopropazine, methdilazine (eg, methdilazine hydrogenated hydrogen), promethazine, thiethylperazine, and trimeprazine); 1084 -9596-PF 38 200848063 (4) Alkylamines (eg, acrivastine, brompheniramine, chlorpheniamine, desbrompheni ramine, dexchlorpheni rami ne, pyrrobutamine, and triprolidine); (5) pyrenes (eg, buclizine, west) (cetirizine, chlorcyclizine, cyclizine, meclizine, hydroxyzine); (6) travel categorization (eg ast: emizo 1 e), azatadine, cyproheptadine, dechlorination Des lor at adi ne, fexofenadine (fexofe Nadine), loratadine, ketotifen, olopatadine, phenindamine and terfenadine; (7) atypical antihistamines (eg nitrogen Azelastine, levocabastine, methapyrilene, and phenylphenyltoxamine). For the methods, kits and compositions described herein, antihistamines which are non-sedating and sedative may be employed. The antihistamines exemplified for the methods, kits and compositions described herein are non-sedating antihistamines such as loratadine and desl〇ratadine. The sedative antihistamines useful in the methods, kits and compositions described herein are described herein. Sedative antihistamines such as azatadine, bromodiphenhydramine, which can be used in the methods, kits and compositions described herein; chlorpheniramine maleate 1084-9596-PF 39 200848063 钂 (chlorpheniramine) Clemizole; cyproheptadine (eg cyproheptadine hydrogen chloride); dimenhydr inate; diphenhydramine; doxylamine; meclizine; promethazine (eg promethazine gasification A); Pyrilamine; thiethyl perazine; A tripelennamine ° Other antihistamines suitable for use in the methods, kits and compositions described herein, are acri vast ine; ahi stan; antazol ine (eg Antazol ine); astemizole; azelastine (eg azelastine hydrogen chloride); bamipine; bepotastine; bietanautine; brompheniram ine (eg brompheniramine maleate); carbinoxamine (eg carbinoxamine maleate) ); cetirizine (eg cetirizine hydrogen chloride); cetoxime; chlorocyclizine; chloropyramine; chi orο let 611; (: 111〇^1 16110 &1111116; cinnarizine ((^1111&1^21116); clastastine (eg clemastine fumarate); clobenzepam; clobenztropine; clocinizine; cyclizi ne (eg cycl izine gas Cyclo izine lactate; deptropine; dexchlorpheniramine; dexchlorph eniramine maleate; dimebon, diphenylpyraline; doxepin; ebastine; embramine; emedastine (eg, emedastine di fumarate); Epinast ine) ; etymeraazine chloro 4b nitrogen; It Sodo _ fp Ding 1084-9596-PF 40 200848063 (fexofenadine) (eg fexofenadine hydrogen chloride); flurin izine hydrogen fluoride (eg fluclitis) Hydrogen chloride); hi stapyrrodine; homochlorcyclizine (iH such as homochlorcycl izine dihydrogen); hydroxyzine (iH hydroxyzine hydrogenated; hydroxyzine pamoate); isopromethazine; i sothi pendy1; 1 evocabast ine (eg Carbastine hydrogenation); mebhydrol ine (eg mebhydro1ine 1,5-naphtha 1enedisu1fonate salt); mequitazine; raethafurylene;methapyrilene;methot rimeprazine;me Tron; mizolastine; olapatadine (eg, olopatadine); orphenadr i ne ; phen i ndami ne (eg phenindamine tartrate); pheniramine; phenyl toloxamine (eg phenyltoloxamine citric acid) Salt);pimei:hixene;p-methylphenhydramine;pyrobutamine;setastine;talastine; terfenadine;thenyldiamine;thiazinamium (eg thiazinamiura methylsulfate); thonzylamine hydrogen chloride; tolpropamine; triprolidine; and tritoqualine Structural analogs that are resistant to histamine can be used. Antihistamine analogs include, but are not limited to, 10 - s-propyl propyl phenazine; 4- ( 3- ( 2-chlorophenoxazin-1 0-yl) propyl)-1 - 嗓 ethanol Barium chloride; 1-(10-(3-(4-methyl-1-piperazinyl)propyl)-10H-phenothiazine-2-yl)-(9Cl) 1-propanone; 3-A Oxycyproheptadine; 4-(3-(2-chloro-10H-10-yl)propyl)piperazine-b 1084-9596-PF 41 200848063 Hydrogenation of ethanol; 10,11-dihydro-5- (3-(4-ethoxydoxy-4-phenylidene))-5H-dibenzo(a,d)cycloheptene; aceprometazine; acetophenazine; al imemazin (eg al imeraazin hydrogen chloride) ;aminopromazine; benzoxanthene n. butaperazine; carfenazine; chlorfenethazine; chl〇r midazole; cinprazole; desraethylastemizole; desmethylcyproheptadine; diethazine (eg diethazine hydrogenated hydrogen) Ethopropaz i ne (eg ethopropazine hydrogenated hydrogen); 2-(p-bromophenyl-(p,-indolyl phenyl) decyloxy)_N,N-dimethyl-ethylamine ruthenium chloride; N, N-dimercapto-2-(diphenylmethoxy)-ethylamine Methyl bromide 4乂-10-542 VIII;161161:11&21116;£叩&2〇16; methyl 10-(3-(4-methyl-1-)-propyl) phen Leprozin-2-yl ketone; lerisetron; medrylamine; mesoridazine; methyl promazine; N-desmethylpromethazine; nilprazole; northioridazine; perphenazine (eg, perphenazine enanthate); 10-(3-dimethylaminopropyl)-2-indolethio-phenophene; 4-(dibenzo(b,e)thiepin-6(11H)-ylidene)-1-indenyl - piperidine hydrogen chloride; prochlorperazine; promazine; propiomazine (eg propiomazine gasification hydrogen); rotoxamine; rupatadine; Sch 37370; Sch 434; tecastemizole; thiazinamium; thi〇pr〇pazate; methyl sulfide 1084-9596-PF 42 200848063 Thioridazine) (e.g., hydrazine sulphate hydrogen chloride); and 3-(10,11-dihydro-511-dibenzo(3,(1)cycloheptene-5-ylidene)- torol. Other antihistamines that may be used are other antihistamine analogs: AD-0261; AHR-5333; alinastine; arpr〇midine; ATI-19 00 0; bermast ine; bilastin; Bron-12; carebastine; Henamine;clofurenadine;c〇rsym;DF-1105501;DF-11062;DF-1111301;EL-301;elbanizine;F-7946T;F-9505;HE-904 81;HE-90512;hivenyl;HSR-609;icotidine ;KAA-276;KY-2 34;lamiakast;LAS-36509;LAS-36674;levocetirizine;le voproti1ine;metoclopramide;NIP-531;noberastine;oxa tomide;PR-881-884A;quisultazine;rocastine;selenoti fen;SK&amp ; F-94461; SODAS-HC; tagor izine; TAK-427; temelas tine; UCB-34742; UCB-35440; VUF-K-8707; Wy-49051; and ZCR-2060 〇 other possible anti-histamines , described in U.S. Patent Nos.: 3, 956, 296; 4, 254, 1 29; 4, 254, 130; 4,282,833; 4,283,4 08; 4, 362, 736; 4, 394, 508; 4, 285, 957;4, 285, 958; 4, 440, 9 33; 4, 51 0, 309; 4, 550, 1 1 6; 4, 692, 456; 4, 742, 1 75; 4, 833, 1 38; 4, 908, 372; 5, 204, 249; 5, 375, 693; 5, 578, 61 0; 5, 581, 0 11; 5, 589, 487; 5, 663, 41 2; 5, 994, 549 ; 6, 201, 124; and 6, 458, 958. Clemastine Chloramastine has the following structure: 1084-9596-PF 43 200848063

Cl

The structural analog of the gas masting is described in the formula (1) of the British Patent No. 942152, and the formula (c) of the US Patent No. 355,042. Exemplary chloromass; butyl analogs, including methyl + [2,-(p-chlorodiphenylmethoxy)-ethyl]-piperidine; N-methyl_2_[2,-diphenyl fluorene () ethyl)-piperidine; N-methyl-2-[2'-(p-bromo-diphenylmethoxy)-ethyl]-piperidine; N-methyl-2-[2'- (p-fluoro-diphenylmethoxy)-ethyl]-piperidine; N-mercapto-2-[2-(p-methyl-diphenylmethoxy)-ethyl]-piperidine; N-decyl -2-[2'-(p-methoxyz-diphenylmethoxy)ethyl]-piperidine; N-mercapto-2-[2'-methyl-diphenylmethoxy)-ethyl] a piperidine; N-methyl-2-[2,-(α-methyl-p-oxy-diphenylmethoxy)-ethyl]-piperidine; N-methyl-2-[2'-( --methyl-p-bromo-diphenyl fluorenyloxy)-ethyl]-piperidine; N-methyl-2 - [2'-(α-methyl-p-fluorenyl-diphenyl fluorenyloxy) Ethyl piperidine; Ν-methyl-2-[2'-(α-mercapto-diphenylmethoxy)-ethyl]-pyrrolidine; Ν-methyl-2-[2'-(α - mercapto-p-chloro-diphenyl fluorenyloxy)-ethyl]-indolyl pyridine; hydrazine-methyl-2-[2'-(α-methyl-p-bromo-diphenylmethoxy)-B ]-pyrrolidine; Ν-mercapto-2-[2 - (Yue group of alpha] - diphenylmethoxy) monoethyl-yl] - Los roar bite. Cyproheptadine 1084-9596-PF 44 200848063 赛heptidine has the following structure:

Structural analogs of cyproheptadine are described in U.S. Patent Nos. 3,014,911. Structural analogs are also described in the following structural formula:

Re R7 r A K9 β2, Βι where Ri, R2, R3, R4, R5, R6, R7 and Rs are each independently selected from: Η, Ci-6 alkyl, perhalogenated Ci-6 alkyl, OH, 0Ci-6 alkyl, OCF3, SH, SCh alkyl or SCF3; Y is CH2, 0, NH, S(0)〇-2, (CH2)3, (CH)2, CH2〇, CH2NH, CHN or CH2S A is a branched or unbranched, saturated or monosaturated hydrocarbon chain containing 1 to 6 carbons; R9 is a ruthenium or a Ch alkyl group; B! and B2 are selected from: H, all-acidized Cl-6 The group, Cl-6 alkyl or Bl is combined with B2, Bl and R9 or B2 and R9 to form a randomly substituted ring.

Ethopropazine

Ethopropazine has the following structure

1084-9596-PF 45 200848063

Structural analogs of Ethopropazine are described in U.S. Patent No. 2,605,773. The analog of Ethopropazine is also referred to by the following structural formula: (f^NRoR,

Wherein Χι and X2 are independently selected from hydrazine, halogen, hydrazine H, CN, n 〇 2, Ci-6; J^^ or 〇〇 1-6 alkyl; 11 is 0, 1, 2, 3, 4, 5 Or 6; and the anti-112 and ^3 are hydrazine or optionally substituted Ci-6 alkyl or R2 and R3 combine to form a ring. Selective serotonin recovery inhibitors The methods, compositions, and kits described herein can employ SSRI or a structural or functional analog thereof. Suitable SSRIs may include: oxaoxapine; BTCP (eg BTCP gasification hydrogen); cericlamine (eg, chloramine hydrochloride); citalopram (eg citrate bromide) Hydrogen); chlorohydrin (ciothvoxaminey; cyanodol (dothiepin); dapoxet; dapoxetine; dothiepin; duloxetine; escitalopram (oxalic acid) Denotex); femoxetine (eg, Fermons hydrogen chloride); fenfluramine (eg, fenfluramine hydrogenation); fluoxetine (eg, fluoxetine hydrogenated); fluvoxamine (f 1 uvoxam i ne) (eg fluvoxamine maleic acid); ifoxetine; indalpine (eg, hydrogen chloride); indeloxazine (eg 茚洛秦) Hydrogenated hydrogen); 1084-9596-PF 46 200848063 ritoxine; litoxetine; metergoline; milnacipran (eg milnacipran hydrogen chloride); paroxetine (eg paroxetine) Hydrogen hemihydrate; paroxetine maleic acid; paroxetine, thiomethic acid ; pr〇tripty 1 ine eg protriptyline hydrogen chloride; sererin (seri: raline) (eg sertraline hydrogenated hydrogen); tametraline hydrogenated hydrogen; vidualine; and Qimei Zime; ldine (eg, zimididine hydrogen chloride). Cereclamine Western serotonin has the following structure:

The structural analog of serotonin is as follows:

R! is C!- and its pharmaceutically acceptable salts, wherein Ch is calcined, R3 is η, Cl_6 alkyl, C2 6 5 to 6 cycloalkylalkylcycloalkyl, 3 to 6 The nitrogen atom to which the cycloalkylcarbonyl group of the ring carbon atom is bonded forms a heterocyclic ring; the heterocyclic ring; the C6 alkyl group and R2 are a bite 6 alkenyl group, a phenylalkyl group or have a [, decyl group, phenylalkyl fluorenyl group Or having (base, or R2 and Rs - saturated with 5 to 7 chains attached to its ring, 2, a hetero atom, oxygen, sulfur, which may have no direct linkage to the nitrogen atom First

1084-9596-PF 47 200848063 or nitrogen 'The latter heterocyclic group may carry a c2-6 alkyl group. An example of a serotonin structural analog is 2 -methyl hydrazine - 1 - ylamine - 3 - (3, 4-dichlorophenyl) - propanol, 2 - pentyl - 2 - amine " u4 -diqi-based)-propanol, 2-methyl-2-methylamino-3-(3,4-dioxa)-propanol 2-methyl-2-dimethylamino 3-(3,4-diphenylphenyl)-propanol and a pharmaceutically acceptable salt of any of j. Citrus (ci talopram) ceplane has the following structure:

The structural analogue of citalopram is of the following formula

And a pharmaceutically acceptable salt thereof, wherein each of R and R2 is independently selected from the group consisting of bromine, gas, fluorine, trifluoromethyl, cyano and R--the middle is a Ch alkyl group. An example of a cepac structure analog (which is an SSRI structural analog)

1084-9596-PF 48 200848063 is: 1-(4'-fluorophenyl)-1-(3-didecylaminopropyl)-5-bromofluorene; 1-(4'-chlorophenyl) 1-(3-dimethylaminopropyl)- 5-chloroindole; 1-(4'-bromophenyl)-1 -(3-didecylaminopropyl)-5-chloroindole Alkane; 1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-chloroindole; 1-(4-chlorophenyl)-1 -(3-diindole Aminopropyl)-5-trifluoromethyl-decane; 1-( 4 ' -bromophenyl)-1 -(3-dimethylaminopropyl)- 5-trifluoromethyl-S Too calcined; 1-(4-propenyl-didecylaminopropyl)-5-trifluoromethyl-methyl oxime; 1-(4'-fluorophenyl)-1 -(3-dimethyl Aminopropyl)-5-fluoroanthracene; 1-(4-heterobenzyl)-1 -(3-dimethylaminopropyl)-5-morpholidine; 1-(4'-gas Phenyl)-1 -(3-dimethylaminopropyl)- 5-decanecarbonitrile; 1-(4'-fluorophenyl)-1 -(3-dimethylaminopropyl)- 5_decane-method; 1-(4-mercaptophenyl)-1 -(3-dimethylaminopropyl)-5-S-tanning carbonitrile; 1-(4'-cyanophenyl) )-1-(3-dimethylaminopropyl)- 5-chloroindole; 1-(4' -cyanophenyl)-1-(3-didecylaminopropyl)-5-trifluoromethyldecane; 1-(4'-fluorophenyl)-1-(3-dimethylamino) Propyl)_5-decanecarbonitrile; 1-(4'-phenylphenyl)-1-(3-dimethylaminopropyl)-5-mercaptopurine; 1-(4-(chlorophenyl) )-1-(3-dimethylaminopropyl)-5-propyl-branched® too-married, and its pharmaceutically acceptable salts. Clovoxamine Aerosols have the following structure:

1084-9596-PF 49 200848063 The structural analog of gas valency amine is the one having the following structure

And pharmaceutically acceptable salts thereof, wherein Hal is a chlorine, bromine or fluorine group, and (iv) cyano 'methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxy Ethoxy or cyanomethyl group. An exemplary gas-floamine structural analog is: 4,-chloro-5-ethoxypentanone-(2-aminoethyl)anthracene; 4,-gas-5-(2-methoxyethyl) Oxy)phenylphenone oxime-(2-aminoethyl)anthracene; 4'-chloro-6-methoxybenzoxanone oxime-(2-aminoethyl) two; 4'-chloro-6- Ethoxy phenoxy ketone oxime-(2-aminoethyl) will be; 4'-bromo-5-(2-decyloxyethoxy) phenylpentanone oxime-(2-aminoethyl) hydrazine; 4'-bromo-5-methoxyphenanone oxime-(2-aminoethyl) hydrazine; 4,-chloro 6-gas is substantially hexane 3 with 0-(2-aminoethyl) jiang; 4'- Gas-5-gas basic 戍嗣〇-(2-aminoethyl) hydrazine; 4,-bromo-5-cyanophenylpenta- oxime (2-aminoethyl) fat; and its pharmaceutically acceptable Salt. Femoxetine Fermons Ding has the following structure: 1084-9596-PF 50 200848063

The och3 Fermons structure analog is of the following formula:

Wherein L represents a Ci-6 alkyl or C2-6 alkynyl group, or a phenyl group is optionally substituted with C!-6 alkyl, Cl-6 alkylthio, C!-6 alkoxy Base, bromine, gas, fluorine, nitro, decylamino, methylsulfonyl, fluorenyldioxy or tetradecylnaphthyl, R2 represents a Cl-6 alkyl or C2-6 fast radical '1?3 represents nitrogen, Cl-6 alkyl, Cl-6 alkoxy, trifluoroalkyl, hydroxy, bromo, gas, fluorine, mercaptosulfide or aralkyloxy.

