Medical application of GLP-1 compound

Abstract

The invention provides a method for treating or preventing dementia and / or neurodegenerative diseases, especially Alzheimer's disease and / or Parkinson's disease, of a GLP-1 compound and a corresponding pharmaceutical application of the GLP-1 compound. Compared with positive control drugs such as semeglutide, donepezil, rasagiline and L-dopamine, the compound shows a better improvement effect.

Description

Medical use of a GLP-1 compound Technical Field

[0001] The present invention belongs to the field of medicine and relates to a new medical use of a glucagon like peptide-1 (GLP-1) compound. Background Art

[0002] Neurodegenerative diseases are a class of complex diseases that are progressive, severely disabling, and even fatal. They can be divided into acute neurodegenerative diseases and chronic neurodegenerative diseases. The former mainly include stroke and brain injury; the latter mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), etc., which worsen over time and cause functional impairment.

[0003] Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disorder with a slow onset and progressive worsening over time. It often affects people over 65 years old and presents clinically with memory impairment, aphasia, agnosia, executive dysfunction, and personality and behavioral changes. Pathological findings reveal the presence of amyloid plaques (Aβ) aggregates and neurofibrillary tangles (TFs) formed by hyperphosphorylated tau (microtubule-associated protein Tau) in the brain. As the disease progresses, synaptic dysfunction and significant neuronal loss may occur (doi:10.1186 / 1756-6606-4-3(2011), doi:10.1523 / JNEUROSCI.1202-06.2006(2006)). The true cause of Alzheimer's disease remains unknown, but as research deepens, nearly 70% of risk factors are believed to be genetic. The amyloid precursor protein gene (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are genes currently known to be associated with familial Alzheimer's disease. Mutations in these three genes affect the splicing of the APP gene, leading to increased production of Aβ42 in cells and the formation of amyloid plaques (doi:10.1016 / j.jalz.2016.01.012(2016)). Currently, there is no treatment that can halt or reverse the progression of Alzheimer's disease, but a few methods may temporarily alleviate or improve symptoms.

[0004] Parkinson's disease (PD) is a complex neurodegenerative disorder caused by the interaction of genetic and environmental factors, and its pathogenesis remains unclear. Typical features include movement disorders, Lewy body (LB) formation, and loss of dopamine (DA) neurons in the substantia nigra (SN). Clinical manifestations include resting tremor, increased muscle tone, and bradykinesia. PD pathology demonstrates degeneration and loss of dopamine (DA) neurons in the substantia nigra reticularis and decreased striatal DA levels. Therefore, levodopa (L-dopa) replacement therapy is the most widely used and effective treatment. However, with the progression of PD and continued L-dopa use, the remaining dopamine neurons lose their ability to produce dopamine, reducing their buffering capacity for exogenous dopamine drugs. At the same time, dopamine levels in the striatum cannot be maintained at a normal physiological state, resulting in abnormal and fluctuating stimulation of dopamine receptors distributed on the surface of medium spiny neurons in the striatum, causing various motor complications that affect the head, face, limbs, trunk, and other parts of the body. Therefore, exploring new therapeutic targets and alternative therapies, and finding new non-dopaminergic drugs, have become research hotspots for the treatment of PD.

[0005] N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide is a long-acting GLP-1 compound. The structural formula of the drug is:

[0006] Therefore, effective drugs for the treatment of Alzheimer's disease and Parkinson's disease are in urgent need of development.

[0007] Summary of the Invention

[0008] In order to address the deficiencies in the prior art and meet practical needs, the present invention provides a new medical use of a GLP-1 compound.

[0009] Use of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, in the preparation of a medicament for treating or preventing dementia and / or neurodegenerative diseases,

[0010] In one embodiment, the dementia is all forms and stages of dementia, preferably mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia;

[0011] In one embodiment, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably Alzheimer's disease, and / or Parkinson's disease.

[0012] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the generation and / or aggregation of Aβ in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate the expression of proteins related to Aβ metabolism in a subject in need thereof and reduce the generation and / or aggregation of Aβ; preferably, the proteins related to Aβ metabolism are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of BACE-1 in a subject in need thereof, increase the expression of PS1 in a subject in need thereof, and / or increase the expression of ADAM10 in a subject in need thereof.

[0013] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the structural abnormalities of the hippocampus of a subject in need thereof and / or increase the number of neurons in a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can increase the structural density of the hippocampus of a subject in need thereof, and / or increase the number of neurons in a subject in need thereof; or

[0014] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the formation of senile plaques in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the formation of senile plaques in the brain of a subject in need thereof by inhibiting Aβ deposition in the hippocampus and / or cortical region of the subject.

[0015] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need thereof, wherein the related proteins in the striatum and / or substantia nigra are selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof;

[0016] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the oxidative stress level in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate the content of MDA and / or SOD in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the content of MDA and / or increase the content of SOD;

[0017] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of inflammatory factors and / or increasing the level of anti-inflammatory factors; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of TNF-α, IL-1β, IL-6, and / or IL-8, and / or increasing the level of IL-4, and / or IL-10;

[0018] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof. Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

[0019] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the subject's cognitive ability, improve the subject's anxiety behavior, improve the subject's autonomic activity dysfunction, and / or improve the subject's motor ability.

[0020] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered subcutaneously or orally, preferably as an injection or tablet.

[0021] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered chronically, preferably for more than 12 months; preferably for more than 16 months; preferably for more than 18 months.

[0022] In one embodiment, the subject in need thereof suffers from metabolic syndrome, preferably one or more of diabetes, cardiovascular disease and hypertension.

[0023] A method for treating or preventing dementia and / or neurodegenerative diseases, comprising administering to a subject in need thereof a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt, amide or ester thereof,

[0024] In one embodiment, the dementia is all forms and stages of dementia, preferably mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; and / or

[0025] The neurodegenerative disease is all forms and stages of neurodegenerative diseases, preferably Alzheimer's disease and / or Parkinson's disease.

[0026] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the generation and / or aggregation of Aβ in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate the expression of proteins related to Aβ metabolism in the subject and reduce the generation and / or aggregation of Aβ; preferably, the proteins related to Aβ metabolism are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of BACE-1 in a subject in need thereof, increase the expression of PS1 in the subject, and / or increase the expression of ADAM10 in the subject.

[0027] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the abnormal structure of the hippocampus region of the subject and / or the number of neurons in the subject; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can increase the density of the hippocampus region of the subject and / or increase the number of neurons in the subject; or

[0028] The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the formation of senile plaques in the brain of the subject; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the formation of senile plaques in the brain of the subject by inhibiting Aβ deposition in the hippocampus and / or cortical region of the subject.

[0029] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need thereof, wherein the protein is selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof;

[0030] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the oxidative stress level in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate the content of MDA and / or SOD in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the content of MDA and / or increase the content of SOD;

[0031] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of inflammatory factors and / or increasing the level of anti-inflammatory factors; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of TNF-α, IL-1β, IL-6, and / or IL-8, and / or increasing the level of IL-4, and / or IL-10;

[0032] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof. Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

[0033] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the subject's cognitive ability, improve the subject's anxiety behavior, improve the subject's autonomic dysfunction, and / or improve the subject's motor ability.

[0034] In one embodiment, the dose of the compound of formula (I) is 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg.

[0035] In one embodiment, the method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a dose of 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg every 24 hours, every 48 hours, every 72 hours, every week or every two weeks.

[0036] In one embodiment, the method comprises administering to a subject in need thereof 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg every 24 hours, every 48 hours, or every 72 hours, every week or every two weeks. , 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, or 70 mg of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof.

[0037] In one embodiment, the method is characterized in that the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered subcutaneously or orally, preferably as an injection or tablet.

[0038] In one embodiment, the method is characterized in that the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered chronically, preferably for more than 12 months; preferably for more than 16 months; preferably for more than 18 months.

[0039] In one embodiment, the method is characterized in that the subject also suffers from metabolic syndrome, preferably one or more of diabetes, cardiovascular disease and hypertension.

[0040] A compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, for use in treating or preventing dementia and / or neurodegenerative diseases,

[0041] In one embodiment, the dementia is all forms and stages of dementia, preferably mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; and / or

[0042] The neurodegenerative disease is all forms and stages of neurodegenerative diseases, preferably Alzheimer's disease and / or Parkinson's disease.

[0043] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the generation and / or aggregation of Aβ in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate proteins related to Aβ metabolism in a subject in need thereof and reduce the generation and / or aggregation of Aβ; preferably, the proteins related to Aβ metabolism are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of BACE-1 in a subject in need thereof, increase the expression of PS1 in a subject in need thereof, and / or increase the expression of ADAM10 in a subject in need thereof.

[0044] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve structural abnormalities in the hippocampus of a subject in need thereof and / or increase the number of neurons in a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can increase the density of the hippocampus structure and / or increase the number of neurons in a subject in need thereof;

[0045] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the formation of senile plaques in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the formation of senile plaques in the brain of a subject in need thereof by inhibiting Aβ deposition in the hippocampus and / or cortical region of the subject.

[0046] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need thereof, wherein the related proteins in the striatum and / or substantia nigra are selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof;

[0047] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the oxidative stress level in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate the content of MDA and / or SOD in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the content of MDA and / or increase the content of SOD;

[0048] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of inflammatory factors and / or increasing the level of anti-inflammatory factors; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of TNF-α, IL-1β, IL-6, and / or IL-8, and / or increasing the level of IL-4, and / or IL-10;

[0049] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof. Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

[0050] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the subject's cognitive ability, improve the subject's anxiety behavior, improve the subject's autonomic activity dysfunction, and / or improve the subject's motor ability.

[0051] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered in a dose of 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg.

[0052] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered to a subject at a dose of 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg every 24 hours, every 48 hours, every 72 hours, every week or every two weeks.

[0053] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered to a subject at a dose of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, or 70 mg.

[0054] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered subcutaneously or orally, preferably as an injection or tablet.

[0055] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered chronically, preferably for more than 12 months; preferably for more than 16 months; preferably for more than 18 months.

[0056] In one embodiment, the subject in need thereof suffers from metabolic syndrome, preferably one or more of diabetes, cardiovascular disease and hypertension.

[0057] A method for treating or preventing dementia and / or neurodegenerative diseases caused by the generation and / or aggregation of Aβ, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0058] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Alzheimer's disease;

[0059] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease, preferably the neurodegenerative disease is Alzheimer's disease.

[0060] A method for treating or preventing dementia and / or neurodegenerative diseases mediated by proteins related to Aβ metabolism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0061] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia;

[0062] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease.

[0063] A method for treating or preventing dementia and / or neurodegenerative diseases mediated by BACE-1, PS1 and / or ADAM10, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0064] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia;

[0065] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease.

[0066] In one embodiment, the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8, Arg34]GLP-1-(7-37) peptide, which can regulate the expression of proteins related to Aβ metabolism in subjects in need and reduce the production and / or aggregation of Aβ; preferably, the Aβ metabolism-related proteins are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of BACE-1 in subjects in need, increase the expression of PS1 in subjects in need, and / or increase the expression of ADAM10 in subjects in need.

[0067] A method for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal hippocampal structure, decreased number of neurons, and / or formation of senile plaques in the brain of a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0068] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia;

[0069] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease.

[0070] In one embodiment, the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can improve structural abnormalities in the hippocampal region of a subject in need thereof and / or increase the number of neurons in a subject in need thereof; preferably the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, can increase the compactness of the hippocampus and / or increase the number of neurons in a subject in need thereof;

[0071] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the formation of senile plaques in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the formation of senile plaques in the brain of a subject in need thereof by inhibiting Aβ deposition in the hippocampus and / or cortical region of the subject.

[0072] A method for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal expression of related proteins in the striatum and / or substantia nigra, the method comprising administering a therapeutically effective amount of a compound of formula (I) or N-ε to a subject in need thereof 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0073] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0074] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease;

[0075] Preferably, the relevant protein in the striatum and / or substantia nigra is selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein.

[0076] A method for treating or preventing dementia and / or neurodegenerative diseases mediated by cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein, and / or ERK protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0077] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0078] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

[0079] In one embodiment, it is preferred that the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8, Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof.

[0080] A method for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal oxidative stress levels in the substantia nigra, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0081] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0082] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

[0083] A method for treating or preventing MDA and / or SOD-mediated dementia and / or neurodegenerative diseases in the substantia nigra, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0084] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0085] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

[0086] In one embodiment, the compound of formula (I) or N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need by regulating the content of MDA and / or SOD in the substantia nigra of a subject in need; preferably the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8, Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can reduce the content of MDA and / or increase the content of SOD.

[0087] A method for treating or preventing inflammation-mediated dementia and / or neurodegenerative diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0088] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0089] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

[0090] A method for treating or preventing dementia and / or neurodegenerative diseases caused by increased and / or decreased levels of inflammatory factors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0091] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0092] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease;

[0093] Preferably, the inflammatory factor is selected from TNF-α, IL-1β, IL-6, and IL-8; preferably, the anti-inflammatory factor is IL-4 or IL-10.

[0094] A method for treating or preventing TNF-α, IL-1β, IL-6, IL-8, IL-10, and / or IL-4 mediated dementia, and / or neurodegenerative diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0095] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0096] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease;

[0097] Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is capable of reducing TNF-α, IL-1β, IL-6, and / or IL-8 levels, and / or increasing IL-4, and / or IL-10 levels.

[0098] A method for treating or preventing dementia and / or neurodegenerative diseases mediated by the activity of dopaminergic neurons in the substantia nigra region, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0099] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0100] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

[0101] A method for treating or preventing tyrosine hydrogenase-mediated dementia and / or neurodegenerative diseases in the substantia nigra, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof,

[0102] Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia;

[0103] Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

[0104] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

[0105] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve a patient's cognitive ability, improve a patient's anxiety behavior, improve a patient's autonomic activity dysfunction, and / or improve a patient's motor ability.

