Compound and application thereof in preparation of medicine for treating Alzheimer disease

Abstract

The invention discloses a compound and application thereof in preparation of a medicine for treating Alzheimer disease. The invention provides a method for constructing a disease animal model by using N-oleoyldopamine (OLDA) and application of the model in drug screening and animal experiment research. The animal model comprises at least one animal model of neurodegenerative diseases, intestinal permeability diseases and inflammatory diseases. According to the application, based on OLDA, it is found that the compound has new application in the aspects of neurodegenerative diseases, intestinal permeability diseases and inflammatory diseases, and based on OLDA, the compound which plays a certain role in treating the diseases is screened out.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and in particular to a compound and its use in the preparation of a medicament for treating Alzheimer's disease. Background Technology

[0002] Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common and typical form of dementia. Clinical diagnosis of AD is usually based on neuropathological features of brain tissue, including abnormal deposition of amyloid-beta protein (Aβ) forming senile plaques and abnormal phosphorylation of tau protein forming neurofibrillary tangles. The main symptoms of AD include memory loss, cognitive decline, language impairment, mood and behavioral changes, and a decline in daily living skills. With the accelerating aging of the population, epidemiological projections also indicate a pressing need for drugs that effectively prevent the onset of AD, slow its progression, or improve symptoms.

[0003] The U.S. Food and Drug Administration (FDA) has approved several small-molecule Alzheimer's disease (AD) drugs, including donepezil, rivastigmine, galantamine, and methemol. These drugs primarily target cognitive symptoms and do not alter the pathological changes in the brains of AD patients, nor do they slow or stop the progression of the disease. Therefore, it is necessary to develop new drugs that address the pathological changes in AD. Summary of the Invention

[0004] This application discloses a compound and its use in the preparation of a medicament for treating Alzheimer's disease.

[0005] A first aspect of this application provides the application of N-oleoyl-dopamine (OLDA) in constructing animal models of diseases. These animal models include, but are not limited to, animal models of neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases.

[0006] In some embodiments of this application, the animal model involves non-human mammals, including rodents (such as mice), primates, etc.

[0007] In some embodiments of this application, neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, Pick's disease dementia, etc.

[0008] Intestinal permeability diseases include, but are not limited to, inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer.

[0009] Inflammatory diseases include, but are not limited to, neuroinflammatory diseases, inflammatory joint diseases, allergies, autism, anxiety disorders, depression, chronic fatigue syndrome, etc. Neuroinflammatory diseases can specifically be neurological inflammation of the brain.

[0010] In some embodiments of this application, the method of administration includes, but is not limited to, oral administration, injection administration, etc.

[0011] In some embodiments of this application, disease animal models are used for animal experimental research and drug screening, etc.

[0012] A second aspect of this application provides a method for constructing animal models of diseases, including administering an effective dose of N-oleoyl dopamine to an animal, the animal models of diseases including animal models of neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases.

[0013] In some embodiments of this application, the animal model involves non-human mammals, including rodents (such as mice), primates, etc.

[0014] In some embodiments of this application, neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, Pick's disease dementia, etc.

[0015] Intestinal permeability diseases include, but are not limited to, inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer.

[0016] Inflammatory diseases include, but are not limited to, neuroinflammatory diseases, inflammatory joint diseases, allergies, autism, anxiety disorders, depression, chronic fatigue syndrome, etc. Neuroinflammatory diseases can specifically be neurological inflammation of the brain.

[0017] In some embodiments of this application, the method of administration includes, but is not limited to, oral administration, injection administration, etc.

[0018] In some embodiments of this application, the effective dose is 0.5 to 1.5 mg / kg.

[0019] A third aspect of this application provides a compound or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or polymorph thereof for use in the prevention or treatment of diseases in animals, or in the preparation of medicaments for the prevention or treatment of diseases in animals, wherein the compound has the chemical structural formula of Formula I as follows:

[0020]

[0021] These diseases include, but are not limited to, neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases.

[0022] In some embodiments of this application, neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, Pick's disease dementia, etc.

[0023] Intestinal permeability diseases include, but are not limited to, inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer.

[0024] Inflammatory diseases include, but are not limited to, neuroinflammatory diseases, inflammatory joint diseases, allergies, autism, anxiety disorders, depression, chronic fatigue syndrome, etc. Neuroinflammatory diseases can specifically be neurological inflammation of the brain.

[0025] In some embodiments of this application, the above-mentioned diseases may be mediated by N-oleoyl dopamine in their occurrence, development, metastasis, or recurrence.

[0026] In some embodiments of this application, animals include mammals, including primates, including humans.

[0027] In some embodiments of this application, the method of administration includes, but is not limited to, oral administration, injection administration, etc.