An exemplary Fermons structure analog of S is disclosed in Examples 7-67 of U.S. Patent No. 3,91 2,743. I fluoxetine fluoxetine has the following structure:

Ch3 1084-9596-PF 51 200848063 The structural analog of fluoxetine is a compound of the formula:

Γ^ι R1 wherein each R1 is independently hydrogen or methyl; R is a pharmaceutically acceptable salt thereof naphthyl or

=\^(R2)n (R3)m wherein each of R2 and R3 is independently m, qi, 螽, 夭 夭 乱 二 鼠 鼠 鼠 methyl, Cl-6 alkyl, CH alkoxy or C3-4 olefin Base; and each site is 〇, 丨 or 2. When ^ is a naphthyl group, it may be an α-naphthyl group or a 10,000-naphthyl group. An exemplary fluoxetine structural analog is 3-(p-isopropoxyphenoxy)-3-phenylpropylamine methanesulfonate, hydrazine, decyldimethyl 3-(3,,4, one Dimethoxyphenoxy)-3-phenylpropylamine p-hydroxybenzate, hydrazine, hydrazine monodimethyl 3(α-naphthyl)-3-phenylpropylamine bromo, & ν-Dimethyl 3 (/5 ^oxy)-3-phenyl-l-mercaptopropylamine iodine, 3-(2,-methyl 4,5-oxyloxy)-3-phenylpropyl Amine nitrate, 3-(p-third, earth-based oxy) 3-propenyl propylamine glutarate, ν-mercapto 3_(2,-chloro-p-tolyloxy S)-3 Phenyl + mercaptopropylamine lactate, (2,4 monophenoxy)-3-phenyl-2-methylpropylamine citrate Ν'Ν monomethyl 3-(isanyloxy) 3-phenyl-1-methylpropylamine: acid _, "yl 3 - (p-tolyloxy)-3-phenylpropylamine sulfate, hydrazine, hydrazine-dimethyl 3-(2,4,-difluorophenoxy)-3 monophenylpropylamine

1084-9596-PF 52 200848063 2,4-Dinitrobenzoate, 3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate, N-methyl 3-(2 Chloro-4,-isopropylphenoxy)-3-phenyl-2-methylpropylamine maleate, N,n-dimethyl 3-(2,-alkyl- 4,fluoro The present oxy-phenyl-propylamine succinic acid S, N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine phenyl acetate, N,N-Dimethyl 3-(o-bromophenoxy)-3-phenyl-propylamine-phenylpropionate, N-methyl 3 (p-Ebenyloxy)-3-phenyl -Propylpropionic acid g is intended to be methyl-n-propylphenoxy)-3-phenyl-propylamine phthalate. Fluvoxamine Fluvoxamine has the following structure: Structural analogue of fluvoxamine Formula (I). Flufusamine eve 4

The structural analog of fluvoxamine is described in U.S. Patent No. 4,085,225 ^ analog, which is also described in the following formula:

And a pharmaceutically acceptable salt thereof, wherein R is cyano, cyanomethyl or methoxy

1084-9596-PF 53 200848063 methyl or ethoxymethyl. 0 bow Indapine Indica has the following structure:

The structural analog of 吲达品 has the following formula: A-(CH2)n

Or a pharmaceutically acceptable salt thereof, wherein R1 is a hydrogen atom, a Cl-c6 alkyl group or an arylalkyl group, wherein the alkyl group has a hydrazine or 2 carbon atoms, ^2 is hydrogen, Ch alkyl, Ch alkoxy or 匕-6 alkylthio, chloro, bromo, fluoro, trifluoromethyl, schlossyl, hydroxy or amine, the latter optionally substituted with 1 or 2 Ci 6 an alkyl group, a mercapto group or a C!-6 alkylsulfonyl group; a represents a -c〇 or -CH2- group; and n is 0, 1 or 2. Illustratively known as Indalpine structural analogs are: mercapto-3 (piperidinyl-4-methyl) ketone; (methoxy-5-fluorenyl-3) (piperidinyl-4) Ketone; (gas-5-mercapto-3)(piperidinyl-4methyl)-;(mercapto-3)-i(piperidinyl-4)-3acetone, fluorenyl- 3 piperidinyl-4 ketone; (methyl-mercapto-3) (Benyl-4-methyl) ketone, (benzyl-J-yl-3) (piperidinyl- 4-methyl) [(Methoxy-5-mercapto-3)-2ethyl]-piperidine, [(methyl-i 吲°木基-3)-2 ethyl]-4-piperidine; [( Mercapto-3(2)-2-ethyl]-4 piperidine; (mercapto-3methyl)-4 piperidine, [(chloro-5-mercapto-3)-2-ethyl]-4pipeline 1084- 9596-PF 54 200848063 ϋ疋;[(σ引σ朵基-b 3) - 3 propyl]-4 派克定;[(节基-1 °引σ基基-3)-2ethyl]- 4 pyridine; and any of its pharmaceutically acceptable salts. Indeloxazine has the following structure:

The structural analog of Luo Luo Qin is of the following formula.

And its pharmaceutically acceptable salts, wherein 1 and R3 each represent hydrogen, Ch alkyl or phenyl; R2 represents hydrogen, Ci6 alkyl C47 cycloalkyl, phenyl or benzyl; (one of the dotted lines means a single a bond, the other means a double bond or a tautomeric mixture thereof, which is an analog of the ruthenium, which is: 2-(7-fluorenyloxymethylisopropylmorpholine; 4-butyl-2-() 7-fluorenyloxymethyl) morphine; 2-(7-nodaloxymethyl)-tetramethylmorpholine; 4-ethyl-1-2 (7-decyloxymethyl) Ma Lin , 2 — (7-fluorenyloxymethyl)-isoline; 2-(7-fluorenyloxymethyl)- 4-propylmorpholine; 4-cyclohexyl-2-(7-fluorenyloxy)曱 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) (4-mercaptooxymethyl)morpholine; 2-(3-indolyl-7-

1084-9596-PF 55 200848063 - 2-(3-Methyl-7-fluorenyloxyindole-4-knotyloxyindenyl)-lin; 4-mercaptooxymethyl)-Merlin; 4~ Iso & base) morpholine; 4-isopropyl-2-(3~-methyl | isopropyl-2-(3-methyl-5-fluorenyl-tert-methyl) morpholine; 4- Isopropyl-2-(1-methyl-3-phenyl-6-nodal benzyl group) phenanthrene; 2-(5-fluorenyloxymethyl)-4-isopropyl- 】, 茚 曱 曱 ) ) 一 一 4- 4- 4- 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及A pharmaceutically acceptable salt.

Metergoline

Me ter go 1 ine has the following structure: ο

〇

Narrated in US patent number

The structural analog of Metergoline is 3,238,211 (I). Milnacipram Minapura has the following structure:

Nh9 Et

The structural analog of milnacipran is 1084-9596-PF 56 200848063

And a pharmaceutically acceptable salt thereof, wherein each R independently represents hydrogen, bromine, gas, gas, C1-6 alkyl, C1-6 alkoxy, thiol, and R2 independently represent hydrogen, C!- a 6 alkyl, aryl or nitro or amine group; each I or C7-H alkylaryl, optionally substituted by bromine, gas or fluorine, preferably para-substituted, or l and h adjacent The nitrogen atoms together form a heterocyclic ring having a 5- to 6-membered ring; 匕 and L represent a hydrogen or C!-6 alkyl group, or R3 and R4 form an additional impurity of 5 sulphur and oxygen with an adjacent nitrogen atom or 6-membered heterocyclic ring, optionally containing nitrogen, sub- exemplified milnacipran structural analog: 丨-phenyl hydrazine - amino group 2

Aminomethylcyclopropane; 1-phenyl 1-ethylaminocarbonyl 2 -dimethylaminoguanidinocyclopropane; 1-phenyl 1-diethylaminocarbonyl 2 -aminomethyl ring Propane; phenyl 2-dimethylaminomethyl^(4,monochlorophenyl)cyclopropanecarboxamide; phenyl 2-dimethylaminomethylmethyl N-(4,-chlorobenzyl Cyclopropane carboxamide; phenyl 2-dimethylaminomethyl N-(2-phenylethyl)cyclopropane carboxamide; (3, 4-dichloro-:!-phenyl) 2 - dimethylaminomethyl n, N-dimethylcyclopropanol rebel; 1-phenylpyrrolidinocarbonyl 2-morpholinomethylcyclopropane; p-chlorophenyl 1-amino Carbonyl 2-aminomethylcyclopropane; o-chlorophenyl-aminocarbonyl 2-dimethylaminomethylcyclopropane; 1-hydroxy-p-hydroxyphenylaminocarbonyl 2-dimethylaminomethyl Cyclopropane; 1-p-nitrophenyl dimethylamino

1084-9596-PF 57 200848063 carbonyl 2-didecylaminomethylcyclopropane; 1-p-aminophenyl hydrazine monodimethylaminocarbonyl 2-dimethylaminomethylcyclopropane; 1 — p-Tolylmethylaminocarbonylcarbonyl 2-dimethylaminomethylcyclopropane; 1-p-methoxyphenyl-aminomethylcarbonyl 2-aminomethylcyclopropane; and any of them Acceptable salt. Paroxetine Paroxetine has the following structure:

The structural analog of paroxetine is of the following formula.

'wherein Ri represents hydrogen, optionally substituted Cw alkenyl, or optionally substituted c2_6 1 Cl-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, "base; X is arbitrary" And optionally, the paroxetine analog can be used in stereochemical mixing with a pharmaceutically acceptable salt thereof, wherein 1 is C!-6 alkyl, optionally substituted Cw alkynyl; R2 is optionally The substituted C 6 alkyl group, the exemplified value is optionally substituted

The national patent number 6, 90 0, 327 (!). C2-C6-heterocyclic or Ce-Cu aryl; X is the position of any ^; and Y is 〇 or S. Parox>, a butyl complex or a stereochemically pure form. R2's example 1,3 - this is not a bad. Paroxetine analog, 3, 912, 743 Formula (I) and Example r The exemplary paroxetine analog is

1084-9596-PF 58 200848063 trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-ethyl british; -)-trans_4-(-4-fluorolphenyl)-3-(3,4-methylenedioxyphenoxyindolyl)-1-propylbend sigma; (-)- Trans-4-(4-fluorophenyl)-3-(3,4-ylidenedioxyphenoxymethyl)-1-butylpiperidine hydrogen chloride; (-)-trans-4 -( - 4 -fluorophenyl)-3 -(3,4-ylidenedioxyphenoxymethyl)-1-octylpiperidine; (-)-trans-4-(-4- Fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-isopentylpiperidine; trans-4-(-4-fluorophenyl)-3-( 3, 4-methylenedioxyphenoxymethyl)-1-(4-phenoxybutyl)pyridine; trans-4-(-4-fluorophenyl)-3-(3) , 4-methylenedioxyphenoxymethyl)-1-hexylpiperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylene Dioxyphenoxyindenyl)-1-(3-phenylpropyl) brigade; (-)-trans-4-(-4-fluorophenyl)-3-(3,4-ya Methyldioxyphenoxymethyl)-1-(2-ethylhexyl)-11 yttrium; (-)-trans _4-(_4-phenyl --3-(3,4-Methylenedioxyphenoxymethyl)-1 -(3,3-dimethylbutyl)-piperidine; (-)-trans-_4-(- 4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1_cyclohexyl"Brigade sigma; (-)-trans-4-(-4- Depleted phenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-heptyl-pie 11 hydrogenated gas; (-)-trans-4-(-4- Fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-cyclopentyl-piperidine; trans-4-(-4-fluorophenyl)-3 (3,4-Methylenedioxyphenoxymethyl)-1-dipropyl-Brigade sigma; (-)-trans-4-(-4-merylphenyl)-3-(3 , 4-methylenedioxyphenoxymethyl)-1-cyclopropylhydrazine piperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3, 4 -methylenedioxyphenoxymercapto)-1-cycloheptyl-piperidine; (-)-trans-4-(-4-1084-9596-PF 59 200848063 phenyl)-3- (3,4-]-indenyldioxyphenoxymethyl)-1-(2-ethoxyethyl)-Brigade sigma; (-)-trans-_4-(-4-gas phenyl --3-(3,4-Methylenedioxyphenoxymethyl)-1-(2-methoxymethyl)-piperidine; (-)- 4-(4- 4 -phenylene)- 3 - (3,4-decylenedioxyphenoxymethyl)-1-(2-trans-butenyl)-piperidine; -)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(3-butenyl)-piperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1 -(5-hexenylpiperidine; -)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(4-pentenyl)-piperidine (-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-(3-methyl-butenyl) - piperidine; cis-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine; (-)- Trans-1-butyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxy-methyl)-piperidine; (-)-trans-1-propyl-4 -(4-fluorophenyl)-3-(4-methoxyphenoxy-indenyl)-Brigade sedative hydrogen chloride; trans-1-ethyl-4-(4-phenylene)-3- (4-decyloxyphenoxy-methyl)-piperidine; trans-isopropyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxy-methyl)- Piperidine (-)-trans- l-(2-(4-methoxyphenoxyethyl))-4 -(4-ILphenyl)-3-(4-methoxyphenoxyfluorenyl) - piperidine; (-)-trans-p-pentyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxy-indolyl)-piperidine; trans-_1-g 4-(4-fluorophenyl)-3-(4-methoxyphenoxy-methyl)-piperidine; (-)-trans-1-cyclohexyl-4-(4-phenylene) ))-3-(4-methoxy-phenoxyindenyl)-° bottom; trans-1_propyl-4-(4-fluorophenyl)·~3-(4 - third Butylphenoxy-fluorenyl) ΐΙ σ ; ;; trans-1-ethyl-4-(4-fluorophenyl)-3-(4-tributyl 1084-9596-PF 60 200848063 phenoxy Base: phenyl)-piperidine; trans + butyl + (4-air phenyl) - 3 - (4-t-butyl phenoxy fluorenyl) - (d); (a) trans 3 - (2-cyclohexyl) Phenoxymethyl)-4-U-fluorophenyl)-indole-methyl-piperidine; trans 4-(4-fluorophenyl)-diphenyl-3-(5, 6, 7, 8,- Tetrahydro-2-naphthyloxymethyl)-piperidine; trans 3-(4-oxophenoxymethyl)-tetra-(4-fluorophenyl)-bu-methylpiperidine; L-form 3-( 4-hydroxyl-3-methoxyphenoxymethyl)+(1)-benzene Methyl pyridine; (1,4'fluorophenyl)+methyl-3-(2-naphthyloxymethyl)-piperidine; trans 3-(2-cyclohexylphenoxymethyl)-4 -(4-fluorophenyl)-piperidine; j-form 3-(4-phenoxyphenoxymethyl)-4-phenylpiperidine; trans 4-(4-fluorophenyl)-3- (5, 6, 7, 8,-tetrahydro-2-naphthyloxymethyl)-piperidine; trans 3 (4-benzyloxyphenoxymethyl)_4_(4-fluorophenyl)-piperidine ;(-)-trans 3 (2 嗟ϋ 基 thiomethyl)-4_(4-fluorophenyl)- 派定; (_)-trans 4-(4-fluorophenyl)- 3-(2-naphthyloxymethyl)-piperidine; (-) trans 3-(2-cyclohexylphenoxymethyl)- 4-(4-fluorophenyl)-pentopylpiperidine; + /-) trans 3-(4-phenoxyphenoxymethyl)-bupentyl-4-phenylpiperidine; (+ / -) trans 1-allyl-3-(4- Benzyloxyphenoxymethyl)- 4-phenylpiperidine; (-) trans 3-(4-Methoxyphenoxymethyl)-bupentyl-4-phenylpiperidine; ―trans 1-1,3-propyl-3-(4-decyloxyphenoxymethyl)- 4-phenylpiperidine; (+) trans 3-(4-Methoxyphenoxymethyl) Base)-Bu (4-) trans 1-allyl-3-(4-methoxyphenoxymethyl)- 4-phenylpiperidine; (-) trans 4- ( 4-fluorophenylbubuyl-tris(5,6,7-8-tetrahydro-2-naphthyloxyfluorenyl); ;trans 3-(2-benzothiazolylthiomethyl) —4—(4-fluorophenyl)-diphenyl group; (-)trans 4-(-fluorophenyl)-3(2-naphthyloxyindolyl bromide-Benyl brigade; (-) anti Formula 1 - Butyl-4-(4-fluorophenyl)-3-(5, 6, 7, 8-tetrahydrogen