[0106] In one embodiment, the method is characterized in that the therapeutically effective amount is 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg.

[0107] In one embodiment, the method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a dose of 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg per 24 hours, per 48 hours, or per 72 hours.

[0108] In one embodiment, the or method comprises administering to a subject in need thereof 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, or 70 mg of a compound of Formula (I), or a pharmaceutically acceptable salt, amide, or ester thereof.

[0109] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered subcutaneously or orally, preferably as an injection or tablet.

[0110] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered chronically, preferably for more than 12 months; preferably for more than 16 months; preferably for more than 18 months.

[0111] In one embodiment, the subject also suffers from metabolic syndrome, preferably one or more of diabetes, cardiovascular disease and hypertension.

[0112] Beneficial effects of the present invention:

[0113] 1) The compound (I) of the present invention has a significant improvement effect on Alzheimer's disease and shows a better improvement effect than the positive control drugs semaglutide and donepezil.

[0114] 2) Compound (I) of the present invention has a significant improvement effect on Parkinson's disease and shows a better improvement effect than the positive control drugs semaglutide, levodopamine, and rasagiline. For example, in one embodiment, the effect of 5 mg / kg of Compound (I) in treating Parkinson's disease is comparable to that of 10 mg / kg of semaglutide.

[0115] 3) The compound (I) of the present invention does not exhibit obvious drug toxicity and side effects and has good tolerability. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] Note: The mark in the figure is ## P<0.01, ### P<0.001 vs NC, *P<0.05, **P<0.01, ***P<0.001 vs MC.

[0117] Figure 1: Changes in body weight of mice in each dosing group (Normal Control (NC), Model Control (MC), semaglutide, Compound (I) low dose: 1 nmol / kg; Compound (I) medium dose: 3 nmol / kg; Compound (I) high dose: 10 nmol / kg).

[0118] Figure 2: Water maze performance of mice in each dosing group (NC, MC, semaglutide, Compound (I) low dose: 1 nmol / kg; Compound (I) medium dose: 3 nmol / kg). Figure 2A shows the water maze traces of mice after 4 weeks of dosing. Figure 2B shows the water maze traces of mice after 9 weeks of dosing. Figures 2C (ad) show the number of platform crossings, platform dwell time, first platform crossing time, and target quadrant percentage after 9 weeks of dosing.

[0119] Figure 3: Comparison of cognitive indices among mice in the novel object recognition test (NC, MC, semaglutide, Compound (I) low dose: 1 nmol / kg; Compound (I) medium dose: 3 nmol / kg; Compound (I) high dose: 10 nmol / kg). Figure 3A shows the comparison of cognitive indices among the mice in the novel object recognition test, calculated based on the number of crossings. Figure 3B shows the comparison of cognitive indices among the mice in the novel object recognition test, calculated based on the duration of contact.

[0120] Figure 4: Comparison of autonomous behavior in mice across the open field test (NC, MC, semaglutide, Compound (I) low dose: 1 nmol / kg; Compound (I) medium dose: 3 nmol / kg; Compound (I) high dose: 10 nmol / kg). Figure 4A is an image of the open field track of mice. Figure 4B (af) compares the number of center zone crossings, center zone dwell time, percentage of center zone dwell time, time to first center zone crossing, speed, and total distance covered by mice across the dosing groups.

[0121] Figure 5: Comparison of memory behavior in the platform jumping test among mice in each drug-treated group (NC, MC, semaglutide, Compound (I) low dose: 1 nmol / kg; Compound (I) medium dose: 3 nmol / kg; Compound (I) high dose: 10 nmol / kg). Figures 5A and 5B compare the latency (time to jump) and number of jumps, respectively, for mice in each drug-treated group on the second day of the platform jumping test.

[0122] Figure 6: Comparison of Aβ deposition in the brains of mice treated with various dosing groups (NC, MC, semaglutide, and Compound (I) low dose: 1 nmol / kg; Compound (I) medium dose: 3 nmol / kg; and Compound (I) high dose: 10 nmol / kg). Figure 6A shows the results of Aβ immunohistochemical staining in the cerebral cortex and hippocampus. Figure 6B shows the results of Aβ immunofluorescence staining in the cerebral cortex and hippocampus. Figure 6C shows the comparison of Aβ immunofluorescence density in the cerebral cortex and hippocampus.

[0123] Figure 7: Comparison of Western blot analysis of Aβ levels in the brains of mice treated with each drug group (NC, MC, semaglutide, Compound (I) low dose: 1 nmol / kg; Compound (I) medium dose: 3 nmol / kg; Compound (I) high dose: 10 nmol / kg) and the levels of PS1, ADAM10, and BACE-1 in vivo. Figure 7A shows a band chart of aggregated Aβ levels in the mouse brain and grayscale value statistics. a: Band chart of Aβ levels in the hippocampus and grayscale value statistics; b: Band chart of Aβ levels in the cortex and grayscale value statistics. Figure 7B shows a band chart of the levels of three Aβ-related proteins in the mouse brain and grayscale value statistics: a: Band chart of PS1 levels and grayscale value statistics; b: Band chart of ADAM10 levels and grayscale value statistics; c: Band chart of BACE-1 levels and grayscale value statistics.

[0124] Figure 8: Comparison of neuronal morphology in the hippocampus of mice in each drug-treated group (NC, MC, low dose of Compound (I): 1 nmol / kg; medium dose of Compound (I): 3 nmol / kg; high dose of Compound (I): 10 nmol / kg).

[0125] Figure 9: Changes in body weight of mice in each dosing group (NC, MC, donepezil, Compound (I) low dose: 5 nmol / kg; Compound (I) medium dose: 10 nmol / kg; Compound (I) high dose: 20 nmol / kg).

[0126] Figure 10: Comparison of voluntary behavior in mice across the open field test (NC, MC, donepezil, Compound (I) low dose: 5 nmol / kg; Compound (I) medium dose: 10 nmol / kg; Compound (I) high dose: 20 nmol / kg). Figure 10A is an image of the open field track of mice. Figure 10B compares the number of center zone crossings, time to first center zone crossing, total distance traveled, and speed achieved by mice across the treatment groups.

[0127] Figure 11: Changes in body weight of mice in each dosing group (NC, MC, rasagiline, L-dopamine, low dose of Compound (I): 5 nmol / kg; medium dose of Compound (I): 10 nmol / kg).

[0128] Figure 12: Comparison of autonomous behavior of mice in the open field test across the drug-treated groups (NC, MC, rasagiline, levodopamine, Compound (I) low dose: 5 nmol / kg; Compound (I) medium dose: 10 nmol / kg; Compound (I) high dose: 20 nmol / kg). Figure 12A is an image of the open field track of mice. Figures 12B-12G compare the number of center zone crossings, center zone dwell time, percentage of center zone dwell time, time to first center zone crossing, total distance traveled, and speed, respectively, across the drug-treated groups.

[0129] Figure 13: Comparison of the time spent climbing the pole in the pole climbing test on days 1 to 6 in mice from each drug-treated group (NC, MC, rasagiline, L-dopamine, low-dose Compound (I): 5 nmol / kg; medium-dose Compound (I): 10 nmol / kg). Figure 13A shows the time spent turning the head while climbing the pole, and Figure 13B shows the total time spent climbing the pole.

[0130] Figure 14: Comparison of the rotarod time of mice in each drug-treated group (NC, MC, rasagiline, L-dopamine, low dose of Compound (I): 5 nmol / kg; medium dose of Compound (I): 10 nmol / kg) on ​​days 1, 2, 4, and 5 in the rotarod test.

[0131] Figure 15: Comparison of AKT, pAKT, ERK, pERK, and cleaved casepase3 protein levels in the striatum and substantia nigra of mice in each drug-treated group (NC, MC, rasagiline, L-dopamine, Compound (I) low dose: 5 nmol / kg; Compound (I) medium dose: 10 nmol / kg). Figure 15A shows a comparison of AKT, pAKT, ERK, and pERK levels in the striatum of mice in each drug-treated group. Figure 15B shows a comparison of ERK, pERK, and cleaved casepase3 protein levels in the substantia nigra of mice in each drug-treated group.

[0132] Figure 16: Comparison of MDA and SOD levels in the substantia nigra of mice in each drug-treated group (NC, MC, rasagiline, L-dopamine, Compound (I) low dose: 5 nmol / kg; Compound (I) medium dose: 10 nmol / kg). Panel A shows the comparison of MDA levels in the substantia nigra of mice in each drug-treated group; Panel B shows the comparison of SOD levels in the substantia nigra of mice in each drug-treated group.

[0133] Figure 17: Comparison of the immune microenvironment in the substantia nigra of mice in each drug-dosing group (NC, MC, rasagiline, levodopamine, low dose of compound (I): 5 nmol / kg; medium dose of compound (I): 10 nmol / kg; high dose of compound (I): 20 nmol / kg). A to D are comparisons of the levels of inflammatory factor IL-1β, anti-inflammatory factor IL-10, inflammatory factor IL-6, and inflammatory factor TNF-α, respectively.

[0134] Figure 18: Comparison of tyrosine hydrogenase TH content in the substantia nigra of mice in each drug-dosing group (NC, MC, rasagiline, L-dopamine, low dose of compound (I): 5 nmol / kg; medium dose of compound (I): 10 nmol / kg; high dose of compound (I): 20 nmol / kg). DETAILED DESCRIPTION

[0135] Below in conjunction with embodiment, embodiment of the present invention is described in detail, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention, and according to the teaching of the present invention, more variations and modifications can also be made, and these variations and modifications all fall within the scope of protection claimed in the present invention. In the embodiment, those not indicating specific conditions are carried out according to the conditions of normal conditions or manufacturer's advice. Reagents used or instruments not indicating manufacturers are conventional products that can be obtained by commercial purchase.

[0136] definition

[0137] GLP-1 compounds

[0138] As used herein, the term "GLP-1 compound" includes GLP-1 analogs and GLP-1 derivatives.

[0139] As used herein, the term "GLP-1 analog" refers to a peptide or compound that is a variant of human glucagon-like peptide-1 (GLP-1(7-37)), wherein one or more amino acid residues of GLP-1(7-37) are replaced, and / or one or more amino acid residues are deleted, and / or one or more amino acid residues are added. Specifically, the sequence of GLP-1(7-37) is shown in SEQ ID NO: 1 in the sequence listing. The peptide having the sequence shown in SEQ ID NO: 1 may also be referred to as "native" GLP-1 or "native" GLP-1(7-37).

[0140] In the sequence listing, the first amino acid residue (histidine) of SEQ ID NO: 1 is numbered 1. However, hereinafter, in accordance with established conventions in the art, the histidine residue is numbered 7, and subsequent amino acid residues are numbered accordingly, ending with glycine at position 37. Therefore, generally, the amino acid residue numbering or position numbering of the GLP-1 (7-37) sequence referred to herein is a sequence starting with His at position 7 and ending with Gly at position 37.

[0141] The [Gly8, Arg34]GLP-1-(7-37) peptide is a GLP-1 analog having Gly and Arg at positions corresponding to positions 8 and 34 of GLP-1(7-37) (SEQ ID NO: 1), respectively. Specifically, the amino acid sequence of the [Gly8, Arg34]GLP-1-(7-37) peptide is shown in SEQ ID NO: 2 in the sequence listing.

[0142] In the context of a GLP-1 peptide or analog thereof, the term "derivative" as used herein refers to a chemically modified GLP-1 peptide or analog wherein one or more substituents have been covalently attached to the peptide. Substituents may also be referred to as side chains.

[0143] Unless otherwise stated, when reference is made to acylation with a lysine residue, this is understood to be to be carried out with the e-amino group thereof.

[0144] The GLP-1 derivatives of formula (I) of the present invention may exist in different stereoisomeric forms, which have the same molecular formula and the sequence of atoms attached, but differ only in the three-dimensional orientation of their atomic space. Unless otherwise specified, the present invention relates to all stereoisomeric forms of the derivatives claimed.

[0145] The term "peptide" when applied to, for example, the GLP-1 analogs of the present invention, refers to a compound comprising a series of amino acids interconnected by amide (or peptide) bonds.

[0146] In a specific embodiment, the peptide is largely or predominantly composed of amino acids linked to each other by amide bonds (e.g., at least 50%, 60%, 70%, 80%, or at least 90% by molar mass). In another specific embodiment, the peptide is composed of amino acids linked to each other by peptide bonds.

[0147] Amino acids are molecules containing an amino group and a carboxylic acid group, optionally with one or more additional groups, often called side chains.

[0148] The term "amino acid" includes proteinogenic amino acids (encoded by the genetic code, including natural amino acids and standard amino acids), as well as non-proteinogenic (not found in proteins and / or not encoded in the standard genetic code), and synthetic amino acids. Non-proteinogenic amino acids are moieties that can be incorporated into peptides via peptide bonds, but are not proteinogenic amino acids. Synthetic non-proteinogenic amino acids include amino acids produced by chemical synthesis, i.e., D-isomers of amino acids encoded by the genetic code, such as D-alanine and D-leucine, Aib (α-aminoisobutyric acid), Abu (α-aminobutyric acid), 3-aminomethylbenzoic acid, anthranilic acid, desamino-histidine, β-analogs of amino acids such as β-alanine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, and homohistidine, etc.

[0149] Non-limiting examples of amino acids not encoded by the genetic code are γ-carboxyglutamate, ornithine, D-alanine, D-glutamine and phosphoserine. Non-limiting examples of synthetic amino acids are the D-isomers of amino acids, such as D-alanine and D-leucine, Aib (α-aminoisobutyric acid), β-alanine and des-amino-histidine (desH, alternative name imidazole propionic acid, abbreviated Imp).

[0150] In the following, all amino acids not indicating the optical isomer are understood to refer to the L-isomer (unless otherwise specified).

