Nerve repair method

Abstract

The present disclosure provides methods of using indole derivative compounds to reverse amyloid-beta toxicity in amyloid-beta-related diseases.

Description

Technical Field

[0001] The present disclosure relates to a method for reversing amyloid-β (Aβ) toxicity, which reverses Aβ toxicity and rapidly improves cell function in Aβ-related diseases including Alzheimer's disease (AD), glaucoma, and age-related macular degeneration of the retina.

Background Art

[0002] Aβ-related diseases or conditions include diseases and conditions in which the function of nerve cells and non-nerve cells is affected by the presence of toxic Aβ aggregates formed from amyloid-β (Aβ) monomers misfolded by aggregation. Aβ-related diseases or conditions include eye or nerve diseases or conditions, including, but not limited to, for example, Alzheimer's disease (AD), glaucoma, and age-related macular degeneration of the retina. FIG. 1 is a schematic diagram showing the progression from normally folded Aβ monomers to toxic Aβ oligomers.

[0003] Alzheimer's disease (AD) is the most common form of dementia, and its incidence is increasing at a startling rate worldwide. The pathophysiology of AD is characterized by chronic, progressive neurodegeneration with initial synaptic toxicity. One of the most obvious pathological features of AD is the accumulation of amyloid-β (Aβ) deposited in the brain. Although normal Aβ is essential for normal nerve cell function, misfolded Aβ is often associated with overproduction of Aβ and is thought to underlie initial synaptic pathology. Therefore, reducing toxic Aβ oligomers in the brain without impairing normal Aβ function could be a promising therapeutic strategy for improving or reversing AD-related dysfunction.

[0004] Glaucoma is the second leading cause of blindness in the United States and has been shown by research to be a neurodegenerative disease, and there is increasing evidence indicating that Aβ toxicity plays an important role in its pathogenesis. The pathological condition of glaucoma is the progressive degeneration of retinal ganglion cells (RGCs) that form the optic nerve and their axons. The classifications of glaucoma include primary angle-closure glaucoma, secondary open-angle glaucoma, steroid-induced glaucoma, traumatic glaucoma, pigment dispersion syndrome, pseudoexfoliation syndrome, secondary angle-closure glaucoma, neovascular glaucoma, glaucoma due to uveitis, and other unspecified eye diseases. In recent years, it has been found that Aβ co-localizes with the death of retinal ganglion cells. Also, animal experiments have demonstrated that, in particular, soluble Aβ 1-42 oligomers are very potent toxins for retinal ganglion cells. Therefore, similar to AD, it is thought that Aβ toxicity also plays an important role in glaucoma and its related diseases.

[0005] Similarly, dry age-related macular degeneration of the retina (dry AMD) is a disease associated with retinal pathology and is closely related to the occurrence of Aβ toxicity in retinal pigment epithelium and photoreceptors, causing progressive loss of vision and ultimately leading to blindness.

[0006] According to the current understanding of the pathology in neurodegenerative diseases such as AD, glaucoma, and dry AMD, affected nerve cells or neurosensory cells suffer from the toxicity of Aβ oligomers over time. These cells do not die immediately but first enter a survival mode with reduced metabolism and membrane potential. In this state, for example, in the retina, the cells do not function normally, and thus their contribution to the visual process decreases. As a result, the cells are alive but not fully functional, and some researchers call this "cells in a dormant state." If there is a drug that can remove or reverse the toxic effects of Aβ oligomers in the retina, it can restore the poorly functioning cell functions and transform the cells in a dormant state into fully functional cells, thereby increasing the number of cells and their net contribution to the visual process. The result of this reversal can improve the visual function of the patient. The same applies to the cells in a dormant state in the brain of Alzheimer's patients suffering from the toxicity of Aβ oligomers. Similarly, if the poorly functioning cell functions can be restored, it will lead to an improvement in cognitive function. However, such drugs do not currently exist.

[0007] Therefore, there is a significant unmet medical need for methods that can reverse the symptoms caused by Aβ toxicity and restore the function of nerve cells or neurosensory cells in Aβ-related neurodegenerative diseases, including but not limited to, for example, dry AMD, glaucoma, and AD.

Summary of the Invention

Means for Solving the Problems

[0008] The present disclosure is a method of using Compound I represented by Formula I below to reverse amyloid β toxicity and rapidly improve the function of nerve cells, non-nerve cells, neurosensory cells, or any combination thereof, and administering Compound I or amyloid β to a subject in need thereof. 1-42Provided is a method comprising the step of administering a non-toxic non-β-sheet amorphous amyloid-β cluster comprising Compound I.

[0009] In one aspect, the present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neurons, non-neuronal cells, neuro-sensory cells, or any combination thereof, the method comprising administering to a subject in need thereof a Compound I represented by the following Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0010] [Chemical Formula]

[0011] Wherein, * refers to a chiral center, ** refers to a chiral center when R5 and R6 are different, R1 is hydrogen, -C 1-6 -alkyl, cyclo-C 3-12 -alkyl, -C(O)R, or -C(O)OR, R2 is hydrogen, C 1-6 -alkyl, or cyclo-C 3-12 -alkyl, R3 is -OR, -NHR, or -N(R)2, R4 is hydrogen, halogen, cyano, trifluoromethyl, -C 1-6 -alkyl, -C 6-10 -aryl, heteroaryl, -OR, -NHR, -N(R)2, -C(O)R, or -C(O)-NHR, R5 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, or R5 and R6 together with the carbon atom bearing them form a cyclic system having 3 to 6 carbon atoms, R6 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, R7 is hydrogen, methyl, ethyl, propyl, or cyclopropyl, and R is hydrogen, -C 1-6 -alkyl, or -C 6-10 -aryl, and X is -C(O)CH2-, -CH(OH)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR.

[0012] In a related aspect, Compound I as described above includes Compound IA represented by Formula IA below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0013]

Chemical formula

[0014] wherein R1, R2, R3, R4, R5, R6, R7, and X are the same as those in Compound I described above.

[0015] In another related aspect, Compound I or Compound IA as described above is selected from Compound 1, Compound 2, Compound 3, Compound 4 below, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0016]

Chemical formula

[0017] In another related aspect, the rapid improvement of the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof includes the rapid recovery of impaired neuronal function or the reduction of cell death in neurons, non-neuronal cells, neurosensory cells, or any combination thereof. In another related aspect, the neurons, non-neuronal cells, or neurosensory cells include retinal ganglion cells (RGCs), retinal pigment epithelial (RPE) cells, photoreceptor cells including rod and cone cells, hippocampal cells, cortical cells, or any combination thereof.

[0018] In a related aspect, the subject has an amyloid-β related disease. In another related aspect, the amyloid-β related disease includes an eye disease or condition, or a nerve disease or condition. In another related aspect, the eye disease or condition includes primary angle-closure glaucoma, secondary open-angle glaucoma, primary open-angle glaucoma, steroid-induced glaucoma, traumatic glaucoma, pigment dispersion syndrome, pseudoexfoliation syndrome, secondary angle-closure glaucoma, neovascular glaucoma, early or intermediate dry (non-exudative) age-related macular degeneration, macular degeneration with geographic atrophy, exudative (wet) macular degeneration, diabetic retinopathy, or any combination thereof. In another related aspect, the functions that are rapidly improved in neurons, non-neuronal cells, neurosensory cells, or any combination thereof include visual functions in the subject such as visual acuity, low-luminance visual acuity, contrast sensitivity, cone contrast sensitivity, color vision, and focus or general retinal light sensitivity under photopic (light adaptation) or scotopic (dark adaptation) conditions, as well as postural stability, gait balance, and mobility.

[0019] In a related aspect, the neurological disease or condition includes type II diabetes, diabetes, Alzheimer's disease (AD), early-onset Alzheimer's disease, late-onset Alzheimer's disease, pre-symptomatic Alzheimer's disease, SAA amyloidosis, hereditary Icelandic syndrome, multiple myeloma, myeloid cancer, aortic medial amyloidosis, insulin injection amyloidosis, prion systemic amyloidosis, chronic inflammatory amyloidosis, senile systemic amyloidosis, pituitary amyloidosis, hereditary renal amyloidosis, familial British dementia, Finnish hereditary amyloidosis, familial non-neuropathic amyloidosis, prion disease, or any combination thereof. In another related aspect, when the neurological disease or condition includes Alzheimer's disease (AD), early-onset Alzheimer's disease, late-onset Alzheimer's disease, or pre-symptomatic Alzheimer's disease, a rapid improvement in the function of neurons, non-neuronal cells, neuro-sensory cells, or any combination thereof includes improvement of cognitive impairment, improvement of memory impairment, reduction of abnormal behavior, reduction of hallucinations, reduction of loss of spatial awareness, reduction of apraxia, reduction of aggressiveness, improvement of the ability to perform activities of daily living, improvement of other symptoms of dementia, or any combination thereof in a subject.

[0020] In a related aspect, administration to a subject is effected by oral administration, topical administration, nasal administration, intravenous administration, subcutaneous administration, administration by an implantable sustained-release depot, direct administration using an indwelling catheter, intrathecal administration, or intraocular administration. In another related aspect, administration to a subject is effected in the form of multiple administrations administered over a predetermined period, where the period includes a predetermined number of days, a predetermined number of weeks, a predetermined number of months, a predetermined number of years, or the lifespan of the subject. In another related aspect, the dose for each of the multiple administrations includes 100% or more of a pharmaceutically effective amount. In another related aspect, the dose for each of the multiple administrations includes 20 to 75% of a pharmaceutically effective amount. In another related aspect, the dose for each of the multiple administrations includes 100% of a pharmaceutically effective amount, 75 to 100% of a pharmaceutically effective amount, 20 to 75% of a pharmaceutically effective amount, or any combination thereof. In another related aspect, the pattern of administration during the above period includes administration at regular intervals, administration at irregular intervals, or a combination of administration at regular intervals and administration at irregular intervals.

[0021] In a related aspect, the above Compound I is amyloid β 1-42 and a non-toxic non-β-sheet amorphous amyloid β cluster containing Compound I.

[0022] In a related aspect, the above Compound I is contained in a pharmaceutically acceptable composition.

[0023] In one aspect, the present disclosure provides a method for reversing amyloid β toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering to a subject in need thereof a non-toxic non-β-sheet amorphous amyloid β cluster in a pharmaceutically effective amount, the cluster comprising amyloid β 1-42 and a Compound I represented by the following formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a ratio of 500:1.

[0024]

Chemical formula

[0025] In the formula, * refers to the chiral center, ** refers to the chiral center when R5 and R6 are different, R1 is hydrogen, -C 1-6 -alkyl, cyclo-C 3-12 -alkyl, -C(O)R, or -C(O)OR, R2 is hydrogen, C 1-6 -alkyl, or cyclo-C 3-12 -alkyl, R3 is -OR, -NHR, or -N(R)2, R4 is hydrogen, halogen, cyano, trifluoromethyl, -C 1-6 -alkyl, -C 6-10 -aryl, heteroaryl, -OR, -NHR, -N(R)2, -C(O)R, or -C(O)-NHR, R5 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, or R5 and R6 together with the carbon atom bearing them form a cyclic system having 3 to 6 carbon atoms, R6 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, R7 is hydrogen, methyl, ethyl, propyl, or cyclopropyl, R is hydrogen, -C 1-6 -alkyl, or -C 6-10 -aryl, X is -C(O)CH2-, -CH(OH)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR.

[0026] In a related aspect, amyloid β 1-42The concentration of [substance] is 50 nM, and the concentration of Compound I above is 0.1 nM. In another related aspect, the non-toxic non-β-sheet amorphous amyloid-β cluster above is included in a pharmaceutically acceptable composition.

[0027] In one related aspect, the non-toxic non-β-sheet amorphous amyloid-β cluster above is prepared by a production method that includes successively diluting the above Compound I in a solution of amyloid-β 1-42 and the production method includes successively diluting the above Compound I to a final concentration of at least 0.1 nM. In another related aspect, the successive dilution includes five successive dilutions.

Brief Description of the Drawings

[0028] The subject matter of the present disclosure regarding the method of using Compound I represented by Formula I is particularly pointed out and clearly claimed in the concluding part of this specification. However, the method of use of the present disclosure will be best understood by reading the following detailed description with reference to the accompanying drawings, both as to its construction and method of operation, and as to its purpose, features, and advantages.

[0029]

Figure 1

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 6

Mode for Carrying Out the Invention

[0030] In the following detailed description, various specific details are set forth in order to provide a thorough understanding of compound I represented by formula I, an indole derivative, and its use for neurorestoration of a subject suffering from an amyloid-β (Aβ)-related disease. In some cases, well-known methods, procedures, and components are not described in detail so as not to obscure the present disclosure.

[0031] The methods of use of the present disclosure reverse the amyloid-β (Aβ) functional toxicity of neurons, non-neuronal cells, or neurosensory cells in a subject in need of treatment. The methods of reversing Aβ functional toxicity of the present disclosure, in some embodiments, provide symptomatic therapy, thereby improving the function of neurons, non-neuronal cells, or neurosensory cells in a subject in need of treatment. In some embodiments, the functions that are improved include functions that have been damaged, reduced, inhibited, or altered by an amyloid-β related disease or condition.

[0032] The method of use of the present disclosure reverses amyloid-β (Aβ) toxicity in nerve cells, non-nerve cells, or nerve sensory cells in a subject in need of treatment. The method of reversing Aβ toxicity of the present disclosure, in some embodiments, provides symptomatic therapy, thereby improving the function of nerve cells, non-nerve cells, or nerve sensory cells in a subject in need of treatment. In some embodiments, the functions to be improved include functions damaged, decreased, inhibited, or altered by amyloid-β related diseases or conditions. In some embodiments, the method of the present disclosure reverses Aβ toxicity and rapidly improves the function of nerve cells, non-nerve cells, nerve sensory cells, or any combination thereof.

[0033] The method of reversing amyloid-β functional toxicity of the present disclosure, in some embodiments, comprises the step of administering an indole derivative, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, or a composition thereof. The method of reversing Aβ toxicity of the present disclosure, in some embodiments, comprises the step of administering an indole derivative, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, or a composition thereof. Some embodiments of indole derivatives, or optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, or compositions thereof, that reverse amyloid-β functional toxicity in nerve cells, non-nerve cells, or nerve sensory cells are disclosed herein. In some embodiments, the indole derivative, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, or a composition thereof, of the present disclosure provides symptomatic therapy for amyloid-β related diseases or conditions. In some embodiments, the indole derivative, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, or a composition thereof, of the present disclosure improves the function of symptoms in a subject suffering from an amyloid-β related disease or condition.