1084-9596-PF 61 200848063 I naphthyloxymethyl)_° bottom; (a) trans 4-(4-1 stupyl) + propyl 3-(5,6,7,8-tetrahydro-2 -naphthyloxymethyl)decaine; (a) trans-formulas; a hexyl-3-(5,6,7,8-tetrahydro-smiling, 1-bu-butylmethyl)-peripipeline (-) trans 1-ethyl-4-(4-phenylphenyl)-3~(5 & 7 〇V,b,7,8-14 gas~2-naphthyloxybine bite; And (a) trans 31 stupid and sigh thiomethyl) _4_ (4_t base)-1 - thiol brigade bite. Sertraline Sertraline has the following structure: NHCH,

The structural analog of sertraline is RVR2 with the following formula

^ Soil, human and Y are selected from the following groups: strontium, fluorine, chlorine, bromine, murine: basal, Ci-C3 alkoxy and cyano; and w are selected from the following groups: Methyl and Ci - C3 alkoxy groups. In some implementations, the hydrogen form is π-rolled methyl and Cl-rolled. In some forms - the koji forest analog is a cis isomeric configuration. The term "cis isomerization" is used to transfer; a day is on the % hexene ring, and NRIR2 and the phenyl structure are related (also p is located on the same side of the ring). Because 1 - and 4- carbon, no

1084-9596-PF 62 200848063 Substitute 'so each cis compound has two optically active mirror image isomers;: carbon” is cis-(1R) and cis-((8) isomerism. 'for the following compounds, (ls), like isomerism or (is) (10) (iv) and its pharmaceutically acceptable salts: cis, "base_4_(3,4_二气:基卜1'2, 3'4-tetrahydro-1-naphthylamine; cis |methyl_4_(4-xibenzene:, 2'3'4-tetrahydro+naphthylamine; cis-methyl-4_(4-chlorobenzene = )], 2' 3' 4-tetrahydro + naphthylamine; cis | methyl _4_(3_trimethylmethyl phenyl 2, 3' 4-tetrahydro-naphthylamine; cis-N- Methyl _4_(3_three unsubstituted methyl 4 fluorenyl)], 2,3,4_tetrahydro+naphthylamine; cis-didecyl+(4-chlorophenylhydrazine, "}tetrahydro+ Naphthylamine; cis_N,N-dimethyl-fluoroindolyl-phenylhydrazine '2'3'4-tetrahydrocilamine; and cis_N_indenyl 4 (tetrachlorophenyl)-7- Chloro+2^,4-tetrahydro-naphthylamine. cis_N_methyl 4 (3,4-monophenyl)- 1,4-tetrahydro-naphthylamine (10) is also of interest. The sertraline analog is described in U.S. Patent No. 4, other related compounds, including (S,S)-N-desmethylsertraline, Cyclo-N-desmethylsertraline, (1S, 4S) - demethylsertraline, b (methylamine)-b-oxy-2-(R,S)-hydroxyl Lin, (1R, 4R) - demethyl sertraline, sertraline sulphate, sertraline (reverse) methanesulfonamide, 1R, 4R sertraline mirror isomer, N, N- Dimethyl sertraline, nitrosertraline, sertraline aniline, sertraline iodine, sertraline sulfonamide 2, sertraline sulfoximine ethanol, sertraline nitrile, sertraline-CME , dimethyl sertraline reverses sulfonamide, sertraline reversed sarcophagus, guanamine (Cih linker), B-ring methoxymethoxy sertraline, A-ring methyl ester sertraline, A- Cyclic ethanol sertraline, sertraline N,N-dimethylsulfonamide, a ring

1084-9596-PF 63 200848063 Sertraline carboxylic acid, B-cyclo-p-phenoxysertraline, B-ring p-trifluoromethane sertraline, B-ring p-trifluoromethane N,N-dimethyl Qu Lin, and UK-41 6244. The structures of these analogs are as follows.

1084-9596-PF 64 200848063 Sertraline analogue

A

Cl

Cl 1R, 4R sertraline mirror isomer

HN

NH

NH

Sertraline aniline

Sertraline reverses the yield of guanamine (CH2 linker)

H2N02S

5

SMe UK-416244 1084-9596-PF 65 200848063 Sertraline analogue nh2 NHMe « Me〇2CvY^Y^^ Γ^Ί X CI Cl (1R,4R)-desmethylsertraline A-ring A舍曲林ΝΗ2 HCI 1 Λ ρι 〇ι racemic-cis-indole-demethylaseCl dimethylsertraline reverses sulfonamide hydrazine gasification hydrogenamine?Η ΪΗΜΘ \2 \ L α Λ IX ^Y^ci ΓΜ Cl sertraline N,N-dimethylsulfonamide Lfl A-cycloethanol sertraline 1084-9596-PF 66 200848063 Sertraline analogue

Sertraline-CME

CI Η

(1S,4S)-desmethylsertraline gasification 氲, ^ΝΗ

1-de(methylamine)-1-o-oxy-2-(R,S)-trans-serforine \^ΝΗ

Sertraline nitrile

1084-9596-PF 67 200848063 Sertraline analogue

Cf3 N,N-dimethylsertraline B-ring pair trifluoro*jiayuan NHMe

HN

NH

A-ring carboxylic acid sertraline NHMe

NH

r^S CF3 B-cyclo-trifluorodecane sertraline 1084-9596-PF 68 200848063

Zimeldine

Zimeldine has the following structure:

A structural analog of Zimeldine, having the following formula:

And a pharmaceutically acceptable salt thereof, wherein the pyridine nucleus is bonded to an adjacent carbon atom in an ortho, meta or para position, and wherein the pyridine nucleus is selected from the group consisting of ruthenium, chlorine, fluorine and bromine . 1084-9596-PF 69 i 200848063 An exemplary zimeldine analogue is: (e) - and (z)-3-(4'-bromophenyl-3-(2"-n-pyridyl)-dimethyl Allylamine; 3-(4,-bromophenyl)-3-mono(3"-~pyridyl)-dimethylallylamine; 3-(4'-bromophenyl)-3-( 4"-Aridinyl)-dimethylallylamine; and pharmaceutically acceptable salts thereof. The above SSRI structural analogs are considered to be SSRI analogs' and may be employed in any of the present invention. In methods, compositions, and kits, pharmaceutically active metabolites of any of the above-described SSRIs of metabolites can also be used in the methods, compositions, and kits of the invention. The metabolites exemplified are di-desmethyl sulphate, Methyl sulphate, desmethyl sertraline, and n〇rflu〇xetine. Methods and compositions of the analogs are as follows. A class of SSRI recovery inhibitors, the functional analogs of SSR I can also be used in the present invention. In the group, exemplary SSR I functional analogs are provided as analogs including SNRI (selective serotonin/epinephrine back includes: venlafaxine and duloxetine).

Venlafaxine

Venlafaxine has the following structure

The structural analog of H3C〇/ Venlafaxine is a compound having the formula: 1084-9596-PF 70 200848063

And a pharmaceutically acceptable salt thereof, wherein A is of the following structure: or4

Wherein the dotted line represents random unsaturation; R! is hydrogen or alkyl; h is 匕-6 alkyl; R4 is hydrogen, Cu6 alkyl, fluorenyl or alkenyl; r3 is hydrogen or 匕-6 alkyl ;r5 and R6 are independently hydrogen, hydroxy, Cl_6 alkyl, (^_6 alkoxy, Ch alkyl decyloxy, cyano, nitro, alkyl fluorenyl, amine, Ch alkylamino, dioxane Amino group, C!-6 decylamino group, halogen, trifluoromethyl group, or together form a methylenedioxy group; and η is 〇, 1, 2, 3 or 4.

Duloxetine

Duloxetine has the following structure:

m, ch3 Η duloxetine structural analogs are compounds described in U.S. Patent No. 4,956,388 and U.S. Patent No. 5,0 2 3,2 6 9 (see, for example, ◦ ^ 1 ^ line 35) and claims 1)). Illustrative dul〇xetine class 1084-9596-PF 71 200848063 The analogy is: N-methyl-3-(1-hhenyloxy)-3-(3-σsecenyl)-propylamine; N-methyl- 3-(2-naphthyloxy)-3-(cyclohexyl)-propylamine; N,N-dimercapto-3(4-(4-naphthalenyloxy)-3-(3-furyl)propylamine N-methyl-3-(5-fluorenyl-2-naphthalenyloxy)-3-(2-thiazolyl)propylamine; N-methyl-3-[3-(trifluoromethyl)-:l -naphthalemyl〇xy]-3-(3-methyl-2-thienyl)propylamine; N-methyl-3-(6-iodo-1-naphthalenyloxy)-3-(4-acridinyl)propylamine N,N-dimethyl-3-(1-naphthyloxy)-3-(cycloheptyl)propylamine; N,N-dimethyl-3-(2-naphthyloxy)-3-(2 -pyridyl)propylamine; ^methyl-3-(1-naphthalenyloxy)-3-(2-furyl)propylamine; N-methyl-3-(4-methylnaphthalenyl 3-(4-. Propylamine; propylamine; n-mercapto-3-(2-n-oxy)-3-(2-°-sepyl)propylamine; N,N-dimercapto-3-6-iodo-2-naphthalene Oxy)-3-(4-bromo-3-thienyl)propylamine; N,N-dimethyl-3-(1-naphthyloxy)-3-(3-acridinyl)propylamine; N,N -didecyl-3-(4-methyl-2-naphthyloxy)-3-(3-furyl)propylamine; N-A -3-(2-naphthyloxy)-3-(cyclohexyl)propylamine; n-methyl-3-(6-η-propyl-1-naphthalenyloxy)-3 -(3-isopropyl- 2-thienyl)propylamine; hydrazine, hydrazine-dimethyl-3-(2-methyl-1-)lactyl-3-(4- stilbyryl)propylamine; 3-(1-naphthyloxy) )-3-(5-ethyl-3-thienyl)propylamine; 3-tris(3-trifluoromethyl)-bheptyloxy]-3-(σ-pyridyl) propyl fe; Ν-methyl- 3-(6-methyl-1 -naphthyl-3 -(4- gas-2-°secenyl)propylamine; 3-(2-naphthalenyloxy)-3-(cyclopentyl)propylamine; 1^ —Methyl—3 —(4-n-butyl-1-naphthyloxy)~3-(3- σ-furanyl)propylamine; 3-(2-Gas-Oxo)-3-(5-thiazole Propylamine; ν-methyl-3-(1-naphthyloxy)-3-(3-furanyl)propylamine; hydrazine, hydrazine-dimethyl-3-(phenoxy)-3 -(2- Furanyl) propylamine; hydrazine, hydrazine-dimethyl-3-[4-(trifluoromethyl) phenyloxy] 3-(cyclohexyl)propylamine; hydrazine-methyl-3-(4-methylbenzene) Oxyl)-3-(4-carbo- 2-thienyl)propene 1084-9596-PF 72 200848063 amine; N-methyl-3-(phenoxy)-3 -(3-° thiol) propylamine ;3-[2-chloro-4-(difluoromethyl)phenoxy] 3-(2-phenyl)propylamine; n,n-dimethyl-3-(3-methoxyphenoxy)-3-(3-bromo-2-propenyl)propylamine; N-A 3-(4-bromophenoxy)-3-(4-thiazolyl)propylamine; N,N-dimethyl-3-(2-ethylbenyloxy 3-(5-methyl-3嗟) Phenyl) propylamine; n-methyl-3-(2-bromophenyloxy)-3-(3-anthranyl)propylamine; N-methyl-3-(2,6-dimethylphenoxy) -3-(3-methyl-2-thienyl)propylamine; 3-mono[3-(trifluoromethyl)phenoxy]-3-(3-furanyl)propylamine; n-methyl-3 (2,5-Dichlorophenoxy)-3-(cyclopentyl)propylamine; 3-3-4-(trifluoromethyl)phenoxy]-3-(2-thiazolyl)propylamine; N-methyl- 3-(phenoxy)-3-(5-methyl-2-thienyl)propylamine; 3-(4-methylphenoxy)-3-(4-oxaridinyl)propylamine; N, n- Dimethyl 3 (3-methyl-5-bromophenoxy)-3-(3-indolyl)propylamine; N-methyl-3-(3-n-propylphenoxy)-3- (2-thienyl)propylamine; N-methyl-3-(phenoxy)-3-(3-thienyl)propylamine; N-methyl-l-(4-methoxyphenoxy)-3 -(cycloheptyl)propylamine; 3-(2-gasphenoxy)-3 (5-thiazolyl)propylamine; 3-2-chloro-4-(trifluoromethyl)phenoxy]-3-mono(3-thienyl)propylamine; 3-(phenoxy)-3-one (4- Methyl-2-thienyl) propylamine; n,N-dimethyl-3-(4-ethylphenoxy)-tris(3-pyridinyl)propylamine; and & n-dioxin-3 -[4-(Trifluoromethyl)phenoxy]-3 mono(2-signyridinyl)propylamine. Other SSRI analogues of the soil are: 1,2,3,4-tetrahydro-methyl-~4*, soil 4~benyl-p-naphthylamine hydrogen chloride; 1,2,3,4-tetrahydro-1methyl-4 ~ Stupid ~ (£) 1 naphthylamine hydrogen chloride; hydrazine, hydrazine-dimercapto-p-phenyl-1-decylpropylamine hydrogenation; gamma-(4-(trifluoromethyl)phenoxy ) - amphetamine hydrogenated gas · βρ 554; CP 53261; 0-demethyl venlafaxine; WY.