[0151] Pharmaceutically acceptable salts, amides or esters

[0152] The GLP-1 compounds and intermediates of the present invention may be in the form of pharmaceutically acceptable salts, amides, or esters. Salts may be basic salts, acidic salts, or neutral salts. Basic salts produce hydroxide ions in water, while acidic salts produce hydronium ions. Salts of the derivatives of the present invention may be formed using added cations or anions that react with anionic or cationic groups, respectively. These groups may be located within the peptide portion and / or within the side chains of the derivatives of the present invention.

[0153] The limiting examples of the anionic group of derivatives of the present invention include free carboxyl groups in side chains (if any) and peptide moieties. The peptide moiety typically includes the free carboxyl groups at C-ends, and it may also include free carboxyl groups at internal acidic amino acid residues such as Asp and Glu.

[0154] Non-limiting examples of cationic groups on the peptide portion include the free amino group at the N-terminus (if any) and any free amino groups on internal basic amino acid residues such as His, Arg and Lys.

[0155] The esters of the derivatives of the present invention can be formed, for example, by reacting a free carboxylic acid group with an alcohol or phenol, which results in at least one hydroxyl group being substituted with an alkoxy or aryloxy group. The formation of esters can involve the free carboxyl group at the C-terminus of the peptide, and / or any free carboxyl group of a side chain.

[0156] The amides of the derivatives of the present invention can be formed, for example, by reacting a free carboxylic acid group with an amine or substituted amine, or by reacting a free or substituted amino group with a carboxylic acid. The formation of amides can involve the free carboxyl group at the C-terminus of the peptide, any free carboxyl group of a side chain, the free amino group at the N-terminus of the peptide, and / or any free or substituted peptide amino group in the peptide and / or side chain.

[0157] In one specific embodiment, the GLP-1 compound or GLP-1 derivative of the present invention is in the form of a pharmaceutically acceptable salt. In another specific embodiment, it is in the form of a pharmaceutically acceptable amide, preferably with an amide group at the C-terminus of the peptide. In yet a further specific embodiment, the peptide or derivative is in the form of a pharmaceutically acceptable ester.

[0158] Methods for preparing the GLP-1(7-37) peptides and GLP-1 analogs of the present invention are well known in the art. For example, the GLP-1 peptide portion (or fragment thereof) of the derivatives of the present invention and the GLP-1 analogs of the present invention can be produced by classical peptide synthesis, such as solid-phase peptide synthesis using t-Boc or Fmoc chemistry, or other well-established techniques, see, for example, Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1999, Florencio Zaragoza, "Organic Synthesis on solid Phase", Wiley-VCH Verlag GmbH, 2000, and "Fmoc Solid Phase Peptide Synthesis", edited by WC Chan and PD White, Oxford University Press, 2000.

[0159] In one embodiment, the complete GLP-1 analogs of the present invention, such as [Gly8, Arg34]GLP-1-(7-37) peptides, can be produced recombinantly by culturing host cells that contain a DNA sequence encoding the analog and are capable of expressing the peptide in a suitable nutrient medium under conditions that allow expression of the peptide. Non-limiting examples of host cells suitable for expressing these peptides include Escherichia coli, Saccharomyces scerevisiae, and mammalian BHK or CHO cell lines. In some embodiments, such a fully recombinant fermentation step of the production process is desirable, for example, for production economics.

[0160] The fusion protein inclusion bodies containing the GLP-1 compound backbone are denatured and renatured to obtain a fusion protein with the correct conformation. After a series of treatments including enzymatic digestion, precipitation, and centrifugation, a high-content GLP-1 compound backbone is obtained. Purification by ion exchange chromatography yields a high-purity GLP-1 compound backbone.

[0161] The GLP-1 compound of the present invention has GLP-1 activity. GLP-1 activity refers to the ability to bind to the GLP-1 receptor and trigger a signal transduction pathway to produce an insulinotropic effect or other physiological effects.

[0162] In this document, the naming of insulin or GLP-1 compounds is carried out according to the following principles: the name is given according to the mutation and modification (e.g., acylation) relative to human insulin, or the mutation and modification (e.g., acylation) relative to native GLP-1 (7-37). The naming of the acyl moiety is carried out according to IUPAC nomenclature and, in other cases, according to peptide nomenclature. For example, the following acyl moiety is named:

[0163] For example, it can be named "eicosanedioyl-γGlu-OEG-OEG", "eicosanedioyl-γGlu-2xOEG" or "eicosanedioyl-gGlu-2xOEG", "19-carboxynonadecanoyl-γGlu-2xOEG" or "19-carboxynonadecanoyl-γGlu-OEG-OEG", where OEG represents the abbreviation of the group -NH(CH2)2O(CH2)2OCH2CO- (i.e., 2-[2-(2-aminoethoxy)ethoxy]acetyl), and γGlu (and gGlu) is a shorthand representation of the amino acid γglutamic acid in the L configuration. Alternatively, the acyl moiety can be named according to IUPAC nomenclature (OpenEye, IUPAC format). According to this nomenclature, the above-mentioned acyl moieties of the present invention are referred to as the following names: “[2-[2-[2-[2-[2-[2-[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]-amino]-ethoxy]-ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]” or “[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]”.

[0164] The term "treatment" includes therapeutic treatment, prophylactic treatment, and use in reducing the risk of a subject developing a disease or other risk factors. Treatment does not require a complete cure of the disease, but includes embodiments in which symptoms are alleviated or underlying risk factors are mitigated.

[0165] The term "prevent" does not require 100% elimination of the likelihood of an event. Rather, it means that the likelihood of an event occurring is reduced in the presence of the compound or method.

[0166] The term "subject" refers to a mammal, preferably a human.

[0167] dementia

[0168] The term "dementia" refers to all forms and stages of the dementia continuum. Dementia is selected from the indications defined in ICD-11 (International Classification of Diseases): dementia due to Alzheimer's disease; dementia due to early-onset Alzheimer's disease; autosomal dominant Alzheimer's disease dementia, presenilin 1 mutation; autosomal dominant Alzheimer's disease dementia, presenilin 2 mutation; autosomal dominant Alzheimer's disease dementia, amyloid precursor protein mutation; dementia due to late-onset Alzheimer's disease; Alzheimer's disease dementia, mixed type, with cerebrovascular disease; Alzheimer's disease dementia, mixed type, with other nonvascular causes; non-amnestic Alzheimer's disease dementia subtype; non-amnestic Alzheimer's disease dementia, logopenic variant; non-amnestic Alzheimer's disease, logopenic variant with primary progressive aphasia; nonamnestic Alzheimer's disease dementia, visuospatial variant; nonamnestic Alzheimer's disease dementia, visuospatial variant with posterior cortical atrophy; nonamnestic Alzheimer's disease dementia, frontal variant; Alzheimer's disease dementia with psychosis; Alzheimer's disease dementia with depression; dementia due to cerebrovascular disease; hemorrhagic subtype of vascular dementia; ischemic subtype of vascular dementia; multi-infarct dementia; single critical infarct dementia; dementia due to subcortical vascular encephalopathy; dementia due to anoxic encephalopathy; dementia due to genetic causes; dementia due to central nervous system Dementia due to systemic vasculitis; Dementia due to hypertensive encephalopathy; Dementia due to intracerebral hypertensive hemorrhage; Dementia due to cerebral amyloid angiopathy; Dementia due to Lewy body disease; Frontotemporal dementia; Frontotemporal dementia, behavioral variant; Frontotemporal dementia, language variant; Frontotemporal dementia, nonfluent or agrammatic variant; Frontotemporal dementia, semantic variant; Frontotemporal dementia, logopenic variant; Frontotemporal dementia with motor neuron disease; Frontotemporal dementia with familial inclusion body myopathy and Paget's disease of bone; Frontotemporal dementia caused by inherited mutations; Frontotemporal dementia caused by mutations in C9orf72; Frontotemporal dementia caused by MAPT Frontotemporal dementia caused by mutations; Frontotemporal dementia caused by VCP mutations; Frontotemporal dementia caused by GRN mutations; Frontotemporal dementia caused by CHMP2B mutations; Frontotemporal dementia caused by FUS mutations; Frontotemporal dementia caused by TARDBP mutations; Frontotemporal dementia caused by other mutations or novel mutations; Dementia caused by psychoactive substances, including drugs; Dementia caused by alcohol abuse; Dementia caused by use of sedatives, hypnotics, or anxiolytics; Post-hallucinogenic perceptual disorder; Dementia caused by use of volatile inhalants; Post-radiation dementia; Dementia caused by carbon monoxide poisoning; Dementia caused by drug poisoning; Dementia or Parkinson's disease caused by manganese poisoning;Dementia due to other classified conditions; dementia due to certain degenerative diseases of the central nervous system; dementia due to Parkinson's disease; dementia due to Huntington's disease; dementia due to corticobasal degeneration; dementia due to progressive supranuclear palsy; dementia due to neurofilament inclusion disease; dementia due to progressive subcortical gliosis; dementia due to multiple system atrophy; dementia due to spinocerebellar ataxia; dementia due to neurodegeneration with brain iron accumulation; dementia due to leukodystrophy; dementia due to Guam Parkinsonism-dementia syndrome; dementia due to certain infectious diseases; dementia due to human immunodeficiency virus; dementia due to neurosyphilis; dementia due to herpes encephalitis Dementia; dementia due to trypanosomiasis; dementia due to neurocysticercosis; dementia due to Lyme disease; dementia due to Whipple's disease; dementia due to progressive multifocal leukoencephalopathy; certain primary degenerative dementias; dementia with neurofibrillary tangles; familial multisystem tauopathy; argyrophilic grain disease; dementia due to certain central nervous system disorders; dementia due to multiple sclerosis; dementia due to prion diseases; dementia due to sporadic Creutzfeldt-Jakob disease; dementia due to variant Creutzfeldt-Jakob disease; dementia due to familial Creutzfeldt-Jakob disease; dementia due to iatrogenic Creutzfeldt-Jakob disease; dementia due to sporadic fatal insomnia; dementia due to fatal familial insomnia; dementia due to Gerstmann-St. Dementia caused by Raussler-Scheinker syndrome; dementia caused by kuru; dementia caused by acute demyelinating encephalomyelitis; dementia caused by subacute sclerosing panencephalitis; dementia caused by Hashimoto's encephalopathy; dementia caused by paraneoplastic encephalitis; dementia caused by autoimmune encephalitis; dementia caused by primary central nervous system tumors; dementia caused by metastatic brain tumors; dementia caused by epilepsy; dementia caused by normal pressure hydrocephalus; dementia caused by metabolic disorders involving the brain; dementia caused by head injury; dementia caused by chronic subdural hematoma; dementia caused by obstructive hydrocephalus; dementia caused by exposure to heavy metals and other toxins; dementia caused by nutritional deficiencies Dementia; dementia caused by thiamine deficiency; dementia caused by vitamin B12 deficiency; dementia caused by folic acid deficiency; dementia caused by vitamin E deficiency; dementia caused by iron deficiency; dementia caused by other nutritional deficiencies; dementia caused by pellagra; dementia caused by metabolic disorders; dementia caused by hypercalcemia; dementia caused by acquired hypothyroidism; dementia caused by Wilson's disease; dementia caused by dialysis; dementia caused by liver failure; dementia caused by renal failure; dementia caused by chromosomal abnormalities; dementia caused by Down syndrome; dementia caused by fragile X syndrome; dementia caused by rheumatic diseases; dementia caused by polyarteritis nodosa; dementia caused by systemic lupus erythematosus;Dementia due to Behçet's disease; dementia due to certain specific causes; behavioral or psychologic disturbances in dementia; psychotic symptoms in dementia; emotional symptoms in dementia; anxiety symptoms in dementia; apathy in dementia; agitation or aggression in dementia; disinhibition in dementia; wandering in dementia; terminal dementia; degenerative dementia; presenile psychotic disorder; delusional dementia; presenile dementia, unspecified; senile dementia; and senile dementia.

[0169] Parkinson's disease

[0170] The term "Parkinson's disease" refers to a condition called a motor system disorder that results from a loss of dopamine-producing brain cells. The main symptoms of PD are tremors or shaking in the hands, arms, legs, jaw, and face; stiffness or rigidity in the limbs and trunk; slow or delayed movements; and postural instability or impaired balance and coordination. As these symptoms become more pronounced, people may have difficulty walking, talking, or completing other simple tasks. PD usually affects people over the age of 50. The early symptoms of PD are subtle and develop gradually. In some people, the disease progresses faster than in others.

[0171] Abbreviations

[0172] PBS refers to Phosphate Buffer Solution

[0173] PBST refers to PBS solution with Tween-20 added

[0174] RI refers to the recognition index

[0175] NC refers to normal control

[0176] MC refers to model control

[0177] SEM stands for Standard Error of Mean

[0178] Aβ refers to amyloid beta protein

[0179] PS1 refers to Presenilin-1

[0180] ADAM10 stands for A Disintegrin And Metalloprotease domain-containing protein 10

[0181] BACE-1 stands for β-site amyloid precursor protein cleaving enzyme-1 (β-site APP cleaving enzyme-1)

[0182] APP stands for amyloid precursor protein (APP)

[0183] PD refers to Parkinson's disease (PD)

[0184] L-DOPA stands for levodopamine

[0185] RM refers to rasagiline

[0186] MPTP refers to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

[0187] DMSO refers to dimethylsulfoxide

[0188] TH refers to tyrosine hydroxylase

[0189] MDA refers to malondialdehyde

[0190] SOD stands for Super Oxide Dismutase

[0191] WB refers to Western blot

[0192] pAKT refers to phosphorylated protein kinase B

[0193] AKT stands for protein kinase B

[0194] ERK stands for mitogen-activated protein kinase (extracellular regulated protein kinases)

[0195] pERK refers to phosphorylated mitogen-activated protein kinase or extracellular regulated protein kinase (ERK)

[0196] Cleaved-Caspase-3 refers to fragmented cysteine-containing aspartate proteinase-3 (Cleaved-cysteinyl aspartate specific proteinase)

[0197] NS means no statistical difference (No Significance)

[0198] Na2HPO4 is disodium hydrogen phosphate;

[0199] NaOH is sodium hydroxide;

[0200] OEG is the amino acid residue -NH(CH2)2O(CH2)2OCH2CO-;

[0201] OSu is succinimidyl-1-yloxy-2,5-dioxo-pyrrolidin-1-yloxy;

[0202] OtBu is tert-butyloxy;

[0203] HCl is hydrogen chloride;

[0204] γGlu is γL-glutamyl;

[0205] NHS is N-hydroxysuccinimide;

[0206] DCC is dicyclohexylcarbodiimide;

[0207] Gly is glycine;

[0208] Arg is arginine;

[0209] TFA is trifluoroacetic acid;

[0210] BSA is bovine serum albumin;

[0211] DAB is diaminobenzidine;

[0212] OCT is a water-soluble mixture of polyethylene glycol and polyvinyl alcohol.