[0028] In some embodiments of this application, the compound or its pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or polymorph is administered as a pharmaceutical composition, which further includes pharmaceutically acceptable excipients.

[0029] Pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, stabilizers, colorants, solvents, chelating agents, dispersants, preservatives, antifreeze agents, thickeners, pH adjusters, protectants, and tension modifiers.

[0030] The composition includes, but is not limited to, any one of liquid formulations, solid formulations, sustained-release formulations, and controlled-release formulations.

[0031] A fourth aspect of this application provides a method for preventing or treating diseases in animals, the method comprising administering to an animal an effective dose of a compound or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or polymorph thereof, the compound having the chemical structural formula of Formula I:

[0032]

[0033] Diseases include, but are not limited to, neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases.

[0034] In some embodiments of this application, neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, Pick's disease dementia, etc.

[0035] Intestinal permeability diseases include, but are not limited to, inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer.

[0036] Inflammatory diseases include, but are not limited to, neuroinflammatory diseases, inflammatory joint diseases, allergies, autism, anxiety disorders, depression, chronic fatigue syndrome, etc. Neuroinflammatory diseases can specifically be neurological inflammation of the brain.

[0037] In some embodiments of this application, animals include mammals, including primates, including humans.

[0038] In some embodiments of this application, the method of administration includes, but is not limited to, oral administration, injection administration, etc.

[0039] In some embodiments of this application, the compound or its pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or polymorph is administered as a pharmaceutical composition, which further includes pharmaceutically acceptable excipients.

[0040] Pharmaceutically acceptable excipients include, but are not limited to, at least one of the following: carriers, diluents, stabilizers, colorants, solvents, chelating agents, dispersants, preservatives, antifreeze agents, thickeners, pH adjusters, protectants, and tension modifiers.

[0041] The composition includes, but is not limited to, any one of liquid formulations, solid formulations, sustained-release formulations, and controlled-release formulations.

[0042] A fifth aspect of this application provides the use of a composition in the prevention or treatment of diseases in animals, or in the preparation of a medicament for the prevention or treatment of diseases in animals, the composition comprising:

[0043] The compound or its pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, polymorphs, and pharmaceutically acceptable excipients;

[0044] The compound has the following chemical structural formula (Formula I):

[0045]

[0046] Diseases include, but are not limited to, neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases.

[0047] In some embodiments of this application, the pharmaceutically acceptable excipients included in the composition include, but are not limited to, carriers, diluents, stabilizers, colorants, solvents, chelating agents, dispersants, preservatives, antifreeze agents, thickeners, pH adjusters, protectants, tension modifiers, etc.

[0048] In some embodiments of this application, the composition includes, but is not limited to, pharmaceutically acceptable dosage forms such as liquid formulations, solid formulations, sustained-release formulations, and controlled-release formulations.

[0049] In some embodiments of this application, neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, Pick's disease dementia, etc.

[0050] Intestinal permeability diseases include, but are not limited to, inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer.

[0051] Inflammatory diseases include, but are not limited to, neuroinflammatory diseases, inflammatory joint diseases, allergies, autism, anxiety disorders, depression, chronic fatigue syndrome, etc. Neuroinflammatory diseases can specifically be neurological inflammation of the brain.

[0052] In some embodiments of this application, animals include mammals, including primates, including humans.

[0053] In some embodiments of this application, the method of administration includes, but is not limited to, oral administration, injection administration, etc.

[0054] This application is based on the discovery of new uses of OLDA in neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases, and on the screening of compounds that play a positive role in the above-mentioned diseases based on OLDA.

[0055] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0056] Figure 1 Plasma metabolite analysis graph. A and B are principal component analysis graphs and differential metabolite statistical analysis results between C57-Ctrl and C57-AD-FMT mice, respectively. C is a heatmap of plasma metabolite analysis of mice in different groups.

[0057] Figure 2 Example 3: Schematic diagram of experimental mouse grouping.

[0058] Figure 3: Statistical graph of mouse behavior experiment. Where A and B are the spontaneous alternation rate (% of alternation) and total entries; C is the escape latency required for the mouse to find the platform when there is one; D is the number of times the mouse crosses the original platform location when there is no platform.

[0059] Figure 4 Immunohistochemical images of Aβ42 (A) and p-Tau181 (C) in the hippocampus of mouse brain, scale bar 250 μm. B and D are the statistical analysis results of A and C, respectively.

[0060] Figure 5 Immunohistochemical images of IBA-1 (A) and GFAP (C) in the mouse hippocampus, scale bar 250 μm. B and D are the statistical analysis results of A and C, respectively.

[0061] Figure 6 HE staining image of mouse colon tissue (A, scale bar: 250μm), B is the comparison result of histological scores in A.

