Relatively small amount supply of amyloid beta aggregation inhibitor for the purpose of improving detoxification effect

Abstract

Provided herein is a method for treating or preventing abnormal protein folding and deposition in a subject by administering a low dose of compound (1) to the subject. Also provided herein is a method for counteracting or preventing the toxic effects of abnormally folded and aggregated protein amyloid beta by using a relatively undersupplied amount (inverse stoichiometric ratio) of compound (1) in order to achieve a more potent detoxifying effect. Also provided are its dosage forms and administration.

Description

Background Art

[0001] Most protein molecules need to be folded into a defined three-dimensional structure in order to acquire functional activity. However, a protein chain can assume a number of conformational states, and its biologically active conformation is often only marginally stable. Proteins in conformational states that do not support their physiological function are described as "misfolded." Aggregation and accumulation of misfolded proteins can cause disease; this is a phenomenon that increases dramatically with aging. The mechanistic explanation for this correlation is that as humans age (or as a result of mutations), the delicate balance of protein synthesis, folding, and degradation can become destabilized, resulting in the production and accumulation of misfolded proteins that form aggregates and induce a pathological state. Protein aggregation diseases can occur not only in the central nervous system but also in peripheral tissues.

[0002] One of the most common protein misfolding diseases is Alzheimer's disease, which is associated with the misfolding of the protein amyloid beta. Abnormally folded amyloid beta has a tendency to aggregate and form oligomeric species, which are known to be highly toxic to nerve cells and cause neurodegeneration.

[0003] This amyloid beta-related pathology is not limited to different types of Alzheimer's disease but is also observed in the following diseases: Type II diabetes, serum amyloid A disease (SAA amyloidosis), hereditary Icelandic syndrome, multiple myeloma, medullary carcinoma, aortic amyloidosis, cardiac amyloidosis, insulin injection site amyloidosis, prion systemic amyloidosis, chronic inflammatory amyloidosis, age-related systemic amyloidosis, pituitary amyloidosis, hereditary renal amyloidosis, familial British dementia, hereditary Finnish amyloidosis, familial non-neuropathic amyloidosis, amyloid beta-related eye diseases, particularly glaucoma and age-related macular degeneration, and other diseases.

[0004] The formation of pathological aggregates of abnormally folded proteins has been shown to be a promising target as a novel therapeutic approach that has the potential to slow down or halt the neurodegenerative process. In particular, soluble toxic amyloid-beta oligomers have recently been shown to be a promising drug target in Alzheimer's disease in the first novel therapies to succeed in clinical development, and the target of two recently approved drugs (aducanumab and lecanemab) for the treatment of Alzheimer's disease.

[0005] Despite the initial success of these novel drug developments targeting toxic amyloid-beta oligomers and protofibrils using antibody-based infusions, their beneficial effects on the progression of Alzheimer's disease remain limited, and there is a high demand for more efficient, better tolerated, easier to administer, and less expensive drug production. SUMMARY OF THE INVENTION

[0006] In some aspects, a method of treating or preventing abnormal protein folding and deposition in a subject in need thereof, the method comprising administering to the subject a low dose of a compound (1):

Chemical formula

[0007] ​In some related scenarios, as a result of the low-dose administration, the concentration at the site of action in the brain is less than 50 nM. In some related scenarios, as a result of the low-dose administration, the concentration at the site of action in the brain is 10 nM. In some related scenarios, as a result of the low-dose administration, the concentration at the site of action in the brain is 3 nM. In some related scenarios, as a result of the low-dose administration, the concentration at the site of action in the brain is 1 nM.

[0008] In some related scenarios, the abnormal folding and deposition of the protein are associated with diseases related to amyloid-beta pathology, namely, Alzheimer's disease (AD), early Alzheimer's disease, late-onset Alzheimer's disease, preclinical Alzheimer's disease, type II diabetes, serum amyloid A disease (SAA amyloidosis), hereditary Icelandic syndrome, multiple myeloma, medullary carcinoma, aortic amyloidosis, cardiac amyloidosis, insulin injection site amyloidosis, prion systemic amyloidosis, chronic inflammatory amyloidosis, age-related systemic amyloidosis, pituitary amyloidosis, hereditary renal amyloidosis, and familial non-neuropathic amyloidosis.

[0009] In some related scenarios, the abnormal folding and deposition of the protein include amyloid-related diseases. In one scenario, the amyloid-related diseases include Alzheimer's disease (AD), early Alzheimer's disease, late-onset Alzheimer's disease, preclinical Alzheimer's disease, or any combination thereof. In one scenario, the amyloid-related disease is Alzheimer's disease (AD).

[0010] In some related aspects, the abnormal folding and deposition of the protein are selected from, but not limited to, Parkinson's disease and related synucleinopathies, Huntington's disease, prion diseases, mad cow disease, Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, frontotemporal dementia spectrum disorder, amyotrophic lateral sclerosis, familial British dementia and Danish dementia, hereditary Finnish amyloidosis, familial non-neuropathic amyloidosis, and retinitis pigmentosa.

[0011] In some related aspects, the administration of compound (1) is systemic administration, using oral administration, rectal administration, transmucosal administration, intranasal administration, intramuscular administration, subcutaneous administration, transdermal administration, subarachnoid administration, direct intraventricular administration, intravenous administration, intraperitoneal administration, or intranasal instillation.

[0012] In some related aspects, the administration is oral administration.

[0013] In some further related aspects, the oral administration includes a dosage in the range of 0.03 to 0.3 mg / kg with respect to compound (1).

[0014] In some further related aspects, the intravenous administration includes a dosage in the range of 0.01 to 0.1 mg / kg with respect to compound (1).

[0015] In some further aspects, the amyloid-related disease is selected from neurodegenerative retinal diseases, particularly glaucoma or age-related macular degeneration (AMD). In some aspects, glaucoma is selected from the group consisting of primary angle-closure glaucoma, open-angle glaucoma (both primary and secondary), wide-angle glaucoma, steroid glaucoma, traumatic glaucoma, secondary angle-closure glaucoma, and neovascular glaucoma. In some aspects, the age-related macular degeneration (AMD) is selected from the group consisting of dry and wet AMD (including geographic atrophy (GA) secondary to AMD).

[0016] In some further aspects, the amyloid-related disease is selected from diabetic retinopathy. In some further aspects, the diabetic retinopathy is non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, or a combination thereof.

[0017] In some aspects, the administration is intravitreal administration.

