Combination product, salt and use thereof for treating neurodegenerative diseases or conditions

Abstract

A novel combination, pharmaceutical composition, salt form, process for their preparation and their use in the treatment, alleviation and / or prevention of neurodegenerative diseases or conditions.

Description

A combination product, salt and use thereof for treating neurodegenerative diseases or conditions Technical Field

[0001] The present invention belongs to the field of medicine and relates to a novel combination product, a pharmaceutical composition, a salt form, a method for preparing the same and its use in treating, alleviating and / or preventing neurodegenerative diseases or disorders. Background Art

[0002] Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by neuronal cell death, cognitive loss, and severe behavioral abnormalities, ultimately leading to death. Currently, there are 2.5 to 4 million AD patients in the United States and 17 to 25 million worldwide. In Western countries, AD has become the fourth leading cause of death after heart disease, cancer, and stroke. An acetylcholinesterase inhibitor, dapoxetine is FDA-approved to slow the progression of Alzheimer's disease. However, the drug is effective only for a limited period of time and in certain patients. To date, there is no proven treatment or cure for this devastating disease.

[0003] Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that affects upper and lower motor neurons in the brainstem and spinal cord. ALS patients develop widespread muscle atrophy 3-5 years after onset, leading to paralysis and death. Its pathological hallmark is the aggregation and accumulation of ubiquitinated protein inclusions in motor neurons. ALS can be divided into familial ALS (fALS), which accounts for approximately 10% of cases, and sporadic ALS (sALS), which occurs in the absence of a family history of the disease and accounts for approximately 90%. The main risk factors for ALS include genes, environment, lifestyle, or a combination of these factors (PARALS Registry et al., "Genome-Wide Association Analyses Identify New Risk Variants and the Genetic Architecture of Amyotrophic Lateral Sclerosis."). In terms of pathogenesis, ALS involves multiple pathophysiological pathways, including glutamate excitotoxicity (Van Den Bosch et al., “The Role of Excitotoxicity in the Pathogenesis of Amyotrophic Lateral Sclerosis.”), neuroinflammation (Liu and Wang, “Role of Neuroinflammation in Amyotrophic Lateral Sclerosis.”), iron accumulation (Ndayisaba, Kaindlstorfer, and Wenning, “Iron in Neurodegeneration—Cause or Consequence?”), microRNA metabolism dysregulation and abnormal RNA binding proteins (Donnelly, Grima, and Sattler, “Aberrant RNA Homeostasis in Amyotrophic Lateral Sclerosis.”), etc. Its pathogenesis has not yet been fully elucidated.

[0004] The incidence and prevalence of ALS increase with age. To date, no treatment or medication can prevent or reverse the disease. Approved drugs are intended to alleviate symptoms or slow disease progression. Since its approval by the US Food and Drug Administration (FDA) in 1995, riluzole has been the only widely recognized treatment, prolonging survival in ALS patients by three months (Miller, Mitchell, and Moore, “Riluzole for Amyotrophic Lateral Sclerosis (ALS) / Motor Neuron Disease (MND).”). In 2017, the US Food and Drug Administration (FDA) approved evadarone, which improves ALS Functional Rating Scale (ALSFRS-R) scores and shows a trend toward slowing disease progression (Al-Chalabi et al., “July 2017 ENCALS Statement on Edaravone.”). In September 2022, AMX0035 was approved by the FDA for the treatment of ALS. In the ITT trial, median survival (OS) was extended by 4.8 months, adjusted for two post-hoc analyses, and by 9.7 months after RPSFTM correction. A survival prediction algorithm based on natural history data predicted a 9.9-month survival benefit. AMX0035 is an oral fixed-dose combination of sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA) developed by Amyyx Pharmaceuticals. Sodium phenylbutyrate is a histone deacetylase inhibitor that inhibits the endoplasmic reticulum stress response; tauroursodeoxycholic acid inhibits mitochondrial-related apoptosis (Mead et al., "Amyotrophic Lateral Sclerosis."). AMX0035 is designed to target the endoplasmic reticulum (ER) and mitochondria of motor neurons in ALS. The ER and mitochondria are connected by the mitochondrial membrane and both play a key role in maintaining neuronal survival.