[0213] experimental animals

[0214] Experimental Animal 1: Examples 2-3 of the present invention used wild-type mice and 4×FAD transgenic mice (an APP / PS1 double transgenic mouse model that simultaneously expresses four familial AD mutant genes. This strain of model mice can express a large amount of Aβ42. Aβ deposits can be detected in the cortex and hippocampus of 1.5-month-old female mice and 2-month-old male mice. Aβ deposits gradually increase with age). 4×FAD transgenic mice can simulate Aβ amyloid protein deposits in the brains of AD patients, have most of the pathological and behavioral characteristics of AD, and are a commonly used and ideal animal model for studying AD.

[0215] Animal grade: SPF grade

[0216] Source of experimental animals: Jiangsu Jicui Pharmaceutical Co., Ltd., production license number SCXK(Guangdong)2020-0054.

[0217] Certificate number: 320727211100406825

[0218] Animals were housed in polycarbonate boxes in an SPF-grade animal room at the Experimental Animal Center of Xiamen University, with no more than five animals per cage. The environmental conditions were controlled at 20.0-26.0°C, relative humidity 40-70%, and a 12h / 12h light / dark cycle.

[0219] Experimental Animal 2: The C57bl / 6 mouse used in Example 4 of the present invention is a widely used experimental animal strain with a long growth cycle and rapid reproduction. It is primarily used in research related to neurological diseases. This strain is sensitive to MPTP and is prone to developing Parkinson's symptoms, making it widely used in the construction of Parkinson's disease models.

[0220] Animal grade: SPF grade

[0221] Source of experimental animals: Jiangsu Jicui Pharmaceutical Co., Ltd., production license number SCXK(Guangdong)2020-0054.

[0222] Animals were housed in polycarbonate boxes in an SPF-grade animal room at the Experimental Animal Center of Xiamen University, with no more than five animals per cage. The environmental conditions were controlled at 20.0-26.0°C, relative humidity 40-70%, and a 12h / 12h light / dark cycle.

[0223] Example 1

[0224] Compound (I) N-ε 26 Preparation of -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide

[0225] 1.1 [Gly8, Arg34]GLP-1-(7-37) peptide was prepared by a general protein recombinant expression method (for specific methods, see Molecular Cloning: A Laboratory Manual (Fourth Edition), Michael R. Green, Cold Spring Harbor Press, 2012). [Gly8, Arg34]GLP-1-(7-37) peptide (5 g, 1.48 mmol) was dissolved in 100 mM aqueous Na2HPO4 solution (150 mL), acetonitrile (100 mL) was added, and the pH was adjusted to pH 10-12.5 with 1N NaOH. tert-Butyldocosanedioyl-γGlu-(2xOEG-OSu)-OtBu (1.63 g, 1.63 mmol) was dissolved in acetonitrile (50 mL) and slowly added to the [Gly8, Arg34]GLP-1-(7-37) peptide solution. The pH was maintained at 10-12.5. After 120 minutes, the reaction mixture was added to water (150 mL) and the pH was adjusted to 5.0 with a 1N HCl aqueous solution. The precipitate was separated by centrifugation and lyophilized. The crude product was added to a mixed solution of trifluoroacetic acid (60 mL) and dichloromethane (60 mL) and stirred at room temperature for 30 minutes. The mixture was concentrated to about 30 mL and poured into ice-cold n-heptane (300 mL). The precipitated product was separated by filtration and washed twice with n-heptane. After vacuum drying, the product was purified by ion exchange chromatography (Ressource Q, 0.25%-1.25% ammonium acetate gradient in 42.5% ethanol, pH 7.5) and reverse phase chromatography (acetonitrile, water, TFA). The purified fractions were combined, the pH was adjusted to 5.2 with 1N HCl, the precipitate was separated, and lyophilized to obtain the title compound.

[0226] LC-MS (electrospray): m / z = 1035.79 (M+4H) 4+

[0227] 1.2 Preparation of the intermediate tert-butyl docosanoyl-γGlu-(2xOEG-OSu)-OtBu

[0228] 1.2.1 tert-Butyleicosandioyl-OSu

[0229] Under nitrogen, mono-tert-butyl docosanedioate (20 g, 46.91 mmol) and NHS (5.40 g, 46.91 mmol) were mixed in dichloromethane (400 mL). Triethylamine (13.95 mL) was added, and the resulting turbid mixture was stirred at room temperature. DCC (10.65 g, 51.60 mmol) was then added and stirred overnight. The mixture was filtered, and the filtrate was concentrated to near dryness. The residue was mixed with cold water and ethyl acetate, stirred for 20 minutes, and separated. The upper organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to near dryness under reduced pressure and dried overnight in vacuo to obtain 23.84 g (97% yield) of tert-butyl docosanedioyl-OSu.

[0230] LC-MS(Scie×100API): m / z=524.39(M+1) +

[0231] 1.2.2 Tert-Butyldocosanedioyl-γGlu-OtBu

[0232] tert-Butyldocosandioyl-OSu (23.84 g, 45.50 mmol) was dissolved in dichloromethane (250 mL) and stirred. H-Glu-OtBu (10.17 g, 50.05 mmol), triethylamine (12.49 mL), and water (25 mL) were added sequentially. The mixture was heated to obtain a clear solution, which was stirred at room temperature for 4 hours. A 10% aqueous citric acid solution (200 mL) was then added, and the layers were separated. The lower organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to near dryness and dried under vacuum overnight. This yielded 26.71 g (96% yield) of tert-Butyldocosandioyl-γGlu-OtBu.

[0233] LC-MS(Scie×100API): m / z=612.48(M+1) +

[0234] 1.2.3 Tert-Butyldocosanedioyl-γGlu-(OSu)-OtBu

[0235] Under nitrogen, tert-butyldocosandioyl-γGlu-OtBu (26.71 g, 43.68 mmol) was dissolved in dichloromethane (300 mL). Triethylamine (11.99 mL) was added and stirred for 10 minutes. NHS (5.03 g, 43.68 mmol) was then added, followed by DCC (9.91 g, 48.05 mmol). The mixture was stirred at room temperature overnight. Filtered, the resulting filtrate was concentrated to near dryness, and the residue was mixed with cold water and ethyl acetate, stirred for 20 minutes. The layers were separated, and the upper organic phase was washed with saturated brine. After separation, the upper organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to near dryness under reduced pressure. Methyl tert-butyl ether was added, stirred for 30 minutes, and filtered. The filter cake was dried under vacuum overnight to yield 25.07 g (81% yield) of tert-butyldocosandioyl-γGlu-(OSu)-OtBu.

[0236] LC-MS(Scie×100API): m / z=709.49(M+1) +

[0237] 1.2.4 tert-Butyldocosanedioyl-γGlu-(2xOEG-OH)-OtBu

[0238] Tert-butyldocosanedioyl-γGlu-(OSu)-OtBu (25.07 g, 35.38 mmol) was dissolved in dichloromethane (250 mL) and stirred. 2xOEG (11.99 g, 38.92 mmol), triethylamine (9.71 mL), and water (25 mL) were added sequentially. The mixture was heated to obtain a clear solution, which was stirred at room temperature for 4 hours. A 10% aqueous citric acid solution (200 mL) was then added to separate the layers. The lower organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to near dryness and dried under vacuum overnight. This yielded 29.66 g (93% yield) of tert-butyldocosanedioyl-γGlu-(2xOEG-OH)-OtBu.

[0239] LC-MS(Scie×100API): m / z=902.62(M+1) +

[0240] 1.2.5 tert-Butyldocosanedioyl-γGlu-(2xOEG-OSu)-OtBu

[0241] Under nitrogen, tert-butyldocosanedioyl-γGlu-(2xOEG-OH)-OtBu (29.66 g, 32.90 mmol) was dissolved in dichloromethane (300 mL). Triethylamine (9.03 mL) was added and stirred for 10 minutes. NHS (3.79 g, 32.90 mmol) was then added, followed by DCC (7.47 g, 36.19 mmol). The mixture was stirred at room temperature overnight. Filtered, the resulting filtrate was concentrated to near dryness, and the residue was mixed with cold water and ethyl acetate, stirred for 20 minutes, and separated. The upper organic phase was washed with saturated brine. After separation, the upper organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to near dryness under reduced pressure and dried overnight in vacuo to obtain 29.90 g (91% yield) of tert-butyldocosanedioyl-γGlu-(2xOEG-OSu)-OtBu.

[0242] LC-MS(Scie×100API): m / z=999.64(M+1) +

[0243] Example 2 Therapeutic Effect of Compound (I) on 4×FAD Double Transgenic Alzheimer's Disease (AD) Mice (Positive Drug is Semaglutide)

[0244] Compound (I) was prepared according to the method in Example 1. The positive drug semaglutide was purchased from Novo Nordisk (China) Pharmaceutical Co., Ltd. (Batch No.: National Medicine Standard SJ20210015). The solvent was homemade in the laboratory (formula: 1.42 mg / ml anhydrous disodium hydrogen phosphate; 14 mg / ml propylene glycol; 5.5 mg / ml phenol; pH 7.3).

[0245] 2.1 Experimental Grouping

[0246] Based on water maze results, 4×FAD transgenic mice exhibiting cognitive impairment were randomly divided into either a vehicle group (i.e., model control group, MC group) or a treatment group. These groups received subcutaneous injections of vehicle, compound (I) at 1 nmol / kg, 3 nmol / kg, and 10 nmol / kg, or the active agent semaglutide at 10 nmol / kg. Wild-type mice (WT) served as the NC group and received subcutaneous injections of vehicle. Drugs were administered once daily for 9 weeks. Grouping and dosing information are shown in Table 1.

[0247] Table 1 Experimental group 1

[0248] 2.2 Visual observation after administration

[0249] Local observation after drug administration: In the last week of drug administration, one mouse in each of the MC group and the compound (I) 10 noml / kg group developed skin ulceration at the subcutaneous injection site, but no nodules were found.

[0250] After 9 weeks of experiment, no mice died or showed other obvious symptoms, indicating that compound (I) of the present invention had no obvious drug toxicity or side effects.

[0251] 2.3 Effect of compound (I) on weight reduction in AD model mice

[0252] In this study, we measured the weight of mice weekly and recorded its changes. The first 45 days were the adaptation period for mice, and drug administration began on day 46, with dosing once a day. As shown in Figure 1, the weight of mice in both the NC and MC groups showed a slow upward trend, with mice in the MC group weighing less than those in the NC group. Before drug administration, 4×FAD mice weighed less than the NC group. After drug administration, the weight of mice in the NC group showed stable fluctuations, except for a decrease during behavioral testing from day 67 to day 83. Compared with the MC group, the weight of mice in the 1 nmol / kg, 3 nmol / kg, and 10 nmol / kg groups of semaglutide and compound (I) showed a decreasing trend after drug administration, but there was no statistical difference (P>0.05).

[0253] 2.4 Water maze experiment for measuring spatial learning and memory

[0254] The water maze is an experimental method that forces animals to swim and learn to locate a platform hidden in water. It is primarily used to test their ability to learn and remember spatial position and orientation (spatial localization). Within a given timeframe, shorter first platform crossing times, more platform crossings, and longer periods spent in the target quadrant indicate better spatial learning and memory abilities. The total distance swum is directly related to the animal's swimming speed, and swimming speed reflects differences in the animal's motor abilities. In this study, water maze testing was performed 4 and 9 weeks after drug administration. The test consisted of a localization navigation test (training phase) and a spatial exploration test (test phase). Testing began daily 30 ± 15 minutes after drug administration, with animals evenly distributed across the groups. In the localization navigation test, animals entered the water from three fixed points for 60 seconds each time. If an animal found the platform within 60 seconds, the system automatically recorded the result. If the animal could not find the platform within 60 seconds, it was guided to the platform and remained there for 5-10 seconds. Each parameter was averaged over three trials. The orientation navigation cycle lasted for 5 days. After the orientation navigation training was completed (the 6th day of each round of water maze test), the spatial exploration test was carried out by removing the platform and placing the animal from the opposite quadrant of the platform for 60 seconds.

[0255] FIG2A is a diagram showing the traces of the water maze test 4 weeks after drug administration.

[0256] Figure 2B shows the water maze test traces after 9 weeks of drug administration. As shown in Figure 2C, compared with the NC group, the MC group showed significant changes in indicators such as "number of platform crossings," "platform dwell time," "first platform crossing time," and "target quadrant occupancy percentage" (P<0.01, P<0.05, P<0.001, and P<0.01), indicating that the course of cognitive dysfunction in AD mice in the MC group was stable. Compared with the MC group, the "first platform crossing time" in the group treated with 1 nmol / kg of Compound (I) was significantly reduced (P<0.01). The group treated with 3 nmol / kg of Compound (I) showed significant changes in all four indicators: "number of platform crossings," "platform dwell time," "first platform crossing time," and "target quadrant occupancy percentage" (P<0.001, P<0.01, P<0.001, and P<0.001), indicating that long-term administration of Compound (I) is most effective in improving cognitive impairment in AD, superior to high-dose semaglutide. Furthermore, these positive effects on cognitive parameters appear to be novel effects of Compound I that are not driven by changes in body weight.