[0018] In some aspects, the intravitreal administration includes administration by eye drops, eye cream, eye ointment, eye spray, administration by intravitreal depot formulation, intravitreal injection, injection including intravitreal or periocular injection, and includes intravitreal fluid, depot formulation, solid and semi-solid intravitreal carriers and matrices, or intravitreal devices (such as contact lenses and films).

[0019] In some aspects, the topical intravitreal administration includes eye drops containing less than 1 mg of compound (1) per drop. In some further aspects, the intravitreal administration includes a dose of less than 3 mg of compound (1) per drop.

[0020] In some aspects, the method includes administering an initial loading dose of compound (1) to the subject, and then further administering a plurality of maintenance doses of the compound. In some aspects, the subsequent maintenance doses are low doses of compound (1).

[0021] In some aspects, after administering the compound to the subject daily for a first period consisting of at least 1 day, a second period of at least 1 week during which the compound is not administered follows, and then a first period consisting of at least 1 day during which the compound is administered to the subject daily is repeated.

[0022] In some aspects, compound (1) is an active ingredient of a pharmaceutical composition, and the pharmaceutical composition also includes a physiologically acceptable carrier. In some further aspects, the pharmaceutical composition is suitable for oral administration. In some further aspects, the pharmaceutical composition is suitable for intravitreal administration.

[0023] In some aspects, the present disclosure provides methods for inhibiting amyloid beta Aβ toxicity in a subject, the method comprising administering a compound (1):

Chemical formula

[0024] In some aspects, the present disclosure provides methods for counteracting or preventing the toxic effects of abnormally folded and aggregated protein amyloid beta, i.e., toxic Aβ oligomers, by using a relatively substoichiometric amount (inverse stoichiometric ratio) of compound (1) to achieve a more potent detoxifying effect.

[0025] The subject matter regarded as the invention is particularly pointed out and distinctly claimed at the end of the specification. However, the best understanding of the invention will be obtained by reference to the following detailed description when considered in conjunction with the accompanying drawings, both as to the organization and method of implementation, together with the objects, features, and advantages thereof.

Brief Description of the Drawings

[0026]

Figure 1

Figure 2

Figure 3

Figure 4A

Figure 4B

[0027] It should be understood that, in emphasizing the simplicity and clarity of the specific examples, the elements shown in the figures are not necessarily to scale. For example, for the sake of clarity, the scale of some elements may be exaggerated compared to other elements. Further, where appropriate, reference values may be repeatedly shown in figures showing corresponding or similar elements.

DETAILED DESCRIPTION OF THE INVENTION

[0028] To fully understand the present invention, the following detailed description shows numerous specific details. However, those skilled in the art will understand that the present invention can be practiced without these specific details. In other instances, well-known methods, means, and elements have not been described in detail so as not to obscure the present invention.

[0029] Unless otherwise specifically defined herein, scientific and technical terms used in connection with the present application have the meanings commonly understood by those skilled in the art. Further, unless the context otherwise indicates, singular terms include the plural, and plural terms include the singular.

[0030] Those skilled in the art will understand that the term "comprising" includes the inclusion of the recited elements, but does not exclude optional other elements.

[0031] When referring to a range of values, those skilled in the art will understand that in another embodiment, one limit value and / or the other limit value of the range may be included. Further, all ranges are inclusive and combinable.

[0032] Treatment method The inventors have surprisingly discovered that, in contrast to the known hypothesis that multiple molecules of an amyloid aggregation inhibitor are required to inhibit one amyloid-beta molecule, in the case of compound (1), its stoichiometry is exactly the opposite. Regarding the structurally related conventional compound GAL-101 (MRZ-99030), which was previously the best among amyloid-beta aggregation inhibitors, it has been revealed that at least 10 molecules of GAL-101 are required to inhibit one amyloid-beta molecule (stoichiometric quantity ratio = 10:1). For other similar compounds such as ALZ-801 and PRI-002, hundreds or thousands of detoxifying compounds are required to inhibit the toxicity caused by one amyloid-beta molecule (the stoichiometric quantity ratio is in the range of approximately 100:1 to 5000:1). The inventors of the present disclosure have discovered that one molecule of compound (1) can inhibit 10 molecules (!) of amyloid-beta (stoichiometric quantity ratio 1:10), or even more molecules. Table 1 shows an overview of the detoxifying effect of a 10-fold sub-stoichiometric amount of compound (1) (stoichiometric quantity ratio = 1:10), which is more than twice as potent as when used in a stoichiometric excess. The clinical significance of this unexpected and astonishing phenomenon is that it is possible to reduce the dose of compound (1) by 90%, and even by 99%, in order to achieve the desired clinical effect.

[0033] In some embodiments, a method of treating or preventing abnormal protein folding and deposition disorders in a subject in need thereof, comprising administering to the subject a low dose of compound (1):

Chemical formula

[0034] In one embodiment, the term "treatment" refers to any process, action, application, therapy, etc. that medically supports a subject for the purpose of directly or indirectly improving the medical condition of the subject, including humans. In another embodiment, the term "treating" refers to reducing the incidence rate, or alleviating symptoms, preventing recurrence, preventing relapse, preventing onset, improving symptoms, improving prognosis, or in other embodiments, a combination thereof.

[0035] In another embodiment, "Treating" includes improving an existing medical condition. As a result of treatment, it will be understood by those skilled in the art that the symptoms will not necessarily be completely eliminated or completely removed. Treatment also includes a temporary alleviating effect, which reduces the likelihood of subsequent medical conditions. Alleviation of symptoms that cause more severe medical conditions is also included in this term.

[0036] In one embodiment, "preventing" may include, inter alia, delaying the onset of symptoms, preventing recurrence of the disease, reducing the number and frequency of symptom recurrences, extending the latency period between symptomatic symptoms, or a combination thereof.

[0037] Of the proteins that continue to increase, one protein (an amyloid-forming protein in its native conformational state, also called an amyloid-forming precursor) acquires another folded state (abnormally folded state), aggregates and begins to form oligomers, and then forms protofilaments and ultimately a fibril structure (called amyloid fibrils, which ultimately deposit in tissues). It will be understood by those skilled in the art that "protein misfolding and deposition disease" occurs. Protein misfolding is considered to be the first step in the pathology of Alzheimer's disease, Creutzfeldt-Jakob disease, and other degenerative and neurodegenerative disorders.

[0038] In some embodiments, a method of inhibiting Aβ toxicity in a subject, the method comprising administering a low dose of compound (1):

Chemical formula

[0039] In one embodiment, in an organism, low-dose administration that results in a high undersupply ratio between compound (1) and amyloid-beta causes the concentration of compound (1) at the site of action, typically in the brain or retina, to be less than 50 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be less than 40 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be less than 30 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be less than 20 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be less than 10 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be less than 5 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be less than 5 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be less than 3 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be less than 1 nM.