[0062] Figure 7 Compound Formula 1 was used to treat cognitive and behavioral abnormalities in AD mice. A and B represent the percentage of alternation and total entries, respectively; C represents the escape latency when a platform is available; and D represents the number of times a mouse crosses the original platform location when no platform is available.

[0063] Note: Each point in the statistical graph represents one experimental mouse. Statistical methods used include t-tests, mean ± SEM, *p<0.05, **p<0.01, ***p<0.001, and ns indicates no significant difference. Detailed Implementation

[0064] The following describes exemplary embodiments of the present invention. It should be understood that such description is not intended to be a limitation on the scope of the invention, but is provided as a description of exemplary embodiments.

[0065] In the description of this application, "several" means one or more, "multiple" means two or more, "greater than," "less than," and "exceeding" are understood to exclude the stated number, while "above," "below," and "within" are understood to include the stated number. The use of "first" and "second" in the description is merely for distinguishing technical features and should not be construed as indicating or implying relative importance, or implicitly indicating the number of indicated technical features, or implicitly indicating the order of the indicated technical features.

[0066] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing embodiments of this application only and is not intended to limit this application.

[0067] In the description of this application, the terms "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0068] N-Oleyl dopamine (OLDA) is a fatty acid derivative of dopamine, produced by the direct N-acylation reaction of dopamine with oleic acid. OLDA can be obtained through two pathways: production by human cells via N-acyltransferases or phospholipid hydrolysis; or production by specific gut symbiotic bacteria. [1] Studies have shown that OLDA exists endogenously in the mammalian brain, and its metabolism may follow a similar pathway to dopamine, particularly through O-methylation catalyzed by catechol-O-methyltransferases. [2] However, no reports have been found regarding the relationship between OLDA and neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other related diseases with similar pathologies or symptoms.

[0069] Therefore, based on relevant experimental results, this application proposes a first aspect relating to the use of N-oleoyl dopamine in constructing animal models of diseases, and the application of such models in drug screening and animal experimental research. The animal models include, but are not limited to, animal models of neurodegenerative diseases, intestinal permeability diseases, inflammatory diseases, etc.

[0070] The term "disease animal model" refers to a pathogenic animal model in which experimental animals reproduce part or all of the occurrence and development of a human disease through induction, surgery, or gene editing. In this application, the application of N-oleoyl dopamine in constructing animal models refers to using compounds, including N-oleoyl dopamine, as one of the induction methods to act on experimental animals, causing a certain degree of damage and changes in function, metabolism, and morphology in their tissues, organs, or the whole body. It is understood that induction methods may also include the single or combined use of other physical, chemical, and biological methods.

[0071] Laboratory animals used in animal models are typically derived from mammals. Since animal models are designed to reproduce the processes associated with human diseases, the animals used in these models include non-human mammals, specifically mice, dogs, monkeys, rabbits, pigs, and other laboratory animals familiar to and used by those skilled in the art, possessing a clear genetic lineage and a legally recognized origin. Considering genetic background, growth cycle, and operability, mice, rats, guinea pigs, beagles, Chinese white rabbits, New Zealand white rabbits, rhesus monkeys, and cynomolgus monkeys are more commonly used.

[0072] The term "neurodegenerative disease" refers to diseases caused by the gradual degeneration of neurons in the spinal cord and brain. It includes acute neurodegenerative diseases and chronic neurodegenerative diseases. The former includes cerebral ischemia (CI), brain injury (BI), epilepsy, etc.; the latter includes Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Pick's disease, etc.

[0073] The term "intestinal permeability" is a measure of the intestinal barrier. Intestinal permeability refers to the process by which molecules diffuse through the intestinal epithelial cell layer via carrier-independent diffusion. It is a barrier function closely related to the gut microbiota and the mucosal immune system. Alterations in intestinal permeability can lead to disproportionate penetration of intestinal antigens through the intestinal mucosa, immune dysregulation, and the development of gastrointestinal or immune system diseases, such as inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer. Damage to the intestinal mucosa resulting in altered intestinal permeability is a characteristic feature of inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. [3,4] Increased intestinal permeability in patients with irritable bowel syndrome is associated with immune activation and inflammatory factors, and conversely increases intestinal permeability. [5] The pathophysiological changes in obesity and related metabolic diseases, such as non-alcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease, are all related to changes in intestinal permeability. [6] Other cancers, such as colon cancer, have also been shown to be closely linked to changes in intestinal permeability. Therefore, increasing or decreasing intestinal permeability can promote or alleviate the development of these intestinal permeability disorders.