[0257] 2.5 Novel Object Recognition Experiment for Studying Recognition Memory

[0258] Novel object recognition is a behavioral method that uses the rodent's natural tendency to approach and explore novel objects to test an animal's fine recognition memory. The mouse's memory ability is evaluated by measuring the number and duration of activity around new and old objects. If the mouse has poor cognitive ability, there will be no difference in the exploration of new and old objects; if the mouse has normal cognitive ability, it will explore new objects longer than old objects. The recognition index (RI) is calculated as follows: RI = new object / (new object + old object) × 100%. There are generally two calculation methods based on the number of times the mouse is exposed to the new object and the duration of exposure to the new object.

[0259] Experimental steps: Prepare a test box. Before each test, wipe the box and the objects to be used with 75% alcohol.

[0260] (a) Novel object recognition adaptation period: Before the start of the experiment, four identical objects were placed in the novel object recognition box (two objects in the first two rounds of behavioral testing). 30 ± 15 min after drug administration, the mice were placed in the novel object recognition box and moved autonomously for 10 min.

[0261] (b) Novel object recognition test: After an interval of 5±0.5 h, the experimental equipment was the same as that of the adaptation period. Before the start of the test, four objects were placed in the novel object recognition box (three of which were the same as those in the adaptation period, and the other was different from the adaptation period as a new object). The mice were placed in the novel object recognition box and moved independently for 5 min.

[0262] As shown in Figure 3, during the training phase (first session), the novel object recognition index of mice in each treatment group was approximately 50%, indicating that each group of mice spent 50% of their time on the two identical objects. During the test phase (second session), the novel object recognition index of mice in the NC group was approximately 70%, higher than that during the training phase, indicating that the NC group mice displayed good memory for the novel object. The novel object recognition index of mice in the MC group was approximately 50%, which was not significantly different from that during the training phase, indicating that the MC group mice did not form good memory for the novel object. The cognitive coefficients (based on the number of traversals and time) of mice in the Compound (I)-treated group during the test phase were improved compared to those during the training phase, and the increase in cognitive coefficients became more significant with increasing dose, indicating that Compound (I) can improve cognitive dysfunction in AD in a dose-dependent manner. Furthermore, at the same dose, the improvement in cognitive coefficients (based on the number of traversals and time) of mice in the Compound (I)-treated group during the test phase compared to the training phase was significantly greater than that of the active drug semaglutide, indicating that Compound (I) has a significantly better improvement effect than semaglutide. Furthermore, the improvement in cognitive performance appears to be a novel effect of Compound I that is not driven by changes in body weight.

[0263] 2.6 Open field experiments for studying free behavior

[0264] The open field test was used to investigate the effects of compound (I) on the autonomous behavior of AD mice. This is a behavioral experiment that observes and studies various neuropsychiatric changes in experimental animals after they enter an open environment. For example, due to fear of new, open environments, animals primarily move in the peripheral areas and less in the central areas. However, their exploratory nature motivates them to move in the central areas, and the resulting anxiety can also be observed. The more times an animal moves in the central area and the longer it spends in the central area, the lower its anxiety level. The total distance and speed of movement reflect the animal's motor function.

[0265] Figure 4A shows an open field trajectory image. It shows that compared to the MC group, the Compound (I) 1, 3, and 10 nmol / kg groups showed an increased tendency to move in the central area, suggesting that Compound (I) can improve anxiety-like behaviors in AD mice. Furthermore, at the same dose, the trajectory of mice in the Compound (I)-treated group was more chaotic than that of mice in the semaglutide group, with more frequent entries into the central area, suggesting that Compound (I) has a greater therapeutic effect than semaglutide.

[0266] Figures 4B(a)-4B(f) show that compared with the MC group, compound (I) at different doses significantly altered the indicators of "number of crossings to the central area," "time spent in the central area," "percentage of time spent in the central area," "time of first crossing to the central area," "speed," and "total distance." Furthermore, these positive effects on cognitive parameters appear to be novel effects of compound I that are not driven by changes in body weight. At the same dose, all indicators of mice treated with compound (I) were superior to those of the semaglutide group, indicating that compound (I) at different doses can improve anxiety-like behavior in AD mice, and the improvement effect is superior to that of semaglutide.

[0267] 2.7 Platform Jumping Experiment for Detecting Fear Memory

[0268] The jumping platform test is a behavioral method for detecting fear memory in animals. In an open area, rodents spend most of their time near walls or in corners. However, when placed on a raised platform, they instinctively jump down quickly, taking shelter near walls or corners. The jumping platform is constructed with an electrically powered base and an insulated platform placed on top. During training, animals receive electric shocks and jump onto the platform to avoid the shock, thereby acquiring a memory. A decline in an animal's memory is reflected by a shorter latency period before jumping off the platform and an increased number of jumps. A shorter latency period and a higher number of errors during the test indicate a poorer fear memory.

[0269] Experimental procedures: Place the animal on the platform and allow it to freely move up and down within the box for 2-3 minutes to fully adapt to the experimenter's gestures and the entire experimental process (acclimatization period). Immediately after the animal has adapted, turn on the electric stimulator to power the copper grid at the bottom of the box. Place the animal on the bottom of the box, and its limbs will immediately receive an electric shock. The animal will jump onto the platform to avoid it, then immediately jump off the platform again. This process will be repeated multiple times (training period). Twenty-four hours after training, the testing phase begins. The animal's memory performance is tested by placing the animal on the platform, and the time from the time the animal is placed on the platform to the time it jumps off the platform (latency period) is recorded, as well as the number of errors it makes within 5 minutes.

[0270] As shown in Figures 5A and 5B, 24 hours after training, the number of platform-jumping errors in the MC group was significantly increased compared to the NC group (P<0.01), suggesting that the MC group weakened the ability of AD mice to maintain fear memory. Compared with the MC group, the low, medium, and high dose groups of Compound (I) all showed a significant improvement in the number of platform-jumping errors in a dose-dependent manner (P<0.01, P<0.001, P<0.001), and were comparable to the NC group, indicating that Compound (I) can improve the ability of AD mice to maintain fear memory to a level comparable to that of normal mice. At the same dose, the number of errors in Compound (I) was far less than that in semaglutide, indicating that Compound (I) has a better therapeutic effect than semaglutide.

[0271] 2.8 Effect of compound (I) on senile plaque formation in the brains of AD mice

[0272] One of the key neuropathological hallmarks of AD is the formation of extracellular senile plaques (SPs). These sticky protein plaques ultimately lead to synaptic damage and are a key pathophysiological process in AD. The core component of SPs is β-amyloid protein (Aβ), which is often surrounded by reactive astrocytes, activated microglia, and dystrophic axons. Studies have shown that abnormal Aβ metabolism and deposition are key factors in the development and progression of AD.

[0273] Experimental steps: Samples were collected from AD mice, and toluidine blue and Aβ immunofluorescence staining were performed to observe the survival of hippocampal CA1 neurons and Aβ deposition: air-dry the slides → wash → defatting → wash → stain → wash → differentiate → wash → dehydrate → transparent → seal the slides → take pictures.

[0274] 2.8.1 Toluidine blue staining to observe neuronal morphology:

[0275] Cardiac perfusion was performed with pre-chilled PBS and 4% paraformaldehyde. Whole brain tissue was dehydrated using a gradient of 20% and 30% sucrose solutions, and 30 μm thick frozen sections were prepared. The sections were stained with 0.5% toluidine blue for 20 minutes, dehydrated with alcohol, cleared with xylene, and mounted with neutral resin. Neuronal morphology in the hippocampal CA1 region was observed and images were captured under a light microscope.

[0276] 2.8.2 Immunofluorescence staining:

[0277] Brain slices at the hippocampus level were selected and immersed in PBS for 5 min to remove the OCT embedding medium;

[0278] Permeabilization: Place the membrane in PBST containing 0.3% TritonX-100 at room temperature for 10 minutes, then let it dry and draw circles with an immunohistochemistry pen;

[0279] Blocking: add one drop of PBST (0.3% TritonX-100) containing 2% normal goat serum to each brain slice, place in a humidified chamber, and block at room temperature for 2 h;

[0280] Primary antibody reaction: discard the blocking serum with filter paper, add the corresponding primary antibody reaction solution: Aβ (1:200), slightly covering the brain slice, and incubate in a refrigerator at 4°C overnight;

[0281] Fluorescent secondary antibody reaction: The next day, the brain slices were washed three times in PBST and incubated with the corresponding fluorescent secondary antibody (1:300) at room temperature in the dark for 2 h. After the secondary antibody incubation, the slices were washed three times with PBST, dried with filter paper, and incubated in DAPI working solution in the dark for about 6 min, and then washed three times with PBST.

[0282] Mounting: Remove moisture from the periphery of the brain slice, add an appropriate amount of anti-fluorescence quenching solution, and cover with a coverslip starting from one end, taking care to prevent the formation of bubbles. Store in a humidified chamber at 4°C and observe and photograph under a confocal fluorescence microscope. Immunohistochemistry and immunofluorescence were used to locate and quantify Aβ deposition in the brains of different mouse groups.

[0283] As shown in Figure 6A, the immunohistochemistry results showed that compared with the NC group mice, a large amount of Aβ deposition was found in the cortex and hippocampus of the MC group mice. The Aβ deposition phenomenon in each drug treatment group showed a relatively significant improvement, and at the same dose, the improvement effect of compound (I) was better than that of semaglutide.

[0284] As shown in the immunofluorescence results of Figures 6B and 6C, compared with the mice in the NC group, the Aβ deposition in the cerebral cortex and hippocampus of the mice in the MC group was significantly increased (cortex: P<0.0001; hippocampus: P<0.001); Compound (I) 1 nmol / kg could significantly improve the Aβ deposition in the cerebral cortex (P<0.0001), and although there was an improvement trend in the hippocampus, there was no significant difference (P>0.05); Compound (I) 3 nmol / kg and Compound (I) 10 nmol / kg both showed significant inhibitory effects on Aβ deposition in the hippocampus and cerebral cortex (Compound (I) 3 nmol / kg: cerebral cortex: P<0.001; hippocampus: P<0.05; Compound (I) 10 nmol / kg: cerebral cortex: P<0.01; hippocampus: P<0.01). The above results indicate that compound (I) may improve AD cognitive dysfunction by reducing extracellular Aβ deposition and inhibiting senile plaque formation.

[0285] 2.9 Effect of Compound (I) on the Expression of Related Proteins Regulating Aβ Metabolism in the Brain of AD Mice

[0286] The occurrence and progression of Alzheimer's disease (AD) are influenced by multiple factors. Mainstream theories suggest that Aβ aggregation is a major etiological factor, and that inhibiting Aβ production or promoting Aβ clearance is essential for AD treatment. Aggregated Aβ is the primary pathogenic factor in Alzheimer's disease (AD). It is formed intracellularly from amyloid precursor protein through a series of processing steps and is secreted into the extracellular space, forming senile plaques. Therefore, this study further examined the expression of aggregated β-amyloid protein (Aβ) in the brains of different mouse groups using Western blot. Amyloid precursor protein (APP) is a transmembrane protein that can be hydrolyzed by α-secretases (such as ADAM10, TACE, and ADAM9), β-amyloid precursor protein cleaving enzyme-1 (BACE-1), and γ-secretases (presenilin-1, presenilin-2, nicastrin, Aph-1, and Pen-2 complexes), releasing secreted APP (sAPPα and sAPPβ) and various active metabolites, including β-amyloid protein (Aβ). Among them, a disintegrin and metalloproteinase 10 (ADAM10) is the predominant α-secretase in neurons, responsible for degrading APP into a non-amyloidogenic form and a key rate-limiting enzyme in inhibiting Aβ production. β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) and γ-secretase (primarily presenilin-1, PS1) produce Aβ by cleaving and enzymatically cleaving amyloid precursor protein (APP). Studies have shown that inhibiting BACE-1, knocking out the BACE-1 gene, or silencing BACE-1 RNA can significantly reduce Aβ production. PS1, as a multifunctional protein, can inhibit Aβ production in different ways. Therefore, to further explore the molecular mechanism by which compound (I) inhibits Aβ production in the brains of AD mice, this study examined the expression of α-secretase (ADAM 10), β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), and γ-secretase (presenilin-1, PS1) in the brains of different mouse groups by Western blot.

[0287] Experimental steps: extract tissue or cell protein; determine protein concentration; perform electrophoresis at a constant voltage of 100V and stop when the dye front migrates to 2-3 cm from the bottom of the gel (about 120 minutes); transfer the membrane at a constant current of 250mA for 2 hours (the time can be adjusted appropriately according to the molecular weight of the target protein); block with 5% skim milk at room temperature for 1 hour; add ADAM10, PS1 and BACE-1 primary antibodies respectively and place in a 4°C refrigerator overnight; collect primary antibodies and wash the membrane three times with PBST, each time for 10 minutes; incubate with secondary antibodies at room temperature for 1 hour; wash the membrane three times with PBST, each time for 10 minutes; develop color.

[0288] As shown in Figure 7A (a), compared with the MC group, compound (I) can reduce the content of aggregated Aβ in the hippocampus at doses of 1 nmol / kg, 3 nmol / kg, and 10 nmol / kg, and the significance of the reduction effect increases with the increase of dose (ns, P<0.05, P<0.05). Moreover, at the same dose, compound (I) reduces the content of aggregated Aβ in the hippocampus much more than semaglutide (ns). The above results indicate that compound (I) can improve the pathological symptoms of AD by reducing the content of aggregated Aβ in the hippocampus, and the improvement effect is better than semaglutide.

[0289] As shown in Figure 7A(b), compared with the MC group, compound (I) at doses of 1 nmol / kg, 3 nmol / kg, and 10 nmol / kg can reduce the content of aggregated Aβ in the cortical region (P<0.01, P<0.05, P<0.01). This indicates that compound (I) can improve AD pathological symptoms by reducing the content of aggregated Aβ in the cortical region.