[0040] In one embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 50 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 40 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 30 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 20 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 10 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 5 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 5 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 3 nM. In another embodiment, the low-dose administration causes the concentration of compound (1) at the site of action to be 1 nM.

[0041] One skilled in the art would understand that the term "site of action" refers to the human body part where the disease state occurs. In one embodiment where the site of action of the disease is the brain, the active concentration of compound (1) in the brain can be measured, for example, in cerebrospinal fluid (CSF) obtained from a human by lumbar puncture in a dose determination test of a Phase I clinical trial. The target oral dose of compound (1) is the dose corresponding to a concentration of 10 nM in CSF.

[0042] In some embodiments, the administration is oral administration.

[0043] In some embodiments where the administration is oral administration, the low dose includes that compound (1) is 10 mg or less. In one embodiment where the administration is oral administration, the low dose includes that compound (1) is 10 mg. In another embodiment where the administration is oral administration, the low dose includes that compound (1) is 9.0 mg. In another embodiment where the administration is oral administration, the low dose includes that compound (1) is 8.0 mg. In another embodiment where the administration is oral administration, the low dose includes that compound (1) is 7.0 mg. In another embodiment where the administration is oral administration, the low dose includes that compound (1) is 6.0 mg. In another embodiment where the administration is oral administration, the low dose includes that compound (1) is 5.0 mg. In another embodiment where the administration is oral administration, the low dose includes that compound (1) is 4.0 mg. In another embodiment where the administration is oral administration, the low dose includes that compound (1) is 3.0 mg.

[0044] In some embodiments, the administration is intravenous (IV) administration.

[0045] In some embodiments where the administration is intravenous administration, the low dose includes that the compound (1) is 3 mg or less. In one embodiment where the administration is intravenous administration, the low dose includes that the compound (1) is 3 mg. In another embodiment where the administration is intravenous administration, the low dose includes that the compound (1) is 2.5 mg. In another embodiment where the administration is intravenous administration, the low dose includes that the compound (1) is 2.0 mg. In another embodiment where the administration is intravenous administration, the low dose includes that the compound (1) is 1.5 mg. In another embodiment where the administration is intravenous administration, the low dose includes that the compound (1) is 1.0 mg.

[0046] In some embodiments, a method is disclosed herein for counteracting or preventing the toxic effects of abnormally folded and aggregated protein amyloid beta, i.e., toxic Aβ oligomers, by using a relatively substoichiometric amount (antistochiometric ratio) of compound (1) to achieve a more potent detoxifying effect.

[0047] Compound (1) Compound (1), known as GAL-201 (previously also known as MRZ-14042), is a unique small molecule having the following IUPAC name: (2R)-2-amino-N-(1-carbamoyl-1-methylethyl)-3-(1H-indol-3-yl)propanamide. The molecular chemical formula of its free base is: C 15 H 20 N 4 O 2 and its molecular weight is 288.34 g / mol.

[0048] Compound (1) has the following chemical formula:

Chemical formula

[0049] Protein misfolding and deposition diseases In some embodiments, the present disclosure relates to methods of treating or preventing protein misfolding and deposition diseases in a subject in need thereof. In some embodiments, the protein misfolding and deposition diseases are related to the misfolding and deposition of amyloid beta. In some embodiments, amyloid beta includes Aβ 1-42 , Aβ 1-40 , Aβ p3-42 , its derivatives, or any combination thereof.

[0050] In some embodiments, the protein misfolding and deposition diseases are diseases related to the pathology of amyloid beta, namely, Alzheimer's disease (AD), early Alzheimer's disease, late-onset Alzheimer's disease, preclinical Alzheimer's disease, type II diabetes, serum amyloid A disease (SAA amyloidosis), hereditary Icelandic syndrome, multiple myeloma, medullary carcinoma, aortic amyloidosis, cardiac amyloidosis, insulin injection site amyloidosis, prion systemic amyloidosis, chronic inflammatory amyloidosis, age-related systemic amyloidosis, pituitary amyloidosis, hereditary renal amyloidosis, and familial non-neuropathic amyloidosis.

[0051] In one embodiment, the abnormal folding and deposition of the protein include Alzheimer's disease (AD). In another embodiment, the abnormal folding and deposition of the protein include early Alzheimer's disease. In another embodiment, the abnormal folding and deposition of the protein include late-onset Alzheimer's disease. In another embodiment, the abnormal folding and deposition of the protein include preclinical Alzheimer's disease. In another embodiment, the abnormal folding and deposition of the protein include type II diabetes. In another embodiment, the abnormal folding and deposition of the protein include serum amyloid A disease (SAA amyloidosis). In another embodiment, the abnormal folding and deposition of the protein include hereditary Icelandic syndrome. In another embodiment, the abnormal folding and deposition of the protein include insulin injection site amyloidosis.

[0052] In another embodiment, the abnormal folding and deposition of the protein include multiple myeloma. In another embodiment, the abnormal folding and deposition of the protein include medullary carcinoma. In another embodiment, the abnormal folding and deposition of the protein include aortic amyloidosis. In another embodiment, the abnormal folding and deposition of the protein include cardiac amyloidosis. In another embodiment, the abnormal folding and deposition of the protein include insulin injection site amyloidosis. In another embodiment, the abnormal folding and deposition of the protein include prion systemic amyloidosis. In another embodiment, the abnormal folding and deposition of the protein include chronic inflammatory amyloidosis. In another embodiment, the abnormal folding and deposition of the protein include age-related systemic amyloidosis. In another embodiment, the abnormal folding and deposition of the protein include pituitary amyloidosis.

[0053] In another embodiment, the abnormal folding and deposition of the protein include hereditary renal amyloidosis. In another embodiment, the abnormal folding and deposition of the protein include familial non-neuropathic amyloidosis.

[0054] In another embodiment, the abnormal folding and deposition of the protein include Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, prion disease or mad cow disease. In another embodiment, the abnormal folding and deposition of the protein include Parkinson's disease. In another embodiment, the abnormal folding and deposition of the protein include Huntington's disease. In another embodiment, the abnormal folding and deposition of the protein include Creutzfeldt-Jakob disease. In another embodiment, the abnormal folding and deposition of the protein include prion disease. In another embodiment, the abnormal folding and deposition of the protein include mad cow disease.

[0055] In another embodiment, the abnormal folding and deposition of the protein include amyloid-related eye diseases and disorders. In another embodiment, the abnormal folding and deposition of the protein include prion disease.