, 1 4b, 818; WY

1084-9596-PF 73 200848063 45,881; N-(3-fluoropropyl) paroxetine; and Lu 19005. Anticholinergics An anticholinergic drug that is a compound that reduces the effects mediated by acetylcholine at the receptor site, for example, in the central nervous system or peripheral nervous system. Anticholinergic drugs include reversible competitive inhibitors of acetylcholine receptors, and are classified according to the affected body: antimuscarinic agents, which act on chlorpyrifos to detect acetylcholine receptors; The agent acts on the nicotinic acid acetylcholine receptor. Anticholinergic drugs can be used to treat neurodegenerative disorders. Anticholinergic agents suitable for use in the compositions, kits and methods described herein, including, for example: atracurium; atropine; benztropine (e.g., benztropine); darif enacin Dicyclomine (eg dicyclomine gasification hydrazine); dimenhydrinate; diphenhydramine; doxacurium; ethopropazine (eg ethopropazine hydrogenation); flavone brigade; iprato i (ipratropiuni); inivacurium Oxybutynin; pancuronium; pirenzepine; scopolamine; sol i fenacin; suxamethonium (eg, chloramphenicol); tiotropium; Tol terodine (eg tolterodine tartrate); trihexyphenidyl (eg, trihexyphenidyl chloride); tr imethaphan; tropicamide; tubocurar ine; and vecuronium 〇1084- 9596-PF 74 200848063

Benztropine

Benztropine has the following structure:

Structural analogues of Benztropine, described in 暮圃奎, 六: 义利马5,792,775 (I); W02007/025005 (η·Β μ π auj, and US Patent No. 5, 506, 359. Benzene Trihexyphenidyl gasified hydrogen catenol hydroformin has the following structure:

Structural analogs of trihexyphenidate are described in U.S. Patent No. 2,682, formulas (I) and (II), and U.S. Patent No. 2,716,121. The structural analog of Benhasso also has the following structure·

Wherein 'R!, R2, R3, R4 and r5 are independently H, halogen, hydrazine H, (3), N〇2, Ch alkyl or 〇Ch alkyl; Al& A2 is H or optionally substituted C! -6 alkyl, or ^ and Α2 combine to form a ring; η is Bu 2, 3, "

1084-9596-PF 75 200848063 5 or 6' and is either η or optionally substituted Ci 2, or & B2 to form a ring. Although Estrogen Modulator estrogen modulators may be used in the compositions, methods and kits described herein. Estrogen modulators include both selective and non-selective hormone receptor regulation and progression includes similar estrogen compounds, and such estrogen-like compounds modulate estrogen levels. Estrogen modulators, including hormone-producing antagonists, such as antiestrogens, and estrogen-producing synergists. A selective estrogen receptor modulator is a high affinity ligand for the estrogen receptor, but acts as a synergist or antagonist depending on the tissue to which it acts. Exemplary estrogen modulators are: acolbifene, af imoxi fene, rzoxifene, bazedoxifene, ci〇mifene (or clomiphene), N-desmethyltamoxifen, tamoxifen, Demethylated arzoxifene, droloxifene, faslodex, 4-fluoro-desmethyl tedarzoxifene, fispemifene, ulvestrant, 4-hydroxytamoxifen, id〇xifene, 1asof oxi f ene λ levormeloxifene ^ miproxi f Ene, nafoxidine, orme1 oxi f ene, ospemi fene, pipendoxifene, raloxifene, toremifene, trioxifene, CI-680, CI-628, CN-55, 956-27, MER-25, U-11, 555A, U-11, 100A, ICI-46, 669, ICI-46, 474, diphenolhydrochrysene, 1084-9596-PF 76 200848063 erythro-MEA, Parke Davis CN-35, 945, GW5638, EM-800, SP-5 0 0263, SRI 6234, ZK1 91 703, MDL 1 03, 323, LY-117018, LY353381, NNC 45-0781, allenolic acid, cyclofenil, ethamoxytriphetol, and triparanol, and US Patent No. 7, 151, 196; 7, 1 38, 426; 7, 045, 54 0;7, 19 6, 119; 6, 927, 224; 6,906,086; 6,906,202; 6,894,0 64; 6,869,969; 6,875,775; 6, 797,719; 6, 750,213; 6,458,811; 6,132,774; 5, 962,475; 5,384,332, 4, 894, 373; 4, 536, 516; 4, 418, 068; and 2,914, 563. Clomiphene Clomiphene has the following structure:

Structural analogs of clomiphene, including Crotone # mirror isomers. Structural analogs are also described in U.S. Patent Mirror Image Isomers. The structure is similar to the formula; the U.S. patent number has the formula; U.S. Patent No. 5, 41 0,080, the number of 1, 5, 189, 212. Raloxifene (Raloxifene) has many other types of smoke. 2 No. 2, 914, 563; and US patent number Raloxifene has the following structure: 1084-9596-PF 77 200848063

OH

Examples of raloxifene non-structural analogs are L γ 117 〇 18 and LY 31 7 7 8 3 . Raloxifene analogs are also described in U.S. Patent No. 5,610,167 (I)' and U.S. Patent Nos. 5,393,763; 5,457,117; 5,478,847; 5,811. 12〇; 5, 972, 383; 6,458,811; 6,797,719; 6,894,064; 6,906, 〇8 6; RE38, 9 68; R E39,049; RE39,050; and RE39,708; and W02000037065. Tamoxifen tamoxifen has the following structure:

The structure of tamoxifen is similar to the following structure:

Wherein 'Rla, Rib, Rlc, Rid, R2a, R2b, R2c, R2d, R2e, R3a, R3b, 1084-9596-PF 78 200848063 K3C, R3d and R3e each alkane η 甘η ς η, national element, Ch alkane Base; R4, K5 and R6 are selected from: H soil is 2, ... ... mentally substituted, 5 or 6. , 0H or 0Ci-6 C 1 - 6 base; and gas (1) = discussion, also described in the US patent number... (7) 5〇47 = (1) 'off patent number 5,8G7,899 (1); US patent Number 6,875,775 (1) and table! Compounds (1) to (46).

.3⁄4 hemo: Illustrative analogs of Fen include: 4 one by methtamoxifen; one part of dextromethorphan; s+[4—(2,3-epoxypropoxyphenyl)-” 2 -diphenyl-a 3,j,3-trifluoro-propane; (E)Bu [4-(2,3-epoxypropoxyl pphenyl)-H diphenyl-3,3,3-tri Fluoro-propene; (£)-1,2-diphenyl-3,3,3-trifluoro 1 [4 (2 [bis-(2-hydroxyethylamino)-ethoxyphenyl)]- Propylene·(E) 1,2-monophenyl-3,3,3-trifluoro-l-[4-(4-[4-methylpiperazine=]ethoxy)-phenyl]-propene; 1-[4-(2-dimethylamino)ethoxy)-phenyl]2-phenyl-3,3,3-trifluoro-; i-(4-methoxyphenyl)-propene, 1 [4-(2-Dimethylaminoethoxyphenyl) 2_phenyl_3,3,3-trifluoro-1 (4-hydroxyphenyl)-propene; (Ε)-丨, 2- Diphenyl-3,3,3-trifluoro-l-[4-(2-[2-hydroxyethylamino]-ethoxy)-phenyl]-propene; 1-[4-(2- Dimethylaminoethoxy)phenylphenyl-p-phenyl-3,3,3-trifluoro-2-(4-hydroxyphenyl)-propene; (E)-l,2-diphenyl- 3, 3, 3-trifluoro- 2-[4-(2-oxaridinyloxy) )-phenyl]-propene; diphenyl 3' 3' 3-difluoro-l-[4-(2-morpholinoethoxy)phenyl]-propene; (E)-l-[4 -(2-diethylaminoethoxy)- phenyl]-12-diphenyl^^-trifluoro-propene ""-----"--azidoethoxybenzene

1084-9596-PF 79 200848063 base]-1,2-diphenyl-3,3,3-trifluoro-propene; —diphenyl-3,3,3-trifluoro-1-[4-(2 -[bis-(2~gasethyl)-amino]-ethoxy)-phenyl]-propene; 1-[4-(2-dimethylaminoethoxy)-phenyl]-3 , 3, 3-Trifluoro-1,2-bis-(4-hydroxyphenyl)-propene; 1-phenyl-2-(4-methoxyphenyl)-1-[4-(2-dimethyl (amino)ethoxy)phenyl]_3,3,3-trifluoro-propene; (E)-1,2-diphenyl-3,3,3-trifluoro-l-[4-(2- [nitroxyl]ethoxy)-phenyl]-propene; (E)-1-[4'(2-dimethylaminoethoxy)phenyl]-1-(3'- mercaptobenzene (b) phenylbutan-1-ene; (e)-1-[4,-(2-dimethylaminoethoxy)phenyl]_1-(3,-phenylphenyl)- 2-(phenyl)-1-ene; (E)-l-[4'(2-diethylaminoethoxy)phenyl]-1-(3,-hydroxyphenyl)-2-phenyl But-1-ene; (E)-1-[4'-(2-diethylaminoethoxy)phenyl]-1-(3'-hydroxyphenyl)2-phenylbut-1- (E)-l-(3,-Hydroxyphenyl)-1-[ 4' -(2-decylaminoethoxy)phenyl]-2-phenylbutyrene; (E) -1 (3 '-Hydroxyphenyl)-1_[4,-(2-decylaminoethoxy)phenyl]-2-phenylbut-1-ene; (e)-1-[4-ethylamino Ethoxy)phenyl]-1-(3-presylphenyl)-2-phenylbutan-1-ene, (E)-1-[4,-ethylaminoethoxy)phenyl ]-1-) 3'-hydroxyphenyl)-2phenylbut-1-ene {5-[4-(1,2-diphenyl-but-1-enyloxyphenethyl)- (4, 4, 5, 5, 5-pentafluoropentyl)-sulfur; {5-[4-(1,2-diphenyl-but-1-enyl)-yloxy]-pentyl} -(4, 4, 5, 5, 5-penta-pentyl)-sulfoxide; {5-[4-(1,2-diphenyl-but-1-enyl)-phenoxypentyl} -(4, 4, 5, 5, 5-pentafluoropentyl)-indole; 4-(ι_{4-[5-(4, 4, 5, 5, 5-pentafluoropentylthio)-pentyl Oxy]-phenyl-2-phenyl-but-1-enyl) is a vain; 4-(l-{4-[5-(4,4,5,5,5-pentafluoropentane) Sulfhydryl)-pentyloxy 1084-9596-PF 80 200848063 yl]-phenyl}-2-phenyl-but-1- yl)-phenol; 4-((E,Z)-l-{4- [5-(4, 4, 5, 5, 5-pentafluoropentanesulfonyl)-pentyloxy]-phenyl}- 2-phenyl-but-1-enyl)-phenol; (4, 4, 5, 5, 5-pentafluoropentyl)-{6-[4-((E,Z)-phenyl-1,2, 3, 4 - tetrahydronaphthalen-1-ylidene)-phenoxy]-hexyl}-suborder; (3-phenylprop-2-ynyl)-{5-[4-((£,2)- Phenyl-1,2,3,4-tetrahydronaphthalene-1-ylidenemethyl)-phenoxy)-pentyl}""Yashi Feng;{5-[4-((Ε,Ζ ,1,2-diphenyl-butenyl)-phenoxy]-pentylbupyridin-2-ylmethyl-sulfoxide; {5-(4-(1,2-diphenyl-butyl) -1_thyl)-phenoxy]-pentyl}_° ratio -2 -ylindolyl-sulfur; 4-((E,Z)-2-phenyl-1-{4-[5 -(σ ratio ° -2 - fluorenylthio)-pentyloxy]-phenyl}-butenyl-p-yl)-phenol; 4-((Ε,Ζ)-2-phenyl-1 - {4-[5-(σιέ*ϋ定-2-yl-methylpyrrolidine)-pentyloxy]-phenyl}-but-1-enyl)-phenol; 4-((Ε,Ζ) -2-phenyl-1-{4-[5-(acridin-2-ylpyridinyl)-pentyloxy]-phenyl}-but-1-enyl)-phenol; (5- {4-[(Ε,Z)-1-(4-iodophenyl)-2-phenyl-but-1-enyl]-phenoxyindole-pentyl)-(4,4,5, 5 , 5-pentafluoropentyl)- ί sulfur; (5-{4-((Ε,Z)-l-(4-mothyl)-2-phenyl-but-1-yl]-phenoxy (i,4-(4-[5-(4, 4, 5, 5)) , 5-pentafluoropentylthio)-pentyloxy]-phenyl}-2-phenyl-but-1-yl)-phenol; 3-((E,Z)-l-{4-[ 5-(4, 4, 5, 5, 5-pentafluoropentanesulfinyl)-pentyloxy]-phenyl}-2-phenyl-butan-1-yl)-phenol; (E, Z)-l-{4-[5-(4, 4, 5, 5, 5-pentafluoropentylsulfinyl)-pentyloxy]phenyl}-1-(4-phenylphenyl) -2-phenyl-but-1- 1084-9596-PF 81 200848063 olefin; (E)-1-{4-[5-(4, 4, 5, 5, 5-pentafluoropentylsulfinyl) )-pentyloxy]-phenyl}-1-(4-phenylphenyl)-2-phenyl-but-1-ene; {5-[4-((E,Z)-1,2_ 2 Phenyl-but-1-enyl)-phenoxy)-pentyl}-σ ratio σ-denyl-2-ylmethyl-lithite; {5-[4-(1,2-diphenyl-butyl) -1(Z)-diyl)-phenoxy]-pentyl}-(4,4,5,5,5-pentafluoropentyl)- sapite; {5-[4-(1,2 -diphenyl-butan-1(E)-dilyl)-phenoxy]-pentyl}-(4, 4, 5, 5, 5-pentafluoropentyl)-arylene; 4-(1- {4_[4-(4, 4, 5, 5, 5-pentafluoropentanesulfinyl)-butoxy]-phenyl}-2-phenyl-butan-1(E,Z)-diluted -Phenyl; 4-(1-{ 4-[6-(4, 4, 5, 5, 5-pentafluoropentanesulfinyl)-hexyloxy]-phenyl-2-phenyl- - 1(E,Z)-alkenyl)-phenol; 4-(l-{4-[(N-mercapto-1^-2-(4,4,5,5,5-pentafluoropentanestone) Yellow-based)-ethyl-amino)-ethoxy]-phenyl}-2-phenyl-but-1-(E,Z)-thyl)-phenol; 4-(1-{4-( 2-(^Methylstate-2-(4,4,5,5,5-pentafluoropentanesulfinyl)-ethyl-amino)-ethoxy]-phenyl}_2-phenyl -butyl-1(E,Z)-thyl)-phenol; (Z)-4-{12-(4, 4, 5, 5, 5-pentafluoropentylsulfinyl / k _ group)-l -[4_(5-(4, 4, 5, 5, 5-pentafluoropentylsulfinyl)-pentyloxy)-phenyl]_2-phenyldodecylad-1-yl} (E)-4-{12-(4,4,5,5,5-pentafluoropentyl)-[4-(5-(4, 4, 5, 5, 5- Pentafluoropentylsulfinyl)-pentyloxy)-phenyl]-2-phenyldodecylad-yl)}-benzene; N-butyl-2-(6-{4-[ 1-(4-fluoro-phenyl)-2-phenyl-butan-1(E,Z)-alkenyl]-phenoxy}-hexylthio)-N-methylethanoamine; N-butyl Benzyl-2-(6-{4-[1-(4-carbyl-phenyl)-2-phenyl-butan-1(E,Z)-diyl]-phenoxy}-hexan 1084-9596-PF 82 200848063 Styrene)-N-methylethylamine; N-butyl-2 -(6 - {4-[1 -(4-yl-phenyl)) 2-phenyl-butyr-1(E,Z)-alkenyl]-phenoxybuhexanesulfonyl)-N-mercaptoacetamide; (Z) - 4 - {12 -(4, 4 , 5, 5, 5-penta-II-pentylsulfonyl)-1_[ 4-(5-( 4, 4, 5, 5, 5-pentafluoropentylsulfonyl)-pentyloxy)-phenyl ]-2-phenyldode-1-enyl}-phenol; 4-(1-{4-[2-(4, 4, 5, 5, 5~pentafluoropentylthio)-ethoxy] -phenyl}-2-phenyl-butan-1(E,Z)-alkenylphenol; 4-(1_{4-[2-(4, 4, 5, 5, 5-pentafluoropentylsulfinyl) Mercapto)-ethoxy]-benph}-2-phenyl-but-1 (E,Z)-thyl)-phenol; 4-U-{4-[2-(N-methyl-N -3-(4, 4, 5, 5, 5-pentafluoropentylthio)-propyl-amino)-ethoxy]-phenyl}-2-phenyl-butan-1 (E, Z) -alkenyl)- phenol; 4-(1-{4-[2-(4, 4, 5, 5, 5-pentafluoropentylsulfonyl)-ethoxy]-phenyl}-2 Phenyl-butyr-1(E,Z)-alkenyl)-benzoquinone; 4-(1-{4-[2-(Ν-methyl-N-3-(4, 4, 5, 5, 5) -五貌戊烧亚亚醯))-propylamino-ethoxy]-phenyl}-2-phenyl-but-1-(E,Z)-alkenyl)- idiot; 4-( 3-{3-[4-(4, 4, 5, 5, 5-pentafluoropentylthio)-propoxy]phenyl}-2-phenyl-but-1(£,2)-alkenyl )-Benzene; 4-(1-{4-[3-(1^-曱) - N-2-(4,4,5,5,5-pentafluoropentylthio)-ethyl-amino)-propoxy]-phenyl}-2-phenyl-butane-1 (E, Z)-alkenyl)-phenol; 4-(1-{4-[3-(N-fluorenyl-N-3-(4, 4, 5, 5, 5-pentafluoropentylthio)-propyl) -amino)-propoxy]-phenyl}-2-phenyl-butan-1(E,Z)-dilute)-benzene age; 4-(1-{4-[3-(4, 4 , 5, 5, 5-pentafluoropentyl sulfite, fluorenyl)-propoxy]-phenyl}-2-phenyl-but-1-(E,Z)-alkenyl)-indolol; 4-(b {4-[3-(N-methyl-N-2-(4, 4, 5, 5, 5-pentafluoropentanesulfinyl)-ethyl-amino)-propoxy]- Phenyl}-2-benyl-but-1 (E,Z)-lean 1084-9596-PF 83 200848063 base)-benzene; 4-(1-{4-[3-(N-fluorenyl-N) —3—(4, 4, 5, 5, 5-pentafluoropentyl sulfhydryl)-propylamino-propoxy]-phenyl b-2-phenyl-but-1 (£, 2) -alkenyl)-phenol; 1^-butyl-2-(4_{4-[1-(4-hydroxy-phenyl)-2-indolyl-but-1(e,Z)-alkenyl-benzene Oxybutyl sulfinyl)-n-methylacetamide; and N-butyl-2-(4-{4-[1-(4-hydroxy-phenyl)-2-phenyl-butyl- 1(E,Z)-alkenyl-phenoxybupentylsulfinyl)-N-f-ethylamine 0 Tory Finland (toremifene) toremifene has the following structure:

The rimifene analog is described in the formula (1) and (2) of U.S. Patent No. 4,696,949, and the formula (1) of EP 1475087. Exemplary analogs of toremifene are: 1-phenyl-1,2-bis(4-hydroxyphenyl)-1-buten-4-ol; 4-bromo-buphenyl- 1,2-double (4-hydroxyphenyl)-butadiene; 2-phenyl-2,3-bis(4-hydroxyphenyl)tetrahydrofuran; 1,2-diphenyl-1-(4-carbazide) Base)-i-penten-5-ol; 2,3-diphenyl-2-(4-pyridylphenyl)tetrazole; 1,-benyl-1-(4-methoxyphenyl) _1_penta-5-acid; 1,2-diphenyl-1-(4-hydroxyphenyl)-buten-4-ol; 2,3-diphenyl-2-(4-hydroxyl) Phenyl)tetrahydrofuran; 1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol; -Chloro-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-butene; 4-1084-9596-PF 84 200848063 Chloro-1,2-diphenyl-(1-azapropion. aziridinyl)ethoxy]benyl]-1~butene; 4-filled~1,2-diphenyl-1-[ 4-[2-(1-11 ratio. each. fixed) ethoxy]phenyl]-butene; 2, 3-diphenyl-2-[4-[2-(N, diethylamine) Ethyl]phenyl]tetramethylene furan; 1-phenyl- 1,2-bis(4-cyanophenyl)butan-4-ol; 4-bromo-1 -phenyl_1,2-bis(4-hydroxyphenyl)butane; 1,2-diphenyl-1-(4-hydroxyphenyl)butan-4-ol; 4-chloro-1,2- Diphenyl-bu [4-(2-piperidinyloxy)phenyl]butane; 1,2-diphenylhydroxyphenyl)butane-1,4-diol; 1-phenylene ; 2, bis(4-hydroxyphenyl)butane-1,4-diol; 1,2-diphenyl 4-(4-methoxyphenyl)4-butene-4-ol; -Bromo-1,2-diphenyl-h4_[2_(n,n-didecylamino)ethoxy]phenyl]-1-butylene; 4-carbo],2-diphenyl+( [Phenylphenyl)butane, decachloro-1,2-diphenyl-1 -(4-#里中的盆,1 &base)-bubutene; and 1,2-diphenylbutyl Alkane-1,4-diol. -H4-[2-(N,N-dimethylamino)ethoxy] phenyl] additional agent Alverine

Alverine has the following structure:

Alverine structural analogues,

The following formula: where or Ch base; R2, R3, r": 6, R7, R8, R!

1084-9596-PF 85 200848063

Rn and Rh are independently selected from: oxime, halogen, 0H, Ch alkyl and 〇Ch alkyl; m is 0, 1, 2, 3, 4, 5 or 6; and 11 is 〇,; [, 2, 3 , 4, 5 or 6.

Amiodarone

Amiodarone has the following structure:

The amiodarone structural analogs are described in U.S. Patent No. 3,248, 401 and in the Examples I, Π and m; U.S. Patent No. 5,849,788 (see, for example, claim 1); Compounds of the number 5,567,728; and U.S. Patent No. 4,851,554 (I) ° amiodarone additional analogs, U.S. Patent Nos. 7,148,240; 6,515,147; 6,31, 487; 981,514.

An exemplary structural analog of Amiodarone: 3, 5-diiodo-4-(2_N,N-diethylaminoethoxy)phenyl-(2-butylbenzofuran-3-yl)nonanol hydrogenated hydrogen ; 2-methyl-3-(3,5-di-diiodo_4 - (2^diethylamino-ethoxy)-benzylidene)benzofuran hydrogen chloride; butyldiiodo-4- slow Benzomethoxy-benzonitrile) benzopyrene; 2_methyl_3_(3,5-die-4-hydroxy-benzylidene)benzopyran; 2_methyl_3_( 3, Bishen moth methoxy-benzyl)benzofuran; 4'-hydroxy-3,-iodo-3,5 diiodo-4-(2-N,N-dimethylamino-B Oxy) _ 八' rolling 丞) a base _ hydrogen chloride; 2 butyl

1084-9596-PF 86 200848063 - 3-(3 - ang-4-yl-benzoyl yl) benzopyran; and 4',4-di-di--3' 3, 5-triiodo-di Phenyl decane. Chloroquine and hydroxychloroquine gas quinoline have the following structure:

Hydroxychloroquinoline has the following structure:

The quinoxaline and hydroxychloroquine structural analogs are described in U.S. Patent No. 2, 233, 970 or have the following structure:

R, N, R8, wherein independently, X is hydrazine or halogen; Ri, R2, R3, R4 and R5 are selected from: H, 1084-9596-PF 87 200848063 Halogen, Ci-6 yard, 0H, 0Ci- 6 alkyl, CN or N〇2; A is a branched or unbranched, saturated or monosaturated with 1 to 6 carbon hydrocarbon chains; R6, R?, R8 and R9 are Η, Ch alkyl or (CH2 n)(CH2〇H), wherein η is 0, 1, 2, 3, 4 or 5 pro 普 pro ( (Chlorprothixene) chloropyrazine has the following structure: CH;

The chlorobutioxol structural analogue has the following structure:

Wherein, independently, Ri, R2, r3, r4, r5, r6, r7, r8 and r9 are each selected from: H, halogen, Ch alkyl, perhalogenated Ch alkyl, OH, OCh alkyl, 0CF3, SH, SCh alkyl or SCF3, wherein at least one of RrR8 is a halogen; Y is Cfh, 〇, NH, S(0) 〇-2, (CH2)3, (CH)2, CH2〇, ClhNH, CHN or CihS ; A is a branched or unbranched, saturated or monosaturated with 1 to 6 carbon fe chains; Βι and B2 are selected from: H, fully halogenated Ci-e, smoldering or B1 combined with B2 Together to form a randomly substituted product

Dicyclomine 1084-9596-PF 88 200848063

Dicyclomine has the following structure:

Dicyclomine structural analogs are described in U.S. Patent 2,474,796. Structural analogue of Dicyclomine, also teaches the name

In the following formula: From: 〇 where, independently, n is 1, 2, 3, 4, 5 or 6; X and γ and S; and Ri and R2 are hydrazine or Ci-6 alkyl. Hexachlorophene six gas distribution with the following structure:

Wherein, independently, Xl, X2, X3, 0, ; 1, 2, 3, 4 or 5. X5 and Xe are 11 or _ and η IMD-0354 IMD-0354 has the following structure:

1084-9596-PF 89 200848063

An analog of IMD-0354, Xiao Gangan, other small molecule foot-/c B inhibitor. The exemplified small molecule NF- /c Β φ: 卩 is 丨 & t. 卩'] 剤 is: antioxidant; SP1 00030; ^ epoxyquinomicin (DHMEQ); W02006/032322 Formula (I). Analogs of IMD-0354 are also condensed in the following formula:

R4 R5

X whereinin independently, X is a halogen at any position on the ring; meaning is 〇 or X; Ri, R2, R3, R4 and R5 are or fully halogenated Ci 6 alkyl; and Re is H or Ci 6 alkyl.

Nitazoxanide

Ni tazoxanide has the following structure.

i

Structural analogues of Nitazoxanide, including tizoxanide or having the following structure:

1084-9596-PF 90 200848063 wherein, independently, Ri and R2 are selected from: H, halogen, CN, N〇2, CF3 or Ci-6 alkyl; R3 is hydrazine or C1-6 alkyl; R4, R5, 1?6, R7 and ί?8 are selected from: H, halogen, CN, N〇2, CF3, Ch alkyl or 0CH alkyl; X, Y and Z are selected from 0, S or NR9; A bond, 0, S or NR9; R9 is a hydrazine or a Ch alkyl group; and B is Η or C(Z)-X-R8. Thioridazine methylthiodazine has the following structure:

The structural analog of sch3 thiodazine has the following structure

Halogen, Cl-6 alkyl, fully halogenated Cl-6 alkyl, 0H, 0Cl-6 alkyl, 0CF3, SH, SCu alkyl or SCF3; Y is CH2, 0, NH, S(0)〇-2 , (CH2)3, (CH)2, CH2O, CH2NH, CHN or CH2S; A is a bond or branched or unbranched, saturated or monosaturated hydrocarbon chain with 1 to 6 carbons; each Β!, B2, B3 , independently of B4, is halogen, halogen, fully halogenated Cl-6 alkyl, Cl-6 alkyl, OCl-6:): complete, 0 (fully halogenated 0Ci-6 alkyl) or Βι and B2 Βι and B3, Βι and B4, B2 and 1084-9596-PF 91 200848063 Optionally, the public number B3, B2 and B4 or & B4 are combined to form a ring. The methylthiodazine analogs are also described in U.S. Patent Application No. 2007-〇287702, formulas (I), (IIA) and (IIB). Varnostrine (factory vanosin has the following structure··

^0^0 4 2. 2 fell: Division: (4), described in US Patent No. 2'896 (Π; US Patent No. 4,476,129, US Patent No. 4, 874, 765 (I) Additional therapeutic Therapy J Seek Needs 'The patient may also receive additional therapeutic therapies. For example, a therapeutic agent can be administered to a concentration known to be effective against the agent or agents described herein. Particularly useful agents include those for the prevention or prevention of death or death or treatment of the nerves, prevention or prevention of neurodegenerative disorders. Examples of treatment categories and medicaments, Listing 2. The categories and combinations of agents of Table 2 can be used. When more than one type of agent is used, the special therapeutic agent can be transferred separately or in advance... early in the formula. Different dosage paths can be used in the presence of the drug. To ==

1084-9596-PF 92 200848063 Included, but not administered intramuscularly, intramuscularly, subcutaneously, inhaled, via a vein, rectal, buccal, transvaginal, intraluminal, intra-articular, transdermal or oral). Alternatively, the agent can be administered intra-abdominal or epidural. Any donor (8) is in a way to bypass the blood or enhance penetration (for example, to give NaVCa++ F early obstruction)

CereP (4) can be useful. Alcohol or in some cases '-agents and additional therapeutic agents, 1 hour, 2 hours, 4 hours, 6 hours, respectively! . Hours, 12 hours, 18 hours, 24 hours, 3 days, 7 days or "days. The dose and frequency of administration of the ingredients in the composition are independently controlled. For example - the compound can be administered every 3 times, and the second compound can be Each sputum is administered owing. Combination therapy can be administered on-and-II cycles including rest periods so that the patient has the opportunity to recover from any unforeseen side effects. The compound can also be formulated to enable delivery. Optionally, the agent of the composition may be administered in a low dose or in a high dose, as defined by a low dose or a high dose; such therapeutic agents may be combined with additional active or pure ingredients, such as conventional The above-mentioned acceptable carrier can be pre-mixed. A pharmaceutical carrier can be compatible, and the composition can be administered to a patient. The pharmaceutically acceptable carrier includes, for example, for example. : Water 'saline, buffer and other compounds ^ are condensed, for example, in Μ(10)k Index, Merck &&, (4)(d), ^

Jersey. A sustained release formulation or a sustained release device can be used for continuous administration. - In addition to administering a therapeutic agent, this additional therapeutic therapy may involve other treatments such as transplanting nerve cells (including anti-inflammatory and/or immune as needed)

1084-9596-PF 93 200848063 Inhibition therapy) or change the lifestyle of the patient to be treated. Conjugates may optionally be attached to each other using the compositions described herein to form a combination of 4 I, as desired. (4), (A) '(L) ~ (B) (1) In Formula 1, (A) is a list of drugs in Table la or lb. The linker (L) is tied to (8), and (8) is listed in Table ia. , the price of any drug in the drug. And the categories of 2 and , '. The oral substance can be administered to an object via any route to treat any of the diseases described herein. And for the treatment of guanamine: the sputum can be _, when the conjugate is cut by intracellular and extracellular enzymes (such as - • 曰 ·, and phospholyase), release the drug = in the two and: package The exogenous enzyme is cut tolerant. The combination of the conjugate in the body is controlled by the design of the linker (L) and the synthesis of the conjugate (A: the covalent bond of the drug and the drug (8). The composition of the drug can be used in this technical field. The preparation of the conjugate is carried out by the method disclosed in G. Hermanson, Bi〇 conjugate u hniques, Academic Press, Inc., 1996, and may involve selective protection and deprotection. The alcohol (A), the linker and/or the alcohol (A) of the drug (B), the amine, the ketone, the sulfhydryl group or the carboxy group b group, for example, the common protecting group for the amine, including the amine carbenyl group,

1084-9596-PF 94 200848063 For example, trisyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsulfoniumethyl, methyl, allyl and m-nitrophenyl. Other common remedies for amines, such as guanamine, acetamide, trifluoroacetamide, yin, guanamine difluorodecane sulfonylsulfonamide, Trimethyldecylethanesulfonamide, and octabutylidene hydrazide. Commonly used protecting groups for ten pairs of fluorenyl groups, such as methyl group, ethyl group, ninth yl group, 9-mercapto group, 2-mono(trimethylfluorenyl)ethoxymethyl group, benzyl group, two earths Methyl, anthracene-based benzyl, orthoester (〇rth〇-ester), and haloester. A common protecting group for the use of a pentadecyl alcohol, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxyindenyl, tetrahydropyranyl Oxyethyl, benzyl, 2-nap thy 1 methyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxyl, 9-phenylxanthyl, trityl (including methoxy) Diphenylmethyl), and mercapto ether. The general use of a sulfhydryl group includes the same as the protecting group with a plurality of hydroxy groups. Further, the sulfhydryl group may be protected in the form of a reduced form (e.g., a disulfide) or an oxidized form (e.g., a sulfonic acid, a sulfonate or a decylamine). The choice of protecting group may necessitate removal of the protecting group in the molecule under selective conditions (eg, acidic conditions, basic conditions, catalyzed by a nucleophile, catalyzed by Lewis, or deuterated), while other protecting groups are not Affected. Conditions for addition of protecting groups to amines, alcohols, sulfhydryl groups and carboxyl functional groups, as well as conditions for their removal, in Tw· Green an (i PGM Wuts, Protective Groups in Organic Synthesis (2nd Ed. ), John Wiley Details are provided by & Sons, 1991 and PJ Kocienski, Protecting Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below.