[0290] As shown in Figure 7B, compared with the MC group, all three dose groups of compound (I) had a reversal effect on the expression of three proteins, PS1, ADAM10, and BACE-1, in the brains of MC mice, and the reversal effect was enhanced with increasing dose. At the same dose, the reversal effect of compound (I) on the expression of the above three proteins was much better than that of semaglutide. The above results indicate that compound (I) can reduce Aβ aggregation in the brain by regulating the activity of three enzymes, PS1, ADAM10, and BACE-1, thereby improving AD pathological symptoms, and the improvement effect is better than that of semaglutide.

[0291] 2.10 Effects of Compound (I) on Neuronal Morphology and Density in the Hippocampus of AD Mice

[0292] In addition to extracellular senile plaques (SP), the neuropathological characteristics of AD also include the selective damage and loss of a large number of neurons in the hippocampus. Abnormal volume and shape of the hippocampus are closely related to cognition, learning and memory. In the early stages of AD, the hippocampus is the first brain region to be damaged, especially the granule cell layer in the CA1 region of the hippocampus, which is the earliest and most susceptible to damage. Neuronal apoptosis is considered to be one of the main reasons for the massive loss of neurons in AD. Toluidine blue staining can be used to stain Nissl bodies in neurons and mark the number and morphology of neurons. In this study, brain sections of mice from different groups were stained with toluidine blue and then scanned panoramically under a 20x microscope. The CA1 region of the hippocampus was selected for magnified observation, and blue-purple Nissl bodies in neurons were visible under the microscope.

[0293] As shown in Figure 8, compared with the NC group, the MC group showed increased structural looseness in the CA1 region of the hippocampus (shown in the box), a decrease in the number of neurons, and more obvious neuronal apoptosis. Compared with the MC group, all drug groups treated with compound (I) showed a certain degree of reversal of the damage to granule neurons in the CA1 region, as shown by the restoration of structural density in the CA1 region and an increase in the number of neurons. These results indicate that compound (I) can play a therapeutic role in AD by reversing structural abnormalities and neuronal death in the hippocampus.

[0294] Example 3 Therapeutic Effect of Compound (I) on 4×FAD Double Transgenic Alzheimer's Disease (AD) Mice (Positive Drug is Donepezil)

[0295] Compound (I) was prepared according to the method in Example 1. The positive drug donepezil was purchased from Weicai (China) Pharmaceutical Co., Ltd., and the solvent was homemade in the laboratory (formula: 1.42 mg / ml anhydrous disodium hydrogen phosphate; 14 mg / ml propylene glycol; 5.5 mg / ml phenol; pH 7.3).

[0296] 3.1 Experimental Grouping

[0297] Before the experiment, 4×FAD transgenic mice were screened using a water maze test to identify mice with AD symptoms. Based on body weight data, the mice were randomly divided into five groups of 10 mice each, half female and half female. WT mice served as the control group, consisting of 10 mice, half male and half female. Dosing was performed once daily for 8 weeks. Grouping and dosing information are shown in Table 2.

[0298] Table 2: Experimental materials

[0299] 3.2 Visual observation after administration

[0300] Local observation: In the last week of drug administration, one mouse in each of the MC group and the compound (I) 10 noml / kg group developed skin ulceration at the subcutaneous injection site, but no nodules were observed.

[0301] After 8 weeks of experiment, no mice died or showed other obvious symptoms, indicating that compound (I) of the present invention had no obvious drug toxicity or side effects and was well tolerated.

[0302] 3.3 Effect of compound (I) on weight reduction in AD model mice

[0303] In this study, we measured the body weight of mice weekly and recorded changes. Days 1 to 21 served as the acclimation period, with dosing beginning on day 28. As shown in Figure 9, the body weight of mice in both the NC and MC groups showed a slow upward trend, with no significant difference between the two groups (P>0.05). Before dosing, the donepezil group weighed less than the MC and NC groups, and after dosing, the donepezil group showed no significant changes in body weight. Compared with the MC group, the body weight of mice in the 5 nmol / kg (low dose), 10 nmol / kg (medium dose), and 20 nmol / kg (high dose) compound (I) groups showed a trend toward differences, but due to significant intra-group variability, no statistical differences were observed (P>0.05). These results indicate that compound (I) has a weight-reducing effect in 4×FAD transgenic mice.

[0304] 3.4 Open field experiment

[0305] The open field test was performed in the same manner as in 2.6. Figure 10 shows the results of the open field test. Figure A shows the open field traces. Compared with the NC group, the activity trajectories of mice in the MC group showed decreased activity in the central region and a shift toward the peripheral region. Compared with the MC group, the drug-treated groups, namely the 5 (low dose), 10 (medium dose), and 20 (high dose) nmol / kg groups of Compound (I), as well as the donepezil group, showed increased activity in the central region, with the enhanced trend being most pronounced in the 20 nmol / kg (high dose) group of Compound (I). Figure B shows the statistical graph of various open field test indicators. As shown, compared with the NC group, the "total distance traveled," "total speed traveled," and "number of crossings through the central region" of mice in the MC group were significantly reduced (P<0.05), indicating decreased motor ability and increased anxiety-like behavior in the MC group. Compared with the MC group, the high-dose Compound (I) group showed significant increases in "total distance traveled" and "total speed traveled" (P<0.0001). Compared with the donepezil group, the "total distance" and "total speed" of the high-dose compound (I) group were also significantly improved (P<0.001), indicating that the ability of compound (I) to improve motor function is better than donepezil; the above results indicate that compound (I) can improve the autonomous activity dysfunction of AD mice.

[0306] Example 4

[0307] Therapeutic effect of compound (I) on MPTP / probenecid-induced Parkinson's disease in mice (positive drugs are levodopa and rasagiline mesylate tablets)

[0308] Compound (I) was prepared according to the method in Example 1. The positive drug levodopa was purchased from Dalian Meilun Biotechnology Co., Ltd., and the positive drug rasagiline mesylate tablets were purchased from Teva Pharmaceutical Industries Ltd. The solvent was homemade in the laboratory (formula: 1.42 mg / ml anhydrous disodium hydrogen phosphate; 14 mg / ml propylene glycol; 5.5 mg / ml phenol; pH 7.3).

[0309] 4.1 Experimental Grouping

[0310] Pre-experimental stimulation: Mice were first intraperitoneally administered with probenecid (dissolved in DMSO, 250 mg / kg), and one hour later, intraperitoneally injected with MPTP (20 mg / kg). The administration was repeated twice a week for 4 consecutive weeks. The NC group was injected with an equal amount of solvent.

[0311] Mice injected with probenecid and MPTP were randomly divided into an MC group, an L-DOPA and RM positive control group, and three low-, medium-, and high-dose groups of Compound (I). Behavioral testing was performed after once-daily administration for 4 consecutive weeks. Grouping and dosing information are shown in Table 3.

[0312] Table 3: Experimental materials

[0313] 4.2 Visual Observation after Administration

[0314] General clinical observations: None of the mice showed abnormal reactions or near-death conditions. The mice's fur remained shiny, their diet and water intake were unaffected, and their bowel movements were normal.

[0315] Local observation: No ulceration or nodules were observed at the injection site. No mice died or suffered other obvious symptoms, indicating that compound (I) of the present invention had no obvious toxic side effects and was well tolerated.

[0316] 4.3 Effect of compound (I) on weight loss in mice with chronic PD induced by probenecid and MPTP

[0317] In this study, we measured and recorded the body weight of mice weekly. Six days before dosing served as an acclimatization period, and body weight was recorded starting on the first day of dosing. As shown in Figure 11, compared to the NC group, the body weight of mice following probenecid and MPTP modeling showed a significant downward trend. Furthermore, both low and medium doses of compound (I) showed a trend toward lower body weight, but due to significant intra-group variability, no significant differences were observed (P>0.05). RM and L-DOPA had no effect on body weight. These results demonstrate that compound (I) has a weight-reducing effect in MPTP-induced chronic PD mice.

[0318] 4.4 Open field experiment

[0319] The open field test was performed in the same manner as in 2.6. Figure 12 shows the results of the open field test. Panel A shows the open field traces. Compared with the NC group, the activity trajectories of mice in the MC group showed decreased activity in the central region and a shift toward the peripheral region. In contrast, compared with the MC group, the drug-treated groups, i.e., the Compound (I) 5 (low dose), 10 (medium dose), and 20 (high dose) nmol / kg groups, showed increased activity in the central region, with the Compound (I) 20 nmol / kg (high dose) group showing the most pronounced increase. Figures B-G show the statistical graphs of various indicators in the open field test. As shown, compared with the NC group, the "number of center zone crossings," "total distance," and "speed" of mice in the MC group were significantly reduced (P<0.05). The "time spent in the center zone" and "percentage of time spent in the center zone" indicators showed a decreasing trend in the MC group, but no statistical difference was found (P>0.05), indicating that the MC group had weakened motor ability and increased anxiety-like behavior. Compared with the MC group, the high-dose compound (I) group significantly improved the "total distance" and "speed" indicators (P<0.0001). Compared with the rasagiline group, the high-dose compound (I) group also significantly increased the "total distance" and "speed" indicators (P<0.001), indicating that the ability of compound (I) to improve motor function is superior to that of the positive drugs rasagiline and levodopamine. For the "time spent in the center zone," "percentage of time spent in the center zone," and "time to first center crossing," all three dose groups of compound (I) showed an increasing trend compared with the MC group. The above results indicate that compound (I) can improve the autonomic dysfunction of PD mice.

[0320] 4.5 Pole climbing experiment

[0321] A mouse was placed on a rough wooden ball, the lower end of which was connected to a rough, round-cross-sectioned wooden stick. The lower end of the stick was placed in a mouse cage. When the mouse climbed from the wooden ball to the stick with its head facing downward, the time at this moment was recorded with a stopwatch as A (i.e., the length of time it took to turn its head). When it climbed to the bottom of the stick, the time at this moment was recorded as B. The time it took for the mouse to climb the entire stick was C (i.e., the total time, C=BA). Each mouse was tested three times, and the average time of the three climbing times was used as a statistical indicator.

[0322] Figure 13A shows the time it takes for mice to turn their heads, and Figure 13B shows the total time it takes for mice to climb the pole. As shown in Figures 13A and 13B, as the number of days of testing increases, the time it takes for mice in the NC group to turn their heads and the total time it takes to climb the pole gradually decreases. Compared with the NC group, the time it takes for mice in the MC group to turn their heads and the total time it takes to climb the pole both tend to increase (P>0.05). Compared with the MC group, the positive drug rasagiline group had a significant improvement on the total time it takes for mice to climb the pole in the tests on the fourth and sixth days (P<0.05), and the low-dose group of compound (I) had an improvement on the total time it takes for mice to climb the pole in the test on the sixth day (P<0.05), suggesting that compound (I) has the effect of improving the motor ability of PD mice.

[0323] 4.6 Rotarod test

[0324] Before the experiment, mice were brought to the laboratory and ensured to be awake. Mice were placed on a 3-cm-diameter rotating rod at a speed of 30 rpm. Five mice were measured simultaneously, with one in each compartment. The time from the moment the mouse was placed on the rod to the moment it fell was recorded. Measurements were repeated five times for 1 minute, with a 1-minute rest period between each measurement. The number of falls within a 1-minute period was recorded.

[0325] As shown in Figure 14, as the test time increased, the residence time of the NC group mice on the rotating rod gradually increased. Compared with the NC group, the MC group had a shorter residence time, indicating that probenecid and MPTP successfully induced a mouse PD model. Compared with the MC group, the positive drugs rasagiline and levodopamine both had an improvement effect, among which the levodopamine group showed significant improvement in the fourth day test (P < 0.05). The low and medium dose groups of compound (I) also showed an improvement effect compared with the MC group. This suggests that compound (I) has the effect of improving the motor coordination ability of PD mice.

[0326] 4.7 Effects of compound (I) on the expression levels of striatum and substantia nigra-related proteins in chronic PD model mice induced by probenecid and MPTP

[0327] After the rotarod test, sacrifice the animal, remove the brain tissue, and isolate the substantia nigra and striatum regions for protein extraction: 1. Pre-chill the centrifuge column and receiving tube cannula on ice. 2. Place 15-20 mg of fresh / frozen tissue onto the centrifuge column and repeatedly triturate with a plastic rod 50-60 times. Add 200 μl of cell lysis buffer and continue triturating for 30-60 times. 3. Cover the tube and incubate at room temperature for 1-2 minutes. Centrifuge at 14,000-16,000 x g for 1-2 minutes. The supernatant in the collection tube contains the extracted total protein. 4. Quantify protein using the BCA assay.

[0328] After electrophoresis, proteins were transferred to a PVDF membrane and blocked at room temperature for 1 hour. Primary antibodies were incubated overnight at 4°C. Secondary antibodies were incubated for 1 hour at room temperature. The PVDF membrane was exposed on a photocatalyst, and the grayscale values ​​of the bands were analyzed using Image J software.

[0329] Protein expression levels in the striatum of mice are shown in Figure 15A. Compared with the NC group, the pAKT, AKT, pERK, and ERK protein levels in the MC group showed a downward trend (P>0.05). Compared with the MC group, the pAKT, AKT, and pERK protein levels in the L-DOPAM group were significantly upregulated (pAKT: P<0.01; AKT: P<0.05; pERK: P<0.05), while the ERK level showed an upward trend. Compared with the MC group, the pAKT, AKT, ERK, and pERK protein levels in the rasagiline group showed an upward trend. Compared with the MC group, the expression of each protein in the low-dose compound (I) group showed an upward trend, with the pAKT protein level showing a significant difference (P<0.05). Compared with the MC group, the pAKT, AKT, pERK, and ERK protein levels in the medium-dose compound (I) group showed an upward trend (P>0.05).