[0056] In another embodiment, the abnormal folding and deposition of the protein include amyloid-related diseases.

[0057] Those skilled in the art will understand that "amyloid-related diseases" are conditions characterized by the accumulation and deposition of amyloid proteins in specific tissues of the body and the associated functional deficits of the respective organs.

[0058] In one embodiment where the amyloid-related disease includes Alzheimer's disease (AD), early Alzheimer's disease, late-onset Alzheimer's disease, preclinical Alzheimer's disease, or any combination thereof, treating or preventing may include improving cognitive impairment, improving memory loss, reducing abnormal behavior, reducing hallucination symptoms, reducing loss of spatial orientation, reducing apraxia, reducing aggression, improving the ability to perform activities of daily living, improving other symptoms of dementia, or any combination thereof. In another embodiment, treating or preventing includes improving cognitive impairment. In another embodiment, treating or preventing includes improving memory loss. In another embodiment, treating or preventing includes reducing abnormal behavior. In another embodiment, treating or preventing includes reducing hallucination symptoms. In another embodiment, treating or preventing includes reducing loss of spatial orientation. In another embodiment, treating or preventing includes reducing apraxia. In another embodiment, treating or preventing includes reducing aggression. In another embodiment, treating or preventing includes improving the ability to perform activities of daily living. In another embodiment, treating or preventing includes improving other symptoms of dementia.

[0059] In another embodiment, the amyloid-related disease includes glaucoma or age-related macular degeneration (AMD). In another embodiment, the amyloid-related disease includes glaucoma. In another embodiment, the amyloid-related disease includes age-related macular degeneration (AMD). In another embodiment, the amyloid-related disease includes geographic atrophy (GA) secondary to AMD.

[0060] One of ordinary skill in the art will understand that glaucoma is a group of eye diseases that damage the optic nerve (or retina) and cause blindness. Risk factors for glaucoma include aging, high intraocular pressure, a family history of glaucoma, and the use of steroid medications.

[0061] In one embodiment, the glaucoma is selected from the group consisting of primary angle-closure glaucoma, open-angle glaucoma (both primary and secondary), wide-angle glaucoma, steroid glaucoma, traumatic glaucoma, secondary angle-closure glaucoma, and neovascular glaucoma.

[0062] In another embodiment, the glaucoma includes primary angle-closure glaucoma. In another embodiment, the glaucoma includes secondary open-angle glaucoma. In another embodiment, the glaucoma includes primary open-angle glaucoma. In another embodiment, the glaucoma includes wide-angle glaucoma. In another embodiment, the glaucoma includes steroid glaucoma. In another embodiment, the glaucoma includes traumatic glaucoma. In another embodiment, the glaucoma includes secondary angle-closure glaucoma. In another embodiment, the glaucoma includes neovascular glaucoma.

[0063] Those skilled in the art will understand that age-related macular degeneration (AMD) is a condition that can cause blurred vision or vision loss at the center of the visual field. It is often asymptomatic in the early stages. However, in some people, it experiences a gradual deterioration of vision that can occur in one or both eyes over time. Although it does not lead to complete blindness, the loss of central vision can make it difficult to recognize faces, drive, read, or perform other activities of daily life. Hallucinations may also occur, but they do not indicate a mental disorder.

[0064] In one embodiment, the AMD is selected from the dry type and the wet type. In another embodiment, the AMD is of the dry type. In another embodiment, the AMD is of the wet type. Those skilled in the art will understand that the difference between these two types is the change in the macula. People with dry-type AMD may have drusen in the macula, which typically increases over time and is associated with damage to photoreceptor cells (photoreceptors and supporting pigment epithelial cells) and blindness. On the other hand, in people with wet-type AMD, blood vessels sprout under the macula, and blood leaks out and fluid flows into the retina.

[0065] In one embodiment, the amyloid-related disease is diabetic retinopathy. In another embodiment, the diabetic retinopathy includes non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, or a combination thereof.

[0066] In one embodiment, the abnormal folding and deposition of the protein is diabetic retinopathy, which can include non-proliferative diabetic retinopathy and each stage of non-proliferative diabetic retinopathy up to and including proliferative diabetic retinopathy. As the disease progresses, associated diabetic macular edema may also become apparent. This retinal disease may or may not be accompanied by amyloid-beta deposition.

[0067] Dosage and Administration In some embodiments, the administration is systemic administration.

[0068] In one embodiment, the systemic administration is by oral administration, rectal administration, transmucosal administration, nasal administration, intramuscular administration, subcutaneous administration, subarachnoid administration, direct intraventricular administration, intravenous administration, intraperitoneal administration, or intranasal instillation.

[0069] In another embodiment, the systemic administration is by oral administration. In another embodiment, the systemic administration is by rectal administration. In another embodiment, the systemic administration is by transmucosal administration. In another embodiment, the systemic administration is by nasal administration. In another embodiment, the systemic administration is by intramuscular administration. In another embodiment, the systemic administration is by subcutaneous administration. In another embodiment, the systemic administration is by subarachnoid administration. In another embodiment, the systemic administration is by direct intraventricular administration. In another embodiment, the systemic administration is by intravenous administration. In another embodiment, the systemic administration is by intraperitoneal administration. In another embodiment, the systemic administration is by intranasal instillation.

[0070] In one embodiment, the oral administration comprises the compound (1) at a dose in the range of 0.03 to 0.3 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.03 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.04 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.05 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.06 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.07 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.08 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.09 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.1 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.12 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.13 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.14 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.15 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.16 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.17 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.18 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.19 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.2 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.21 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.22 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.23 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.24 mg / kg. In another embodiment, the oral administration comprises the compound (1) at a dose of 0.25 mg / kg.In another embodiment, the oral administration contains compound (1) at a dose of 0.26 mg / kg. In another embodiment, the oral administration contains compound (1) at a dose of 0.27 mg / kg. In another embodiment, the oral administration contains compound (1) at a dose of 0.28 mg / kg. In another embodiment, the oral administration contains compound (1) at a dose of 0.29 mg / kg. In another embodiment, the oral administration contains compound (1) at a dose of 0.3 mg / kg.

[0071] In one embodiment, the intravenous administration contains compound (1) at a dose in the range of 0.01 - 0.1 mg / kg. In one embodiment, the intravenous administration contains compound (1) at a dose of 0.01 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.02 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.03 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.04 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.05 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.06 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.07 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.08 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.09 mg / kg. In another embodiment, the intravenous administration contains compound (1) at a dose of 0.1 mg / kg.

[0072] In some embodiments, the administration is an intravitreal administration.