[0005] Parkinson's disease (PD) is a chronic neurodegenerative disorder that primarily affects the elderly. The most common clinical features are motor tremor (a rhythmic shaking), muscle stiffness, and slow movements (called bradykinesia); however, nonmotor symptoms can also occur, including sleep disturbances, constipation, anxiety, depression, and fatigue. Its primary pathological features are the loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain and dopaminergic nerve fibers in the striatum, as well as the formation of intraneuronal protein inclusions called Lewy bodies (LBs), which are primarily composed of alpha-synuclein (John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, UK et al., "Parkinson's Disease."). PD is multifactorial, caused by genetics, environment, or a combination of both (Bloem, Okun, and Klein, "Parkinson's Disease."). Parkinson's disease is divided into two forms: sporadic (late-onset) and familial (early-onset) (Ryan et al., "Mitochondrial Dysfunction and Mitophagy in Parkinson's."). Epidemiological studies have shown that familial Parkinson's disease accounts for only a minority of Parkinson's disease patients, while the vast majority of Parkinson's disease patients have sporadic Parkinson's disease (Zeng, Geng, and Jia, "Neurotoxin-Induced Animal Models of Parkinson's Disease."). Between 1990 and 2016, the total number of people with Parkinson's disease exceeded 6 million (Dorsey et al., "Global, Regional, and National Burden of Parkinson's Disease, 1990-2016."), and this number is expected to double to over 12 million by 2040 (Rossi et al., "Projection of the Prevalence of Parkinson's Disease in the Coming Decades."). The cause of Parkinson's disease is still unclear but may be related to various risk factors such as excitotoxicity, oxidative stress, and neuroinflammation.

[0006] Currently, PD treatments include levodopa, dopamine agonists, monoamine oxidase (MAO) inhibitors, and amantadine, which aim to improve symptoms and slow disease progression. However, none of these treatments can completely cure the disease and are associated with several side effects.

[0007] Current treatments for neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) suffer from numerous problems. It is only effective for a limited period of AD and certain patients. The treatment of ALS is often costly and partially ineffective. Current treatments or measures can only achieve limited improvement, leaving a huge unmet clinical need. Parkinson's disease has a great social impact and is currently the fastest growing neurological disease and the leading cause of disability in the world. Current treatments or measures are designed to improve symptoms and slow disease progression, but they also have multiple side effects, so there is still a huge gap in clinical needs.

[0008] Therefore, given the complex pathogenesis of neurodegenerative diseases or disorders, there is an urgent need in the art for a new treatment for neurodegenerative diseases or disorders that is more effective and safer than existing therapies.

[0009] Summary of the Invention

[0010] The inventors of this application have solved the above-mentioned needs through creative work.

[0011] Specifically, the present invention relates to the following technical solutions:

[0012] In one embodiment, the present application relates to a combination product comprising:

[0013] (a) a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof:

[0014] where R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, wherein the hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl and phenyl;

[0015] or R1 、R 2 and R 3 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;

[0016] or R 4 、R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;

[0017] (b) bile acid or its derivative or analogue or its pharmaceutically acceptable salt, solvate, hydrate or stereoisomer;

[0018] The molar ratio of the component (a) to the component (b) is 1:1000-1000:1.

[0019] In another embodiment, the present invention relates to a pharmaceutical composition comprising:

[0020] (a) a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof:

[0021] where R 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined herein;

[0022] (b) bile acid or its derivative or analogue or its pharmaceutically acceptable salt, solvate, hydrate or stereoisomer;

[0023] (c) pharmaceutically acceptable carriers, excipients and / or diluents;

[0024] The molar ratio of the component (a) to the component (b) is 1:1000-1000:1.

[0025] In yet another embodiment, the present invention relates to an acid-base addition salt of formula (II):

[0026] (A + ) m (B - ) n (C - ) p

[0027] (II)

[0028] in,

[0029] (a)A + is the cationic portion of the compound of formula (I);

[0030] where R 1 、R 2 、R 3 、R 4 、R 5 and R 6 As defined herein;

[0031] (b)B - is the anionic portion of a bile acid, a derivative thereof, or an analog thereof; and

[0032] (c)C - It is an acid anion;

[0033] wherein m, n and p are each independently an integer selected from 1-6 such that the salt configuration achieves charge balance, and when m=n, p is 0.