1084-9596-PF 95 200848063 Linker (1 inker) The simplest component of the linker is the drug (the magical and drug bond, but the 疋 generally provides a linear, ring or branched molecular skeleton with a hanging group Covalently linking the drug (A) to the drug (B). Therefore, the linking drug (A) to the drug (B) is achieved by a covalent method involving one or more of the drug (A) and the drug (B). The functional groups form linkages. Examples of chemically reactive functional groups that can be used for this purpose include, but are not limited to, amine groups, hydroxyl groups, sulfhydryl groups, carboxyl groups, carbonyl groups, carbohydrate groups, adjacent diols, thioethers, a 2-amino alcohol, a 2-amino mercaptan, a mercapto group, an imidazolyl group, and a phenolic group. A covalent linkage of the drug (A) and the drug (B), which can be used, including the presence of the drug ( A) a linker of a reactive structure which reacts with a functional group in the drug (B). For example, an amine group of the drug (A) may react with a carboxyl group of a linker or an activated derivative thereof to cause a linkage between the two. Indoleamine formation. Examples of structures that can react with sulfhydryl groups, including xch2co- (where X-Br, C1 I) a type of halogenated vinyl compound which exhibits particular reactivity to thioindolyl groups, but can also be used to modify imidazolyl, sulfur scale, phenol, and amine groups, such as Gurd, 卯人1 1 : 532 ( 1 967). The N-maleimide derivative is also considered to be selective for sulfhydryl groups, but may be used for coupling to an amine group under certain conditions. For example, 2-iminotetrahydrogen 11 The reagent of Traut et al. (12: 3266 (1 973)) introduces a thiol group via a conversion of an amine group, and if it is linked via a disulfide bond, it can be regarded as a sulfur. Base reagents. Reactive structures capable of reacting with amine groups, such as alkylating and thiolation drugs 1084-9596-PF 96 200848063. Representative alkylating agents, including: (i) α-haloethenyl The compound, in the absence of a reactive thiol group, exhibits specificity for the amine group and is of the type XCH2C0- (wherein Χ = Π, Br or ί), as described, for example, in Wong Wan 24: 5337 (1 979); (Π) N-maleimide derivatives which can be thiolated via Michael type reaction or via addition to the cyclocarbonyl group to react with an amine group. Smyth e*ta 1 ·, see j (see Soc· 8 2 : 4 6 0 0 (1 9 6 0 ) and B / 见 乂 91: 589 (1 964); / (iii) aryl halogenation For example, a reactive nitro-aromatic compound; (iv) an alkyl halide, as described, for example, in McKenzie et al, Λ Protein Chem. 7: 581 (1988); (v) ketone, which forms an amine group Schiff's test, the formed adduct is usually stabilized by reduction to a stable amine; (vi) epoxy derivatives, such as epichlorohydrin (jrin) and bisoxirane, with amines, sulphur a phenolic hydroxyl group; ((vii) s - a gas-containing derivative of a diazine" is very reactive with nucleophiles such as an amine group, a sufhydryl group, and a hydroxyl group; (乂:^〇 aziridine (&;:2; [1^(^1^), based on the above triazine compound, such as Ross, /· as shown in & 2:1 (1 954), by ring opening with a nucleophile such as an amine group; (lx) squaric acid diethyl ester, described in Tietze, et al., 124:1215 (1991); and (X) alpha-haloalkyl ether, due to activation of the ether oxygen atom, compared to the usual alkyl group Halide, more counterproductive Alkylating agent. Described in (10) (9)

1084-9596-PF 97 200848063 et al·, set up a factory /· Yu Yi see 28:463 (1 993). Representative amine-reactive thiolation agents, including: (1) isocyanates and isothiocyanates, especially aromatic steroids, each forming stable veins and sulfur veins a derivative; (ii) a sulphate chloride as described in Herzig et al Biopo Jy/ners 2: 349 (1 964); (iii) an acid halide; (iv) an active ester such as nitrophenyl ester Or N-hydroxyamber succinimide; (v) anhydride, such as a mixed, symmetric or N-carboxy anhydrate; (vi) other reagents useful for the formation of guanamine bonds, as described, for example, in M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, 1984; (vii) Mercapto azide, for example wherein the azide group is produced from a hydrazide derivative using sodium nitrite, as described in Wetz et al., ocAe See 58:347 (1 974); and i (vi ii) sulfhydryl ester, which forms a stable lung when reacted with an amine group, as described, for example, in Hunter and Ludwig, /, see Soc. 84:3491 (1962) ). The aldehydes and ketones can be reacted with an amine to form a Schiff base, which is advantageously stabilized by reductive amination. The alkoxyamino structure readily reacts with ketones and aldehydes to produce stable oxime amines, for example, as described in Webb et al., in 1: 1:96 (1 990). A reactive structure capable of reacting with Wei Ke, including diazo compound 1084-9596-PF 98 200848063, such as diazoacetate and diazonium, and a specific reaction to produce a vine group For example, condensed in Herriot, . 3:169 (1 947). A carboxyl group-modifying agent such as carbodiimide can be formed by the formation of a guanamine bond after the formation of hydrazine-hydrazino. ^ It should be understood that the functional groups in the drug (A) and/or drug (B) can be converted to other functional groups before the reaction, if desired, for example to bring additional: reactivity or selectivity. Useful methods for this purpose include, for example, converting an amine using a reagent such as a dicarboxylic anhydride to a carboxyl group; using, for example, n-acetamido-cysteine thiol acetone, S-ethyl decyl succinic anhydride, 2-imine Base = thiophene or a mercaptan-containing sulfonium imino derivative, converting an amine to a thiol W converting a thiol using a reagent such as α-haloacetic acid vinegar to a few groups; using a thiol for 4 days such as ethylene Conversion of the amine or 2-bromoethylamine to an amine; conversion of the carboxyl group to a amine using a reagent such as carbodiimide followed by a diamine; and the use of a reagent such as toluenesulfonyl chloride in the alcohol followed by thioacetate It is transesterified and hydrolyzed with sodium acetate to a mercaptan. The so-called zero-length linker involves a reactive chemical group which is a direct covalently bonded drug (A) and a reactive chemical group of the drug (B), without introducing an additional linking material as needed. Most commonly, however, the linker will include more than two reactive structures, as described above, joined by a spacer element. The presence of such a spacer element enables the bifunctional linker to react with a particular functional group in the drug (A) and drug (B) to cause a covalent bond between the two. The reactive structure in the linker can be the same (homobifunctional linker) or different (heterobifunctional linker' or 'heteropolyfunctional when there are several dissimilar reactive structures

1084-9596-PF 99 200848063 Linker) provides potential reagent diversity and covalent attachment between drug (A) and drug (B). The spacer elements in the linker are generally composed of a straight chain or a branched chain, and may include a C-C1G alkyl group, a c2-c1Q alkenyl group, and a C2-Cl group. Alkynyl, c2-c6 heterocyclyl, C6-Ci2 aryl, CrC "alkylaryl, C3_Ci nonylheterocyclyl or Cl-Cl0 heteroalkyl. In some cases, the linker is of the formula ("丨) Description: G1-(Z1)〇~(Y1)u-(z2)s-(R30)-(z3)t-(Y2)v-(Z4)p~ G2 (Π) In formula (II), G1 is Between the drug (a) and one of the linkers; g2 is a bond between the linker and the drug (B); Z1, Z2, Z3 and Z4, each independently selected from 〇, S And NR31; R31 is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-c6 heterocyclic, c6-Ci2 aryl, Ct-Cu alkaryl, c3 - c10 a cyclic group or a Ci-C? heteroalkyl group; γ1 and γ2 are each independently selected from a carbonyl group, a thiocarbyl group, a fluorenyl group, and a squary group; and 0, p, s, t, u, and ν are each independently , is 0 or 1; and R3 is a Cl-Cl. Acryl group, C2-Cl. Dilute group, C2~~Cl〇 block group, C2 - Ce heterocyclic group, Ce-Cl2 aryl group, C7-Cl4 Aryl, C3-Cl. A heterocyclic or Ci-CH heteroalkyl group or a chemical bond to G1-(ZOa-aJu-Ui- to -(Z3)r(Y2)v-(Z4)P-G2. Examples of the preparation of the same bifunctional linker of the conjugate, including but not limited to: diamine and , selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexane Alkanediol, and polycaprolactone diol. Formulation 1084-9596-PF 100 200848063

Any of the agents described herein may comprise any suitable amount in a suitable carrier material, and typically present at 5% of the total weight of the composition. The composition may be provided in an oral, parenteral dosage form (e.g., intravenous, intramuscular), transrectally, transdermally, nasally, vaginally, inhaled, dermal (applied) or ocular route. Accordingly, the composition may be in the form of, for example, tablets, capsules, tablets, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, Drenches, osmotic delivery devices, suppositories, suppositories, enemas, injectables, implants, sprays or aerosols. The pharmaceutical composition can be formulated according to the conventional pharmaceutical practice (see, for example, Remingtc) n: The Seienee and Practice of Pharmacy, 20th edition, 2000, ed. A. R.

Gennaro, Lippincott Wi11iams & Wilkin S5 Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York) o Formulations can be formulated in a variety of pharmaceuticals known in the art using various agents. . Preferably, the medicament is formulated to be administered to the medicament simultaneously or nearly simultaneously. The composition of such a co-formulation comprises two agents which are formulated together in the same form as pills, capsules, liquids and the like. It should be understood that winter refers to the formulation of such combinations. This formulation technique is also used in formula combinations: individual agents' and other combinations described herein. #Depending on the different formulation strategies for different agents, the pharmacokinetic curves for each agent can be appropriately matched with 0 individual or separate formulas.

1084-9596-PF 101 200848063 Group. The non-limiting examples include kits including, for example, 2 pills, one pill and one powder, one suppository and one bottle of liquid, two external creams, and the like. The 誃 kit may include optional ingredients to aid in the administration of a unit dose to the patient, eg, vials for reconstituting the powder, syringes for injection, customized IV delivery systems, inhalers, and the like. In addition, the unit dose kit can include instructions for preparation and administration of the composition. This kit can be made into a single-use unit dose for patients with sputum, for multiple doses in a specific patient (fixed dose or each compound has different potency); or the kit can include multiple doses Suitable for large packages of multiple patients.) The kit can be assembled in cartons, blister packs, bottles, tubing, etc. Formulations and methods for delivering agents to the brain to treat nerves Degenerative disorders such as HD may be impeded by the inability of active, therapeutic compounds to cross the blood-brain barrier (BBB). Strategies for delivering the compositions described herein to the brain, including bypassing the face (eg, by craniotomy) Intrathecal administration, and by (for example, adding a compound for Bbb penetration, a composition described herein, systemically, and modifying the composition described herein to increase its Permeability or transport through. Craniotomy is a procedure known in the art, and any of the compositions described herein can be used together for delivery to the brain. In this method, in patients The cranium makes an opening, and The compound is delivered by a catheter. This method can be used to target a compound to a specific region of the brain. Intra-oral administration provides another means of bypassing the BBB for drug delivery. Briefly, the drug is administered to the spinal cord, for example Trans-lumbar puncture or use

1084-9596-PF 102 200848063 device. Lumbar puncture can be used for single or infrequent administration, and fixed and / or sputum administration can be achieved by using any commercially available pump attached to a ridged V official, such as pumps and catheters. Manufactured by Medtronic (Minneapolis, Minn.). To allow delivery through the BBB, the compositions described herein can be administered with one or more compounds that induce temporary sputum plus BBB opacity. Such compounds include mannitol, Cerep〇rt (·ρ-7), and KB_R7943, Na + /Ca + + exchange blockers. The compounds described herein may be modified (e.g., lipidated or acetaminolated) to increase delivery through the beta oxime after systemic administration (e.g., non-oral), modified using standard chemical modifications in the art. In some embodiments, the compound ' described herein is bound to a peptide carrier and transported through the BBB. For example, the compound, cr 0 can be described as a monoclonal antibody against a human receptor, such as i dge (Jpn J. Pharmacol 87. 97-103, 2001), thereby allowing the compound to After systemic administration, it is transported through the BBB. The compounds described herein can be used, for example, with biotin-streptavidin (bi〇tin) to bind to such a peptide carrier. Dosage Generally, the dose of any of the combinations described herein when administered to humans It will depend on the nature of the agent and can be readily determined by those skilled in the art. Generally, this dose is normally from about 0.001 mg to about 2 mg per mg, about 1 mg per day. 1, 〇〇〇mg, or about 5 nig to 5 〇〇mg per day.

1084-9596-PF 103 200848063 Each drug administered in the combination can be administered independently 1 to 4 times a day from the next day to the next year. In many cases, habitual/long-term medications are indicated. Additional applications can be used to treat, prevent, or alleviate neurodegenerative disorders (eg, using a compound in a mechanical analysis, using assays generally known in the art to determine if there are other combinations or single agents' as a combination. Any of HD or its associated conditions) is effective. For example, the candidate compound can be administered alone or in combination with one or more compounds independently selected from the agents of Tables la and ib, and administered to a cell such as a neural cell or a mouse striatum-introduced cell line STAMQ11. It exhibits a toxic mutant polyglutamine repeat protein. After an appropriate period of time, the immunoreactivity of these cells was examined using an antibody, 1F8. If the control group cells which are not treated with the candidate compound show a decrease in peripheral staining of the cell, it means that the candidate compound or combination of agents is an effective agent for treating, preventing or alleviating a neurodegenerative disorder. The agent described herein can also be used as a useful tool to resolve information about the biological pathways involved in neuronal cell deterioration and death. Such information can lead to the development of new compositions or single agents for the treatment, prevention or alleviation of neurodegenerative disorders. Methods for determining biological pathways known in the art can be used to determine the pathway or network pathway that is affected by contacting a cell, such as, for example, a neural cell, with a compound described herein. Such methods may include comparison to untreated, positive control or negative controls

1084-9596-PF 104 200848063 == and/or new single agents and compositions for analysis of cellular components that are 'expressed or re-expressed after exposure to 5, "Analysis of other - some cellular activities" eg Enzyme activity, nutrient uptake, and cellular components that can be included in the analysis, including gene transcripts and protein expression: appropriate: The method 'can include standard biochemical techniques, radioactive calibration of the compounds described herein (eg, 14c or 3h calibration), And using 21) gel observation and protein compound human 'gene expression rim. Once identified, compounds such as & can be used in in vivo models to further validate the tool or develop new agents or strategies to treat, prevent or ameliorate neurodegenerative disorders. As indicated above, the methods described herein can also be used prophylactically to develop a neurodegenerative disorder #HD or a condition associated with this disorder with increased risk. Risk factors 'include, for example, age, family history of neurodegenerative disorders, and psychology or pr〇fiie. Illustrative candidate compounds peptide structure peptides, peptide mimetics, and peptide fragments (natural, synthetic, or chemically modified) are applicable. Exemplary compounds include compounds that reduce the level of the stem protein or the level of the target (eg, antisense compounds, dsRNA, ribozyme) and compete with endogenous glial kine sin or protein tyrosine phospholyase A compound of a partner (eg, a dominant negative protein or a polynucleotide encoding the same). Antisense compound

1084-9596-PF 105 200848063 The biological activity of any protein that increases cell death, such as mutation H11, can be reduced, for example, by using an antisense compound directed to the rna encoded as the target protein. Reducing the antisense compound that exhibits the target molecule can utilize standard technical means. For example, an RNA2 structure can be used, such as MFOLD (M. Zuker, D. H. Mathews & D. H. Turner, Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide.

In. RNA Biochemistry and Biotechnology, J. Barciszewski & B. F. C. Clark, eds., NATO ASI Series, Kluwer Academic Publishers, (1 999)) to predict the accessible region of the mRNA of the target enzyme. A suboptimal fold with a free energy value within 5% of the most stable fold of the mRNA can be predicted using a window range of 2 2 bases. Within this range, a residue can find a complementary base to form a Base pair bonding. The open region where no base pair is formed and the suboptimal fold are added together. These regions, which are predicted to be open, are considered to have better accessibility to the binding to the antisense nucleus. Other methods of antisense design are described, for example, in U.S. Patent No. 6,472,521, Antisense Nucleic Acid Drug Dev. 1 997 7.439-444, Nucleic Ac ids Research 28.2597 2604, 2000, and Nucleic Acids Research 31: 4989-4994, 2003. RNA interference The biological activity of sputum can be achieved by using RNA interference (RNAi), such as a double-stranded RNA that targets the target molecule in question.