[0073] In one embodiment, the intraocular administration includes administration by eye drops, eye creams, eye ointments, eye sprays, administration by intraocular depot formulations, intraocular injections, and injections including intraocular or periocular injections, and includes intraocular fluids, depot formulations, solid and semi-solid intraocular carriers and matrices, or intraocular devices (such as contact lenses and films). In another embodiment, the intraocular administration is administration by eye drops. In another embodiment, the intraocular administration is administration by eye cream. In another embodiment, the intraocular administration is administration by eye ointment. In another embodiment, the intraocular administration is administration by eye spray. In another embodiment, the intraocular administration is administration by intraocular depot formulation. In another embodiment, the intraocular administration is injections including intraocular injections, intraocular or periocular injections, and includes intraocular fluids, depot formulations, solid and semi-solid intraocular carriers and matrices. In another embodiment, the intraocular administration is administration by intraocular devices (such as contact lenses and films).

[0074] In one embodiment, the intraocular administration includes a single dose of less than 1 mg of compound (1) per eye. In another embodiment, the intraocular administration includes a single dose of less than 0.8 mg of compound (1) per eye. In another embodiment, the intraocular administration includes a single dose of less than 0.6 mg of compound (1) per eye. In another embodiment, the intraocular administration includes a single dose of less than 0.4 mg of compound (1) per eye. In another embodiment, the intraocular administration includes a single dose of less than 0.2 mg of compound (1) per eye. The above single dose is typically repeated once to three times a day over a long-term treatment period up to lifelong treatment at most.

[0075] In one embodiment, the method includes administering an initial loading dose to the subject, and then further administering a plurality of maintenance doses of compound (1). In one embodiment, the subsequent maintenance doses are low doses of compound (1).

[0076] In one embodiment, the initial loading dose is administered 1 to 3 times a day for 1 day to 1 month.

[0077] In another embodiment, the initial loading dose is administered once a day for 1 day to 1 month. In another embodiment, the initial loading dose is administered twice a day for 1 day to 1 month. In another embodiment, the initial loading dose is administered three times a day for 1 day to 1 month.

[0078] In another embodiment, the initial loading dose is administered 1 to 3 times a day for 1 day. In another embodiment, the initial loading dose is administered 1 to 3 times a day for 5 days. In another embodiment, the initial loading dose is administered 1 to 3 times a day for 10 days. In another embodiment, the initial loading dose is administered 1 to 3 times a day for 15 days. In another embodiment, the initial loading dose is administered 1 to 3 times a day for 20 days. In another embodiment, the initial loading dose is administered 1 to 3 times a day for 25 days. In another embodiment, the initial loading dose is administered 1 to 3 times a day for 30 days.

[0079] In one embodiment, the maintenance dose is administered once a week, once every two weeks, or once every four weeks. In another embodiment, the maintenance dose is administered once a week. In another embodiment, the maintenance dose is administered once every two weeks. In another embodiment, the maintenance dose is administered once every four weeks.

[0080] In one embodiment, the maintenance dose is 10% to 75% of the initial loading dose. In another embodiment, the maintenance dose is 10% of the initial loading dose. In another embodiment, the maintenance dose is 20% of the initial loading dose. In another embodiment, the maintenance dose is 30% of the initial loading dose. In another embodiment, the maintenance dose is 40% of the initial loading dose. In another embodiment, the maintenance dose is 50% of the initial loading dose. In another embodiment, the maintenance dose is 60% of the initial loading dose. In another embodiment, the maintenance dose is 70% of the initial loading dose. In another embodiment, the maintenance dose is 75% of the initial loading dose.

[0081] In one embodiment, the compound is administered daily to a subject for a first period consisting of at least one day, followed by a second period of at least one week during which the compound is not administered, and then the first period of daily administration of the compound to the subject consisting of at least one day is repeated.

[0082] Pharmaceutical composition The compositions described herein can be incorporated into pharmaceutical compositions suitable for administration. In one embodiment, "pharmaceutical composition" or "pharmaceutical formulation" refers to a formulation of one or more of the active ingredients described herein, with other chemical components (such as physiologically suitable carriers and excipients). The purpose of the pharmaceutical composition or "pharmaceutical formulation" is to facilitate the administration of the compound to a subject. In certain embodiments, "pharmaceutical composition" or "pharmaceutical formulation" provides a pharmaceutical dosage form of the drug.

[0083] In some embodiments, "active ingredient" refers to a molecule capable of eliciting a biological effect. In some embodiments, the active ingredient includes compound (1).

[0084] In some embodiments, the pharmaceutical composition includes an excipient. It will be understood by those skilled in the art that the excipient is selected according to the delivery mode of the pharmaceutical composition.

[0085] In one embodiment, compound (1) is an active ingredient of a pharmaceutical composition that also includes a physiologically acceptable carrier.

[0086] The pharmaceutical composition typically includes a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like that are compatible with pharmaceutical administration. Suitable carriers are described in the latest edition of "Remington's Pharmacy," a standard reference in the art; this document is incorporated herein by reference.

[0087] Examples of substances that can act as pharmaceutically acceptable carriers or components thereof include: Sugars (such as lactose, glucose, and sucrose); starches (such as corn starch and potato starch); cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose); powdered tragacanth; malt; gelatin; talc; solid lubricants (such as stearic acid and magnesium stearate); calcium sulfate; vegetable oils (such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter); polyols (such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol (PEG)); alginic acid; emulsifying agents (such as emulsifying agents of the Tween™ brand); wetting agents (such as sodium lauryl sulfate); coloring agents; flavoring agents; tablet-forming agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions. The selection of the pharmaceutically acceptable carrier to be used with the compound is essentially determined by the method of administration of the compound. When the subject compound is to be injected, in one embodiment, the pharmaceutically acceptable carrier is sterile physiological saline containing a blood-compatible suspending agent and having a pH adjusted to about 7.4.

[0088] In some embodiments, the pharmaceutical composition further comprises a binder (e.g., acacia, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), a disintegrant (e.g., corn starch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), buffers of various pH and ionic strengths (e.g., Tris-HCL, acetic acid, phosphoric acid), additives (such as albumin or gelatin) to prevent absorption on the surface, surfactants (e.g., Tween 20, Tween 80, Pluronic F68, bile salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), penetration enhancers, solubilizers (e.g., glycerol, polyethylene glycol), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose), thickeners (e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g., aspartame, citric acid), preservatives (e.g., thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol (PEG), sodium lauryl sulfate), flow aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coating agents (e.g., poloxamers or poloxamines), coating and film-forming agents (e.g., ethyl cellulose, acrylates, polymethacrylic acids), adjuvants, or any combination thereof.