[0034] In some embodiments, "amyloid-β", "Aβ peptide", "Aβ" 1-42", and the terms "Aβ" are used interchangeably and have the same meaning and quality as each other. Aβ 1-42 is an example of a toxic Aβ peptide. A more general type in the Aβ peptide, which is slightly less toxic, is, for example, Aβ 1-40 . There are also peptides of other lengths and modified forms after translation, some of which are considered to be more toxic than Aβ 1-42 . Aβ 1-42 is considered to be the most toxic form among Aβ, but there are also other highly toxic forms. A person skilled in the art will understand that a reference to "Aβ" includes the toxic forms of amyloid-β peptides. In some embodiments, Aβ is Aβ 1-42 peptide. In some embodiments, Aβ includes, in addition to the Aβ 1-42 peptide, other types of toxic Aβ peptides. In contrast, the term "Aβ cluster" includes non-toxic non-β-sheet amorphous Aβ cluster formation.

[0035] The present disclosure provides a method for reversing the amyloid-β functional toxicity of neurons, non-neuronal cells, or neurosensory cells, the method comprising administering to a subject in need thereof a compound I represented by the following formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0036] [Chemical formula]

[0037] In the formula, * refers to a chiral center, ** refers to a chiral center when R5 and R6 are different, R1 is hydrogen, -C 1-6 -alkyl, cyclo-C 3-12 -alkyl, -C(O)R, or -C(O)OR, R2 is hydrogen, C 1-6 -alkyl, or cyclo-C 3-12-alkyl, R3 is -OR, -NHR, or -N(R)2, R4 is hydrogen, halogen, cyano, trifluoromethyl, -C 1-6 -alkyl, -C 6-10 -aryl, heteroaryl, -OR, -NHR, -N(R)2, -C(O)R, or -C(O)-NHR, R5 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, or R5 and R6 together with the carbon atom bearing them form a cyclic system having 3 to 6 carbon atoms, R6 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, R7 is hydrogen, methyl, ethyl, propyl, or cyclopropyl, R is hydrogen, -C 1-6 -alkyl, or -C 6-10 -aryl, X is -C(O)CH2-, -CH(OH)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR.

[0038] In formula I, * and ** As shown by, the compound I having the structure of formula I above may have at least one chiral center, and in some cases two chiral centers. * and ** each independently represent the (R) configuration or the (S) configuration. One of the main obstacles in using short peptide-like fragments for therapy is proteolysis by stereospecific cellular proteases. Therefore, in order to avoid the metabolism of the active ingredient of the therapy by specific stereospecific proteases, there is an advantage in using any stereoisomer in the treatment methods of the present disclosure. In some embodiments of the methods of the present disclosure, one or both of the optional asymmetric carbons (shown in formula I as * and ** ) have the (R) configuration. In some embodiments of the methods of the present disclosure, the asymmetric carbon (shown in formula I as *shown by (R) has an (R) configuration.

[0039] The present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering to a subject in need thereof a compound I represented by the following formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0040]

Chemical formula

[0041] In the formula, * refers to a chiral center, ** refers to a chiral center when R5 and R6 are different, R1 is hydrogen, -C 1-6 -alkyl, cyclo-C 3-12 -alkyl, -C(O)R, or -C(O)OR, R2 is hydrogen, C 1-6 -alkyl, or cyclo-C 3-12 -alkyl, R3 is -OR, -NHR, or -N(R)2, R4 is hydrogen, halogen, cyano, trifluoromethyl, -C 1-6 -alkyl, -C 6-10 -aryl, heteroaryl, -OR, -NHR, -N(R)2, -C(O)R, or -C(O)-NHR, R5 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, or R5 and R6 together with the carbon atom bearing them form a cyclic system having 3 to 6 carbon atoms, R6 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, R7 is hydrogen, methyl, ethyl, propyl, or cyclopropyl, R is hydrogen, -C 1-6 -alkyl, or -C 6-10 -aryl, X is -C(O)CH2-, -CH(OH)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR.

[0042] In some embodiments, * the carbon is an asymmetric carbon having an (R) configuration.

[0043] In some embodiments, the method of the present disclosure includes the use of a compound IA represented by the following formula IA, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0044]

Chemical formula

[0045] wherein R1, R2, R3, R4, R5, R6, R7, and X are the same as those in the above compound IA.

[0046] The method of using the compound of the present disclosure to reverse amyloid-β toxicity or functional toxicity of nerve cells and / or neurosensory cells is beneficial for reversing the progression of amyloid-related diseases or disorders in a subject in need thereof. Those skilled in the art will understand that reversing the progression of amyloid-related diseases or disorders may include the following (1) to (5). (1) Reduction of amyloid plaque deposition present in the pathological state. (2) Reversal of the function of nerve cells and / or neurosensory cells; including, but not limited to, for example, reversal of long-term potentiation in nerve cells and / or neurosensory cells. (3) Restoration of the function of nerve cells and / or neurosensory cells; including, but not limited to, for example, promotion of long-term potentiation of nerve cells and / or neurosensory cells present in the pathological state. (4) Restoration of the function of nerve cells and / or nerve sensory cells in a subject suffering from an amyloid-β pathological condition of the eye (including, but not limited to, glaucoma, dry age-related macular degeneration, etc.); including, but not limited to, improvement in, for example, visual acuity, low-light visual acuity, retinal light sensitivity, or any combination thereof. (5) Restoration of the function of nerve cells and / or nerve sensory cells in a subject suffering from an amyloid-β pathological condition of the nerve (including, but not limited to, Alzheimer's disease, etc.); including, but not limited to, improvement in, for example, cognitive impairment, memory impairment, ability to perform activities of daily living, or any combination thereof. In some embodiments, reversal of the course of an amyloid-related disease or disorder includes a decrease in drusen in addition to a decrease in amyloid plaques. In dry age-related macular degeneration, drusen are formed subretinally or within the optic nerve.

[0047] Before describing the methods of using the compounds of the present disclosure, the following section describes the indole derivative compounds of the present disclosure.

[0048] Indole derivative

[0049] In one embodiment, the method of the present disclosure uses a compound I represented by the following formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0050] [Chemical formula]

[0051] In the formula, * refers to a chiral center, ** refers to a chiral center when R5 and R6 are different, R1 is hydrogen, -C 1-6 -alkyl, cyclo-C 3-12 -alkyl, -C(O)R, or -C(O)OR, R2 is hydrogen, C 1-6 -alkyl, or cyclo-C3-12 -alkyl, R3 is -OR, -NHR, or -N(R)2, R4 is hydrogen, halogen, cyano, trifluoromethyl, -C 1-6 -alkyl, -C 6-10 -aryl, heteroaryl, -OR, -NHR, -N(R)2, -C(O)R, or -C(O)-NHR, R5 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, or R5 and R6 together with the carbon atom bearing them form a cyclic system having 3 to 6 carbon atoms, R6 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, R7 is hydrogen, methyl, ethyl, propyl, or cyclopropyl, R is hydrogen, -C 1-6 -alkyl, or -C 6-10 -aryl, X is -C(O)CH2-, -CH(OH)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR.

[0052] In one embodiment, the method of the present disclosure uses a compound IA represented by the following formula IA.

[0053]

Chemical formula

[0054] Wherein, R1, R2, R3, R4, R5, R6, R7, and X are the same as those in the above compound I.

[0055] In one embodiment, the method of the present disclosure uses a compound II represented by the following formula II.

[0056]

Chemical formula

[0057] In the formula, R3, R5, R6, and X are the same as those in the above compound I.

[0058] In one embodiment, the method of the present disclosure uses a compound IIA represented by the following formula IIA.

[0059]

Chemical formula

[0060] In the formula, R3, R5, R6, and X are the same as those in the above compound I.

[0061] In one embodiment, R1 is hydrogen. In another embodiment, R1 is -C 1-6 -alkyl. In one embodiment, R1 is -C(O)R. In a specific embodiment, R1 is -C(O)-CH3. In one embodiment, R1 is -C(O)-t-butyl. In one embodiment, R1 is -C(O)-2,2-dimethylpropyl. In one embodiment, R1 is -C(O)OR. In another embodiment, R1 is -C(O)OCH3.

[0062] In one embodiment, R2 is hydrogen. In another embodiment, R2 is -C 1-6 -alkyl.

[0063] In one embodiment, R1 is hydrogen and R2 is hydrogen. In another embodiment, R1 is -C(O)R and R2 is hydrogen.

[0064] In one embodiment, R3 is -OH. In one embodiment, R3 is -OCH3. In one embodiment, R3 is -NH2. In one embodiment, R3 is -NH-CH3. In one embodiment, R3 is -NH-t-butyl. In one embodiment, R3 is -N(CH3)2.

[0065] In some embodiments, R1 and R2 are, independently of each other, hydrogen, or -C 1-3 -alkyl.

[0066] In one embodiment, R4 is hydrogen.

[0067] In one embodiment, R5 is hydrogen, or -C 1-6 -alkyl. In one embodiment, R6 is hydrogen, or -C 1-6 -alkyl.

[0068] In one embodiment, R5 and R6 are identical to each other. In one embodiment, R5 and R6 are -CH3.

[0069] In one embodiment, the two substituents R5 and R6, together with the carbon atom bearing them, can form a cyclic system having 3 to 6 carbon atoms. In one embodiment, this cyclic system can contain one ring element selected from the group consisting of -O-, -S-, and NH-. In one embodiment, the cyclic system includes, but is not limited to, cyclohexane, cyclopentane, cyclobutane, cyclopropane, oxetane, and azetidine rings.

[0070] In one embodiment, X is -C(O)CH2-, -CH(OH)CH2-, -CH=CH-, -CH2CH2NRC(O)-, or -C(O)NR-. In one embodiment, X represents -CH=CH-. In one embodiment, X represents -CH2NRC(O)-. In one embodiment, X represents -C(O)NR-.

[0071] In one embodiment, the X group has an orientation such that its left side is bonded to a chiral carbon atom bearing an amino group.

[0072] In one embodiment, R7 is hydrogen or methyl. In one embodiment, R7 is hydrogen.

[0073] In one embodiment, the compounds used in the methods of the present disclosure include all optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs of compounds represented by Formula I, Formula IA, Formula II, or Formula IIA (Compound I, Compound IA, Compound II, or Compound IIA). Further, the compounds for use in the present disclosure relate to analogs and derivatives of Compound I, Compound IA, Compound II, or Compound IIA.

[0074] As used herein, in one embodiment, the term "C 1-6 -alkyl" represents a straight-chain or branched alkyl group such as methyl, ethyl, n-propyl, 2-propyl, n-butyl, and tert-butyl. In one embodiment, the alkyl group may optionally be substituted with 1 to 5 substituents selected from halogen, amino, hydroxyl, and CF3.

[0075] As used herein, in one embodiment, the term "C 2-6 -alkenyl" represents a straight-chain or branched alkenyl group.

[0076] As used herein, in one embodiment, the term "cyclo C 3-12 -alkyl" represents a monocyclic or bicyclic alkyl group including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, the cycloalkyl group may optionally be substituted with 1 to 5 substituents selected from C 1-6 -alkyl, halogen, amino, and hydroxyl.

[0077] As used herein, in one embodiment, the term "C 6-10 -aryl" represents phenyl or naphthyl. In one embodiment, the phenyl group or naphthyl group may optionally be substituted with 1 to 5 substituents selected from C 1-6 -alkyl, cyclo C 3-12 -alkyl, halogen, amino, and hydroxyl.

[0078] As used herein, in one embodiment, the term "heteroaryl" refers to an aromatic 5- or 6-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, or a benzene ring, or a bicyclic group containing a 5- or 6-membered ring condensed with a 5- or 6-membered ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen. In one embodiment, the heteroaryl group is optionally C 1-6 -alkyl, cyclo C 3-12 -alkyl, and may be substituted by one or two substituents selected from halogen, amino, and hydroxyl.

[0079] As used herein, in one embodiment, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0080] In some embodiments, the compounds of the present disclosure exist in the form of pharmaceutically acceptable salts. It will be understood by those skilled in the art that "pharmaceutically acceptable salts" refer to salts that possess the biological effectiveness and properties of the parent compound and are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical as long as it is non-toxic and does not substantially inhibit the desired pharmacological activity.

[0081] As used herein, in one embodiment, the term "analogue" or "derivative" refers to a molecule that is structurally similar to a reference molecule but is modified in a targeted and controlled manner by substituting one or more specific substituents of the reference molecule with alternative substituents, thereby generating a molecule that is structurally similar to the reference molecule. Synthesizing and screening analogues to identify slightly improved versions of known compounds (e.g., versions with higher potency and / or selectivity for a particular target receptor / protein type, higher penetration ability into the eye, fewer side effects) is a common approach in drug design.

[0082] Compound I or Compound IA used in the method of the present disclosure, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is represented by Formula I or Formula IA above, wherein in the above formula, R1 is hydrogen, -C 1-6 -alkyl, -C(O)R, or -C(O)OR; R2 is hydrogen or C 1-6 -alkyl; R3 is -OR, -NHR, or -N(R)2; R4 is hydrogen, halogen, cyano, trifluoromethyl, or -C 1-6 -alkyl; R5 is hydrogen or -C 1-6 -alkyl, especially -C 1-3 -alkyl; R6 is hydrogen or -C 1-6 -alkyl, especially -C 1-3 -alkyl, or R5 and R6 together with the carbon atom bearing them form a cyclic system having 3 to 6 carbon atoms; R is hydrogen or -C 1-6 -alkyl, especially -C 1-3 -alkyl; X is -C(O)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR; R7 is hydrogen or methyl.

[0083] In one embodiment, Compound I or Compound IA used in the method of the present disclosure, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is represented by Formula I or Formula IA above, wherein in the above formula, R1 is hydrogen, -C 1-6 -alkyl, or -C(O)-CH3; R2 is hydrogen or -C 1-3 -alkyl; R3 is -OR, -NHR, or -NR2; R4 is hydrogen or halogen; R5 is -C 1-3-alkyl, R6 is -C 1-3 -alkyl, R is hydrogen, or -C 1-3 -alkyl, X is -C(O)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR, R7 is hydrogen.

[0084] In one embodiment, the compound I or compound IA used in the method of the present disclosure, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is represented by the above formula I or formula IA, wherein in the above formula, R1 is hydrogen, -C 1-3 -alkyl, or -C(O)-CH3, R2 is hydrogen, R3 is -OR, or -NHR, R4 is hydrogen, R5 is hydrogen, or -C 1-3 -alkyl, R6 is hydrogen, or -C 1-3 -alkyl, R is hydrogen, or -C 1-3 -alkyl, X is -C(O)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR, R7 is hydrogen.

[0085] In one embodiment, the compound I or compound IA used in the method of the present disclosure, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is represented by the above formula I or formula IA, wherein in the above formula, R1 is hydrogen, or -C(O)-CH3, R2 is hydrogen, R3 is -OR, or -NHR, R4 is hydrogen, R5 is -C 1-3 -alkyl, R6 is -C 1-3-alkyl, R is hydrogen or -C 1-3 -alkyl, X is -C(O)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR, R7 is hydrogen.