1084-9596-PF 106 200848063 (dsRNA) or small interfering RNA (siRNA), but reduced (see, for example, Miyamoto et al., Prog. Cell Cycle Res. 5:349-360, 2003; US Patent Application Publication No. 20030157030 Methods for designing such interfering RNAs are known in the art. , software for designing interfering RNA is available from Oligoengine (Seattle, WA). Dominant Negative Protein A person familiar with the art will learn how to make a dominant inhibitory protein against the target molecule. Such dominant inhibitory proteins are described, for example, in In Gupta et al., J. Exp. Med., 186: 473-478, 1 997; Maegawa et al., J. Biol. Chem. 274: 30236-30243, 1 999; Wo〇dford-Thomas et al., J. Cell Biol 117:401-414, 1992). The following examples are for the purpose of understanding the invention and are not intended to limit the invention. Example 1: Screening assays Screening methods are provided for screening for candidate compounds for the treatment, prevention or alleviation of neurodegenerative disorders such as HD. Many model systems, including cellular and animal models, have demonstrated that exon M, which contains an expanded polyglutamine region, is sufficient to cause disease, such as ST^%Q1 derived from the HD gene-introduced mouse model. Cell lines, with the correct gene network showing endogenous levels of mutations, have been

1084-9596-PF 107 200848063 Widely used and well characterized. This cell line reproduces many hd pathogenic features such as granulocyte dysfunction and energy deficiency and is therefore considered to be one of the most relevant cell models of HD. In order to carry out the screening, a high content screening (HCS) test method based on ICC influence has been developed, and P〇lyQ antibody 1F8 and STA/AQl11 cell strains are optimized on Cell〇micsArrayScanVTi. A number of HD-related endpoints have been identified which distinguish between mutant i-cell strains and their wild-type counterparts and are primarily used at the end of this assay to stain the nucleus of the 1F8 antibody. The objective of the screening was to identify a single agent and combination that reduced the staining intensity of the nucleus around the nucleus of the 1F8 antibody among the ST#〇7?Qiii cell lines. In addition, information on cell density is collected after drug treatment to monitor cytotoxicity due to drug treatment. The results of the test were evaluated by observing various parameters such as z, the factor (described below), disc-to-disk variation, and the result of the positive control compound hexachlorophene (15 // M). The following formula was used to calculate the nuclear staining inhibition of the 1F8 antibody by the tested chemical synthesis: • % inhibition = [(treated by DMS0 - treated with compound) / treated with DMS0] X 1 0 0 compared to cells treated with DMSO The mortality rate of more than 50% was continued for 72 hours after the treatment with Liuqifen. For single agent sequencing, this test was applied to a 384 well plate with a dose ratio of f = 2 in the range of one thousand in 12 steps to obtain a double dose response curve.

1084-9596-PF 108 200848063 Single agent activity, using the downhill 311111)1 algorithm, with the least square approximation s-type equation 丨=IraaxCV[ca+EC5()a] (c is the concentration, EG. The concentration of the agent required to obtain a 50% maximum effect, q is sigmoidicity). The uncertainty of each approximation parameter is evaluated from the following range: · Reduced i chi-squared change is less than work, or when the minimum value exceeds 1 then less than the minimum decrease to underestimate the σ I error. Single agent curve data was used to define a dilution series for each compound for screening combinations in a 6x6 matrix format. Depending on the degree of the single agent curve, use a dilution factor f of 2, 3 or 4 to select 5 dose levels, where the 'central concentration is close to the near (four) heart. For compounds with undetected single agent activity, use a dilution factor of 4 starting from the highest concentration. By combining the effects, it is easy to define the model of the combined reference from the single-agent curve by comparing the suppression of each data point with the model of the combined reference. Use two models to combine effects: (1) The highest single-agent (HSA) model / HSA (^Y) = maxUx, /Y), is a simple reference model, where the concentration of LAX and γ compounds, / χ γ is single - The agent inhibits J (2) Loewe addition, and the towel / L_e (I) satisfies the inhibition of (Guangan) + (&/orphan) =!, 1 is the effective concentration of the drug curve 'A_e . L〇ewe addition is -z is generally an acceptable reference for Synergy, which means that if the fork and Y are the same, the combination produces a combined response. /hsa can be easily calculated from A", but the decision /uewe requires interpolation and numerical root solution. # Combination start according to the threat Excess VQl hidden, then Yi Tang

1084-9596-PF 109 200848063

Excess V〇1_ arranged. Also use the "Synergy Score" ‘the towel’ common effect score s=1〇gfxi〇gf^idata(i_-

h. "0, all non-single-agent concentration pairs are summed, and the towel lQg fxY is the natural logarithm of the dilution factor for each single-agent. This effectively measures the volume of the measured and Loewe addition response, and the high inhibition = 榷, and is corrected for various dilution factors. Based on the 值(4) and standard error material (prQpagatiQn) for the value of ^, the nose uncertainty is calculated for each-common effect score (7 δ. In order to qualitatively select the desired combination for tracking, the following criteria (1) are established, such as significant common effects, such as In the HSA volume measurement with a critical value = 〇 5 addition mode, - (7) # qualitative activity, when the maximum efficacy is greater than or equal to 50% of the fish for the combination, then the co-effect and / or sufficient efficiency shift occurs. The above combination screening identifies the combination agents listed in Table 3a. After reading the flat disk, the raw data is analyzed, and the automated quality control criteria are used to evaluate the flat disks based on the control group data contained in the flat disk. This automated analysis, for the first time, determines whether to verify, reject, or not. All flats are manually evaluated on a piece-by-piece basis and, if necessary, specify the status of acceptable or rejected. The individual data blocks on the flat panel can be manually marked for exclusion. For the quality control of automated analysis, called Z, the factor is defined as follows: Z3 =1 - 3 SD DMSO+ 3 SD Control group DMSO-median System fine

1084-9596-PF 110 200848063 of the plant. Control but no 2 resistance Here, SD indicates the standard deviation, and D_ indicates that the treatment group represents the background value, which is defined as the well of all the analysis steps. According to Z, factor, automated quality control, labeling (z, > 0.3), rejection (Z, <0.3 or 2, ^ for reading..^^, will be rejected by automatic or visual...rejected, further excluded Analyze and re-do it. Divide the boundary Z' heads to 'manually verify the flat plate, and visually inspect all the flat plates to find the well-infected wells or "spikes". The wells with a lot of data values in the neighboring wells (in the same processing category) are marked and the subsequent analysis is excluded. The flats containing unusual large 篁 insert values are rejected together. The data is displayed using ST#fl The Icc-based HCS test of %Qlll cells and 1F8 antibody showed quite good performance, Z score was excellent (between 0.3 and 0.8), and the variation between the plates was very small. Selecting 1F8 antibody to inhibit 20% nuclear peripheral staining As a critical value for picking, all compounds that are at least 2% inhibited for at least one dose are included. The ones selected from the sequencing experiments are shown in Tables la and lb. The details of the ICC Cellomics test are as follows. Chromosome cell line of Cenomics- ICC test protocol Inoculate cells on day 1 and add compound I to make complete DMEM medium containing 10% FBS, 1% penicillin/streptomycin 〇·4 mg/ml G418

1084-9596-PF 111 200848063

2. Warm the medium '0.25% trypsin-EDTA water bath to 33 〇C 3 ·Pump the old medium' and wash once with 25ml PBS. 4. Add 7 ml of 0.25% trypsin-EDTA to the T175 flask and let stand. 5 to 6 minutes, gently shake for 2 to 3 minutes to ensure separation of all cells 5 · Add 8 m 1 of medium to the flask, trypsin to deactivate 6 · Pipette the cells several times to ensure adequate cell separation 7. Centrifuge at l〇〇〇 rpm for 5 minutes 8. Resuspend in 5 ml (each flask) of complete medium and develop 9. Count the number of cells in a hemocytometer or cytometer 1 〇 Make a final cell solution at a density of 1 78000 cells/ml Inoculate 45 / 1 (8, 〇〇〇) cells / well to 384 well plate 11 with multiple adders. Put the plate into the 3 3 C incubator for about 2 hours, do not stack flat plates. 12. Remove the compound pan from the dry box. 13. Prepare the dilution plate using PlateMate. In a clean 384 well plate, at room temperature, each well is 1〇〇# } intact cell culture medium. 14. MiniTrak is used to make compound dilution. Flat plate, take the original: each well of the flat plate takes i #丨, add 1〇〇^^ medium, dilute the flat plate, and dilute to 1:100 (1〇χ original concentration in culture

1084-9596-PF 112 200848063 Base)). Add 5 / 1 dilution of the original concentration to each well in the cells of the analysis plate 15 · Incubate the plate at 33 ° C overnight (~ 24 hours) Day 2 _ cell fixation, permeabilization, and 1 antibody staining 1. Prepare the following flask or original concentration solution

5% BSA in PBS

5% Triton X-100 in PBS

1M glycine (〇·75%) in PBS PBS+ (PBW and 0.5% BSA and 0.15% glycine) 4% formaldehyde-MeOH free in PBS (freshly diluted from 16% original concentration) 0. 5〇/〇Triton X-100 in PBS (freshly diluted) 2. Fix at 4% FA for 15 minutes. The multi-drip was perfused with 4% fa'. Biotek autowash was perfused with 100 mi pbs, washed once with β 0 u 1 PBS, and finally aspirated. The following steps were performed on one plate at a time: 1. Suction ii· Add 4% FA 60ul/well iii · Incubate for 15 minutes at room temperature (10 flat plates can be randomly arranged alternately, there are many times to prepare for self-cleaning and multiple drops for the next step. When handling more than 1 inch flat plate , batching the plate) 3·Set the self-cleaning program for 2X cleaning (60 mi pbs/well), and finally pumping, inject the multi-dropper with 5〇ml 〇. 5%

1084-9596-PF 113 200848063

Triton X-l〇〇 4. Perform the following steps on a flat plate at a time, each batch of flat plates: i • Wash 2X with PBS. Suction 11·Add 0.5% Triton X-1 00 60 ml/well ιιι· Start timing, each plate is in PBS/ 〇 5%

Triton X-1〇〇 was incubated for 15 minutes, and the next flat plate was processed. 5. Change the self-cleaning program to 2 χ wash and aspirate. Inject the multiplexer into PBS+, and perform the following steps on one plate at a time. i. Clean with PBS. , aspirate ii · add BS + 60 ml / well ill · incubate at RT > 30 minutes (allow for long interruptions) 6 - dilute 1 antibody (for 11 to 8, 1:2 〇〇〇) in PBS + 7 · Inject the multi-dripper with 1 〇m 1 1 antibody, set the self-cleaning to aspiration 8. Aspirate and add 1 antibody 40 ml/well to the line (column M~23, manually add 4 〇ml/well PBS+ to Line 24 9. Incubate for 1 hour at room temperature with 1 antibody, gently shake, place the plate in plastic packaging, and incubate overnight at 4 °C for 2 days _ 2 antibody incubation and Cellomics matrix Dye 10· to warm the temperature and shake for 30 minutes to 1 hour, warm the flat plate 11. Set the automatic cleaning, pour the multiple drops into the pbs. Perform the following steps on a flat plate: i. Pumping 1084-9596 -PF 114 200848063 ii·Add PBS 60 ml/well iii· Incubate at RT > 5 minutes (5~15 minutes) Repeat 2 times 12. Prepare 2 times antibody (l:500)/Ho Echst 33342 (1 : 1 000) in PBS + 13. Infuse the multi-drip adder 2 times of antibody. Perform the following steps on a flat plate at once: i. aspirate ii · add diluted 2 times antibody 40ml / well iii · warm Breeding at RT > 1 hr (allowable for long interruptions) 14·5 Self-cleaning for suction'. Infuse the multi-dropper with pBS. Perform the following steps on one plate at a time: i. aspirate, ii· add PBS 60 ml / well iii · Incubate at RT > 5 minutes (5 to 15 minutes) to repeat the above cleaning in the well PBS 2 times 1 5 · Seal with heat seal or aluminum seal 16 · Scan the plate with Cel lomic ArrayScanVTi Scanning can be done overnight using Twister II. Day 4: Outputting data to the flat panel manager and analyzer The selection method described here can vary. For example, CAG can be used to include the extended CAG repeat region. Any cell line that repeats a gene. A screening test directed to a defined polyglutamine repeat disorder can be varied, for example, by utilizing a polyglutamate-repeating protein that is associated with the disorder.

1084-9596-PF 115 200848063 or a cell line thereof. The critical value of picking is 5%, 1 heart 5%, and 3. %, 4. %, 5. 2_such as 1%, 2%, DU/ο, 60%, 70%, βη〇 / + 90% ° In addition, 'How to analyze cell survival rate _ Example 2 · · Further screening test: Rat The TMRE test of striated cell strains is a neurodegenerative disorder of 10,000 teas. This method is used to screen for compounds that are identified by further screening methods that provide for the identification of a candidate compound for the treatment, prevention, or amelioration of, for example, HD, each of which is selected from the combination agents of Tables la and lb Table 3b. The protocol used for this screening method is provided below. 1 · Preparation of complete medium and original concentration solution: DMEM, containing 10% FBS, 1% penicillin / streptomycin, Q 4 G418, tetramethyl dextran (Rh〇damine), ethyl ester, diluted in complete medium ( Above) perchlorate ("TMRE") 1〇〇nM, and carbonyl cyanide ^ -4-(trifluoromethoxy)-phenyl hydrazine ("Fccp,") original solution: 5 〇 # M in DMSO 2) Add the overflow medium and 〇.25% trypsin-EDTA to 33〇C in the water bath; 3) Aspirate the old medium and wash it once with ρβς; 4. Add 7 ml 〇· 25% trypsin Edta to Τ175 flask, and let stand for 5 to 6 minutes, gently shake; 5 · Incubate for 2 - 3 minutes to ensure separation of all cells; 6. Add 8 m 1 of medium to the flask to deactivate trypsin; 1084 -9596-PF 116 200848063 7. The cells were pipetted several times to ensure sufficient separation of the cells; 8. Centrifuge at l〇〇〇 rpm for 5 minutes; 9. Resuspend in 5 ml (each flask) of complete medium and drip Several times; 1 〇· Calculate the number of cells by blood cell counter or cell counter; H· Make the final cell solution to a density of 178 〇〇〇 cells/ml, and Multiple drops of genus inoculation 45 / 1 (8, 000) cells / well to 384 well plate; 12 · put the flat plate into the incubator for about 2 hours, do not stack the flat plate 13 · suction and add 50 TMRE (final 1 〇〇nM) to column l-23, and add the original intact medium to line 24. Incubate the plate for 30 minutes at room temperature in the dark; 14·Aspirate and add 45 // 1 medium, add 5 #丨 compound The original concentration solution was incubated in the dark for 丨 hours at room temperature; 15. Add FCCP 15 minutes before reading; 16. Use self-cleaning, wash with complete medium for 2 χ 5 minutes; and U· with bottom mirror, at Ex/Em: 53 〇 Nm / 59 〇 nm to "read the flat disk with (10). Other Embodiments All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference in their entirety in their entirety in the the the the the the the The various modifications and variations of the present invention are apparent to those skilled in the art. Although the invention has been particularly

1084-9596-PF 117 200848063

Description of the connection of the form, the extension of the library ^ 〇 ffl -iA 1- 1-m solution is not limited to this particular embodiment. It is to be understood that the various embodiments of the present invention are applicable to those skilled in the art. Other embodiments are within the scope of the present invention. [Simple diagram description] None [Main component symbol description] None

1084-9596-PF

Claims (1)