[0089] In one embodiment, the pharmaceutical composition is suitable for oral administration, rectal administration, transmucosal administration, nasal administration, intramuscular administration, subcutaneous administration, subarachnoid administration, direct intraventricular administration, intravenous administration, intraperitoneal administration, nasal instillation, or intraocular administration.

[0090] In one embodiment, the pharmaceutical composition is suitable for oral administration. In another embodiment, the pharmaceutical composition is suitable for rectal administration. In another embodiment, the pharmaceutical composition is suitable for transmucosal administration. In another embodiment, the pharmaceutical composition is suitable for nasal administration. In another embodiment, the pharmaceutical composition is suitable for intramuscular administration. In another embodiment, the pharmaceutical composition is suitable for subcutaneous administration. In another embodiment, the pharmaceutical composition is suitable for subarachnoid administration. In another embodiment, the pharmaceutical composition is suitable for direct intraventricular administration. In another embodiment, the pharmaceutical composition is suitable for intravenous administration. In another embodiment, the pharmaceutical composition is suitable for intraperitoneal administration. In another embodiment, the pharmaceutical composition is suitable for intranasal instillation. In another embodiment, the pharmaceutical composition is suitable for intraocular administration.

[0091] In some embodiments, a composition comprising a formulation disclosed herein, formulated in a compatible pharmaceutical carrier, is also prepared, placed in a suitable container, and labeled for the treatment of the indicated condition.

[0092] It will be understood by those skilled in the art that a foam composition is typically formulated in a single-phase or multiphase liquid form and packaged in a suitable container, optionally with a propellant that facilitates the discharge of the composition from the container, thereby causing the composition to foam upon application. Other foaming techniques include, for example, the "Bag-in-a-can" formulation technique. Such formulated compositions typically contain a low-boiling hydrocarbon, such as isopropanol. When such a composition is shaken at body temperature, it causes vaporization and foaming of the isopropanol in a manner similar to a pressurized aerosol foaming system. The foam may be water-based or alcohol-based, but is often formulated with a high alcohol content and rapidly evaporates when applied to the user's skin, delivering the active ingredient from the upper layer of the skin to the treatment site.

[0093] In one embodiment, the formulations provided herein include preservatives (such as benzalkonium chloride and thimerosal); chelating agents (such as sodium edetate and others); buffers (such as phosphoric acid, citric acid, and acetic acid); tonicity agents (such as sodium chloride, potassium chloride, glycerin, mannitol, and others); antioxidants (such as ascorbic acid, acetylcysteine, sodium metabisulfite, and others); fragrances; viscosity modifiers (such as polymers including cellulose and its derivatives); and polyvinyl alcohol, as well as acids and bases for adjusting the pH of these aqueous compositions as needed. The composition also includes a local anesthetic or other active substances. The composition can be used as a spray, mist, drops, etc.

[0094] Examples Example 1: Target Affinity of Compound (1) for Amyloid Beta Aβ 1-42 to The purpose of this experiment was to evaluate the target affinity of Compound (1) for abnormally folded Aβ 1-42 monomers. This affinity was determined using in vitro surface plasmon resonance (SPR) technology. The SPR experiment made it possible to examine the binding of the compound to low concentrations of Aβ 1-42 and directly evaluate the affinity of such binding. A real-time binding test was carried out using a Biacore X100 SPR instrument equipped with two flow cells on the sensor chip.

[0095] Aβ in hexafluoroisopropanol (HFIP) 1-42(American Peptide Company, Sunnyvale, California, USA) was dissolved at 1 mg / ml. The tube was incubated at room temperature for 1.5 hours with shaking, and 100 pg aliquots were prepared in low-binding Eppendorf tubes and frozen at -80 °C for 30 - 60 minutes. After lyophilization overnight, the aliquots were stored at -20 °C until use. To prepare the monomer, one of the HFIPs treated with Aβ aliquot was thawed and freshly dissolved in DMSO (anhydrous). This 5 mM stock solution was centrifuged (13,000 g for 5 minutes), and immediately before immobilization, the supernatant was diluted to 100 μM with 10 mM sodium acetate (pH 4.0).

[0096] About 1 pg / mm 2 of Aβ 1-42 monomers were covalently attached to the flow cell of the CM7 sensor chip (coated with a carboxymethylated dextran matrix on the gold surface) at a density. Human Aβ 1-42 For the purpose of immobilizing the monomer, the HFIP-treated peptide (5 mM) was dissolved in DMSO and immediately diluted to 100 μM with 10 mM sodium acetate (pH 4.0), and then coupled to the surface of one of the flow cells of the sensor chip. The second flow cell was used as a reference and treated with ethanolamine instead of Aβ. To determine the affinity, HBS-EP, 0.1% DMSO was used as the running buffer, and compounds (1) at concentrations ranging from 0.3 nM to a maximum of 1000 nM were tested at 25 °C.

[0097] The resonance units (RU) generated by the compound injected into the ethanolamine control flow cell were used as the reference response and subtracted from the RU generated by the same compound injected into the Aβ-saturated flow cell. The relationship between each RU obtained at the steady state of binding (the plateau of the binding curve) and each concentration of the compound was plotted. Biacore X100 software version 1.1 was used for the purpose of recording and analyzing the binding curve (plotting each RU at the steady state vs. the concentration of the test substance, performing fitting of the plot, and determining the Kd value). The dissociation equilibrium constant Kd of the test substance for immobilized Aβ was determined from the steady state level; the Rmax of the maximum RU was estimated, and the Kd was calculated as the concentration of the compound that is half of Rmax.

[0098] The Kd of compound (1) for Aβ monomer is 2.5 ± 0.6 nM (n = 4). The results are shown in Figure 1. Compared with GAL-101, which was previously the best among the compounds, the target affinity was 4 times stronger.

[0099] Example 2: Pharmacokinetics of Compound (1) in Rat Brain The purpose of this experiment was to evaluate the pharmacokinetics of compound (1) in rat brain. Compound (1) was administered subcutaneously to anesthetized animals or awake freely moving animals. A microdialysis probe was placed in the prefrontal cortex of these adult male Sprague Dawley rats, and the concentration of compound (1) in the brain interstitial fluid (ISF) was measured using an HPLC system equipped with an MS / MS detector.

[0100] The results are shown in Figure 2.