[0086] In one embodiment, the term "optical isomer" means including the optical isomers of the indole derivative compounds represented by Formula I, Formula IA, Formula II, or Formula IIA. It will be understood by those skilled in the art that the indole derivative compounds of the present disclosure may contain at least one chiral center. Therefore, the indole derivative compounds used in the methods of the present disclosure may exist in optically active form or racemic form, or may be isolated in such forms. Some compounds also exhibit polymorphism. It should be understood that the use of the compounds of the present disclosure includes the use of any racemate, optically active form, polymorph, stereoisomer, or combination thereof having properties useful in the treatment of the amyloid β diseases or conditions described herein.

[0087] In another embodiment, the methods of use of the present disclosure include the use of a compound represented by Formula I, Formula IA, Formula II, or Formula IIA (Compound I, Compound IA, Compound II, or Compound IIA) and any hydrate of Compounds 1-25. In one embodiment, the term "hydrate" refers to hemihydrate, monohydrate, dihydrate, trihydrate, etc., as known in the art.

[0088] In one embodiment, in Compound I or Compound II represented by Formula I or Formula II used in the methods of the present disclosure, the chiral center carrying the amino group and the X group has the R configuration.

[0089] In one embodiment, the compounds used in the methods of the present disclosure are Compounds 1-4 represented by the following Formulas 1-4.

[0090]

Chemical formula

[0091] In one embodiment, the compound used in the method of the present disclosure is one of the above Compounds 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0092] In one embodiment, the compound used in the method of the present disclosure is Compounds 5 to 25 represented by the following Formulas 5 to 25.

[0093]

Chemical formula

[0094]

Chemical formula

[0095] In one embodiment, the compound used in the method of the present disclosure is one of the above Compounds 5 to 25, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0096] In one embodiment, the compound used in the method of the present disclosure is one of the above Compounds 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0097] In addition, the compound used in the method of the present disclosure is an analog or derivative of one of the above Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25.

[0098] In some embodiments, the present disclosure provides a method for reversing Aβ toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising a compound I represented by formula I above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and Aβ 1-42 and providing a method comprising the step of administering.

[0099] Preparation of Compounds

[0100] The compounds used in the methods of the present disclosure, such as compounds represented by formula I, formula IA, formula II, or formula IIA (Compound I, Compound IA, Compound II, or Compound IIA), or optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, can be prepared using methods known in the art. In one embodiment, the compounds used in the methods of the present disclosure can be prepared based on the preparation procedures described in published patent applications such as Patent Document 1 (International Publication WO2012 / 066549) and Patent Document 2 (International Publication WO2012 / 055945A1).

[0101] For example, in some embodiments, the peptide D-Trp-Aib, referred to herein as Compound 1, can be synthesized as disclosed in Example 1 of Patent Document 1 and "Frydman-Marom, A., Rechter, M., Shefler, I., Bram, Y., Shalev, D.E. and Gazit, E. (2009). Cognitive-performance recovery of Alzheimer's disease model mice by modulation of early soluble amyloidal clusters. Angew Chem Int Ed Engl 48(11): 1981-1986, supplementary information" (both of the above documents are hereby incorporated by reference in their entirety). Briefly described, the synthesis of D-Trp-Aib is carried out as follows. The peptide was synthesized using a customized protocol including standard amide bond formation methods according to classical liquid-phase peptide synthesis methods. That is, protection of the N-terminal amine and C-terminal carboxylic acid functions, coupling of two protected amino acids, and cleavage of the protecting groups were performed to obtain the desired product in free peptide form. The crude product was purified by reverse-phase preparative HPLC, the purity was determined by reverse-phase analytical HPLC analysis (>95%), and the structure was confirmed by mass spectrometry (MW 289.33).

[0102] Some embodiments of the synthesis of Compound 2 are described in Patent Document 1. In Patent Document 1, the Compound 2 described herein is referred to as Compound "D" (see the description of the compound prepared using Scheme 8 in Example 1 of Patent Document 1). The description of the synthesis of Compound 2 described in Patent Document 1 is hereby incorporated by reference in its entirety. Briefly described, Compound 2 is prepared as shown in Scheme 1 below.

[0103] [Chemical formula]

[0104] In addition, Patent Document 2 describes some embodiments of the synthesis of Compound 3 and Compound 4. In Patent Document 2, Compound 3 described herein is referred to as Compound "171" (see "Synthesis of Compound (171)" in Example 2 of Patent Document 2). Briefly described, Compound 3 is prepared according to the following steps.

[0105]

Chemical formula

[0106] Also, in Patent Document 2, Compound 4 described herein is referred to as Compound "121" (see "Synthesis of Compound (121)" in Example 1 of Patent Document 2). Briefly described, Compound 4 is prepared according to the following steps.

Chemical formula

[0107] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA used in the methods of the present disclosure provides an active ingredient (active component). In some embodiments, Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 used in the methods of the present disclosure provide an active ingredient.

[0108] One skilled in the art will understand that the terms "pharmaceutically active agent" or "active agent", "pharmaceutically active ingredient", or "active ingredient" are used interchangeably and include agents in which the ingredient is biologically active.

[0109] Preparation of non-toxic non-β-sheet amorphous Aβ clusters

[0110] Aβ 1-42 A method for preparing a non-toxic non-β-sheet amorphous Aβ cluster containing Aβ and Compound I represented by Formula I is described in detail below and schematically shown in FIG. 6.

[0111] In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and Compound I represented by Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and Compound IA represented by Formula IA, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and Compound II represented by Formula II, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and Compound IIA represented by Formula IIA, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and any one of Compounds 1 to 25 represented by Formulas 1 to 25, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and Compound 1 of Formula 1, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and Compound 2 of Formula 2, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and Compound 3 of Formula 3, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42and a compound 4 of Formula 4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0112] In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure comprise Aβ 1-42 and essentially do not contain a compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0113] In some embodiments, a compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is mixed with Aβ 1-42 and continuously diluted to maintain the concentration of Aβ 1-42 and reduce the concentration of the compound I of Formula I. In some embodiments, a compound IA of Formula IA, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is mixed with Aβ 1-42 and continuously diluted to maintain the concentration of Aβ 1-42 and reduce the concentration of the compound IA of Formula IA. In some embodiments, a compound II of Formula II, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is mixed with Aβ 1-42 and continuously diluted to maintain the concentration of Aβ 1-42 and reduce the concentration of the compound II of Formula II. In some embodiments, a compound IIA of Formula IIA, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is mixed with Aβ 1-42 and continuously diluted to maintain the concentration of Aβ 1-42 and reduce the concentration of the compound IIA of Formula IIA. In some embodiments, any one of Compounds 1-25, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is mixed with Aβ 1-42 and continuously diluted to maintain the concentration of Aβ 1-42 and reduce the concentration of Compounds 1-25.

[0114] In some embodiments, a series of dilutions begins with a stoichiometric excess of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, over Aβ 1-42 at a ratio of 20:1. In some embodiments, a series of dilutions begins with a stoichiometric excess of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, over Aβ 1-42 at a ratio of about 20:1. In some embodiments, a series of dilutions begins with a stoichiometric excess of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, over Aβ 1-42 at a ratio of about 30:1 to 20:1. In some embodiments, a series of dilutions begins with a stoichiometric excess of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, over Aβ 1-42 at a ratio of about 20:1 to 10:1.

[0115] In some embodiments, a series of dilutions includes dilution steps of about 2 to 10 steps. In some embodiments, a series of dilutions includes dilution steps of about 3 to 10 steps. In some embodiments, a series of dilutions includes dilution steps of about 4 to 10 steps. In some embodiments, a series of dilutions includes dilution steps of about 5 to 10 steps. In some embodiments, a series of dilutions includes dilution steps of about 2 to 5 steps. In some embodiments, a series of dilutions includes dilution steps of about 3 to 5 steps. In some embodiments, a series of dilutions includes dilution steps of about 4 to 5 steps. In some embodiments, a series of dilutions includes 2 dilution steps. In some embodiments, a series of dilutions includes 3 dilution steps. In some embodiments, a series of dilutions includes 4 dilution steps. In some embodiments, a series of dilutions includes 5 dilution steps. In some embodiments, a series of dilutions includes 6 dilution steps. In some embodiments, a series of dilutions includes 7 dilution steps. In some embodiments, a series of dilutions includes 8 dilution steps. In some embodiments, a series of dilutions includes 9 dilution steps. In some embodiments, a series of dilutions includes 10 dilution steps.

[0116] In some embodiments, the starting concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is 1 μM, and the maintenance concentration of Aβ 1-42 is 50 nM, and a series of dilutions is initiated with a stoichiometric excess of Compound I to Aβ 1-42 at a ratio of 20:1 and is performed in 5 dilution steps.

[0117] In some embodiments, in a method of reversing Aβ toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the final dilution mixture used is Aβ in a stoichiometric excess of 500:1 relative to Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof 1-42It includes. In some embodiments, in a method for reversing Aβ toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the final dilution mixture used is a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 250:1 to 500:1 1-42 It includes. In some embodiments, the final dilution mixture is a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 250:1 to 1000:1 1-42 It includes. In some embodiments, the final dilution mixture is a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 250:1 to 500:1 1-42 It includes.

[0118] In some embodiments, the final dilution mixture is a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 250:1 1-42 It includes. In some embodiments, the final dilution mixture is a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 300:1 1-42 It includes. In some embodiments, the final dilution mixture is a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 350:1 1-42 It includes. In some embodiments, the final dilution mixture is a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 400:1 1-42 It includes. In some embodiments, the final dilution mixture is a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 450:1 1-42It includes. In some embodiments, the final dilution mixture has a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 500:1 1-42 It includes. In some embodiments, the final dilution mixture has a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 550:1 1-42 It includes. In some embodiments, the final dilution mixture has a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, of 650:1, 700:1, 750:1, 800:1, 850:1, 900:1, 950:1, or 1000:1 1-42 It includes. In some embodiments, the final dilution mixture has a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, greater than 250:1 1-42 It includes. In some embodiments, the final dilution mixture has a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, greater than 500:1 1-42 It includes. In some embodiments, the final dilution mixture has a stoichiometric excess of Aβ with a ratio to Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, greater than 1000:1 1-42 It includes. In some embodiments, the final dilution mixture contains Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, at a concentration that can be ignored. In some embodiments, the final dilution mixture contains Compound I of Formula I, or its optical isomers, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, in an amount that can be ignored.

[0119] In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is about 0.1 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is about 0.5 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is about 0.5 nM to 0.05 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is about 0.1 nM to 0.01 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is less than 0.5 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is less than 0.1 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is less than 0.05 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is less than 0.01 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is less than 0.005 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is less than 0.001 nM. In some embodiments, the final concentration of Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof contained in the amorphous cluster is a negligible concentration.

[0120] In some embodiments, the present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neuro-sensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising a compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.5 nM to 0.05 nM. In some embodiments, the present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neuro-sensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising a compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.1 nM to 0.01 nM. In some embodiments, the present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neuro-sensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising a compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.005 nM to 0.0005 nM. In some embodiments, the present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neuro-sensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising a compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.001 nM to 0.0001 nM.

[0121] In some embodiments, the present disclosure provides a method of reversing amyloid-β toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.5 nM. In some embodiments, the present disclosure provides a method of reversing amyloid-β toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.1 nM. In some embodiments, the present disclosure provides a method of reversing amyloid-β toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.05 nM. In some embodiments, the present disclosure provides a method of reversing amyloid-β toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.01 nM. In some embodiments, the present disclosure provides a method of reversing amyloid-β toxicity and rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.005 nM.In some embodiments, the present disclosure provides a method of reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a concentration of about 0.001 nM. In some embodiments, the present disclosure provides a method of reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster comprising Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, at a negligible concentration. In some embodiments, the present disclosure provides a method of reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering a non-toxic non-β-sheet amorphous Aβ cluster that does not contain Compound I of Formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0122] In some embodiments, the use of the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure detoxifies misfolded amyloid-β monomers. In some embodiments, the use of the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure detoxifies misfolded amyloid-β oligomers.

[0123] In some embodiments, the non-toxic non-β-sheet amorphous Aβ clusters of the present disclosure are included in a pharmaceutically acceptable composition.

[0124] Composition

[0125] In one embodiment, a "pharmaceutical composition" refers to a formulation in which one or more active ingredients described herein are combined with other chemical components such as physiologically suitable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to a living body. In certain embodiments, the "pharmaceutical composition" provides a pharmaceutical dosage form (drug form) of the drug. In certain embodiments, the "pharmaceutical composition" includes any dosage form known in the art. As used herein, the terms "pharmaceutical composition", "composition", or "formulation" all have the same meaning and quality and can be used interchangeably.

[0126] One of ordinary skill in the art will understand that the expression "pharmaceutically acceptable" as used in connection with the compositions described herein refers to molecular entities and other ingredients of a composition that are physiologically acceptable and generally do not cause an adverse reaction when administered to a mammal (e.g., a human). The term "pharmaceutically acceptable" also means that use in mammals, particularly humans, is approved by a regulatory agency of the Federal or State government or is listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias.

[0127] An active ingredient, for example, Compound I, Compound IA, Compound II, or Compound IIA, but not limited thereto, for example, any one of Compounds 1 to 25, can be combined with one or more conventional excipients (adjuvants, carriers, diluents) for use in the methods of the present disclosure to form a pharmaceutical composition and its unit dosage forms. In some embodiments, the pharmaceutical compositions described herein include sterile formulations. In some embodiments, the pharmaceutical compositions described herein include excipients.

[0128] The compositions of the present disclosure can be used as solids such as coated or uncoated tablets and capsules filled with the composition, or as liquids such as solutions, suspensions, emulsions, or capsules filled with them, or as aerosols such as sprays or mists. Further, the compositions of the present disclosure may be prepared for oral administration. Further, the compositions of the present disclosure may be in the form of suppositories or capsules for rectal administration. In some embodiments, the compositions of the present disclosure may be prepared for nasal administration, for example, in the form of nasal sprays or mists. In some embodiments, the compositions of the present disclosure may be in the form of eye drops for use in the eyes, or may be prepared as a sterile injection solution for intraocular administration. In some embodiments, the compositions of the present disclosure are prepared in the form of injection solutions for systemic use, including, but not limited to, for example, intrathecal administration, subcutaneous administration, administration by implanted sustained-release depot, direct administration using an indwelling catheter, intramuscular administration, or intravenous administration. In some embodiments, the compositions of the present disclosure are prepared in the form of topical ointments, patches, or skin patches for systemic or local use.

[0129] The compositions of the present disclosure can be in the form of sterile injection solutions for parenteral use (including intrathecal administration, subcutaneous administration, intramuscular administration, direct administration using an indwelling catheter, administration by implanted sustained-release depot, or intravenous administration). Further, when applied to the eyes, the compositions of the present disclosure can be in a liquid or semi-liquid form (including eye drops or intraocular injections). In some embodiments, when applied to the eyes, the compositions of the present disclosure can be in the form of eye drops, ophthalmic creams, and intravitreal depot preparations. In some embodiments, the compositions of the present disclosure are in the form of nasal sprays or mists for the treatment of eye diseases. In some embodiments, the compositions of the present disclosure are in the form of nasal sprays or mists for the treatment of neurological diseases.