200848063 X. Patent application scope: 1 · A composition comprising: (:) a first agent, selected from the agents of the table la and lb; and - a second agent, the agent is different from the first agent From the categories and pharmaceuticals of Tables 1a, 1b and Table 2. The composition of claim 1, wherein the first sword and the second medicament are selected from one of the tables 3a and 3b. The composition of claim 1 or 2, wherein the first drug and the sputum 2 agent are administered in a dose sufficient to treat, prevent or alleviate a neurodegenerative disorder. 4. The composition of claim 1 or 2, further comprising one or more additional agents selected from the table "and lb. 5. The composition of claim [...], Included in one or more of the classes and agents of Table 2. [6] The composition of claim 1, wherein the first agent or the agent is selected from the group consisting of : Shenhuan anti-inhibition agent ~ ionophore antibiotic ^ (10) 叩 "^ (10) to "cure cannabinoid receptor synergist, channel blocker, antihistamine, selective serotonin reuptake inhibitor, anticholinergic drugs The PDE inhibitor, and the estrogen modulator. The composition of claim 2, wherein the second agent is an anti-apoptotic agent selected from the group consisting of: A minocycline, troglitaz 〇ne, pioglitazone, and taurosodeoxycholic aci (j. 8. The composition of claim 1 wherein the 1084-9596-PF 119 200848063 The ethnic group and go • Mouse West $ The dylinol agent is an antidepressant selected from the group consisting of fluoxetine, sertraline, and nortripty1. 9. The composition as described in the scope of claim 2 is an antioxidant. It is selected from the following group 2 (lipoic acid), H number (melat〇nin), βΝ^ acid OPC-1411 7, and ascorbate. 1 〇·such as the scope of the patent application The composition wherein the drug is an antipsychotic or psychotropic drug, which is selected from the group consisting of haloperidol, clozapine, and chlorine. The composition of the first aspect of the invention, wherein the second agent is a bioenergy substance (Bi〇energetic), It is selected from the group consisting of coenzyme Q1 肌, creatine, and dichloroacetate. 1 2 The composition of claim 1, wherein the second agent is a C0X inhibition Agent or NSAID, which is selected from the group consisting of: flurbiprofen Naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac (su 1 indac), di f luni sa 1, piroxicam (pi roxi cam), called indomethacin, ibuprofen, nabumetone, choline magnesium salicylate, sodium salicylate, salicylic acid, fenoprofen , _ ketoprofen, meclofenamate sodium, meloxicam 1084-9596-PF 120 200848063 oxaprozin, sulindac, tolmetin, rofecoxib, celecoxib, valdecoxib, And lumiracoxib 〇13. The composition of claim i, wherein the second agent is a dopamine antagonist selected from the group consisting of olanzapine and sulphur (quetiapine), and tetrabenazine 〇14. The composition of claim 1, wherein the second agent is a glutamate antagonist selected from the group consisting of : riluzole (ri luz Ole), remacemide, amantadine, memantine, ifendprodil, and el iprodi 1. The composition of claim 2, wherein the second agent is a group of protein deacetylase inhibitors or transcriptional regulators selected from the group consisting of: butyric acid Sodium, phenylbutyrate, suberoylanilide hydroxamic acid, and mithramycin. The composition of claim 1, wherein the second agent is a heat shock protein regulator selected from the group consisting of geldanamycin, celastrol, bimoclomol, Ώ. and arimoclomol ° 1 7 The composition of claim 2, wherein the agent is an immunomodulatory factor Copolymer 1. The composition of claim 1, wherein the medicinal agent is an emotional stabilizer selected from the group consisting of lithium, sodium valproate, and carbamazepine. 1 9 · The composition of claim 1 of the patent scope, A μ 八τ边 2 1084-9596-PF 121 200848063 The medicament is an antipsychotic drug selected from the following groups: a composition according to the above-mentioned claim, wherein the second agent is a protein agglutination inhibition. The composition of the second aspect of the invention is hai 〇 id id id per per per per per per per per per per per per per 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 The agent 'selects from the following group: cystamine, and trehalose (trehai〇se). 21. The composition of claim 2, wherein the first agent is a tranquilizer selected from the group consisting of benz〇diazepine, paroxet> Ding, venlafaxine, and beta-blockers. The composition of claim 2, wherein the second agent is a nutrient or a tonic, selected from the group consisting of GDNF, BDNF, CNTF, and fetal striated cells. The composition according to claim 2, wherein the pharmaceutical agent is selected from the group consisting of: cannabinoids ((3) face bi η. 丄d) BCTC, lithium, ethyl-EPA, one Free fatty acids, rapamycin, KW6〇〇2 and botulinum toxin. The composition of claim 1 or 2, further comprising at least one agent selected from the group of Table 2 and an agent. 25. The composition of claim 3, wherein the neurodegenerative disorder is a polyglutamine dilatation disorder. The composition of claim 25, wherein the polyglutamine dilating disorder is Huntington's disease. The combination of 1084-9596-PF 122 200848063, wherein the composition is formulated for oral administration, as described in any one of claims 1 to 26. The composition of any one of claims 6 to 6, wherein the composition is formulated for systemic administration. 29. If the scope of the patent application is the first item, the combination of any one of the items Z 6 or any one of them is formulated in the form of a submarine, or an epidural. 30. A method for treating, boxing, preventing or alleviating neurodegenerative disorders. 5 Hai method includes administering an effective 詈^ another double or a plurality of agents selected from the table la to A patient with treatment, nourishing the sputum or relieving the neurodegenerative disorder. 31. A method for treating or preventing a neurodegenerative disorder. The method comprises administering a first agent selected from Table lb and a second agent selected from Table 2 to a disease. Suffering to treat, prevent or alleviate this neurodegenerative disorder. 3 2 - A method for treating, preventing or ameliorating a neurodegenerative disorder, the method comprising administering at least two different agents independently selected from Tables 1a and 1b to the patient, wherein the 帛1 and the 2 The agents are administered simultaneously or at 28 days each other in a combined dose sufficient to treat, prevent or ameliorate the neurodegenerative disorder. 33. The method of claim 32, wherein the first and second medicaments are selected from Table 3a and a single column. 34. The method of claim 32, wherein the first and second medicaments are administered within 14 days of each other. 35. The method of claim 34, wherein the first and second medicaments are administered within 7 days of each other. 36. The method of claim 35, wherein the 1 1084-9596-PF 123 200848063 and the second medicament are administered within 24 hours of each other. The method of any one of claims 3 to 36, wherein the neurodegenerative disorder is a polyglutamine-expanding disorder. 38. The method of claim 3, wherein the polyglutamine dilatation disorder is Huntington's disease. 39. The method of any of claims 3 to 36, wherein the neurodegenerative disorder is selected from the group consisting of: Alexandria, Alper's disease, Alzheimer's disease, muscular atrophy Lateral sclerosis, cerebellar ataxia telangiectasia, Batten's disease, a disease, Cockayne syndrome, cortical basal ganglia degeneration, creutzfeidt-Jakob disease, dentate red globus pallidus atrophy, fragility$ comprehensive Symptoms, fragile XE mental retardation, FHedreieh's cerebellar ataxia, ischemic stroke, celebral disease, Lewy body dementia, multiple sclerosis, multiple systemic atrophy, myotonic dystrophy, Parkinson's disease , Pelizaeus Merzbacher disease, Pick disease, primary lateral sclerosis, RefSUm's disease, Sandhoff's disease, Schilder's disease, spinal cord injury, spinal muscular atrophy, spinocerebellar ataxia, type 2, 2 Type, Type 3, Type 6, Type 7, Type 8, Type 12, Type 17, Steele-Richardson^Olszewski Γ, ^ ^ ^ # (Tabes dorsal is) 4, as in Patent Application Nos. 3 to 36 The party mentioned in the item The law, in which the father of the car is in the control group's hometown phantom A 7L mortality, the agent reduces neuronal mortality in the patient. 41. The method of claim 1084-9596-PF 124 200848063, wherein the agent is selected from the following structures & + # carrier antibiotics, cannabinoids: ginseng Depressants, ion-selective serotonin are further mediated from 4-channel blockers, antihistamines, I-dan absorption inhibitors, and estrogen modulators. Several alkali music, PDE inhibitors, 42. For example, the scope of the patent is 3rd, wherein the patient is a human. The method according to any one of the preceding paragraphs, 43, and the red of the patent scopes 30 to 36 include an additional treatment method. 36. The method according to any one of the preceding claims, wherein the method of claim 43 includes administering the medicament to the patient, the second, the additional table la and lb of the medicament, and the second therapeutic agent. The dose of the therapeutic agent from the treatment and prevention of $ # k 〇 is sufficient to treat or prevent a neurodegenerative disorder. 45. The method of claim 44, wherein the therapeutic agent of claim 1 is selected from the classes and agents of Table 2. Resolving the method of claim 45, wherein the additional therapeutic agent is a primary antibody, a weekly death agent selected from the group consisting of: mitomycin (mi prison yeline), The method of claim 45, wherein the additional therapeutic agent is an antidepressant, the method of claim 45, wherein the method of claim 45, wherein the additional therapeutic agent is exemplified by the method of claim 45, wherein the remedy is an antidepressant, It is selected from the group consisting of fluoxetine, sertraline hydrogenated hydrogen, and nortriptyline. 48. The method of claim 45, wherein the additional The therapeutic agent of 1084-9596-PF 125 200848063 is an antioxidant selected from the group consisting of lipoic acid, melatin, 825, 0PC-14117, and ascorbate. 49. The method of claim 45, wherein the additional therapeutic agent is an antipsychotic or psychotropic drug selected from the group consisting of haloperidol (hai〇perid〇1) ), clozapine, 〇 〇 rom rom rom 〇 ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol ol The method is selected from the group consisting of coenzyme Q1 肌, creatine, and diacetate acetate. 51. The method of claim 45, wherein the additional therapeutic agent is a COX inhibitor or NSAID It is selected from the group consisting of flifluprofen, napr〇xen sodium, diclofenac sodium, and diclofenac potassium. ), aspirin, sulindac%, · (sulindac), diflunisal, ° piroxicam, called indomethacin, ibuprofen, nabumetone, choline Magnesium salicylate, sodium salicylate, salicylic acid, fenoprof en, ketoprofen, meclofename sodium, meloxicam Meloxicam), oxaprozin, sulindac, tolmetin, rofecoxib, ce The method of claim 45, wherein the additional therapeutic agent of 1084-9596-PF 126 200848063 is a dopamine antagonist selected from the group consisting of: · olanzapine, quetiapine, and tetrabenazine 〇53. The method of claim 45, wherein the additional therapeutic agent is a glutamine antagonism The agent is selected from the group consisting of: riluzole, remacemide, amantadine, memantine, ifendprodil, and e1iprodi 1 ° 54 as set forth in claim 45 The method wherein the additional therapeutic agent is a group of protein deacetylase inhibitors or transcriptional regulators selected from the group consisting of sodium butyrate, phenylbutyrate, suberoylanilide hydroxamic acid, And mithramycin. 55. The method of claim 45, wherein the additional therapeutic agent is a heat shock protein regulator selected from the group consisting of geldanamycin, celastrol, bim〇cl〇m〇i, And ar i moc1omo1 ° 56. The method of claim 45, wherein the additional therapeutic agent is the immunomodulator C〇p〇lymerl. 57. The method of claim 45, wherein the additional therapeutic agent is a mood stabilizer which is selected from the group consisting of: lithium, valproate, and . 58. The method of claim 1, wherein the therapeutic agent is an antipsychotic drug selected from the group consisting of: 1088-9596-PF 127 200848063 Group: haloperidol (haloper idol) The method of claim 45, wherein the additional therapeutic agent is a protein agglutination inhibitor, selected from the group consisting of the following: The group of constituents: cyst amine, and trehalose. 60. The method of claim 45, wherein the additional therapeutic agent is a tranquilizer selected from the group consisting of clonazepam, benzodiazepine, parosy > Ding, venlafaxine, and beta-blockers. 61. The method of claim 45, wherein the additional therapeutic agent is a nutrient or tonic, selected from the group consisting of GDNF, BDNF, NTF, and fetal striated cells. 62. The method of claim 45, wherein the additional therapeutic agent is selected from the group consisting of cannabinoids, BCTC, lithium, ethyl-EPA, free fatty acids, rapamycin, KW6002, and botulinum toxin. 63. The method of claim 44, wherein the agent or agents from Tables 1 a and 1 b, and the additional therapeutic agent, are administered within 14 days of each other. 64. The method of claim 63, wherein the medicament or agents from Tables la and lb, and the additional therapeutic agent are administered within 7 days of each other. 65. The method of claim 64, wherein the agent or agents from Tables 1 and 1b, and the additional therapeutic agent, 1084-9596-PF 128 200848063 s are administered within 24 hours of each other. . 6 6. The method of any one of claims 3 to 65, wherein the medicinal agent or the plurality of medicinal agents of Tables 1a and 1b are administered orally. 67. The method of any one of claims 3 to 65, wherein the agent or agents from Tables 1 a and b or the additional therapeutic agent are administered systemically. 68. The method according to any one of claims 30 to 65, wherein the medicament or the plurality of medicaments or the additional therapeutic agent derived from Tables 1 a and 丨b are intracranial and spinal canal Intra or epidural administration. 69·—a kit comprising: (1) a medicament selected from the agents of Tables 1 a and 丨b; and (1 1) means a non-instruction for the treatment of the agent with or without neurodegenerative Patients with risk of disorder are given. 7 0 - a kit comprising: (i) a composition comprising two agents selected from the agents of Tables la and lb; and (1 i) an instruction indicating that the composition is afflicted with or Patients who are at risk for neurodegenerative disorders are administered. 71. - a set of kits, including (i) a first potion, selected from the pots of la and ^; (ii) a second potion, selected from the pots of tables ia and lb, and (iii) The instruction manual is for instructing the first and second medicaments to be administered to a patient suffering from or at risk of developing neurodegenerative disorders. 1084-9596-PF 129 200848063 72. If the kit of claim 7 or 71 is selected, the selection is from: a single column ', 7 3 of Tables 3a and 3b, a set including: (1) a medicament selected from the agents of Tables 1 and 1b; and (ii) instructions for the treatment of the medicament and the neurological degeneration of the medicament selected from the "and the second medicament" selected from the table "and lb" A patient with a risk of sexual disorder is administered, wherein the second agent is not the agent of (1). 7 4 · a kit comprising: (i) a composition comprising: (a) a first medicament, Selected from Tables 1 & and "pharmaceutical; and () second agent, selected from the categories and agents of Table 2; and (11) instructions indicating that the composition is or has neurodegenerative disorders Patients with risk are given. 75. - a set of kits, comprising: (Ο - the first potion, selected from the pots of la and lb; (ι 〇 a second potion, selected from the categories and medicaments of Table 2; and (iii) instructions For administering the i-th and the second agent to a patient suffering from or at risk of developing neurodegenerative disorders. 7 6 · a kit comprising: (i) a medicament selected from the table And (1) an instruction manual for administering the medicament and a second medicament to a patient suffering from or at risk of developing neurodegenerative disorders, wherein the second medicament is selected from Table 2 Category and Pharmacy. 77·—Groups, including: 1084-9596-PF 130 200848063 (1) One agent, selected from Table 2, and Pharmacy; and (11) “Instructions for use—will The agent and one of the agents selected from the la and lb agents are administered to patients suffering from or having the right to be at risk of degenerative disorders due to arsenic. 78. A method for preventing or alleviating a combination of neurodegenerative P premature hamstrings, comprising the steps of: (4) providing a cell comprising a coded polyglutamine weight Multi-peptide-gene's such that the multi-peptide repeats the multi-peptide with wild-type polyglutamine, including an expanded polyglutamine repeat region; (b) induces the gene expression; (c) The cells are contacted with the agents of Tables 1 & and lb_ and a candidate compound; and '(d) comparing cells that are in contact with the agent but are not in contact with the candidate compound, whether the agent is combined with the candidate compound, reduces p Peripheral staining of the 〇iyQ antibody, wherein the perinuclear staining (as determined, for example, by immunocytochemistry (ICC) analysis), may be useful for treating, preventing, or ameliorating a neurodegenerative disorder. The method of claim 7, wherein the polyglutamine repeat polypeptide comprising the expanded polysitride repeat region comprises Htt Qin. 80 0 as described in claim 7 The method, wherein the nuclear peripheral staining is measured by immunocytochemical analysis. The method of claim 78, wherein the p〇ly Q antibody comprises a 1F8 antibody. 1084-9596-PF 131 2 00848063 82. The method of claim 78, wherein the striatum cells are ST-valent MQ111 cells as described in claim 82. 132 1084-9596-PF 200848063 VII. Designated representative map: (1) The representative representative figure of this case is: None (2) The symbol of the symbol of the representative figure is simple: No. 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: No. 1084-9596- PF