[0330] The changes in protein levels in the substantia nigra of mice are shown in Figure 15B: Compared with the mice in the NC group, the ERK and pERK in the mice in the MC group showed a downward trend (P>0.05), and the cleaved Casepase3 protein content was significantly increased (P<0.05). Compared with the MC group, the ERK and pERK protein levels in the rasagiline group were slightly increased (P>0.05), and the cleaved-Casepase3 protein level was slightly decreased; compared with the MC group, the ERK and pERK protein levels in the L-dopamine group showed an upward trend (P>0.05), and the cleaved-Casepase3 protein level was significantly decreased (P<0.05); compared with the MC group, the pAKT and pERK protein levels in the low-dose compound (I) group were slightly increased (P>0.05), and the cleaved-Casepase3 level was slightly decreased; compared with the MC group, the ERK and pERK levels in the medium-dose compound (I) group were slightly increased, and the cleaved-Casepase3 level was significantly decreased (P<0.001); compared with the MC group, the ERK and pERK protein levels in the high-dose compound (I) group were slightly increased, and the cleaved-Casepase3 level was also significantly decreased (P<0.001). As can be seen from FIG15B , compared with the positive drugs rasagiline and L-dopamine, the high-dose group of compound (I) has a more significant effect on down-regulating ERK and pERK and up-regulating the content of cleaved-Casepase3 protein.

[0331] The above results suggest that compound (I) may improve the pathological symptoms of PD by inhibiting the cleaved-Casepase3 apoptosis-related pathway in the striatum and substantia nigra of PD mice and upregulating ERK protein and pERK protein to improve the pathological symptoms of PD.

[0332] 4.8 Effect of compound (I) on the expression levels of MDA and SOD in the substantia nigra of MPTP-induced chronic PD model mice

[0333] The experimental procedures were the same as those in 4.7. Changes in MDA and SOD levels in the substantia nigra of mice are shown in Figure 16 . As shown in Figure 16A , compared with the NC group, the MDA level in the MC group was significantly increased (P < 0.05). Compared with the MC group, the low, medium, and high doses of rasagiline, levodopamine, and compound (I) all significantly reduced MDA levels (rasagiline and compound (I) low-dose group: P < 0.05; levodopamine and compound (I) medium and high-dose groups: P < 0.01). As shown in Figure 16B , compared with the NC group, the SOD level in the MC group was significantly decreased (P < 0.05). Compared with the MC group, the rasagiline and levodopamine groups significantly increased SOD levels (rasagiline: P < 0.001; levodopamine: P < 0.01). Furthermore, the medium-dose compound (I) group significantly increased SOD levels (P < 0.05). The above results suggest that probenecid and MPTP can induce oxidative stress response in the substantia nigra of PD mice, and compound (I) can improve the oxidative stress level of the substantia nigra by downregulating MDA and upregulating SOD, thereby protecting the substantia nigra. This may be one of the mechanisms of action of compound (I) in improving motor dysfunction in PD mice.

[0334] 4.9 Effect of compound (I) on the immune microenvironment in the substantia nigra of MPTP-induced chronic PD model mice

[0335] Extract total RNA from tissues or cells using Trizol reagent. Place total RNA (10 pg-5 μg) in a centrifuge tube, add 3 μL of 5×g DNA digester mix, and make up to 15 μL with RNase-free ddH2O. Incubate at 42°C for 2 minutes to remove residual genomic DNA. Add 4× Prepare the reverse transcription reaction system using III SuperMix plus. Reverse transcription was performed at 25°C for 5 minutes, 55°C for 15 minutes, and 85°C for 5 minutes to generate first-strand cDNA. SYBR Premix Ex Taq and upstream and downstream primers were then added for qPCR. The conditions were 95°C for 5 seconds, 55°C for 30 seconds, and 72°C for 30 seconds for 40 cycles. The relative CT value of the target gene was compared with the internal control and calculated using 2-ΔΔCT.

[0336] As shown in Figure 17: Compared with the NC group, the levels of inflammatory factors IL-1β, IL-6 and TNF-α in the MC group were significantly increased (IL-1β: P<0.05; IL-6: P<0.01; TNF-α: P<0.01;), and the level of anti-inflammatory factor IL-10 was significantly decreased (P<0.05); compared with the MC group, the level of inflammatory factor IL-1β in the rasagiline group was decreased, and the levels of TNF-α and IL-6 were significantly decreased (TNF-α: P<0.001; IL-6: P<0.05); compared with the MC group, the inflammatory factor TNF-α in the levodopamine group was significantly decreased (P<0.001); compared with the MC group, the low, medium and high doses of compound (I) significantly inhibited the expression of inflammatory factors TNF-α, IL-1β and IL-6 (P<0.01, P<0.001, P<0.001). Compared with the MC group, the low, medium, and high doses of rasagiline, levodopamine, and compound (I) all had effects on the anti-inflammatory factor IL-10. These results suggest that compound (I) may regulate the immune microenvironment of PD mice by inhibiting the production of inflammatory factors, thereby improving PD motor dysfunction.

[0337] 4.10 Effects of Compound (I) on Tyrosine Hydroxylase-Positive Neurons in the Substantia Nigra of MPTP-Induced Chronic PD Model Mice

[0338] The experimental procedures are as follows: 1. Preparation of frozen sections: After anesthesia, the experimental animals were perfused intracardially with pre-chilled PBS and 4% paraformaldehyde solution, dehydrated with a gradient of 20% and 30% sucrose solutions, cryo-embedded in OCT, and cut into 30-μm-thick frozen sections using a cryostat. 2. Immunohistochemistry: 30-μm-thick frozen sections were permeabilized (PBS containing 0.3% Triton X-100) for 20 minutes, blocked (PBS containing 1% BSA) for 60 minutes, and incubated with the primary antibody (1:200 dilution) at 4°C overnight. The secondary antibody (1:200 dilution) was incubated at room temperature for 1 hour, followed by development with DAB and counterstaining with hematoxylin. The sections were mounted with neutral gum and scanned under a panoramic microscope.

[0339] As shown in Figure 18, compared with the NC group, the TH content in the substantia nigra of MPTP-induced PD mice in the MC group showed a downward trend; compared with the MC group, the low, medium and high doses of rasagiline, L-dopamine and compound (I) significantly increased the expression of TH in the substantia nigra (P<0.01, P<0.001, P<0.001), suggesting that compound (I) can increase the activity of dopaminergic neurons in the substantia nigra region of PD mice.

[0340] In summary, compound (I) can improve the motor dysfunction of PD mice, and its molecular mechanism may be through inhibiting the inflammatory response of the substantia nigra, improving the level of oxidative stress in the substantia nigra, and inhibiting the apoptosis of substantia nigra-striatal neurons.

[0341] Example 5 Effect of Compound (I) on Gait of MPTP / Probenecid-Induced Chronic PD Model Mice (Positive Drugs are L-dopa and Semaglutide)

[0342] Compound (I) was prepared according to the method in Example 1. The positive drug levodopa was purchased from Dalian Meilun Biotechnology Co., Ltd., and the positive drug semaglutide was purchased from Novo Nordisk (China) Pharmaceutical Co., Ltd. (Batch No.: National Medicine Standard SJ20210015). The solvent was homemade in the laboratory (formula: 1.42 mg / ml anhydrous disodium hydrogen phosphate; 14 mg / ml propylene glycol; 5.5 mg / ml phenol; pH 7.3).

[0343] 5.1 Experimental Materials

[0344] 6-8 week old male C57BL / 6J mice, SPF grade, weighing 22-25 g; housing conditions: temperature 21-23°C, relative humidity 30%-60%, 12h / 12h light / dark cycle.

[0345] 5.2 Experimental Grouping

[0346] Pre-experimental stimulation: Mice were first intraperitoneally administered with probenecid (dissolved in DMSO, 250 mg / kg), and one hour later, intraperitoneally injected with MPTP (20 mg / kg). The administration was repeated twice a week for 4 consecutive weeks. The NC group was injected with an equal amount of solvent.

[0347] Mice injected with probenecid and MPTP were randomly divided into the MC group, the L-DOPA group, the semaglutide positive control group, and the low, medium, and high dose groups of Compound (I). Behavioral testing was performed after once-daily administration for 4 consecutive weeks. Grouping and dosing information are shown in Table 4.

[0348] Table 4 Experimental groups

[0349] 5.3 Visual Observation after Administration

[0350] General clinical observations: None of the mice showed abnormal reactions or near-death conditions. The mice's fur remained shiny, their diet and water intake were unaffected, and their bowel movements were normal.

[0351] Local observation: No ulceration or nodules were observed at the injection site. No mice died or suffered other obvious symptoms, indicating that compound (I) of the present invention had no obvious toxic side effects and was well tolerated.

[0352] 5.4 Gait analysis experiment

[0353] This experiment evaluates the natural locomotor behavior and coordination of mice. The test was performed using a small animal gait analyzer (CatWalk XT, Noldus, the Netherlands), with a 3-day pre-experimental training period. During the test, mice were allowed to freely traverse a test tunnel of a predetermined length. Footprints captured by a camera were efficiently processed using an internal light source refraction technique, allowing for efficient computer processing of the footprints to assess the mice's locomotor performance during natural gait. This procedure was performed entirely in a darkroom, with each mouse undergoing at least three tests.

[0354] Detect and calculate the mouse's swing speed, step length, walking cycle, speed, speed change rate, and regularization index.

[0355] The results of the above indicators show that the compound (I) of the present invention has a better motor improvement effect on PD mice than semaglutide, and the effect of 5 mg / kg of compound (I) is equivalent to that of 10 mg / kg of semaglutide, indicating that the compound of the present invention has a better effect in treating Parkinson's disease.

[0356] sequence

[0357] SEQ ID NO: 1:

[0358] GLP-1-(7-37) peptide

[0359] SEQ ID NO.2:

[0360] [Gly8, Arg34]GLP-1-(7-37) peptide

Claims

1. Use of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, in the preparation of a medicament for treating or preventing dementia and / or neurodegenerative diseases, 2. The use according to claim 1, characterized in that The dementia is all forms and stages of dementia, preferably mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; and / or The neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably Alzheimer's disease, and / or Parkinson's disease.

3. The use according to claim 1 or 2, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the generation and / or aggregation of Aβ in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can regulate the expression of proteins related to Aβ metabolism in a subject in need thereof and reduce the generation and / or aggregation of Aβ; preferably, the proteins related to Aβ metabolism are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of BACE-1 in a subject in need thereof, increase the expression of PS1 in a subject in need thereof, and / or increase the expression of ADAM10 in a subject in need thereof.

4. The use according to any one of claims 1 to 3, characterized in that: The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the structural abnormality of the hippocampus region of a subject in need and / or increase the number of neurons in a subject in need; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the structural density of the hippocampus region of a subject in need and / or increase the number of neurons in a subject in need; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of a subject in need thereof by inhibiting Aβ deposition in the hippocampus and / or cortical region of the subject.

5. The use according to claim 1 or 2, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need thereof, wherein the related proteins in the striatum and / or substantia nigra are selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the oxidative stress level of the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate the content of MDA and / or SOD in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the content of MDA, and / or increase the content of SOD; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of inflammatory factors and / or increasing the level of anti-inflammatory factors; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of TNF-α, IL-1β, IL-6, and / or IL-8, and / or increasing the level of IL-4, and / or IL-10; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof. Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

6. The use according to any one of claims 1 to 5, wherein the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the cognitive ability of a subject, improve the anxiety behavior of a subject, improve the autonomous activity dysfunction of a subject, and / or improve the motor ability of a subject.

7. The use according to any one of claims 1 to 6, characterized in that: The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered subcutaneously or orally, preferably in the form of an injection or tablet.

8. The use according to any one of claims 1 to 7, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered chronically, preferably for more than 12 months; preferably for more than 16 months; preferably for more than 18 months.

9. The use according to any one of claims 1 to 8, characterized in that The subject in need thereof suffers from metabolic syndrome, preferably one or more of diabetes, cardiovascular disease and hypertension.

10. A method for treating or preventing dementia and / or neurodegenerative diseases, comprising administering to a subject in need thereof a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt, amide or ester thereof, 11. The method according to claim 10, characterized in that The dementia is all forms and stages of dementia, preferably mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; and / or The neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably Alzheimer's disease, and / or Parkinson's disease.

12. The method according to claim 10 or 11, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the generation and / or aggregation of Aβ in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can regulate the expression of proteins related to Aβ metabolism in the subject and reduce the generation and / or aggregation of Aβ; preferably, the proteins related to Aβ metabolism are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of BACE-1 in a subject in need thereof, increase the expression of PS1 in the subject, and / or increase the expression of ADAM10 in the subject.

13. The method according to any one of claims 10 to 12, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the abnormal structure of the hippocampus region of the subject and / or the number of neurons of the subject; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the density of the hippocampus region structure of the subject, and / or increase the number of neurons of the subject; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of the subject; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of the subject by inhibiting the deposition of Aβ in the hippocampus and / or cortical region of the subject.

14. The method according to claim 10 or 11, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need thereof, wherein the related proteins in the striatum and / or substantia nigra are selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the oxidative stress level of the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate the content of MDA and / or SOD in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the content of MDA, and / or increase the content of SOD; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of inflammatory factors and / or increasing the level of anti-inflammatory factors; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of TNF-α, IL-1β, IL-6, and / or IL-8, and / or increasing the level of IL-4, and / or IL-10; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof. Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

15. The method according to claim 10 or 11, wherein the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the subject's cognitive ability, improve the subject's anxiety behavior, improve the subject's autonomic activity dysfunction, and / or improve the subject's motor ability.

16. The method according to any one of claims 10 to 15, characterized in that The dosage of the compound of formula (I) is 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg.

17. The method according to any one of claims 10 to 16, wherein: The method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a dose of 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg every 24 hours, every 48 hours, every 72 hours, every week or every two weeks.

18. The method according to any one of claims 10 to 17, wherein: The method comprises administering to a subject in need thereof 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg every 24 hours, every 48 hours, every 72 hours, every week or every two weeks. 67mg, 68mg, 69mg, or 70mg of a compound of Formula (I), or a pharmaceutically acceptable salt, amide or ester thereof.