[0130] Such pharmaceutical compositions and their unit dosage forms may contain conventional or novel ingredients in conventional or special ratios, and may or may not contain additional active compounds. Such unit dosage forms may contain any appropriate effective amount of the active ingredient of the compounds of Formula I, Formula IA, Formula II, or Formula IIA that is commensurate with the intended dosage range of use. In some embodiments, the unit dosage form may contain any appropriate effective amount of the active ingredient of Compounds 1 to 25 that is commensurate with the intended dosage range of use. In some embodiments, the unit dosage form may contain any appropriate effective amount of the active ingredient of Compounds 1 to 4 that is commensurate with the intended dosage range of use.

[0131] In some embodiments, a composition containing 0.5 to 1000 mg, preferably 1 to 100 mg, of the active ingredient per dosage unit is a suitable representative unit dosage form. In some embodiments, a composition containing about 0.01 to 10 mg / kg body weight for oral administration and 0.001 to 10 mg / kg body weight for parenteral administration of the active ingredient is a suitable unit dosage form.

[0132] In one embodiment, as used herein, the term "excipient" as applied to a pharmaceutical composition for the methods of the present disclosure refers to a diluent, adjuvant, or carrier used in the administration of an active compound of Formula I, Formula IA, Formula II, or Formula IIA, or of Compounds 1 to 25. Such pharmaceutical excipients are often sterile liquids such as water or physiological saline. Other excipients include aqueous dextrose solutions, aqueous glycerol solutions, and oils such as those of animal, plant, or synthetic origin, depending on the type of administration (see "Remington and AR. Gennaro, 20th Edition, (2000) 'Remington: The Science and Practice of Pharmacy', published by Lippincott, Williams, and Wilkins"). In some embodiments, a pharmaceutical composition containing any one of the active compounds of Formula I, Formula IA, Formula II, or Formula IIA, or of Compounds 1 to 25, contains cyclodextrin as an excipient.

[0133] In ophthalmic applications (applications to eye diseases or conditions), topical formulations are often applied. Topical formulations are often aqueous solutions or dispersions. Note that solutions or suspensions that do not contain water can also be used.

[0134] Compound I, Compound IA, Compound II, or Compound IIA, or any of Compounds 1 - 25 can also be administered orally in the form of capsules, tablets, etc. Such oral administration compositions can be administered in the form of time - controlled release vehicles, such as diffusion - controlled systems, osmotic pressure devices, dissolution - controlled matrices, and erosive / degradable matrices.

[0135] In the case of oral administration in the form of tablets or capsules, the compounds of Formula I, Formula IA, Formula II, or Formula IIA, or any of Compounds 1 - 25 (but not limited to, for example, Compounds 1 - 4) can be combined with non - toxic pharmaceutically acceptable excipients, such as binders (e.g., pre - gelatinized corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose), fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, other reducing or non - reducing sugars, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate), disintegrants (e.g., potato starch, sodium starch glycolate), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavors, gelatin, sweeteners, natural rubbers, synthetic rubbers (e.g., acacia, tragacanth, alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, or waxes, etc. Tablets containing Compound I, Compound IA, Compound II, or Compound IIA, or any of Compounds 1 - 25 (but not limited to, for example, Compounds 1 - 4) may be coated by methods known in the art.

[0136] In the case of oral administration in liquid form, the pharmaceutical ingredient may be combined with a non-toxic pharmaceutically acceptable inert carrier or solvent (e.g., ethanol, glycerol, water), a suspending agent (e.g., sorbitol syrup, cellulose derivatives, hydrogenated edible fat), an emulsifying agent (e.g., lecithin, acacia), a non-aqueous vehicle (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oil), or a preservative (e.g., methyl or propyl p-hydroxybenzoic acid or sorbic acid). Also, stabilizers such as antioxidants (BRA, BRT, propyl gallate, sodium ascorbate, citric acid) may be added to stabilize the dosage form.

[0137] In addition, the compositions used in the methods of the present disclosure containing Compound I, Compound IA, Compound II, or Compound IIA, or any one of Compounds 1 to 25 (but not limited thereto, e.g., Compounds 1 to 4) may be introduced, for example, into beads, microspheres, or microcapsules made of polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration may be in the form of solutions, syrups, emulsions, or suspensions, or may be provided as dry products that are reconstituted with water or other suitable vehicles before use. Formulations for oral administration may be appropriately prepared to provide controlled or delayed release of the active compound.

[0138] In addition, the active compounds of Formula I, Formula IA, Formula II, or Formula IIA, or any one of Compounds 1 to 25, but not limited thereto, e.g., Compounds 1 to 4, may be administered in the form of a liposomal delivery system such as small unilamellar liposomes, large unilamellar liposomes, or multilamellar liposomes. As is well known, liposomes can be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine.

[0139] Furthermore, the active compounds of formula I, formula IA, formula II, or formula IIA, or any of compounds 1 to 25, including but not limited to, for example, compounds 1 to 4, may be conjugated with a soluble polymer as a targetable drug carrier. Such soluble polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide phenol, polyhydroxyethyl-aspartamide phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Additionally, compound I, compound IA, compound II, or compound IIA may be conjugated with a class of biodegradable polymers useful for achieving controlled release of a drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, or crosslinkable or amphiphilic block copolymers of hydrogels.

[0140] For administration by inhalation, the formulations (therapeutic agents) used in the methods of the present disclosure that contain compound I, compound IA, compound II, or compound IIA, or any of compounds 1 to 25 (including but not limited to, for example, compounds 1 to 4) as the active compound can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane or other suitable gas.

[0141] For administration by aerosol spray (such as, but not limited to, nasal spray or mist), the formulations (therapeutic agents) used in the methods of the present disclosure that contain compound I, compound IA, compound II, or compound IIA, or any of compounds 1 to 25 (including but not limited to, for example, compounds 1 to 4) as the active compound can be conveniently delivered in the form of an aerosol spray or mist from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane or other suitable gas.

[0142] The formulations used in the methods of the present disclosure that contain Compound I, Compound IA, Compound II, or Compound IIA, or any one of Compounds 1 to 25 (but not limited thereto, for example, Compounds 1 to 4) are administered parenterally, i.e., intravenous administration (i.v.), intracerebroventricular administration (i.c.v.), subcutaneous administration (s.c.), intraperitoneal administration (i.p.), intramuscular administration (i.m.), subdermal administration (s.d.), intrathecal administration (i.th.), intravitreal administration (intraocular administration), periocular administration, administration by an implantable sustained-release depot, direct administration using an indwelling catheter, intradermal administration (i.d.), or direct administration (e.g., bolus administration or continuous administration).

[0143] In the case of administration by injection (particularly in the case of intravitreal administration for application to the eye), the formulations used in the methods of the present disclosure that contain Compound I, Compound IA, Compound II, or Compound IIA, or any one of Compounds 1 to 25 (but not limited thereto, for example, Compounds 1 to 4) may be provided in unit dosage forms with added preservatives, for example, in ampoules or multi-dose containers. Such compositions may be, for example, suspensions, solutions, or emulsions in an aqueous vehicle and may also contain excipients such as suspending agents, stabilizers, and / or dispersing agents. Alternatively, the compounds of formula IA, formula II, or formula IIA, or any one of Compounds 1 to 25 (but not limited thereto, for example, Compounds 1 to 4) may be in powder form for reconstitution with a suitable excipient, for example, sterile pyrogen-free water.

[0144] For administration by injection, the formulations used in the methods of the present disclosure that contain Compound I, Compound IA, Compound II, or Compound IIA, or any one of Compounds 1 to 25 (but not limited thereto, for example, Compounds 1 to 4) may be provided in unit dosage forms with preservatives added, such as ampoules or multi-dose containers. Such compositions may be, for example, suspensions, solutions, or emulsions in aqueous vehicles, and may also contain excipients such as suspending agents, stabilizers, and / or dispersing agents. Alternatively, the compounds of Formula IA, Formula II, or Formula IIA, or any one of Compounds 1 to 25 (but not limited thereto, for example, Compounds 1 to 4) may be in powder form for reconstitution with suitable excipients, such as sterile pyrogen-free water.

[0145] For rectal administration, the formulations used in the methods of the present disclosure that contain Compound I, Compound IA, Compound II, or Compound IIA, or any one of Compounds 1 to 25 (but not limited thereto, for example, Compounds 1 to 4) may be formulated, for example, as suppositories or retention enemas (including conventional suppository bases such as cocoa butter and other glycerides).

[0146] Compositions containing Compound I, Compound IA, Compound II, or Compound IIA, or any one of Compounds 1 to 25 (but not limited thereto, for example, Compounds 1 to 4) may be provided in a pack or dispenser device. The pack or dispenser device may contain one or more unit dosage forms containing the active ingredient, or may include different dosage levels from each other to facilitate titration of the dosage. The pack may include a metal or plastic foil such as a blister pack. The pack or dispenser device may be provided with instructions for administration. Also, the compositions for the methods of the present disclosure may be prepared by formulating in a mixable pharmaceutical carrier, placed in a suitable container, and labeled on the container for the indicated state of treatment.

[0147] As disclosed in this specification, the dosage of the components in the composition for the method of the present disclosure is determined such that the continuously or intermittently administered dosage does not exceed an amount determined in consideration of the results in experimental animals and the condition of the affected patients. The specific dosage will necessarily vary depending on the method of administration, the condition or state of the patient or test animal, such as age, weight, gender, sensitivity, diet, administration period, co-administered drugs, severity of the disease, etc. The appropriate dosage and administration time under specific conditions can be determined by tests based on the above indicators, but can be refined and finally determined according to the judgment of the physician and the situation of each patient (age, general condition, severity of symptoms, gender, etc.) in accordance with standard clinical techniques.

[0148] The toxic effects and therapeutic effects of the composition for the method of the present disclosure can be determined by standard pharmaceutical procedures in experimental animals, for example, LD 50 (the dose lethal to 50% of the population) and ED 50 (the dose therapeutically effective for 50% of the population). The dose ratio of the therapeutic effect to the toxic effect is the therapeutic index, which can be expressed as the ratio of ED 50 / LD 50 , and a pharmaceutical composition with a higher therapeutic index is preferred.

[0149] In some embodiments, each dosage used in the method of the present disclosure comprises 100% of the therapeutically effective dosage (pharmaceutically effective amount). In some embodiments, each dosage used in the method of the present disclosure comprises 20 - 75% of the therapeutically effective dosage. In some embodiments, each dosage used in the method of the present disclosure comprises 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75% of the therapeutically effective dosage.

[0150] As used herein, the singular forms "a", "an", and "the" include the plural forms of their referents unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" can include a plurality of compounds, such as mixtures thereof, etc.

[0151] Throughout this application, various embodiments of the invention may be presented in a range format. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention (including, but not limited to, percentages of a therapeutically effective amount). Thus, a description of a range should be considered to specifically disclose not only the individual numerical values within that range but also all possible sub-ranges contained within that range. For example, a description of a range from 1 to 6 should be considered to specifically disclose sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as the individual numerical values contained within that range (e.g., 1, 2, 3, 4, 5, and 6). This applies regardless of the width of the range.

[0152] When specifying a numerical range in this specification, it always means including all numerical values (fractions or integers) within the specified numerical range. The expressions "range between" a first specified number and a second specified number, and "range from" a first specified number "to" a second specified number are used interchangeably in this specification and mean including the first and second specified numbers, as well as all fractions and integers between them.

[0153] As used herein, the term "about" refers to ±10% of the recited value.

[0154] In some embodiments, the dose for each of multiple administrations includes 100% of the therapeutically effective dose (pharmaceutically effective amount), 75 - 100% of the therapeutically effective dose, or 20 - 75% of the therapeutically effective dose, or any combination thereof.

[0155] In some embodiments, the method of use of the present disclosure includes the step of administering Compound I, Compound IA, Compound II, or Compound IIA, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the above compounds are included in a pharmaceutically acceptable composition. In some embodiments, the method of use of the present disclosure includes the step of administering any one of Compounds 1-25, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the above compounds are included in a pharmaceutically acceptable composition. In some embodiments, the method of use of the present disclosure includes the step of administering any one of Compounds 1-4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the above compounds are included in a pharmaceutically acceptable composition. In some embodiments, the method of use of the present disclosure includes the step of administering Compound 1, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the above compounds are included in a pharmaceutically acceptable composition. In some embodiments, the method of use of the present disclosure includes the step of administering Compound 2, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the above compounds are included in a pharmaceutically acceptable composition. In some embodiments, the method of use of the present disclosure includes the step of administering Compound 3, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the above compounds are included in a pharmaceutically acceptable composition. In some embodiments, the method of use of the present disclosure includes the step of administering Compound 4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the above compounds are included in a pharmaceutically acceptable composition. In some embodiments, the method of use of the present disclosure includes the step of administering a non-toxic, non-β-sheet, amorphous Aβ cluster included in a pharmaceutically acceptable composition.

[0156] Method of use

[0157] Misfolded (mis-folded) amyloid β 1-42 (Aβ 1-42is the major endogenous pathogen underlying the etiology of amyloid β diseases or conditions. The misfolded Aβ 1-42 monomers bind to each other to form soluble Aβ oligomers with toxicity, causing synaptic dysfunction and neurodegeneration in amyloid β diseases or conditions. Such toxic soluble Aβ 1-42 oligomers can cause damage, dysfunction, inhibition, or functional changes in neurons, non-neuronal cells, and / or sensory cells affected by amyloid β diseases or conditions.

[0158] In some embodiments, the present disclosure provides a method for reversing the amyloid β functional toxicity in neurons, non-neuronal cells, or neurosensory cells, the method comprising administering to a subject in need thereof a compound I represented by the following formula I, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0159]

Chemical formula

[0160] Wherein, * refers to a chiral center, ** refers to a chiral center when R5 and R6 are different, R1 is hydrogen, -C 1-6 -alkyl, cyclo-C 3-12 -alkyl, -C(O)R, or -C(O)OR, R2 is hydrogen, C 1-6 -alkyl, or cyclo-C 3-12 -alkyl, R3 is -OR, -NHR, or -N(R)2, R4 is hydrogen, halogen, cyano, trifluoromethyl, -C 1-6 -alkyl, -C 6-10 -aryl, heteroaryl, -OR, -NHR, -N(R)2, -C(O)R, or -C(O)-NHR, R5 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, or R5 and R6 together with the carbon atom(s) to which they are attached form a cyclic system having 3 to 6 carbon atoms, R6 is hydrogen, -C 1-6 -alkyl, or -C 2-6 -alkenyl, R7 is hydrogen, methyl, ethyl, propyl, or cyclopropyl, R is hydrogen, -C 1-6 -alkyl, or -C 6-10 -aryl, X is -C(O)CH2-, -CH(OH)CH2-, -CH=CH-, -CH2-NR-C(O)-, or -C(O)NR.