[0034] In yet another embodiment, the present invention relates to a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments, for use in improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by reactive oxidative metabolites in the cells, regulating redox homeostasis in the cells or reducing mitochondrial dysfunction in the cells.

[0035] In yet another embodiment, the present invention relates to a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments for use in treating, alleviating and / or preventing a neurodegenerative disease or disorder.

[0036] In yet another embodiment, the present invention relates to a method for increasing cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by reactive oxidative metabolites in the cells, regulating redox homeostasis in the cells or reducing mitochondrial dysfunction in the cells, comprising contacting the cells with a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0037] In yet another embodiment, the present invention relates to a method for treating, alleviating and / or preventing a neurodegenerative disease or disorder, comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0038] In yet another embodiment, the present invention relates to a kit comprising:

[0039] A combination product, an acid-base addition salt, a pharmaceutical composition or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof and instructions for use according to any one of the preceding embodiments,

[0040] The kit is used for treating and / or preventing neurodegenerative diseases or disorders.

[0041] The details of the present application are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are now described. Other features, objects and advantages of the present application will be apparent from the specification and claims. In the specification and the appended claims, the singular also includes the plural, unless the context clearly provides otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present application belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

[0042] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are hereby expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1. Depicts the effects of Compound Y, Compound T, Compound B, Compound N, Compound combination Y + T, Compound combination B + N, Compound combination PB + T, and a novel salt of YT on the viability of hydrogen peroxide-induced SH-sy5y cells. The control group is a cell culture group without any drug or H2O2 stimulation; the model group is a cell culture group without any drug but with H2O2 stimulation. The DMSO group is a cell culture group without any drug or H2O2 stimulation but with DMSO alone. In the dosing groups, the concentration of Compound Y was 100 μM; the concentration of Compound T was 100 μM; the concentration of Compound B was 100 μM; the concentration of Compound N was 100 μM; the concentrations of the compound combination Y+T were 100 μM (Compound Y) + 100 μM (Compound T), respectively; the concentrations of the compound combination B+N were 100 μM (Compound B) + 100 μM (Compound N), respectively; the concentrations of the compound combination PB+T were 500 μM (Compound T) + 200 μM (Compound PB), respectively; and the concentration of YT salt was 100 μM. All dosing groups were stimulated with H2O2. Data are presented as mean ± SEM. One-way ANOVA was used, **** indicates P < 0.0001, *** indicates P < 0.001, ** indicates P < 0.01, * indicates P < 0.05, vs YT; #### indicates P < 0.0001, # indicates P < 0.05, vs model.

[0044] Figure 2 shows the effects of Compound Y, Compound T, Compound Y + T, YT salt, and UDCA (U) on CD4-positive T cell proliferation. The YT salt concentration is 100 μM, which translates to a Compound Y concentration of 100 μM, a Compound T concentration of 100 μM, a Compound Y + T concentration of 100 μM (Compound Y) + 100 μM (Compound T), and a Compound U concentration of 100 μM.

[0045] Figure 3 shows the effects of Compound Y, Compound T, Compound Y + T, YT salt, and UDCA (U) on CD8-positive T cell proliferation. The YT salt concentration is 100 μM, which translates to a Compound Y concentration of 100 μM, a Compound T concentration of 100 μM, a Compound Y + T concentration of 100 μM (Compound Y) + 100 μM (Compound T), and a Compound U concentration of 100 μM.

[0046] [Corrected 21.06.2024 according to Article 91] Figure 4. Describes the effect of YT salt on SOD1 G93AThe effects of the mutant on the pathogenesis of ALS model mice were examined. The model group received no treatment, while the YT salt group received 496 mg / kg (administered orally once daily). Data were analyzed using the Log-rank test, with P < 0.05 indicating statistically significant differences between groups.