[0074] The term "inflammation" refers to a vascular-centered defensive response of vascularized tissue to inflammatory factors, including biological factors, physicochemical factors, abnormal immune responses, necrotic tissue, and foreign bodies. Correspondingly, inflammatory diseases refer to diseases involving inflammation in their causative factors and disease progression, including but not limited to neuroinflammatory diseases, inflammatory arthritis, allergies (such as food allergies), autism, anxiety disorders, depression, and chronic fatigue syndrome. It also includes asthma, chronic sinusitis (CRS), allergic rhinitis (AR), and eosinophilic esophagitis (EoE). In some embodiments, the animal model of inflammatory disease includes at least one of the following: a neuroinflammatory animal model, an inflammatory arthritis animal model, an allergy model, an autism model, an anxiety disorder model, a depression model, and a chronic fatigue syndrome model; for example, it could be a neuroinflammatory animal model of the brain.

[0075] Accordingly, this application proposes a method for constructing the aforementioned animal model, comprising administering an effective dose of N-oleoyl dopamine to the animal to chemically intervene and complete the modeling process. It is understood that the aforementioned chemical intervention may further include other chemical reagents, or be combined with physical or biological intervention methods to achieve better modeling results.

[0076] In some embodiments, N-oleoyl dopamine is administered via methods including, but not limited to, oral administration, injection, or one or more other methods. In some embodiments, the administration frequency may be once or multiple times; the dosing interval may be once every 6 to 48 hours; and the effective dose of N-oleoyl dopamine is 0.5 to 1.5 mg / kg.

[0077] Therefore, in a third aspect of this application, a compound having therapeutic effects on the relevant disease, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or polymorph thereof, is constructed, wherein the compound has the following structural formula:

[0078]

[0079] The compounds described in the embodiments of this application can be prepared by the following methods, which can be referred to synthetic methods well known to those skilled in the art. [7-9] The synthesis method is easily understood by professionals in the relevant field.

[0080]

[0081] Starting material A is dissolved in a solvent to form a first solution; EDC·HCl and HOBT·H2O are added to the first solution, and the mixture is stirred at room temperature for a period of time. Then intermediate B is added, and the mixture is stirred at room temperature for a period of time to generate the desired target product C.

[0082] This application also relates to a composition comprising the aforementioned compound or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or polymorph thereof, and a pharmaceutically acceptable excipient, such as a mixture formed by homogeneous mixing of the two or otherwise. In some embodiments, the pharmaceutically acceptable excipients included in the composition include, but are not limited to, at least one of the following: carrier, diluent, stabilizer, colorant, solvent, chelating agent, dispersant, preservative, antifreeze, thickener, pH adjuster, protectant, and tension modifier.

[0083] In some embodiments, the dosage form of the composition includes, but is not limited to, liquid dosage forms and solid dosage forms. Specific dosage forms of liquid dosage forms may include injections and solutions. Specific dosage forms of solid dosage forms may include capsules and tablets. In some embodiments, the dosage form of the composition is either a sustained-release formulation or a controlled-release formulation, such as sustained-release and controlled-release matrix tablets or sustained-release and controlled-release capsules. In some embodiments, the uses of the composition include, but are not limited to, pharmaceuticals and health products.

[0084] The above-mentioned compounds can be used alone, in compound form, and / or in combination with acceptable excipients, as pharmaceutical formulations for the treatment of neurodegenerative diseases, intestinal permeability disorders, inflammatory diseases, etc. Those skilled in the art will readily understand the appropriate dosage and route of administration of the compounds to humans and / or mammals requiring such treatment. Routes of administration may include, but are not limited to, oral administration, intravenous injection, etc., administered according to the described routes of administration and acceptable pharmaceutical procedures. [10,11] The instructions are used to formulate compound preparations.

[0085] In some embodiments, the compound, or its pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, polymorphs, etc., are administered in various dosage forms (including immediate-release, sustained-release, or controlled-release dosage forms), such as tablets, capsules, injections, etc. The compound can be administered alone, and the appropriate dosage form is generally selected based on the chosen route of administration and standard pharmaceutical procedures.

[0086] The above dosing regimen will be modified based on known factors, such as the pharmacokinetic properties of the specific drug and its administration mode and route, the subject's species, age, sex, health status, medical status, weight, nature and severity of symptoms, type of concurrent treatment, frequency of administration, route of administration, patient's renal and hepatic function, and desired therapeutic effect. Physicians or veterinarians may prescribe an effective dose of the drug based on the need for prevention, treatment, or inhibition of disease progression.

[0087] In these pharmaceutical compositions, the active ingredient is typically present in an amount of approximately 0.01 to 95% by weight based on the total weight of the composition.