[0161] In some embodiments, the present disclosure provides a method of reversing amyloid-β functional toxicity in neuronal cells, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering to a subject in need thereof a non-toxic non-β-sheet amorphous Aβ cluster comprising a compound I represented by formula I below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount. In some embodiments, the present disclosure provides a method of reversing amyloid-β functional toxicity in neuronal cells, non-neuronal cells, or neurosensory cells, or any combination thereof, the method comprising administering to a subject in need thereof a non-toxic non-β-sheet amorphous Aβ cluster that does not contain a compound I represented by formula I below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0162] In some embodiments, the present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering to a subject in need thereof a compound I represented by formula I below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount. In some embodiments, the present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering to a subject in need thereof a non-toxic non-β-sheet amorphous Aβ cluster comprising a compound I represented by formula I below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount. In some embodiments, the present disclosure provides a method for reversing amyloid-β toxicity and rapidly improving the function of neuronal cells, non-neuronal cells, neurosensory cells, or any combination thereof, the method comprising administering to a subject in need thereof a non-toxic non-β-sheet amorphous Aβ cluster not comprising a compound I represented by formula I below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0163] Detailed embodiments of the compound of formula I are as described above. The embodiments of the compound of formula I above are hereby incorporated by reference in their entirety. Detailed embodiments of the non-toxic non-β-sheet amorphous Aβ cluster are as described above. The embodiments of the non-β-sheet amorphous Aβ cluster above are hereby incorporated by reference in their entirety.

[0164] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses amyloid β (Aβ) functional toxicity. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses Aβ functional toxicity in vivo. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses Aβ functional toxicity to neurons, non-neuronal cells, or neurosensory cells. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses Aβ functional toxicity to neurons in the central nervous system, including, but not limited to, for example, pyramidal neurons in the hippocampus and cerebral cortex and other excitatory neurons. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses Aβ functional toxicity to retinal ganglion cells (RGCs). In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses Aβ functional toxicity to retinal pigment epithelial (RPE) cells.

[0165] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses Aβ functional toxicity to photoreceptor cells including rod cells and cone cells. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses Aβ functional toxicity to hippocampal cells.

[0166] In some embodiments, neurons include hippocampal cells, cortical pyramidal cells, inhibitory interneurons, place cells, basket cells, granule cells, retinal ganglion cells (RGCs), bipolar cells, horizontal cells, and amacrine cells. In some embodiments, non-neuronal cells include retinal pigment epithelial (RPE) cells, astrocytes, and oligodendrocytes. In some embodiments, neurosensory cells include photoreceptor cells, including, but not limited to, for example, rod cells and cone cells.

[0167] In some embodiments, the present disclosure provides a method for reversing the amyloid-β functional toxicity of neuronal cells, non-neuronal cells, or neurosensory cells, the method comprising administering to a subject in need thereof a compound IA represented by formula IA below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0168]

Chemical formula

[0169] Wherein, R1, R2, R3, R4, R5, R6, R7, and X are the same as those in the above compound IA.

[0170] In some embodiments, the present disclosure provides a method for reversing the amyloid-β functional toxicity of neuronal cells, non-neuronal cells, or neurosensory cells, the method comprising administering to a subject in need thereof a compound 1 represented by formula 1 below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0171]

Chemical formula

[0172] In some embodiments, the present disclosure provides a method for reversing the amyloid-β functional toxicity of neuronal cells, non-neuronal cells, or neurosensory cells, the method comprising administering to a subject in need thereof a compound 2 represented by formula 2 below, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0173]

Chemical formula

[0174] In some embodiments, the present disclosure provides a method for reversing the amyloid-β functional toxicity of neuronal cells, non-neuronal cells, or neurosensory cells, the method comprising administering to a subject in need thereof a compound 3 represented by the following formula 3, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0175]

Chemical formula

[0176] In some embodiments, the present disclosure provides a method for reversing the amyloid-β functional toxicity of neuronal cells, non-neuronal cells, or neurosensory cells, the method comprising administering to a subject in need thereof a compound 4 represented by the following formula 4, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0177]

Chemical formula

[0178] In some embodiments, the present disclosure provides a method for reversing the amyloid-β functional toxicity of neuronal cells, non-neuronal cells, or neurosensory cells, the method comprising administering to a subject in need thereof a compound 5-25 represented by the following formula 5-25, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount.

[0179]

Chemical formula

[0180]

Chemical formula

[0181] One of ordinary skill in the art would understand that nerve cells include, but are not limited to, retinal ganglion cells (RGCs), hippocampal cells, cortical pyramidal cells, inhibitory interneurons, place cells, basket cells, granule cells, bipolar cells, horizontal cells, and amacrine cells. A subject suffering from an amyloid-β related disease or condition may experience damage, reduction, inhibition, or change in the function of the above-mentioned nerve cells. In some embodiments, the nerve cells include RGCs.

[0182] One of ordinary skill in the art would understand that non-nerve cells include retinal pigment epithelium (RPE) cells, astrocytes (star-shaped glial cells), and oligodendrocytes (few-projection glial cells). A subject suffering from an amyloid-β related disease or condition may experience damage, reduction, inhibition, or change in the function of the above-mentioned non-nerve cells. In some embodiments, the non-nerve cells include RPE cells.

[0183] One of ordinary skill in the art would understand that nerve sensory cells include nerve cells that convert a specific type of stimulus through receptors into action potentials or graded potentials. Examples of nerve sensory cells are rod cells and cone cells, which are light sensory cells of the eye. A subject suffering from an amyloid-β related disease or condition may experience damage, reduction, inhibition, or change in the function of the above-mentioned nerve sensory cells. In some embodiments, the nerve sensory cells include retinal ganglion cells (RGCs), cone cells, and rod cells.

[0184] In some embodiments, any one of Compounds 1-25 reverses amyloid-β (Aβ) functional toxicity. In some embodiments, any one of Compounds 1-25 reverses Aβ functional toxicity in vivo. In some embodiments, any one of Compounds 1-25 reverses Aβ functional toxicity against neuronal cells, non-neuronal cells, or neurosensory cells. In some embodiments, any one of Compounds 1-25 reverses Aβ functional toxicity against retinal ganglion cells (RGCs). In some embodiments, any one of Compounds 1-25 reverses Aβ functional toxicity against retinal pigment epithelial (RPE) cells. In some embodiments, any one of Compounds 1-25 reverses Aβ functional toxicity against cone cells. In some embodiments, any one of Compounds 1-25 reverses Aβ functional toxicity against rod cells.

[0185] In some embodiments, Compound 1 reverses amyloid-β (Aβ) functional toxicity. In some embodiments, Compound 1 reverses Aβ functional toxicity in vivo. In some embodiments, Compound 1 reverses Aβ functional toxicity against neuronal cells, non-neuronal cells, or neurosensory cells. In some embodiments, Compound 1 reverses Aβ functional toxicity against retinal ganglion cells (RGCs). In some embodiments, Compound 1 reverses Aβ functional toxicity against retinal pigment epithelial (RPE) cells. In some embodiments, Compound 1 reverses Aβ functional toxicity against cone cells. In some embodiments, Compound 1 reverses Aβ functional toxicity against rod cells.

[0186] In some embodiments, compound 2 reverses amyloid-β (Aβ) functional toxicity. In some embodiments, compound 2 reverses Aβ functional toxicity in vivo. In some embodiments, compound 2 reverses Aβ functional toxicity against nerve cells, non-nerve cells, or neurosensory cells. In some embodiments, compound 2 reverses Aβ functional toxicity against retinal ganglion cells (RGCs). In some embodiments, compound 2 reverses Aβ functional toxicity against retinal pigment epithelial (RPE) cells. In some embodiments, compound 2 reverses Aβ functional toxicity against cone cells. In some embodiments, compound 2 reverses Aβ functional toxicity against rod cells.

[0187] In some embodiments, compound 3 reverses amyloid-β (Aβ) functional toxicity. In some embodiments, compound 3 reverses Aβ functional toxicity in vivo. In some embodiments, compound 3 reverses Aβ functional toxicity against nerve cells, non-nerve cells, or neurosensory cells. In some embodiments, compound 3 reverses Aβ functional toxicity against retinal ganglion cells (RGCs). In some embodiments, compound 3 reverses Aβ functional toxicity against retinal pigment epithelial (RPE) cells. In some embodiments, compound 3 reverses Aβ functional toxicity against cone cells. In some embodiments, compound 3 reverses Aβ functional toxicity against rod cells.

[0188] In some embodiments, compound 4 reverses amyloid-β (Aβ) functional toxicity. In some embodiments, compound 4 reverses Aβ functional toxicity in vivo. In some embodiments, compound 4 reverses Aβ functional toxicity against nerve cells, non-nerve cells, or neurosensory cells. In some embodiments, compound 4 reverses Aβ functional toxicity against retinal ganglion cells (RGCs). In some embodiments, compound 4 reverses Aβ functional toxicity against retinal pigment epithelial (RPE) cells. In some embodiments, compound 4 reverses Aβ functional toxicity against cone cells. In some embodiments, compound 4 reverses Aβ functional toxicity against rod cells.

[0189] In some embodiments, in the methods of the present disclosure, Compound 1, Compound 2, Compound 3, or Compound 4 reverses amyloid-β functional toxicity in a subject in need of treatment. One of ordinary skill in the art will understand that, in some embodiments, reversal of amyloid-β functional toxicity includes restoration of impaired neuronal function.

[0190] In some embodiments, reversal of amyloid-β functional toxicity results in rapid restoration of impaired neuronal function. In some embodiments, neuronal function includes sending signals to the spinal cord or brain in response to light that affects cells of a sensory organ (e.g., the eye). In some embodiments, neuronal function includes receiving signals from the brain and spinal cord and controlling everything from muscle contraction to glandular output. In some embodiments, neuronal function includes, but is not limited to, transmitting or receiving signals such as action potentials (potentials).

[0191] In some embodiments, restoration of impaired neuronal function includes restoration of response to light. In some embodiments, restoration of impaired neuronal function includes restoration of the ability to transmit signals of potential. In some embodiments, restoration of impaired neuronal function includes restoration of the ability to receive signals of potential.

[0192] One skilled in the art would understand that if the recovery of nerve cell function is rapid, the recovery of the ability to transmit or receive electrical potential signals will occur within minutes. One skilled in the art would understand that the rapid recovery of nerve cell function is rapid in a disease or condition. In some embodiments, the rapid recovery of nerve cell function, such as the recovery of the ability to transmit or receive electrical potential signals, occurs within hours. In some embodiments, the rapid recovery of nerve cell function, such as the recovery of the ability to transmit or receive electrical potential signals, occurs within days. In some embodiments, the rapid recovery of nerve cell function, such as the recovery of the ability to transmit or receive electrical potential signals, occurs within months. Non-invasive methods for detecting the recovery of nerve cell function, such as in the retina of the eye, are known in the art and include, but are not limited to, for example, microperimetry, measurement of low-luminance vision, measurement of dark adaptation, and measurement of low-luminance reading speed.

[0193] In some embodiments, the recovery of nerve cell function is a 25-100% recovery. In some embodiments, the recovery of nerve cell function is a 50-100% recovery. In some embodiments, the recovery of nerve cell function is a 75-100% recovery. In some embodiments, the recovery of nerve cell function is a 50-75% recovery. In some embodiments, the recovery of nerve cell function includes at least a 25% recovery. In some embodiments, the recovery of nerve cell function includes at least a 35% recovery. In some embodiments, the recovery of nerve cell function includes at least a 45% recovery. In some embodiments, the recovery of nerve cell function includes at least a 55% recovery. In some embodiments, the recovery of nerve cell function includes at least a 65% recovery. In some embodiments, the recovery of nerve cell function includes at least a 75% recovery. In some embodiments, the recovery of nerve cell function includes at least an 85% recovery. In some embodiments, the recovery of nerve cell function includes at least a 95% recovery.

[0194] In some embodiments, the restoration of nerve cell function includes a restoration of about 25 - 35%. In some embodiments, the restoration of nerve cell function includes a restoration of about 35 - 45%. In some embodiments, the restoration of nerve cell function includes a restoration of about 45 - 55%. In some embodiments, the restoration of nerve cell function includes a restoration of about 55 - 65%. In some embodiments, the restoration of nerve cell function includes a restoration of about 65 - 75%. In some embodiments, the restoration of nerve cell function includes a restoration of about 75 - 85%. In some embodiments, the restoration of nerve cell function includes a restoration of about 85 - 95%. In some embodiments, the restoration of nerve cell function includes a restoration of about 90 - 100%.

[0195] In some embodiments, the restoration of nerve cell function includes a restoration of about 25%. In some embodiments, the restoration of nerve cell function includes a restoration of about 35%. In some embodiments, the restoration of nerve cell function includes a restoration of about 45%. In some embodiments, the restoration of nerve cell function includes a restoration of about 55%. In some embodiments, the restoration of nerve cell function includes a restoration of about 65%. In some embodiments, the restoration of nerve cell function includes a restoration of about 75%. In some embodiments, the restoration of nerve cell function includes a restoration of about 85%. In some embodiments, the restoration of nerve cell function includes a restoration of about 95%. In some embodiments, the restoration of nerve cell function includes a restoration of about 100%.

[0196] In some embodiments, reversal of amyloid β functional toxicity results in a decrease in cell death of neurons, non-neuronal cells, neurosensory cells, or any combination thereof. In some embodiments, the methods of the present disclosure reduce cell death of neurons. In some embodiments, the methods of the present disclosure reduce cell death of retinal ganglion cells (RGCs). In some embodiments, the methods of the present disclosure reduce cell death of non-neuronal cells. In some embodiments, the methods of the present disclosure reduce cell death of retinal pigment epithelial (RPE) cells. In some embodiments, the methods of the present disclosure reduce cell death of astrocytes (stellate glial cells). In some embodiments, the methods of the present disclosure reduce cell death of neurosensory cells. Non-invasive methods for detecting cell death in the eye, for example, are known in the art and include, but are not limited to, for example, fundus autofluorescence imaging and detection of apoptotic retinal cells (DARC).

[0197] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA binds to misfolded toxic Aβ 1-42 monomers. In some embodiments, the binding of Compound I, Compound IA, Compound II, or Compound IIA to Aβ 1-42 has a higher affinity than the affinity that misfolded Aβ 1-42 monomers have for each other. When Compound I, Compound IA, Compound II, or Compound IIA binds to misfolded toxic Aβ 1-42 monomers, harmless non-toxic clusters of misfolded Aβ monomers (amorphous Aβ) are formed, and the non-toxic clusters formed are naturally removed from the circulatory system, intracellular space, or extracellular space. Further, in some embodiments, the binding of the above compounds to misfolded toxic Aβ 1-42 monomers does not interfere with the normal function of amyloid β (Aβ) and does not cause toxicity in other ways.