[0047] Figure 5. Describes the effect of YT salt on SOD1 G93A The effects of the mutant on the development of severe ALS in mice were investigated. The model group received no treatment, while the YT salt group received 496 mg / kg (administered orally once daily). Data were analyzed using the Log-rank test, with P < 0.05 indicating statistically significant differences between groups.

[0048] Figure 6. Describes the effect of YT salt on SOD1 G93A The effect of the YT salt on the survival of ALS model mice was investigated. The model group received no treatment, while the YT salt group received 496 mg / kg (administered once daily by oral gavage). Data were analyzed using the Log-rank test, with P < 0.05 indicating statistically significant differences between groups.

[0049] Figure 7 shows the effect of YT salt on grip strength in a MPTP-induced Parkinson's disease mouse model. The sham-operated group consisted of C57BL / 6 mice injected intraperitoneally with 10 mL / kg normal saline. The model group consisted of C57BL / 6 mice injected intraperitoneally with 30 mg / kg of MPTP to establish the model and received no drug treatment. The L-DOPA group served as the positive control group, in which model mice were treated with 40 mg / kg L-DOPA (gavage twice daily). The low-dose YT salt group consisted of model mice administered 167.5 mg / kg YT salt (gavage twice daily). The high-dose YT salt group consisted of model mice administered 248 mg / kg YT salt (gavage twice daily). Data are expressed as mean ± standard error (SEM). P < 0.05 indicates statistical significance, * indicates P < 0.05, ** indicates P < 0.01, *** indicates P < 0.001, and **** indicates P < 0.0001.

[0050] Figure 8 shows the effects of YT salt on the rotarod test in an MPTP-induced Parkinson's disease mouse model, which assesses the time it takes for the animals to maintain balance on the rotarod until they fall to the ground. The sham-operated group consisted of C57BL / 6 mice injected intraperitoneally with 10 mL / kg of normal saline. The MPTP model group consisted of C57BL / 6 mice injected intraperitoneally with 30 mg / kg of MPTP and received no treatment. The L-DOPA group served as the positive control, receiving 40 mg / kg of L-DOPA (gavage twice daily). The low-dose YT salt group received 167.5 mg / kg of YT salt (gavage twice daily). The high-dose YT salt group received 248 mg / kg of YT salt (gavage twice daily). Data are presented as mean ± standard error (SEM). P < 0.05 indicates statistical significance, * indicates P < 0.05, and ** indicates P < 0.01.

[0051] Figure 9 shows the effect of YT salt on the number of TH-positive cells in the substantia nigra of a mouse model of MPTP-induced Parkinson's disease. The sham-operated group consisted of C57BL / 6 mice injected intraperitoneally with 10 mL / kg of saline; the model group consisted of C57BL / 6 mice injected intraperitoneally with 30 mg / kg of MPTP and received no treatment; the L-DOPA group served as the positive control group, receiving 40 mg / kg of L-DOPA (gavage twice daily); the low-dose YT salt group received 167.5 mg / kg of YT salt (gavage twice daily); and the high-dose YT salt group received 248 mg / kg of YT salt (gavage twice daily). Data are presented as mean ± standard error (SEM). P < 0.05 indicates statistical significance, and **** indicates P < 0.0001.

[0052] Figure 10 shows the effect of YT salt on the percentage of TH-positive cells in the striatum of a mouse model of MPTP-induced Parkinson's disease. The sham-operated group consisted of C57BL / 6 mice injected intraperitoneally with 10 mL / kg of saline. The model group consisted of C57BL / 6 mice injected intraperitoneally with 30 mg / kg of MPTP and received no treatment. The L-DOPA group served as the positive control group, receiving 40 mg / kg of L-DOPA (gavage twice daily). The low-dose YT salt group received 167.5 mg / kg of YT salt (gavage twice daily). The high-dose YT salt group received 248 mg / kg of YT salt (gavage twice daily). Data are presented as mean ± standard error (SEM). P < 0.05 indicates statistical significance, ** indicates P < 0.01, and **** indicates P < 0.0001.