[0088] In some embodiments, the compound formulation is generally prepared by uniformly mixing suitable excipients according to different dosage forms and in accordance with conventional pharmaceutical operating procedures. For example, in tablets or capsules, the active pharmaceutical ingredient may be combined with one or more pharmaceutically acceptable excipients such as, but not limited to, starch, sucrose, methylcellulose, magnesium stearate, etc. For liquid formulations to be administered orally, the excipient components may be combined with one or more pharmaceutically acceptable excipients or carriers such as, but not limited to, ethylene glycol, water, etc. If necessary, suitable binders, flavoring agents, lubricants, disintegrants, and colorants may also be added. Suitable binders include, but are not limited to, starch, gelatin, carboxymethyl cellulose, polyethylene glycol, etc.; flavoring agents include, but are not limited to, glucose, corn sweeteners, etc.; lubricants include, but are not limited to, sodium stearate, magnesium stearate, etc.; disintegrants include, but are not limited to, starch, methylcellulose, etc.; and colorants include, but are not limited to, carmine, carotene, etc.

[0089] In some embodiments, tablets or capsules, and both, can be manufactured as sustained-release products to provide continuous release of the drug over a period of hours or longer. Tablets may be sugar-coated or film-coated to mask unpleasant tastes and isolate the tablet from air; or they may be enteric-coated for selective disintegration and release in the gastrointestinal tract. In some embodiments, orally administered liquid formulations may contain colorants and flavoring agents to improve medication compliance.

[0090] Suitable pharmaceutical excipients are described in the book.

[10] As described herein, this reference is a standard reference text in the field and is well known to those skilled in the art in the pharmaceutical or related fields.

[0091] This application also relates to the use of a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, polymorph, or the aforementioned composition in the prevention or treatment of animal diseases, or in the preparation of a medicament for the prevention or treatment of animal diseases, including administration to animals in an effective dose of a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or polymorph.

[0092] Diseases include, but are not limited to, neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases.

[0093] Neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, Pick's disease dementia, etc.

[0094] Intestinal permeability diseases include, but are not limited to, inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer.

[0095] Inflammatory diseases include, but are not limited to, neuroinflammatory diseases, inflammatory joint diseases, allergies, autism, anxiety disorders, depression, and chronic fatigue syndrome.

[0096] In some embodiments, the aforementioned diseases may be mediated by N-oleoyl dopamine in their occurrence, development, metastasis, or recurrence. In other embodiments, the aforementioned diseases may also occur, develop, metastasize, or recur without the intervention or mediation of N-oleoyl dopamine, but under one or more intrinsic or extrinsic factors such as genetics and environment.

[0097] In some implementations, the animal includes mammals, such as primates, and can also be a human being, including but not limited to children, adults, and other human individuals of different ages.

[0098] In some implementations, the method of administration includes, but is not limited to, oral administration, injection administration, etc.

[0099] This application also relates to a method for preventing or treating neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases, comprising administering to animals an effective dose of a compound of the aforementioned Formula I or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, polymorph, or a combination thereof.

[0100] In some implementations, neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, Pick's disease dementia, etc.

[0101] Intestinal permeability diseases include, but are not limited to, inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer.

[0102] Inflammatory diseases include, but are not limited to, neuroinflammatory diseases, inflammatory joint diseases, allergies, autism, anxiety disorders, depression, chronic fatigue syndrome, and other diseases.

[0103] In some implementations, the animal includes mammals, such as primates, and specifically can be a human, including but not limited to children, adults, and other human individuals of different ages.

[0104] In some implementations, the method of administration includes, but is not limited to, oral administration, injection administration, etc.

[0105] Abbreviations

[0106]

[0107]

[0108] References:

[0109] [1] Chang F Y, Siuti P, Laurent S, et al. Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids[J]. Nat Microbiol, 2021, 6(6): 792 - 805.

[0110] [2] Zajac D, Spolnik G, Roszkowski P, et al. Metabolism of N-acylated-dopamine[J]. PLoS One, 2014, 9(1): e85259.

[0111] [3] Hering N A, Fromm M, Schulzke J D. Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics[J]. J Physiol, 2012, 590(5): 1035 - 44.

[0112] [4] Duckworth C A, Watson AJ. Analysis of epithelial cell shedding and gaps in the intestinal epithelium[J]. Methods Mol Biol, 2011, 763: 105 - 14.

[0113] [5]Camilleri M,Lasch K,Zhou W.Irritable bowel syndrome:methods,mechanisms,and pathophysiology.The confluence of increased permeability,inflammation,and pain in irritable bowel syndrome[J].Am J PhysiolGastrointest Liver Physiol,2012,303(7):G775-85.

[0114] [6]Donath M Y,Shoelson S E.Type 2diabetes as an inflammatory disease[J].Nat Rev Immunol,2011,11(2):98-107.

[0115] [7]Kürti L,Czako B,Corey E J,et al.Strategic applications of namedreactions in organic synthesis:background and detailed mechanisms[C],2005.

[0116] [8]Smith M B,March J.March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure[C],2001.

[0117] [9]Vollhardt K P C,Schore N E.Organic Chemistry:Structure andFunction[C],1987.