[0198] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA is misfolded toxic Aβ1-42 In some embodiments, any of compounds 1-25 binds to misfolded, toxic Aβ monomers. 1-42 In some embodiments, Compound 1 binds to misfolded, toxic Aβ monomers. 1-42 In some embodiments, Compound 2 binds to misfolded, toxic Aβ monomers. 1-42 In some embodiments, Compound 3 binds to misfolded, toxic Aβ monomers. 1-42 In some embodiments, compound 4 binds to misfolded, toxic Aβ monomers. 1-42 Binds to monomers.

[0199] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA is administered to treat a pre-existing toxic Aβ 1-42 In the presence of 1-42 (FIG. 1). Such amorphous Aβ clusters include non-toxic non-β-sheet amorphous Aβ clusters. As used herein, the term "non-toxic non-β-sheet amorphous Aβ clusters" is used interchangeably with "Aβ blobs," "blobs," "Aβ assemblies," "assemblies," "non-toxic Aβ aggregates," "non-toxic aggregates," "non-toxic Aβ clusters," "non-toxic clusters," "amorphous clusters," "amorphous Aβ clusters," "amorphous aggregates," "amorphous Aβ aggregates," or "Aβ clusters," all of which have the same meaning and properties. In any case, one of skill in the art will appreciate that non-toxic non-β-sheet amorphous Aβ clusters include non-toxic formation of amyloid β (Aβ). In some embodiments, such clusters have the ability to prevent toxic Aβ oligomer formation. In some embodiments, such clusters have the ability to reverse toxic Aβ oligomer formation, as seen by the reversal of Aβ functional toxicity exemplified in Example 2 below.

[0200] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA is administered to treat a pre-existing toxic Aβ 1-42form amorphous Aβ clusters in the presence thereof, thereby reversing the toxicity of Aβ in vivo 1-42 in vivo. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to neurons, non-neuronal cells, or neurosensory cells 1-42 in vivo. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to retinal ganglion cells (RGCs) 1-42 in vivo. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxic accumulation of Aβ in retinal pigment epithelial (RPE) cells / Bruch's membrane 1-42 In some embodiments, any one of Compounds 1-25 forms amorphous Aβ clusters in the presence of existing toxic Aβ

[0201] thereby reversing the toxicity of Aβ 1-42 in vivo. In some embodiments, any one of Compounds 1-25 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ 1-42 in vivo. In some embodiments, any one of Compounds 1-25 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ in vivo 1-42 In some embodiments, any one of Compounds 1-25 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to neurons, non-neuronal cells, or neurosensory cells 1-42 In some embodiments, any one of Compounds 1-25 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to retinal ganglion cells (RGCs) 1-42form amorphous Aβ clusters in the presence thereof, thereby reversing the toxic accumulation of Aβ in retinal pigment epithelial (RPE) cells / Bruch's membrane 1-42 in some embodiments, any of compounds 1-25 form amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 form amorphous Aβ clusters in the presence thereof, thereby reversing the toxicity of Aβ to cone cells 1-42 in some embodiments, any of compounds 1-25 form amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 form amorphous Aβ clusters in the presence thereof, thereby reversing the toxicity of Aβ to rod cells 1-42 in some embodiments, any of compounds 1-25 form amorphous Aβ clusters in the presence of existing toxic Aβ

[0202] in some embodiments, compound 1 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ 1-42 in some embodiments, compound 1 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ in vivo 1-42 in some embodiments, compound 1 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to neurons, non-neuronal cells, or neurosensory cells 1-42 in some embodiments, compound 1 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to retinal ganglion cells (RGCs 1-42 in some embodiments, compound 1 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxic accumulation of Aβ in retinal pigment epithelial (RPE) cells / Bruch's membrane 1-42 in some embodiments, compound 1 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to cone cells 1-42 in some embodiments, compound 1 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42form amorphous Aβ clusters in the presence thereof, thereby reversing the toxicity of Aβ to rod cells 1-42 and reversing its toxicity.

[0203] In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ in vivo. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ to neurons, non-neuronal cells, or neurosensory cells. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ to retinal ganglion cells (RGCs). In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxic accumulation of Aβ in retinal pigment epithelium (RPE) cells / Bruch's membrane. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxic accumulation of Aβ. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ to cone cells. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ. In some embodiments, Compound 2 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ to rod cells. 1-42 and reverses the toxicity of Aβ.

[0204] In some embodiments, Compound 3 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ. In some embodiments, Compound 3 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and reverses the toxicity of Aβ. In some embodiments, Compound 3 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42form amorphous Aβ clusters in the presence thereof, thereby reversing the toxicity of Aβ in vivo 1-42 in some embodiments, compound 3 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to neurons, non-neuronal cells, or neurosensory cells 1-42 in some embodiments, compound 3 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to retinal ganglion cells (RGCs) 1-42 in some embodiments, compound 3 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxic accumulation of Aβ in retinal pigment epithelial (RPE) cells / Bruch's membrane 1-42 in some embodiments, compound 3 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to cone cells 1-42 in some embodiments, compound 3 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to rod cells 1-42 in some embodiments, compound 4 forms amorphous Aβ clusters in the presence of existing toxic Aβ

[0205] thereby reversing the toxicity of Aβ 1-42 in some embodiments, compound 4 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ 1-42 in some embodiments, compound 4 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ in vivo 1-42 in some embodiments, compound 4 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 thereby reversing the toxicity of Aβ to neurons, non-neuronal cells, or neurosensory cells 1-42 in some embodiments, compound 4 forms amorphous Aβ clusters in the presence of existing toxic Aβ thereby reversing the toxicity of Aβ to retinal ganglion cells (RGCs)1-42 Reverse the toxicity of. In some embodiments, Compound 4 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and thereby reverses the toxic accumulation of Aβ in retinal pigment epithelial (RPE) cells / Bruch's membrane 1-42 Reverse the toxicity of. In some embodiments, Compound 4 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and thereby reverses the toxicity of Aβ to cone cells 1-42 Reverse the toxicity of. In some embodiments, Compound 4 forms amorphous Aβ clusters in the presence of existing toxic Aβ 1-42 and thereby reverses the toxicity of Aβ to rod cells 1-42 Reverse the toxicity of.

[0206] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA removes toxic amyloid-β deposits from the cell surface. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reduces amyloid-β deposits from the cell surface. In some embodiments, the use of Compound I, Compound IA, Compound II, or Compound IIA results in the formation of amorphous aggregates of amyloid-β along the cell surface. In some embodiments, the use of Compound I, Compound IA, Compound II, or Compound IIA results in the formation of amorphous aggregates of amyloid-β along the surface of nerve cells. In some embodiments, the use of Compound I, Compound IA, Compound II, or Compound IIA results in the formation of amorphous aggregates of amyloid-β along the surface of non-neuronal cells. In some embodiments, the use of Compound I, Compound IA, Compound II, or Compound IIA results in the formation of amorphous aggregates of amyloid-β along the surface of neurosensory cells. In some embodiments, the use of Compound I, Compound IA, Compound II, or Compound IIA results in the formation of amorphous aggregates of amyloid-β along retinal ganglion cells (RGCs). In some embodiments, the use of Compound I, Compound IA, Compound II, or Compound IIA results in the formation of amorphous aggregates of amyloid-β along retinal pigment epithelium (RPE) cells / Bruch's membrane. In some embodiments, the use of Compound I, Compound IA, Compound II, or Compound IIA results in the formation of amorphous aggregates of amyloid-β along cone cells. In some embodiments, the use of Compound I, Compound IA, Compound II, or Compound IIA results in the formation of amorphous aggregates of amyloid-β along rod cells.

[0207] In some embodiments, any one of Compounds 1-25 removes toxic amyloid-β deposits from the cell surface. In some embodiments, any one of Compounds 1-25 reduces amyloid-β deposits from the cell surface. In some embodiments, the use of any one of Compounds 1-25 results in the formation of amorphous aggregates of amyloid-β along the cell surface. In some embodiments, the use of any one of Compounds 1-25 results in the formation of amorphous aggregates of amyloid-β along the surface of nerve cells. In some embodiments, the use of any one of Compounds 1-25 results in the formation of amorphous aggregates of amyloid-β along the surface of non-neuronal cells. In some embodiments, the use of any one of Compounds 1-25 results in the formation of amorphous aggregates of amyloid-β along the surface of neurosensory cells. In some embodiments, the use of any one of Compounds 1-25 results in the formation of amorphous aggregates of amyloid-β along retinal ganglion cells (RGCs). In some embodiments, the use of any one of Compounds 1-25 results in the formation of amorphous aggregates of amyloid-β along retinal pigment epithelium (RPE) cells / Bruch's membrane. In some embodiments, the use of any one of Compounds 1-25 results in the formation of amorphous aggregates of amyloid-β along cone cells. In some embodiments, the use of any one of Compounds 1-25 results in the formation of amorphous aggregates of amyloid-β along rod cells.

[0208] In some embodiments, Compound 1 removes toxic amyloid-β deposits from the cell surface. In some embodiments, Compound 1 reduces amyloid-β deposits from the cell surface. In some embodiments, the use of Compound 1 results in the formation of amorphous aggregates of amyloid-β along the cell surface. In some embodiments, the use of Compound 1 results in the formation of amorphous aggregates of amyloid-β along the surface of nerve cells. In some embodiments, the use of Compound 1 results in the formation of amorphous aggregates of amyloid-β along the surface of non-neuronal cells. In some embodiments, the use of Compound 1 results in the formation of amorphous aggregates of amyloid-β along the surface of neurosensory cells. In some embodiments, the use of Compound 1 results in the formation of amorphous aggregates of amyloid-β along retinal ganglion cells (RGCs). In some embodiments, the use of Compound 1 results in the formation of amorphous aggregates of amyloid-β along retinal pigment epithelium (RPE) cells / Bruch's membrane. In some embodiments, the use of Compound 1 results in the formation of amorphous aggregates of amyloid-β along cone cells. In some embodiments, the use of Compound 1 results in the formation of amorphous aggregates of amyloid-β along rod cells.

[0209] In some embodiments, Compound 2 removes toxic amyloid-β deposits from the cell surface. In some embodiments, Compound 2 reduces amyloid-β deposits from the cell surface. In some embodiments, the use of Compound 2 results in the formation of amorphous aggregates of amyloid-β along the cell surface. In some embodiments, the use of Compound 2 results in the formation of amorphous aggregates of amyloid-β along the surface of nerve cells. In some embodiments, the use of Compound 2 results in the formation of amorphous aggregates of amyloid-β along the surface of non-neuronal cells. In some embodiments, the use of Compound 2 results in the formation of amorphous aggregates of amyloid-β along the surface of neurosensory cells. In some embodiments, the use of Compound 2 results in the formation of amorphous aggregates of amyloid-β along retinal ganglion cells (RGCs). In some embodiments, the use of Compound 2 results in the formation of amorphous aggregates of amyloid-β along retinal pigment epithelium (RPE) cells / Bruch's membrane. In some embodiments, the use of Compound 2 results in the formation of amorphous aggregates of amyloid-β along cone cells. In some embodiments, the use of Compound 2 results in the formation of amorphous aggregates of amyloid-β along rod cells.

[0210] In some embodiments, Compound 3 removes toxic amyloid-β deposits from the cell surface. In some embodiments, Compound 3 reduces amyloid-β deposits from the cell surface. In some embodiments, the use of Compound 3 results in the formation of amorphous aggregates of amyloid-β along the cell surface. In some embodiments, the use of Compound 3 results in the formation of amorphous aggregates of amyloid-β along the surface of nerve cells. In some embodiments, the use of Compound 3 results in the formation of amorphous aggregates of amyloid-β along the surface of non-neuronal cells. In some embodiments, the use of Compound 3 results in the formation of amorphous aggregates of amyloid-β along the surface of neuro-sensory cells. In some embodiments, the use of Compound 3 results in the formation of amorphous aggregates of amyloid-β along retinal ganglion cells (RGCs). In some embodiments, the use of Compound 3 results in the formation of amorphous aggregates of amyloid-β along retinal pigment epithelium (RPE) cells / Bruch's membrane. In some embodiments, the use of Compound 3 results in the formation of amorphous aggregates of amyloid-β along cone cells. In some embodiments, the use of Compound 3 results in the formation of amorphous aggregates of amyloid-β along rod cells.

[0211] In some embodiments, Compound 4 removes toxic amyloid-β deposits from the cell surface. In some embodiments, Compound 4 reduces amyloid-β deposits from the cell surface. In some embodiments, the use of Compound 4 results in the formation of amorphous aggregates of amyloid-β along the cell surface. In some embodiments, the use of Compound 4 results in the formation of amorphous aggregates of amyloid-β along the surface of nerve cells. In some embodiments, the use of Compound 4 results in the formation of amorphous aggregates of amyloid-β along the surface of non-neuronal cells. In some embodiments, the use of Compound 4 results in the formation of amorphous aggregates of amyloid-β along the surface of neurosensory cells. In some embodiments, the use of Compound 4 results in the formation of amorphous aggregates of amyloid-β along retinal ganglion cells (RGCs). In some embodiments, the use of Compound 4 results in the formation of amorphous aggregates of amyloid-β along retinal pigment epithelium (RPE) cells / Bruch's membrane. In some embodiments, the use of Compound 4 results in the formation of amorphous aggregates of amyloid-β along cone cells. In some embodiments, the use of Compound 4 results in the formation of amorphous aggregates of amyloid-β along rod cells.

[0212] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ 1-42 aggregates, thereby reversing the toxicity of Aβ 1-42 In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ 1-42 aggregates in vivo. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ 1-42 aggregates in neurosensory cells.

[0213] In some embodiments, any one of Compounds 1-25 reverses the toxicity of existing Aβ 1-42Reverse the inhibition of long-term potentiation (LTP) caused by aggregates, thereby reversing the toxicity of Aβ 1-42 Reverse the toxicity of Aβ. In some embodiments, any one of Compounds 1-25 reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates in vivo 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates. In some embodiments, any one of Compounds 1-25 reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates in neurosensory cells 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates. In some embodiments, the neurosensory cells include retinal ganglion cells (RGCs), retinal pigment epithelial (RPE) cells, cone cells, and rod cells

[0214] In some embodiments, Compound 1 reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates, thereby reversing the toxicity of Aβ oligomers 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates, thereby reversing the toxicity of Aβ 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates in vivo. In some embodiments, Compound 1 reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates in nerve cells, non-nerve cells, or neurosensory cells 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates. In some embodiments, Compound 1 reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates in nerve cells, non-nerve cells, or neurosensory cells 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates. In some embodiments, the nerve cells, non-nerve cells, or neurosensory cells include retinal ganglion cells (RGCs)

[0215] In some embodiments, Compound 2 reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates, thereby reversing the toxicity of Aβ oligomers 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates, thereby reversing the toxicity of Aβ 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates in vivo. In some embodiments, Compound 2 reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates in nerve cells, non-nerve cells, or neurosensory cells 1-42 Reverse the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates. In some embodiments, Compound 2 reverses the inhibition of long-term potentiation (LTP) caused by existing toxic Aβ aggregates in nerve cells, non-nerve cells, or neurosensory cells 1-42Reverses the inhibition of long-term potentiation (LTP) caused by aggregates. In some embodiments, the nerve cell, non-nerve cell, or neurosensory cell includes a retinal ganglion cell (RGC).