19. The method according to any one of claims 10 to 18, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered subcutaneously or orally, preferably in the form of an injection or tablet.

20. The method according to any one of claims 10 to 19, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered chronically, preferably for more than 12 months; preferably for more than 16 months; preferably for more than 18 months.

21. The method according to any one of claims 10 to 20, characterized in that The subject also suffers from metabolic syndrome, preferably one or more of diabetes, cardiovascular disease and hypertension.

22. A compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, for use in treating or preventing dementia, and / or neurodegenerative diseases, 23. The compound of formula (I) for use according to claim 22, or a pharmaceutically acceptable salt, amide or ester thereof, characterized in that The dementia is all forms and stages of dementia, preferably mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; and / or The neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably Alzheimer's disease, and / or Parkinson's disease.

24. The compound for use according to claim 22 or 23, or a pharmaceutically acceptable salt, amide or ester thereof, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the generation and / or aggregation of Aβ in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can regulate the expression of proteins related to Aβ metabolism in a subject in need thereof and reduce the generation and / or aggregation of Aβ; preferably, the proteins related to Aβ metabolism are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of BACE-1 in a subject in need thereof, increase the expression of PS1 in a subject in need thereof, and / or increase the expression of ADAM10 in a subject in need thereof.

25. The compound for use according to any one of claims 22 to 24, or a pharmaceutically acceptable salt, amide or ester thereof, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the structural abnormality of the hippocampal region of a subject in need thereof and / or increase the number of neurons in a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the structural density of the hippocampal region and / or increase the number of neurons in a subject in need thereof; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of a subject in need thereof by inhibiting Aβ deposition in the hippocampus and / or cortical region of the subject.

26. The compound for use according to claim 22 or 23, or a pharmaceutically acceptable salt, amide or ester thereof, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need thereof, wherein the related proteins in the striatum and / or substantia nigra are selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the oxidative stress level of the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can regulate the content of MDA and / or SOD in the substantia nigra of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can reduce the content of MDA, and / or increase the content of SOD; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of inflammatory factors and / or increasing the level of anti-inflammatory factors; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can improve the inflammatory condition in the brain of a subject by reducing the level of TNF-α, IL-1β, IL-6, and / or IL-8, and / or increasing the level of IL-4, and / or IL-10; or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof. Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

27. The compound of formula (I) for use according to claim 22 or 23, or a pharmaceutically acceptable salt, amide or ester thereof, can improve the subject's cognitive ability, improve the subject's anxiety behavior, improve the subject's autonomic activity dysfunction, and / or improve the subject's motor ability.

28. A compound of formula (I) for use according to any one of claims 22 to 27, or a pharmaceutically acceptable salt, amide or ester thereof, in a dosage of 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg.

29. A compound of formula (I) for use according to any one of claims 22 to 28, or a pharmaceutically acceptable salt, amide or ester thereof, wherein: A dose of 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg is administered to a subject every 24 hours, every 48 hours, every 72 hours, every week or every two weeks.

30. A compound of formula (I) for use according to any one of claims 22 to 29, or a pharmaceutically acceptable salt, amide or ester thereof, wherein: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, or 70mg.

31. A compound for use according to any one of claims 22 to 30, or a pharmaceutically acceptable salt, amide or ester thereof, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered subcutaneously or orally, preferably in the form of an injection or tablet.

32. A compound for use according to any one of claims 22 to 31, or a pharmaceutically acceptable salt, amide or ester thereof, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered chronically, preferably for more than 12 months; preferably for more than 16 months; preferably for more than 18 months.

33. A compound of formula (I) for use according to any one of claims 22 to 32, or a pharmaceutically acceptable salt, amide or ester thereof, characterized in that The subject in need thereof suffers from metabolic syndrome, preferably one or more of diabetes, cardiovascular disease and hypertension.

34. A compound of formula (I) or N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]]Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia and / or neurodegenerative diseases caused by the generation and / or aggregation of Aβ, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Alzheimer's disease Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease, preferably the neurodegenerative disease is Alzheimer's disease.

35. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]]Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing protein-mediated dementia and / or neurodegenerative diseases related to Aβ metabolism, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease, and / or Parkinson's disease.

36. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]]Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia and / or neurodegenerative diseases mediated by BACE-1, PS1 and / or ADAM10, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease, and / or Parkinson's disease.

37. The use according to any one of claims 34 to 36, characterized in that The compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, which can regulate the expression of proteins related to Aβ metabolism in subjects in need and reduce the generation and / or aggregation of Aβ; preferably, the Aβ metabolism-related proteins are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of BACE-1 in subjects in need, increase the expression of PS1 in subjects in need, and / or increase the expression of ADAM10 in subjects in need.

38. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal hippocampal regional structure, decreased number of neurons, and / or formation of senile plaques in the brain of a subject, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease, and / or Parkinson's disease.

39. The use according to claim 38, characterized in that The compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can improve the structural abnormalities of the hippocampal region of a subject in need thereof and / or increase the number of neurons in a subject in need thereof; preferably the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can increase the compactness of the hippocampal structure of a subject in need thereof, and / or increase the number of neurons in a subject in need thereof; and / or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of a subject in need thereof by inhibiting Aβ deposition in the hippocampus and / or cortical region of the subject.

40. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]]Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal expression of related proteins in the striatum and / or substantia nigra, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease; Preferably, the related proteins in the striatum and / or substantia nigra are selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein.

41. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia and / or neurodegenerative diseases mediated by cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein, and / or ERK protein, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

42. The use according to claim 40 or 41, characterized in that Preferably, the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof.

43. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]]Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal oxidative stress levels in the substantia nigra, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

44. A compound of formula (I) or N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]]Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing MDA and / or SOD-mediated dementia and / or neurodegenerative diseases in the substantia nigra, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

45. The use according to claim 43 or 44, characterized in that The compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need thereof by regulating the content of MDA and / or SOD in the substantia nigra of a subject in need thereof; preferably the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can reduce the content of MDA and / or increase the content of SOD.

46. ​​A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]]Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing inflammation-mediated dementia and / or neurodegenerative diseases, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

47. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia and / or neurodegenerative diseases caused by increased and / or decreased levels of inflammatory factors, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease; Preferably, the inflammatory factor is selected from TNF-α, IL-1β, IL-6, and IL-8; preferably, the anti-inflammatory factor is IL-4 or IL-10.

48. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]]Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing TNF-α, IL-1β, IL-6, IL-8, IL-10, and / or IL-4 mediated dementia, and / or neurodegenerative diseases, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease; Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce TNF-α, IL-1β, IL-6, and / or IL-8 levels, and / or increase IL-4, and / or IL-10 levels.

49. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia and / or neurodegenerative diseases mediated by the activity of dopaminergic neurons in the substantia nigra region, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

50. A compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or its pharmaceutically acceptable salt, amide or ester in the preparation of a drug for treating or preventing dementia mediated by tyrosine hydrogenase in substantia nigra, and / or neurodegenerative diseases, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

51. The use according to claim 49 or 50, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

52. A method for treating or preventing dementia and / or neurodegenerative diseases caused by the generation and / or aggregation of Aβ, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Alzheimer's disease Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease, preferably the neurodegenerative disease is Alzheimer's disease.

53. A method for treating or preventing dementia and / or neurodegenerative diseases mediated by proteins related to Aβ metabolism, the method comprising administering a therapeutically effective amount of a compound of formula (I) or N-ε to a subject in need thereof. 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease, and / or Parkinson's disease.

54. A method for treating or preventing dementia and / or neurodegenerative diseases mediated by BACE-1, PS1 and / or ADAM10, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease, and / or Parkinson's disease.

55. The method according to any one of claims 52 to 54, characterized in that The compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, which can regulate the expression of proteins related to Aβ metabolism in subjects in need and reduce the generation and / or aggregation of Aβ; preferably, the Aβ metabolism-related proteins are selected from BACE-1, PS1 and ADAM10; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of BACE-1 in subjects in need, increase the expression of PS1 in subjects in need, and / or increase the expression of ADAM10 in subjects in need.

56. A method for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal hippocampal regional structure, decreased number of neurons, and / or formation of senile plaques in the subject's brain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease, and / or Parkinson's disease.

57. The method according to claim 56, characterized in that The compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can improve the structural abnormalities of the hippocampal region of a subject in need thereof and / or increase the number of neurons in a subject in need thereof; preferably the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can increase the compactness of the hippocampal structure of a subject in need thereof, and / or increase the number of neurons in a subject in need thereof; and / or The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of a subject in need thereof; preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce the formation of senile plaques in the brain of a subject in need thereof by inhibiting Aβ deposition in the hippocampus and / or cortical region of the subject.

58. A method for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal expression of related proteins in the striatum and / or substantia nigra, the method comprising administering a therapeutically effective amount of a compound of formula (I) or N-ε to a subject in need thereof. 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease; Preferably, the related proteins in the striatum and / or substantia nigra are selected from cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein and ERK protein.

59. A method for treating or preventing dementia and / or neurodegenerative diseases mediated by cleaved Casepase3 protein, pAKT protein, AKT protein, pERK protein, and / or ERK protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

60. The method according to claim 58 or 59, characterized in that Preferably, the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can reduce the expression of cleaved Casepase3 protein in a subject in need thereof, and / or increase the expression of pAKT protein, AKT protein, pERK protein and / or ERK protein in a subject in need thereof.

61. A method for treating or preventing dementia and / or neurodegenerative diseases caused by abnormal oxidative stress levels in the substantia nigra, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

62. A method for treating or preventing MDA and / or SOD-mediated dementia and / or neurodegenerative diseases in substantia nigra, the method comprising administering a therapeutically effective amount of a compound of formula (I) or N-ε to a subject in need thereof. 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

63. The method according to claim 61 or 62, characterized in that The compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can improve the expression level of related proteins in the striatum and / or substantia nigra of a subject in need thereof by regulating the content of MDA and / or SOD in the substantia nigra of a subject in need thereof; preferably the compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyheneicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof can reduce the content of MDA and / or increase the content of SOD.

64. A method for treating or preventing inflammation-mediated dementia and / or neurodegenerative diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

65. A method for treating or preventing dementia and / or neurodegenerative diseases caused by increased and / or decreased levels of inflammatory factors, the method comprising administering a therapeutically effective amount of a compound of formula (I) or N-ε to a subject in need thereof. 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease; Preferably, the inflammatory factor is selected from TNF-α, IL-1β, IL-6, and IL-8; preferably, the anti-inflammatory factor is IL-4 or IL-10.

66. A method for treating or preventing TNF-α, IL-1β, IL-6, IL-8, IL-10, and / or IL-4-mediated dementia and / or neurodegenerative diseases, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease; Preferably, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can reduce TNF-α, IL-1β, IL-6, and / or IL-8 levels, and / or increase IL-4, and / or IL-10 levels.

67. A method for treating or preventing dementia and / or neurodegenerative diseases mediated by the activity of dopaminergic neurons in the substantia nigra region, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

68. A method for treating or preventing tyrosine hydrogenase-mediated dementia and / or neurodegenerative diseases in the substantia nigra, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or N-ε 26 -[2-(2-[2-(2-[2-(2-[4-(21-carboxyhenicosanoylamino)-4(S)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37) peptide, or a pharmaceutically acceptable salt, amide or ester thereof, Preferably, the dementia is all forms and all stages of dementia, preferably the dementia is mild cognitive impairment, Alzheimer's disease, and / or Parkinson's disease dementia; preferably, the dementia is Parkinson's disease dementia; Preferably, the neurodegenerative disease is all forms and all stages of neurodegenerative diseases, preferably the neurodegenerative disease is Alzheimer's disease and / or Parkinson's disease; preferably the neurodegenerative disease is Parkinson's disease.

69. The method according to claim 67 or 68, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof can improve the activity of dopaminergic neurons in the substantia nigra region of a subject in need thereof by increasing the expression of tyrosine hydrogenase in the substantia nigra.

70. According to the use according to any one of claims 34-51 or the method according to any one of claims 52-69, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can lead to improved cognitive ability, improved anxiety behavior, improved autonomic activity dysfunction, and / or improved motor ability of patients.

71. The use according to any one of claims 34 to 51 or the method according to any one of claims 52 to 69, characterized in that The therapeutically effective amount is 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg.

72. The use according to any one of claims 34 to 51 or the method according to any one of claims 52 to 69, wherein The use or method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a dose of 0.1-100 mg, preferably 0.25-100 mg, preferably 0.5-90 mg, preferably 1-80 mg, preferably 2-80 mg, preferably 2-70 mg, preferably 3-70 mg, preferably 3-60 mg, preferably 3-55 mg, preferably 3-48 mg, preferably 3-36 mg, preferably 3-28 mg, preferably 3-20 mg, preferably 3-18 mg, preferably 3-14 mg, preferably 7-60 mg, preferably 7-55 mg, preferably 7-48 mg, preferably 7-36 mg, preferably 7-28 mg, preferably 7-20 mg, preferably 7-18 mg, preferably 7-14 mg per 24 hours, per 48 hours, or per 72 hours.

73. The use according to any one of claims 34 to 51 or the method according to any one of claims 52 to 69, wherein The uses or methods comprise administering to a subject in need thereof 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, or 70mg of a compound of Formula (I), or a pharmaceutically acceptable salt, amide or ester thereof.

74. The use or method according to any one of claims 34 to 73, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered subcutaneously or orally, preferably in the form of an injection or tablet.

75. The use or method according to any one of claims 34 to 74, characterized in that The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof is administered chronically, preferably for more than 12 months; preferably for more than 16 months; preferably for more than 18 months.

76. The use or method according to any one of claims 34 to 75, characterized in that The subject also suffers from metabolic syndrome, preferably one or more of diabetes, cardiovascular disease and hypertension.

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