[0118]

[10] Remington J P.Remington:the science and practice of pharmacy[M].1.Lippincott Williams&Wilkins,2006.

[0119]

[11] Goodman LS, Gilman A, Koelle G B. The pharmacological basis of therapeutics[C], 1975.

[0120] Example 1

[0121] This embodiment provides a general method for synthesizing Formula I, the preparation method of which refers to the following synthetic route, and the specific steps are as follows:

[0122]

[0123] (1) Add 3.0 g of starting material A to dimethylformamide (DMF) solvent to form a solution.

[0124] (2) Add 3.45 g of EDC·HCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and 2.76 g of HOBT·H2O (1-hydroxybenztriazole hydrate) to the solution and stir at room temperature for 20-30 minutes.

[0125] (3) Add 2.22 g of intermediate B to the mixture in step (2) and continue stirring at room temperature for 20 to 24 hours.

[0126] (4) After the reaction is complete, the reaction solution is concentrated under reduced pressure.

[0127] (4) Dissolve the concentrated residue in ethyl acetate, wash with 1N hydrochloric acid solution, dry with anhydrous sodium sulfate for 24 hours, and concentrate again under reduced pressure.

[0128] (5) The concentrate was purified by alkaline alumina column chromatography with ethyl acetate as the eluent. The ethyl acetate eluent was concentrated and crystallized to obtain the final product (target product C). LCMS: [M+H] + =288.08.

[0129] Example 2: Study on mouse gut microbiota transplantation and its plasma metabolites

[0130] Following the standard operating procedure for gut microbiota transplantation (GMT) experiments, the experimental mice were divided into four groups: normal wild-type mice (C57-AD-FMT) transplanted with gut microbiota from 3×Tg mice (AD mice), control wild-type mice (C57-Ctrl), 3×Tg mice, and wild-type mice in the same cage as 3×Tg mice (WT). Gut microbiota from AD mice was collected and transplanted into 4-week-old wild-type mice (C57-AD-FMT). During the first week of transplantation, transplantation was administered orally via gavage for the first 6 days, and then 4 times per week from the second week onwards. Correspondingly, the control mice were given the same volume of sterile phosphate-buffered saline (PBS). GMT was performed for a total of 8 weeks. At 12 weeks of age, plasma was collected from all four groups of mice, and non-targeted metabolomics techniques were used to analyze the metabolites in the plasma samples.

[0131] There were significant metabolic differences between C57-Ctrl mice and C57-AD-FMT mice. Figure 1 (A) Differential analysis showed that 74 metabolites were significantly downregulated and 34 were significantly upregulated. The differential metabolism was mainly reflected in lipid and fatty amide metabolism disorders. Figure 1 (B in the text). Joint analysis of non-target metabolome sequencing of the four groups of mice revealed that OLDA was not only specifically elevated in 3×Tg mice, but also showed high levels in C57-AD-FMT mice. Figure 1 The C in the text indicates that OLDA may play a role in the pathogenesis of AD.

[0132] Example 3: Feeding wild-type mice with OLDA, Formula I and their behavioral studies

[0133] Following the standard operating procedures for mouse drug control experiments, the experimental grouping was designed as follows: Figure 2 As shown, 6-week-old female wild-type mice C57BL / 6J were randomly divided into a control group (Ctrl) injected with saline, a pathogenic group (injected with OLDA), and a treatment group (Formula I-OLDA). Administered via intraperitoneal injection, the pathogenic group (OLDA, 0.5–1.5 mg / kg), the control group (injected with the same volume of saline as the pathogenic group), and the treatment group (administered a mixed solution of OLDA 0.5–1.5 mg / kg and Formula I 0.5–1.5 mg / kg). All groups received the medication once daily for 8 weeks. After administration, the learning and memory abilities of the mice in each group were assessed using the Y-maze and Morris water maze paradigms.

[0134] Compared with the control group, the spontaneous alternation rate and total number of arm entries in the diseased group mice were significantly reduced; the time spent finding the platform was significantly prolonged; and the number of times the original platform location was crossed was also significantly reduced after the platform was removed, indicating that OLDA leads to a decrease in the learning and memory ability of mice.

[0135] Compared with the diseased group, the spontaneous alternation rate and total number of arm advances were significantly increased in the treatment group mice. Figure 3 The time spent finding platforms (A and B in the original text) was significantly reduced. Figure 3 (C in the text); After the platform was removed, the number of times the original platform location was traversed increased significantly (C in the text); Figure 3 The D in the formula indicates that formula I can improve OLDA-induced cognitive dysfunction in mice.

[0136] Example 4: Mouse dissection and tissue collection in Example 3

[0137] According to the standard operating procedure for mouse brain anatomy, the mice in the control group, disease group and treatment group described in Example 3 were sacrificed and their brain tissue and colon tissue were collected and stored at -80°C.