[0216] In some embodiments, Compound 3 1-42 Reverses the inhibition of long-term potentiation (LTP) caused by aggregates, thereby 1-42 Reversing the toxicity of Aβ oligomers. In some embodiments, Compound 3 1-42 Reverses the inhibition of long-term potentiation (LTP) caused by aggregates. In some embodiments, Compound 3 1-42 Reverses the inhibition of long-term potentiation (LTP) caused by aggregates. In some embodiments, the nerve cell, non-nerve cell, or neurosensory cell includes a retinal ganglion cell (RGC).

[0217] In some embodiments, Compound 4 1-42 Reverses the inhibition of long-term potentiation (LTP) caused by aggregates, thereby 1-42 Reversing the toxicity of Aβ oligomers. In some embodiments, Compound 4 1-42 Reverses the inhibition of long-term potentiation (LTP) caused by aggregates. In some embodiments, Compound 4 1-42 Reverses the inhibition of long-term potentiation (LTP) caused by aggregates. In some embodiments, the nerve cell, non-nerve cell, or neurosensory cell includes a retinal ganglion cell (RGC).

[0218] In some embodiments, in the methods of the present disclosure, the subject has an amyloid-β related disease or condition. One of ordinary skill in the art will understand that amyloid-β related diseases or conditions include a group of diseases in which abnormal proteins known as amyloid fibrils accumulate in tissues. For example, but not limited to, in some embodiments, amyloid-β related diseases or conditions include diseases or conditions of the eye or nervous system.

[0219] In some embodiments, amyloid-β eye diseases or conditions include primary angle-closure glaucoma, secondary open-angle glaucoma, wide-angle glaucoma, steroid-induced glaucoma, traumatic glaucoma, pigment dispersion syndrome, pseudoexfoliation syndrome, secondary angle-closure glaucoma, neovascular glaucoma, early or mid-stage dry (non-exudative) age-related macular degeneration, macular degeneration with geographic atrophy, exudative (wet) macular degeneration, diabetic retinopathy, or any combination thereof. In some embodiments, the methods of the present disclosure that reverse amyloid-β functional toxicity relatively rapidly improve visual acuity, low-luminance visual acuity, contrast sensitivity, cone contrast sensitivity, color vision, focus or general retinal light sensitivity under photopic (light adaptation) or scotopic (dark adaptation) conditions in the subject, and, indirectly, improve the subject's postural stability, walking balance, and mobility.

[0220] When the methods of use of the present disclosure are performed on subjects having all types of glaucoma, reversal of amyloid-β functional toxicity in retinal eye cells, such as retinal ganglion cells (RGCs) or retinal pigment epithelium (RPE) cells, can be measured using OCT, visual field testing, microperimetry, measurement of low-luminance visual acuity, measurement of dark adaptation, or measurement of low-luminance reading speed.

[0221] In some embodiments, the amyloid-β neurological disease or condition includes type II diabetes, diabetes, Alzheimer's disease (AD), early-onset Alzheimer's disease, late-onset Alzheimer's disease, pre-symptomatic Alzheimer's disease, SAA amyloidosis, hereditary Icelandic syndrome, multiple myeloma, myeloid cancer, aortic medial amyloidosis, insulin injection amyloidosis, prion systemic amyloidosis, chronic inflammatory amyloidosis, senile systemic amyloidosis, pituitary amyloidosis, hereditary renal amyloidosis, familial British dementia, Finnish hereditary amyloidosis, familial non-neuropathic amyloidosis, prion disease, or any combination thereof.

[0222] In some embodiments, the amyloid-β neurological disease or condition includes diabetes. In some embodiments, the amyloid-β neurological disease or condition includes type II diabetes.

[0223] When the amyloid-β neurological disease or condition includes Alzheimer's disease (AD), early-onset Alzheimer's disease, late-onset Alzheimer's disease, or pre-symptomatic Alzheimer's disease, in some embodiments, the methods of the present disclosure provide an improvement in cognitive impairment, an improvement in memory impairment, a reduction in abnormal behavior, a reduction in hallucinations, a reduction in loss of spatial awareness, a reduction in apraxia, a reduction in aggression, an improvement in the ability to perform activities of daily living, an improvement in other symptoms of dementia, or any combination thereof, in a subject.

[0224] Compound I, Compound IA, Compound II, or Compound IIA, or any one of Compounds 1 to 25, exhibits a favorable therapeutic index due to its high biological activity and low local and systemic toxicity. Therefore, for symptoms or conditions sensitive to these compounds, or symptoms or conditions described herein, to treat, alleviate, relieve, mitigate, reverse, or eliminate them, in a subject (e.g., a living mammal including a human), preferably in the form of a pharmaceutical composition, in combination with or together with one or more pharmaceutically acceptable excipients, is administered in an effective amount by oral administration, enteral administration, transdermal administration, or topical administration. In some embodiments, the compounds of the present disclosure are administered by oral administration, topical administration, or nasal administration. In some embodiments, the compounds of the present disclosure are administered by intravenous administration, subcutaneous administration, administration by an implanted sustained-release depot, direct administration using an indwelling catheter, intrathecal administration, or intraocular administration.

[0225] As used herein, the term "method" refers to a way, means, technique, and procedure for accomplishing a given task, and such includes, but is not limited to, methods, means, techniques, and procedures known to or readily derivable by experts in the fields of chemistry, pharmacology, biology, biochemistry, and medicine.

[0226] A suitable dosage range is 1 to 1000 mg per day, preferably 5 to 500 mg per day, particularly 10 to 500 mg per day, and is usually determined according to the exact administration method, administration form, the symptoms of the subject, the subject and the subject's weight, and the preference and experience of the attending physician or veterinarian. In one embodiment, the term "therapeutically effective" as applied to a dosage or dose refers to an amount of a compound or pharmaceutical composition sufficient to produce the desired activity when administered to a living body in need thereof.

[0227] In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA, or any of Compounds 1-25 used in the methods of the present disclosure, can be administered orally, nasally, topically, parenterally, or transmucosally (e.g., buccal, inhalation, or rectal) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients. In some embodiments, Compound I, Compound IA, Compound II, or Compound IIA, or any of Compounds 1-25 used in the methods of the present disclosure, can be administered intravenously, subcutaneously, by implanted sustained-release depot, by direct administration using an indwelling catheter, intrathecally, or intravitreally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients.

[0228] In some embodiments, administration is in the form of multiple administrations administered over a predetermined period, which includes a predetermined number of days, a predetermined number of weeks, a predetermined number of months, or a predetermined number of years. In some embodiments, administration is in the form of multiple administrations administered over 1 to 7 days. In some embodiments, administration is in the form of multiple administrations administered over 1 to 4 weeks. In some embodiments, administration is in the form of multiple administrations administered over 1 to 12 months. In some embodiments, administration is in the form of multiple administrations administered for up to 1 year or for several years. In some embodiments, administration is in the form of multiple administrations administered over the lifetime of the subject. In some embodiments, administration is in the form of multiple administrations continued as long as amyloid-β functional toxicity persists and is required to reverse the persistence of the toxicity. In some embodiments, administration is in the form of multiple administrations continued as long as amyloid-β functional toxicity persists and is required to reduce the toxicity.

[0229] In some embodiments, the method of use of the present disclosure involves administering a compound of the present disclosure in a predetermined pattern of dosages over a predetermined period. In some embodiments, the administration may be at regular intervals, at irregular intervals, or a combination thereof. In some embodiments, the administration is carried out at regular intervals. In some embodiments, the administration is carried out at irregular intervals. Some embodiments of intermittent interval therapy are described in detail in Patent Document 3 (International Publication WO2013 / 018960) (this patent document is hereby incorporated by reference in its entirety).

[0230] As used herein, the expression "intermittent interval administration" encompasses certain embodiments of interval administration where the second dosage is equal to a predetermined percentage (%) of the first dosage. In many cases, the second period is made longer than the first period. For example, the first period can be one day, and the second period can be one week or more or one month or more. Or, the first period can be one week, and the second period can be two weeks or more or one month or more. In many cases, the second period is made within a period of one year or less. In some embodiments, the interval or a part thereof repeats itself.

[0231] As used herein, the terms "continuous administration" or "non-interval administration" include administering a predetermined dosage regularly at equal intervals.

[0232] Examples

[0233] Example 1: Amyloid β 1-42 Test of the pharmacological properties of Compound (I) of Formula (I) in the presence of

[0234] Objective: Amyloid β 1-42 (Aβ 1-42 ) To compare the pharmacological properties of four compounds of Formula (IA) in the presence of. Specifically, for Compounds 1, 2, 3, and 4, (1) the ability to bind to Aβ 1-42 and (2) the ability to form amorphous aggregates with Aβ 1-42 ​1-42 ability to detoxify), (3) ability to reverse LTP inhibition caused by the presence of Aβ 1-42 in vitro and in vivo, and (4) ability to cause depolarization of the resting membrane potential were compared.

[0235] Method:

[0236] The method presented here is described, at least, in "Parsons, C.G., et al. (2015), MRZ - 99030 - A novel modulator of Abeta aggregation: I - Mechanism of action (MoA) underlying the potential neuroprotective treatment of Alzheimer's disease, glaucoma and age - related macular degeneration (AMD). Neuropharmacology 92: 158 - 169". It is briefly described below. MRZ - 99030 is the former code for Compound 1.

[0237] Surface plasmon resonance

[0238] Surface plasmon resonance (SPR) experiments enable the investigation of the binding of compounds to low - concentration amyloid - β 1-42 (Aβ 1-42 ) and provide the possibility of directly evaluating the affinity of such binding.

[0239] Atomic force microscopy (AFM)

[0240] AFM is one of the methods for measuring the effects of various compounds on the disappearance rate of toxic oligomer Aβ 1-42 species and the promotion of the formation of large amorphous non - toxic aggregates from Aβ 1-42 .

[0241] Dynamic light scattering (DLS)

[0242] DLS is for Aβ1-42 Another method for measuring the effect of various compounds on promoting the formation of large spherical non-toxic aggregates from

[0243] Long-Term Potentiation (LTP) In Vitro and In Vivo

[0244] Details of the method for measuring LTP are described, at least, in "Rammes, G., Gravius, A., Ruitenberg, M., Wegener, N., Chambon, C., Sroka-Saidi, K., Jeggo, R., Staniaszek, L., Spanswick, D., O'Hare, E., Palmer, P., Kim, E.M., Bywalez, W., Egger, V. and Parsons, C.G. (2015). MRZ-99030 - A novel modulator of Abeta aggregation: II - Reversal of Abeta oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice. Neuropharmacology 92: 170-182". LTP provides a criterion for evaluating synaptic activity between two neurons. MRZ-99030 is the former code of Compound 1.

[0245] Results: Table 1 below shows a comparative overview of the pharmacological properties of Compound IA of formula (IA), and Compounds 1-4 show the effect of successfully reversing or improving the symptoms of amyloid-β disease or condition. Improvement of symptoms in chronic diseases such as amyloid-β disease or condition is regarded as reversal of existing pathology or palliative treatment of symptoms.

[0246] Table 1: Overview of the pharmacological properties of Compounds 1, 2, 3, and 4

[0247] [Table 1]

[0248] The underline indicates that it is equal to or greater than Compound 1, and the double underline indicates that it is different compared to Compound 1.

[0249] Summary: The preclinical data shown in Table 1 suggest that Compounds 2, 3, and 4 may have different mechanisms of action compared to Compound 1. In addition, the activity measurements indicate that Compound 2 appears to be superior to Compound 1.

[0250] Example 2: Amyloid β in the hippocampus 1-42 Reversal of functional toxicity

[0251] Objective: To examine the effect of Compound IA of formula (IA) on the functional toxicity of amyloid β 1-42 (Aβ 1-42 ) in the brain, particularly in the hippocampus, and further in other brain regions involved in synaptic plasticity and / or learning.

[0252] Method:

[0253] Preparation of brain slices for recording field excitatory postsynaptic potential (fEPSP) and excitatory postsynaptic current (EPSC)

[0254] The experimental protocol was approved by the Ethics Committee for the Care and Use of Animals of the Bavarian State Government, Germany. Adult C57Bl / 6 mice (about 2 months old) were anesthetized with isoflurane and then decapitated to obtain sagittal slices of the hippocampus (350 mM thick). The sagittal slices of the hippocampus were immediately placed in an ice-cold Ringer's solution-composition saturated with carbogen gas (95% O2, 5% CO2; hereinafter simply referred to as carbogen) (125 mM NaCl, 2.5 mM KCl, 25 mM NaHCO3, 2 mM CaCl2, 1 mM MgCl2, 25 mM D-glucose, and 1.25 mM NaH2PO4 were bubbled with a 95% O2 / 5% CO2 mixture to obtain a final pH of 7.3). The tissue was stored in this Ringer's solution and used for all subsequent treatments. The brain was removed within 1 minute after decapitation, the cerebellum was cut off, and the remaining brain was separated into two hemispheres with a razor blade.

[0255] Transverse slices (350 μm thick) were prepared using a microtome (HM650V; Microm International, Waldorf, Germany). The slices were immersed in standard artificial cerebrospinal fluid (aCSF) at 34°C for 45 minutes and then transferred to a recording chamber. The slices were fixed to the bottom of the recording chamber using a platinum ring with a nylon filament and continuously perfused with aCSF (8 mL / min).

[0256] Recording of fEPSP

[0257] Extracellular recordings of fEPSP were performed in the CA1 radial layer of the hippocampus using a borosilicate glass micropipette (manufactured by Hugo Sachs Elektronik-Harvard Apparatus, March-Hugstetten, Germany) filled with aCSF and having an open tip resistance of 1-2 MΩ. fEPSP was induced by alternately delivering test stimuli (50 μs, 5-20 V) through one of two bipolar tungsten electrodes (manufactured by Hugo Sachs Elektronik-Harvard Apparatus, insulated to the tip; tip diameter 50 μm) placed on both sides of this recording pipette to stimulate the Schaffer collateral-commissural pathway. The stimulation frequency was 0.033 Hz per electrode.

[0258] In the baseline recording, the stimulation intensity was adjusted to a value that induced a response of approximately 25-30% of the maximum response. To enable measurement of the internal control within the same slice by taking advantage of the input specificity of long-term potentiation (LTP), both stimulation electrodes were used. 50 nM Aβ 1-42 was applied via the bath solution for 90 minutes, after which high-frequency stimulation (HFS) was performed via the first electrode to induce LTP.