[0101] Example 3: Dose-Dependent Effect of a Very Low Concentration of Compound (1) on In Vivo LTP in Anesthetized Rats The purpose of this experiment was to evaluate the dose-dependent effect of a very low concentration of compound (1) on in vivo LTP in anesthetized rats. Compound (1) was administered subcutaneously at doses of 0.08 mg / kg, 0.4 mg / kg, and 2.0 mg / kg. Amyloid beta Aβ at a concentration that strongly inhibits LTP 1-42It was injected into the cerebral ventricle. As is clear from Fig. 3, unexpectedly, even at an estimated inactive dose of only 0.4 mg / kg at which the peak concentration in the brain was 10 nM (gray in the center), it showed a strong effect on at least LTP.

[0102] Example 4: Dose-dependent effect of compound (1) in in vitro LTP experiment For the long-term potentiation (LTP) experiment, brain slices from 2-month-old mice were used. After decapitation under isoflurane anesthesia, hippocampal transverse slices (350 μm thick) were obtained. All slices were left in a holding chamber for at least 60 minutes and then transferred to a surface perfusion chamber for extracellular recording. The flow rate of the solution passing through the chamber was 4 ml / min. The composition of the above solution was 124 mM NaCl, 3 mM KCl, 26 mM NaHCO 3 , 2 mM CaCl 2 , 1 mM MgSO 4 , 10 mM D-glucose, and 1.25 mM NaH 2 PO 4 , and it was aerated with a 95% O 2 / 5% CO 2 mixed gas to make it bubble, and the final pH was 7.3. All experiments were carried out at room temperature. A DMSO stock solution of Aβ 1-42 was added to the bath solution at a final concentration of 50 nM. Extracellular recordings of excitatory postsynaptic field potentials (fEPSPs) were obtained from the dendritic region of the CA1 region of the hippocampus using a glass micropipette filled with the surface perfusion solution. In all recordings, both stimulating electrodes were used; this was for the purpose of utilizing the input specificity of LTP, thereby enabling internal control measurements within the same slice. Recordings of a steady baseline were made at least 30 minutes before applying the tetanus stimulation. For LTP induction, high-frequency stimulation (HFS) conditioning pulses (100 Hz / sec; 4 - 5 V) were applied to the Schaffer collateral / commissural pathway by two independent inputs. Before LTP induction, Aβ 1-42 was added for 90 minutes. HFS was performed from one of the electrodes under the condition in the presence of compound (1), and the synergistic effect of the reaction was observed for at least 60 minutes after tetanus. Next, after HFS was performed from the second electrode, for 90 minutes before LTP induction in the second input, either Aβ was introduced via the bath solution.1-42 It was added. Filtering (3 kHz), digitization (15 kHz), measurement, and plotting of the amplified fEPSP were performed (Figure 4A). The slope of the fEPSP was measured between 20% and 80% of the peak intensity. The slope of the fEPSP was normalized based on the 20-minute control period before tetanus stimulation.

[0103] In these LTP experiments, compound (1) was used at various concentrations. Surprisingly, when compound (1) was used at the lowest concentration of only 10 nM, it best prevented the harmful effect of 50 nM Aβ on hippocampal LTP. 1-42 The beneficial effect of 1-42 by different Aβ 1-42 / compound (1) stoichiometric ratios (10:1, 2:1, 1:5) are shown in Figure 4B. The LTP signal (fEPSP synergy), calculated as the average between 50 and 60 minutes after the final HFS, is shown in a bar diagram.

[0104] Compound (1) and amyloid beta Aβ 1-42 The reversal of the stoichiometric ratio between and is shown in Table 1 below.

[0105]

Table 1

[0106] Table 1: This table shows the reversal of the stoichiometric ratio between compound (1) and amyloid beta Aβ 1-42 which enhances the detoxification strength of compound (1). The data in this table were obtained from the experiments shown in Figure 4B. The control experiment was defined as a 100% normalized LTP response, and the toxic effect of 50 nM Aβ 1-42 oligomers was defined as a 0% normalized LTP change. If a normal stoichiometric excess of compound (1) (i.e., 500 nM or 100 nM) is used, weak detoxification effects of 40.2% and 34.7% are obtained, respectively. However, if the stoichiometric ratio is reversed and compound (1) is used at a very low concentration (10 nM), which is a 5-fold undersupply, the detoxification strength is significantly improved, reaching 88.1%.

[0107] Define the LTP response normalized to 100% of the control experiment, and define the normalized LTP change under the toxic effect of 50 nM Aβ 1-42 oligomers as 0%. If normal stoichiometric excess (i.e., 500 nM or 100 nM) is used for compound (1), moderate detoxification effects of 40.2% and 34.7% were observed, respectively. However, if a concentration of compound (1) of only 10 nM is used with the stoichiometric ratio reversed, which is a 5-fold stoichiometric under-supply, the detoxification intensity is significantly improved, and the improvement reaches an effect size of 88.1%.

[0108] Combining the calculations obtained from in vitro and in vivo LTP experiments, when compound (1) is used at a subcutaneous (s.c.) dose of 0.4 mg / kg, the concentration of compound (1) in the extracellular space of the brain becomes 10 nM, and the existing toxic Aβ 1-42 is completely detoxified, indicating that the LTP signal is completely restored (see Figure 3).

[0109] In animals injected intracerebroventricularly (i.c.v.) with 6 μL of oligomeric Aβ 1-42 solution (1.67 mM), significant LTP deficits were observed (Figure 3). At the end of the recording period (80 - 90 minutes after LTP induction), the measured PS intensity after intracerebroventricular (i.c.v.) administration of oligomeric Aβ 1-42 was 138.1 ± 4.1% of the baseline, compared to 179.2 ± 8.7% in animals injected with PBS (n = 12) (n = 18). In animals injected intracerebroventricularly (i.c.v.) with 6 μL of oligomeric Aβ 1-42 oligomers, oligomeric Aβ 1-42Before i.c.v. injection, compound (1) was administered at three different s.c. doses (i.e., 0.08, 0.4, and 2 mg / kg). For compound (1) at 0.4 mg / kg and 2 mg / kg, the post-TBS responses were close to those observed in control animals (P < 0.05, one-way ANOVA and accompanying Bonferroni post hoc test). At the end of the recording period (80 - 90 minutes after LTP induction), the PS intensity after subcutaneous (s.c.) administration of compound (1) and intracerebroventricular (i.c.v.) administration of oligomeric Aβ 1-42 was measured as 170.0 ± 11.9% of baseline (n = 7) at a dose of 2 mg / kg, 174.7 ± 16.0% of baseline (n = 6) at a dose of 0.4 mg / kg, and 139.6 ± 13.1% of baseline (n = 4) at a dose of 0.08 mg / kg, compared to 179.2 ± 8.7% of the vehicle-treated controls (n = 12) and 138.1 ± 4.1% of the animals i.c.v.-injected with oligomeric Aβ 1-42 (n = 18). These results confirm that compound (1) potently suppresses Aβ 1-42 toxicity, as observed in the above in vitro experiments (shown in Figure 4B).