[0138] Example 5: Brain pathology examination of OLDA wild-type mice

[0139] The brain tissues of the pathogenic group and control group mice described in Example 4 were used to detect AD-related biochemical indicators and brain neuroinflammatory indicators using IHC technology.

[0140] Compared with the control group, the area of ​​Aβ and p-Tau181 in the hippocampus of the brain of the diseased mice was significantly increased. Figure 4 The results showed that continuous administration of OLDA could induce AD ​​symptoms in mice; the number of IBA-1 and GFAP positive cells increased in the diseased mice, indicating that continuous administration of OLDA could cause neuroinflammation in the mouse brain.

[0141] Example 6: Colon tissue analysis of OLDA wild-type mice

[0142] The colon tissues of the pathogenic group and the control group in Example 4 were examined for colonic epithelial histopathology using HE staining technology.

[0143] Compared with the control group, the colon tissue of the diseased mice showed inflammatory cells infiltrating the muscularis mucosae and a reduced number of crypts, indicating that OLDA can damage the colon tissue of mice.

[0144] Example 7: Application of Formula I in AD-related diseases

[0145] The brain tissue of the mice in the treatment group in Example 4 was analyzed using IHC technology to detect AD-related biochemical indicators and compared with those of the diseased group.

[0146] Compared with the pathogenic group, the treatment group mice had Aβ (in the hippocampus) Figure 4 (A and B in) and p-Tau181 ( Figure 4 The area of ​​C and D in the formula was significantly reduced, indicating that Formula I can improve the pathological symptoms of AD caused by OLDA.

[0147] Example 8: Application of Formula I in Neuroinflammatory Brain Disease

[0148] The brain tissue of the mice in the treatment group in Example 4 was analyzed using IHC technology to detect relevant indicators of neuroinflammatory brain disease and compared with those of the pathogenic group.

[0149] Compared with the pathogenic group, the number of IBA-1 and GFAP positive cells was reduced in the treatment group mice. Figure 5 The results (AD) indicate that Formula I can improve OLDA-induced neuroinflammatory brain disease.

[0150] Example 9: Application of Formula I in intestinal mucosal permeability-related diseases

[0151] The colon tissue of the mice in the treatment group in Example 4 was examined using HE staining to detect the histopathology of the colonic epithelial tissue and compared with that of the pathogenic group.

[0152] Compared with the pathogenic group, the treatment group mice showed increased inflammatory cell infiltration in the muscularis mucosae and an increased number of crypts in their colon tissue. Figure 6 (A and B in the text) indicates that Formula I can improve colonic epithelial damage caused by OLDA.

[0153] Example 10

[0154] In Example 2, 3×Tg mice (AD mice) were directly injected with the composition containing Formula 1 (treatment group). Compared with the control group injected with saline, the treatment group mice showed a decrease in the area of ​​Aβ and p-Tau181 in the hippocampus, and a reduction in the number of IBA-1 and GFAP positive cells, indicating that Formula I can treat AD pathological symptoms and improve neuroinflammation in the brain. In the colonic tissue of the treatment group mice, inflammatory cells infiltrated the muscularis mucosae, and the number of crypts increased, indicating that Formula I can improve colonic epithelial damage. In addition, the spontaneous alternation rate and total number of arm insertions were significantly increased in the treatment group mice. Figure 7 The time spent finding platforms (A and B in the original text) was significantly reduced. Figure 7 (C in the text); After the platform was removed, the number of times the original platform location was traversed increased significantly (C in the text); Figure 7 The presence of D in formula I indicates that the compound can improve cognitive dysfunction in AD mice.

[0155] The present application has been described in detail above with reference to the embodiments. However, the present application is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present application. Unless otherwise specified, the embodiments and features described in the embodiments of the present application can be combined with each other.

Claims

1. Application of N-oleoyl dopamine in the construction of animal models of diseases, including animal models of neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases; Optionally, the animals used in the disease animal model include non-human mammals; Optionally, the animals used in the disease animal model include at least one of rodents and primates; Optionally, the animals used in the disease animal model include mice; Optionally, the neurodegenerative disease includes at least one of Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Pick's disease dementia. Optionally, the intestinal permeability disease includes at least one of inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer; Optionally, the inflammatory disease includes at least one of neuroinflammatory diseases, inflammatory arthritis, allergies, autism, anxiety disorders, depression, and chronic fatigue syndrome; Optionally, the neurological inflammation includes neurological inflammation of the brain; Optionally, the disease animal model is used for at least one of animal experimental research and drug screening.