[0259] After recording LTP for 60 minutes, the bath solution was exchanged with a serially diluted one (see the protocol below). This solution still contained 50 nM Aβ 1-42 but only 0.1 nM of compound 1 or compound 2. After further incubating the slice for 90 minutes, an attempt was made to induce LTP in the second input, followed by recording for an additional 60 minutes.

[0260] As a result of the control experiment, it was confirmed that the degree of LTP did not depend on the time the slice was placed in the chamber, at least not on the maximum duration of up to 5 hours used in this experiment. Recordings were made using a laboratory interface board (ITC-16, Instrutech Corp, New York, USA) and "LTP Program" software ("Anderson and Collingridge (2001) The LTP Program: a data acquisition program for on-line analysis of long-term potentiation and other synaptic events. Journal of Neuroscience Methods 108, 71-83, available from http: / / www / ltp-program.com.") for amplification, filtering (3 kHz), and digitization (9 kHz). Stimuli were applied alternately to each input. The two signals for each input were averaged into one and analyzed once per minute. The data were reanalyzed offline using the analysis program Igor Pro v6.1 (Wavemetrics, Lake Oswego, Oregon, USA) software. The slope of the fEPSP was measured between 20% and 80% of the peak amplitude. The slope of the fEPSPs was normalized to the 30-minute control period before tetanus stimulation.

[0261] Amyloid β 1-42 (Aβ 1-42 ) Preparation

[0262] Aβ 1-42 (Order number H-1368; Bachem, CH-Bubendorf) was suspended in 100% hexafluoroisopropanol (HFIP) (Sigma Aldrich), dispensed into 50 μg aliquots, then the HFIP was removed using a Speedvac for approximately 30 minutes and dried completely, and the peptide was stored at -20°C. Aβ 1-42 was dissolved in dry DMSO (Sigma Aldrich) and brought to a concentration of 100 μM using an ultrasonic water bath. This solution was further diluted with Ringer's solution.

[0263] The prion-like seeding hypothesis and the reversal of existing Aβ induction deficiency in LTP 1-42 To test the reversal of the induction deficiency, serial dilutions of compound 1 (1 μM) or compound 2 (1 μM) were started from a stoichiometric excess with a ratio of 20:1 to 50 nM Aβ 1-42 The compound mixture of Aβ 1-42 / compound 1 or compound 2 was incubated for 20 minutes, and then the mixture was transferred to a prepared solution containing Aβ 1-42 This dilution step was repeated 5 times, and finally, the stoichiometric excess of Aβ 1-42 to compound 1 or compound 2 was made to be 500:1. Then, the final solution (containing only 0.1 nM of compound 1 or compound 2 and still containing 50 nM of Aβ 1-42 was tested for its ability to reverse the deficiency of long-term potentiation (LTP) in hippocampal slices. Figure 6 is a schematic diagram of one embodiment of the serial dilution step.

[0264] All experiments were carried out at room temperature.

[0265] Results: When hippocampal slices were pre-incubated with 50 nM αβ aggregated under serial dilution conditions without using compound 1 or compound 2, strong inhibition of LTP occurred (black circles in Figures 2A and 3A). Surprisingly, this inhibition of LTP was reversed by adding 50 nM of αβ aggregated after "seeding" with compound 1 or compound 2 under serial dilution conditions (starting concentration of compound 1 or compound 2 = 1 μM, final concentration of compound 1 or compound 2 = 0.1 nM) in the same hippocampal slices. The measurement results of the percent difference between LTP recordings are shown in Figures 2B and 3B, comparing the percent of LTP in the last 10 minutes of the recordings of αβ alone or αβ 1-42 and compound 1 or compound 2. A significant detoxifying effect (reversal of LTP activity) was observed in the presence of the compound of formula X or formula Y. 1-42 50 nM was added. 1-42 alone, or subsequent 1-42 comparing the percent of LTP from the last 10 minutes of the recordings of αβ and compound 1 or compound 2. A significant detoxifying effect (reversal of LTP activity) was observed in the presence of the compound of formula X or formula Y.

[0266] These results show the reversal of the toxic effects of αβ on fEPSP and the corresponding nerve recovery caused by the administration of Compound 1 or Compound 2. Therefore, Compound 1 and Compound 2 have the ability to reverse the existing deficits in neuroplasticity caused by Aβ. A novel aspect of these data is that they do not simply prevent these Aβ-induced deficits, but rather actually reverse them. In some embodiments, Compound 1 or Compound 2 restores neurological deficits induced by Aβ. Furthermore, LTP is also a functional and electrophysiological model of synaptic plasticity that underlies memory formation and learning. The reversal of the toxic effects observed here is an indicator of the possibility of reversing memory loss or improving learning achieved by the use of Compound 1 or Compound 2. 1-42 These results show the reversal of the toxic effects of αβ on fEPSP and the corresponding nerve recovery caused by the administration of Compound 1 or Compound 2. Therefore, Compound 1 and Compound 2 have the ability to reverse the existing deficits in neuroplasticity caused by Aβ. A novel aspect of these data is that they do not simply prevent these Aβ-induced deficits, but rather actually reverse them. In some embodiments, Compound 1 or Compound 2 restores neurological deficits induced by Aβ. Furthermore, LTP is also a functional and electrophysiological model of synaptic plasticity that underlies memory formation and learning. The reversal of the toxic effects observed here is an indicator of the possibility of reversing memory loss or improving learning achieved by the use of Compound 1 or Compound 2.

[0267] Conclusion: The reversal of the toxic effects was surprising and unexpected. These compounds are designed to bind to misfolded Aβ monomers and prevent them from adopting the β-sheet structure that normally promotes aggregation. The reversal of the toxicity of ongoing Aβ oligomers indicates that these compounds can further reverse the toxicity even after these oligomers have formed. In other words, the compounds of formula (I), such as Compound 1 and Compound 2, are not classical β-sheet breakers. Furthermore, the degree of reversal of the reaction was unexpectedly large and, for example, could even return to the control level.

[0268] Example 3: Reduction of Toxic Aβ by Compound IA of Formula (IA) in the Retina of a Glaucoma Mouse Model 1-42 in the retina of a glaucoma mouse model

[0269] Objective: To examine the effect of a compound of formula (IA), such as Compound 1, Compound 2, Compound 3, or Compound 4, on amyloid β 1-42 (Aβ 1-42 ) deposits in the retina of a glaucoma mouse model.

[0270] Method: Using the Morrison rat model of glaucoma, an in vivo rat model of glaucoma, Aβ was administered along the retina in the region of the optic nerve fiber layer.1-42 examined the reversal of the ongoing pathological process in which [substance] accumulates. Figures 4A and 4B are representative images showing the increase in amyloid-β in the retina of human patients (Figure 4A) and its localization by immunostaining (Figure 4B) relative to the control. A similar distribution pattern is expected to be observed in the retina of the Morrison rat model.

[0271] Compounds of formula (IA), such as Compound 1, Compound 2, Compound 3, or Compound 4, were administered to the Morrison rat model, for example, in the form of eye drops and / or intravitreal injection. The starting concentration of Compound 1, Compound 2, Compound 3, or Compound 4 in the eye drops was 0.5% or 2.0%, and the control eye drops consisted of vehicle only.

[0272] Results: As expected, the results show the reversal of the pathology present along the retina and optic nerve fiber layer of the glaucomatous eyes of Morrison model rats compared to the control.

[0273] Example 4: Reduction of Toxic Aβ by Compound 1 and Complement Component C3b in the Retina of an Age-Related Macular Degeneration (AMD) Mouse Model 1-42 and complement component C3b in the retina of an age-related macular degeneration (AMD) mouse model

[0274] Objective: To examine the effect of Compound 1 on the accumulated amyloid-β 1-42 (Aβ 1-42 ) deposits in age-related macular degeneration (AMD).

[0275] Method: Using C57BL / 6 (C57) mice, an in vivo mouse model of age-related macular degeneration, the reversal of the ongoing pathological process in which Aβ 1-42 accumulates along the retina (retinal pigment epithelium (RPE) cell layer / Bruch's membrane) in the optic nerve fiber layer region was examined.

[0276] In 5- to 6-month-old AMD mice treated three times a day for 3 months, Aβ 1-42The retinal expression (photoreceptor layer) was analyzed. Treatment method: Eye drops containing only vehicle, 0.5% of Compound 1, or 2.0% of Compound 1 were administered. In 24-month-old C57BL / 6 (C57) mice with a large amount of amyloid-β deposited along the retinal pigment epithelium (RPE) cells / Bruch's membrane, toxic Aβ in the retina 1-42 The reduction of deposits and complement component C3b was analyzed. Mice were treated with 0.5% of Compound 1 or 2.0% of Compound 1 three times a day for one month. For immunostaining, the enucleated eyeballs (n = 10 for each group) were left standing in 4% paraformaldehyde in phosphate-buffered saline (PBS) at pH 7.4 for 1 hour, cryopreserved in 30% sucrose in PBS, and embedded in OCT compound (Agar Scientific Ltd). The antibodies used were a mouse monoclonal antibody against amyloid-β (Aβ) 4G8 conjugated with Alexa Fluor 568, a goat polyclonal antibody against complement C3, and a mouse monoclonal antibody against amyloid-β (Aβ) 12F4 conjugated with Alexa Fluor 568.

[0277] Results: Aβ 1-42 The mice used in both experiments to analyze the retinal expression and localization of Aβ already had pathological changes in the retina before the start of treatment. Figure 5A: Only vehicle shows significantly higher Aβ 1-42 measurement values at the start point compared to after administration of the eye drops containing Compound 1. Figure 5B: The bottom microscope photographs on the left and right show a large amount of Aβ (red fluorescence) deposited along the retinal pigment epithelium (RPE) cells / Bruch's membrane. When the eye drops containing Compound 1 were administered, the total amount of toxic Aβ 1-42 expression along Bruch's membrane (BM) decreased. In mice treated at a high dose, aggregated (non-toxic) amyloid-β (the part surrounded by a circle) was seen, while in mice treated with vehicle, the Aβ distribution remained thick and linear.

[0278] Conclusion: The reversal of the pathological states in these animals was surprising and unexpected for various reasons. These compounds are designed to bind to misfolded Aβ monomers and prevent them from adopting the β-sheet structure that normally promotes aggregation. The reversal of ongoing Aβ oligomer toxicity indicates that the compounds of formula (I), such as compound 1, can further reverse the toxicity even after the formation of these oligomers, i.e., this compound is not a classical β-sheet breaker. Furthermore, the degree of the effect was unexpectedly large.

[0279] In this specification, specific features of the invention have been illustrated and described, but various modifications, substitutions, changes, and equivalents will be apparent to those skilled in the art. Accordingly, it is to be understood that the appended claims are intended to embrace all such modifications and changes as fall within the scope of the gist of the invention.

Claims

1. A composition for use in reversing amyloid-β toxicity in a subject in need of treatment, rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, reversing the progression of amyloid-related diseases or disorders in said subject, and improving the symptoms of said amyloid-related diseases or disorders, comprising: Compound 1 represented by the following formula, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, in a pharmaceutically effective amount; Said composition, wherein said amyloid-related diseases or disorders include eye diseases or conditions.

2. The composition according to claim 1, wherein: Said rapid improvement in the function of said neurons, said non-neuronal cells, said neurosensory cells, or any combination thereof: Comprises rapid restoration of impaired neuronal function or reduction of cell death in said neurons, said non-neuronal cells, said neurosensory cells, or any combination thereof.

3. A composition for use in reversing amyloid-β toxicity in a subject in need of treatment, rapidly improving the function of neurons, non-neuronal cells, neurosensory cells, or any combination thereof, reversing the progression of amyloid-related diseases or disorders in said subject, and improving the symptoms of said amyloid-related diseases or disorders, comprising: Non-toxic non-β-sheet amorphous amyloid-β clusters in a pharmaceutically effective amount; The non-toxic non-β-sheet amorphous amyloid-β cluster comprises amyloid-β １－４２ and Compound 1 according to Claim 1, Said composition, wherein said amyloid-related diseases or disorders include eye diseases or conditions.

4. The composition according to claim 3, wherein: Said rapid improvement in the function of said neurons, said non-neuronal cells, said neurosensory cells, or any combination thereof: Comprises rapid restoration of impaired neuronal function or reduction of cell death in said neurons, said non-neuronal cells, said neurosensory cells, or any combination thereof.

5. The composition according to any one of claims 1 to 4, wherein: Said neurons, said non-neuronal cells, or said neurosensory cells include retinal ganglion cells (RGCs), retinal pigment epithelial (RPE) cells, photoreceptor cells including rod and cone cells, hippocampal cells, cortical cells, or any combination thereof.

6. The composition according to any one of claims 1 to 5, wherein: Said amyloid-related diseases or disorders include amyloid-β related diseases.

7. The composition according to claim 6, wherein: The eye disease or condition includes primary closed-angle glaucoma, secondary open-angle glaucoma, wide-angle glaucoma, steroid-induced glaucoma, traumatic glaucoma, pigment dispersion syndrome, pseudoexfoliation syndrome, secondary closed-angle glaucoma, neovascular glaucoma, early or intermediate dry (non-exudative) age-related macular degeneration, macular degeneration with geographic atrophy, exudative (wet) macular degeneration, diabetic retinopathy, or any combination thereof, the composition.

8. The composition according to claim 7, The function that is rapidly improved in the nerve cells, non-nerve cells, neurosensory cells, or any combination thereof is The composition includes visual functions in the subject, including visual acuity, low-luminance visual acuity, contrast sensitivity, cone contrast sensitivity, color vision, and focus or general retinal light sensitivity under photopic (light adaptation) or scotopic (dark adaptation) conditions.

9. The composition according to any one of claims 1 to 8, The composition is administered by oral administration, topical administration, nasal administration, intravenous administration, subcutaneous administration, administration by an implanted sustained-release depot, direct administration using an indwelling catheter, intrathecal administration, or intraocular administration.

10. The composition according to any one of claims 1 to 9, The administration to the subject is performed in the form of multiple administrations administered over a predetermined period, The period includes a predetermined number of days, a predetermined number of weeks, a predetermined number of months, a predetermined number of years, or the lifespan of the subject, Optionally, the administration pattern during the period includes administration at regular intervals, administration at irregular intervals, or a combination of administration at regular intervals and administration at irregular intervals.

11. The composition according to claim 10, The dose for each of the multiple administrations includes 100% or more of the pharmaceutically effective amount, 75 to 100% of the pharmaceutically effective amount, 20 to 75% of the pharmaceutically effective amount, or any combination thereof.

12. The composition according to claim 3, The compound 1 and the non-toxic non-β-sheet amorphous amyloid-β cluster are included in a pharmaceutically acceptable composition.

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