[0110] Although specific features of the invention have been shown and described herein, those skilled in the art will immediately conceive of many variations, alternatives, modifications, and equivalents. Accordingly, it is to be understood that the appended claims are intended to cover all such variations and modifications as fall within the true spirit of the invention.

Claims

**Claim 1** A method for treating or preventing abnormal protein folding and deposition disorders in a subject, comprising administering to the subject in need thereof a low dose of compound (1): 【Chemical 1】 ; Thereby treating or preventing abnormal protein folding and deposition disorders in the subject. **Claim 2** A method according to claim 1, wherein as a result of said low dose administration, the concentration of compound (1) at the site of action is less than 50 nM. **Claim 3** A method according to claims 1 and 2, wherein as a result of said low dose administration, the concentration of compound (1) at the site of action is 10 nM. **Claim 4** A method according to claims 1 and 2, wherein as a result of said low dose administration, the concentration of compound (1) at the site of action is 3 nM. **Claim 5** A method according to claims 1 and 2, wherein as a result of said low dose administration, the concentration of compound (1) at the site of action is 1 nM. **Claim 6** A method according to claim 1, wherein the abnormal protein folding and deposition disorders are: Selected from Alzheimer's disease (AD), early Alzheimer's disease, late-onset Alzheimer's disease, preclinical Alzheimer's disease, type II diabetes, serum amyloid A disease (SAA amyloidosis), hereditary Icelandic syndrome, multiple myeloma, medullary carcinoma, aortic amyloidosis, cardiac amyloidosis, insulin injection site amyloidosis, prion systemic amyloidosis, chronic inflammatory amyloidosis, age-related systemic amyloidosis, pituitary amyloidosis, hereditary renal amyloidosis, and familial non-neuropathic amyloidosis. **Claim 7** A method according to claim 1, wherein the abnormal protein folding and deposition disorders are: Selected from Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, prion disease, and mad cow disease. **Claim 8** A method according to claim 1, wherein the abnormal protein folding and deposition disorders include amyloid-related diseases. **Claim 9** A method according to claim 8, wherein the amyloid-related diseases include Alzheimer's disease (AD), early Alzheimer's disease, late-onset Alzheimer's disease, preclinical Alzheimer's disease, or any combination thereof. **Claim 10** A method according to claim 9, wherein said treating or preventing comprises improving cognitive impairment, improving memory loss, reducing abnormal behavior, reducing hallucination symptoms, reducing loss of spatial orientation, reducing apraxia, reducing aggressiveness, improving the ability to perform activities of daily living, improving other symptoms of dementia, or any combination thereof, in the subject.

11. A method according to claim 8, wherein said amyloid-related disease comprises diabetic retinopathy.

12. A method according to claims 1 to 11, wherein said administration is systemic administration.

13. A method according to claim 12, wherein said systemic administration is by oral administration, rectal administration, transmucosal administration, intranasal administration, intramuscular administration, subcutaneous administration, transdermal administration, subarachnoid administration, direct intraventricular administration, intravenous administration, intraperitoneal administration, or intranasal instillation.

14. A method according to claim 13, wherein said oral administration comprises a dose of compound (1) in the range of 0.03 to 0.3 mg / kg.

15. A method according to claim 13, wherein said intravenous administration comprises a dose of compound (1) in the range of 0.01 to 0.1 mg / kg.

16. A method according to claim 8, wherein said amyloid-related disease is selected from glaucoma or age-related macular degeneration (AMD).

17. A method according to claim 16, wherein said glaucoma is selected from the group consisting of primary angle-closure glaucoma, open-angle glaucoma (both primary and secondary), wide-angle glaucoma, steroid glaucoma, traumatic glaucoma, secondary angle-closure glaucoma, and neovascular glaucoma.

18. A method according to claims 16 to 17, wherein said administration is intraocular administration.

19. A method according to claim 18, wherein said intraocular administration is by administration of eye drops, eye cream, eye ointment, eye spray, administration by an intravitreal depot formulation, intravitreal injection, injection including intravitreal or periocular injection, and includes intravitreal fluid, depot formulation, solid and semi-solid intravitreal carriers and matrices, or intravitreal devices (such as contact lenses and films).

20. A method according to claim 19, comprising administering less than 1 mg of compound (1) as a single dose to one eye of a subject in need thereof.

21. A method according to claims 1 to 20, wherein the method comprises administering the compound (1) to the subject at an initial loading dose and then further administering it at multiple maintenance doses.

22. A method according to claim 21, wherein the initial loading dose is administered 1 to 3 times a day for a period of 1 day to 1 month.

23. A method according to claim 21, wherein the maintenance dose is administered once a week, once every two weeks, or once every four weeks.

24. A method according to claims 21 to 23, wherein the maintenance dose is 10% to 75% of the initial loading dose.

25. A method according to claim 1, wherein the compound is administered to the subject daily for a first period consisting of at least 1 day, followed by a second period consisting of at least 1 week during which the compound is not administered, and then the first period consisting of at least 1 day during which the compound is administered to the subject daily is repeated.

26. The method of claim 1, wherein the compound (1) is an active ingredient of a pharmaceutical composition that also contains a physiologically acceptable carrier.

27. A method according to claim 26, wherein the pharmaceutical composition is suitable for oral administration.

28. A method according to claim 26, wherein the pharmaceutical composition is suitable for intraocular administration.

29. A method for inhibiting Aβ toxicity in a subject, comprising administering a low dose of compound (1): 【Chemical 2】 thereby inhibiting Aβ toxicity in the subject. Method.

30. A method according to claim 29, wherein as a result of the low-dose administration, the concentration at the site of action is less than 50 nM.

31. A method according to claims 29 and 30, wherein the low-dose administration results in a concentration at the site of action reaching 10 nM.

32. A method according to claims 29 and 30, wherein the low-dose administration results in a concentration at the site of action reaching 3 nM.

33. A method according to claims 29 and 30, wherein the low-dose administration results in a concentration at the site of action reaching 1 nM.

34. A method of counteracting or preventing the toxic effects of abnormally folded and aggregated protein amyloid beta, i.e., toxic Aβ oligomers, using a compound (1) in a relatively undersupplied amount (inverse stoichiometric ratio) to achieve a more potent detoxifying effect.

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