2. A method for constructing an animal model of a disease, characterized in that, This includes administering an effective dose of N-oleoyl dopamine to animals, wherein the animal models of the disease include animal models of neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases; Optionally, the animals used in the disease animal model include non-human mammals; Optionally, the animals used in the disease animal model include at least one of rodents and primates; Optionally, the animals used in the disease animal model include mice; Optionally, the neurodegenerative disease includes at least one of Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Pick's disease dementia. Optionally, the intestinal permeability disease includes at least one of inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer; Optionally, the inflammatory disease includes at least one of neuroinflammatory diseases, inflammatory arthritis, allergies, autism, anxiety disorders, depression, and chronic fatigue syndrome; Optionally, the neurological inflammation includes neurological inflammation of the brain; Optionally, the method of administration includes at least one of oral administration and injection administration; Optionally, the effective dose is 0.5 to 1.5 mg / kg.

3. The use of a compound or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or polymorph thereof in the prevention or treatment of diseases in animals, or in the preparation of medicaments for the prevention or treatment of diseases in animals, wherein the compound has the chemical structural formula of Formula I: The diseases mentioned include at least one of neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases; Optionally, the neurodegenerative disease includes at least one of Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Pick's disease dementia. Optionally, the intestinal permeability disease includes at least one of inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer; Optionally, the inflammatory disease includes at least one of neuroinflammatory diseases, inflammatory arthritis, allergies, autism, anxiety disorders, depression, and chronic fatigue syndrome; Optionally, the neurological inflammation includes neurological inflammation of the brain; Optionally, the animal includes mammals; Optionally, the animals include primates; Optionally, the animal may include a human; Optionally, the compound or its pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and polymorphs may be administered as a pharmaceutical composition, the pharmaceutical composition further comprising pharmaceutically acceptable excipients; Optionally, the method of administration includes at least one of oral administration and injection administration; Optionally, the pharmaceutically acceptable excipients include at least one of the following: carrier, diluent, stabilizer, colorant, solvent, chelating agent, dispersant, preservative, antifreeze, thickener, pH adjuster, protectant, and tension modifier. Optionally, the composition is any one of a liquid formulation, a solid formulation, a sustained-release formulation, or a controlled-release formulation.

4. A method for preventing or treating diseases in animals, characterized in that, The method comprises administering an effective dose of the compound or its pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or polymorph to the animal, the compound having the chemical structural formula of Formula I: The diseases mentioned include at least one of neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases; Optionally, the neurodegenerative disease includes at least one of Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Pick's disease dementia. Optionally, the intestinal permeability disease includes at least one of inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer; Optionally, the inflammatory disease includes at least one of neuroinflammatory diseases, inflammatory arthritis, allergies, autism, anxiety disorders, depression, and chronic fatigue syndrome; Optionally, the neurological inflammation includes neurological inflammation of the brain; Optionally, the animal includes mammals; Optionally, the animals include primates; Optionally, the animal may include a human; Optionally, the method of administration includes at least one of oral administration and injection administration; Optionally, the compound or its pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and polymorphs may be administered as a pharmaceutical composition, the pharmaceutical composition further comprising pharmaceutically acceptable excipients; Optionally, the pharmaceutically acceptable excipients include at least one of the following: carrier, diluent, stabilizer, colorant, solvent, chelating agent, dispersant, preservative, antifreeze, thickener, pH adjuster, protectant, and tension modifier. Optionally, the composition is any one of a liquid formulation, a solid formulation, a sustained-release formulation, or a controlled-release formulation.

5. The use of the composition in the prevention or treatment of diseases in animals, or in the preparation of a medicament for the prevention or treatment of diseases in animals, characterized in that, The composition comprises: The compound or its pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, polymorphs, and pharmaceutically acceptable excipients; The compound has the following chemical structural formula I: The diseases mentioned include at least one of neurodegenerative diseases, intestinal permeability diseases, and inflammatory diseases; Optionally, the neurodegenerative disease includes at least one of Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Pick's disease dementia. Optionally, the intestinal permeability disease includes at least one of inflammatory bowel disease, irritable bowel syndrome, celiac disease, obesity, non-alcoholic fatty liver disease, type 2 diabetes, cardiovascular disease, and cancer; Optionally, the inflammatory disease includes at least one of neuroinflammatory diseases, inflammatory arthritis, allergies, autism, anxiety disorders, depression, and chronic fatigue syndrome; Optionally, the neurological inflammation includes neurological inflammation of the brain; Optionally, the animal includes mammals; Optionally, the animals include primates; Optionally, the animal may include a human; Optionally, the pharmaceutically acceptable excipients include at least one of the following: carrier, diluent, stabilizer, colorant, solvent, chelating agent, dispersant, preservative, antifreeze, thickener, pH adjuster, protectant, and tension modifier. Optionally, the composition is any one of a liquid formulation, a solid formulation, a sustained-release formulation, or a controlled-release formulation.

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