[0053] Figure 11 shows the effect of YT salt on the number of missteps in the grid-walking test in 6-OHDA-induced Parkinson's disease rats. The sham-operated group consisted of SD rats without any treatment; the model group consisted of SD rats injected with 4 μL of 6-OHDA (5 μg / μL) intracranially (in the medial forebrain bundle, MFB) on the right side of the brain to establish the model and received no other treatment; the istradefylline group served as the positive control group, in which model rats were treated with 10 mg / kg istradefylline (orally administered once daily); and the YT salt group consisted of model rats treated with 248 mg / kg YT salt (orally administered once daily). Data are presented as mean ± standard error (SEM). P < 0.05 indicates statistical significance; * indicates P < 0.05.

[0054] Figure 12 shows the effect of YT salt on the misstep rate in the grid-walking test in 6-OHDA-induced Parkinson's disease rats. The sham-operated group received a 4 μL (0.2 mg / mL) ascorbic acid solution injected into the right cranial medial forebrain bundle (MFB) of SD rats. The model group received a 4 μL (5 μg / μL) 6-OHDA injection into the right MFB of SD rats to establish the model and received no drug treatment. The istradefylline group served as the positive control group and received 10 mg / kg istradefylline (orally administered once daily). The YT salt-treated group received 248 mg / kg YT salt (orally administered once daily). Data are presented as mean ± standard error (SEM). P < 0.05 indicates statistical significance; * indicates P < 0.05. DETAILED DESCRIPTION

[0055] definition

[0056] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, terms and laboratory procedures related to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology used herein are those widely used in the respective fields and are standard procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0057] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0058] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, and most preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0059] As used herein, the term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl or cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0060] As used herein, the terms "halo" and "halogen" refer to fluoro, chloro, bromo, and iodo.

[0061] As used herein, the term "haloalkyl" by itself or as part of another substituent refers to an alkyl group in which some or all of the hydrogen atoms are replaced by halogen atoms. For alkyl, haloalkyl can have any suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluoro" can be used to define a compound or group in which all hydrogen atoms are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0062] As used herein, the term "hydroxy" refers to an -OH moiety.

[0063] The present invention also includes various deuterated forms of formula (I). Each available hydrogen atom connected to the carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) with reference to relevant literature. When preparing the deuterated form of formula (I), commercially available deuterated starting materials can be used, or they can use conventional techniques to adopt deuterated reagents to synthesize, and the limiting examples of deuterated reagents include: deuterated borane, trideuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane etc.

[0064] "Pharmaceutically acceptable" means that the ingredients in question are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a compound when used herein. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, hydrochloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as acetate ion, succinate ion, or other counterion. Counterion can be any organic or inorganic module that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In the case where multiple charged atoms are part of a pharmaceutically acceptable salt, multiple counterions may be present. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0066] As used herein, the term "acid anion" refers to an anion produced when an acid ionizes. Common acid anions include chloride, bromide, iodide, carbonate, bicarbonate, sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, formate, acetate, and the like. The acid anion may be -1, -2, -3, -4, and the like.

[0067] As used herein, the term "pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation adjuvant, or carrier conventional in the art used with a therapeutic agent, which together constitutes a "pharmaceutical composition" for administration to an individual. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration employed and is compatible with the other ingredients of the formulation. A pharmaceutically acceptable carrier is suitable for the formulation employed.

[0068] As used herein, the term "pharmaceutically acceptable excipient" refers to a substance that facilitates administration of an active agent to an individual. Useful pharmaceutical excipients include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coating agents, sweeteners, flavorings, and coloring agents.

[0069] Depending on the position and properties of the various substituents desired, the compounds of the present invention may contain one or more asymmetric centers. Asymmetric carbon atoms may exist in (R)- and / or (S)- configurations, resulting in racemic mixtures in the case of a single asymmetric center and in the case of multiple asymmetric centers, resulting in diastereomeric mixtures. In some cases, asymmetry may also exist due to hindered rotation around a specific bond, such as two substituted aromatic rings of a specific compound connected by the central bond. The substituents on the ring may also exist in cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention. Preferred compounds are those that produce more desired biological activity. Separated, pure or partially purified isomers and stereoisomers, or racemic mixtures or diastereomeric mixtures of the compounds of the present invention are included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

[0070] Tautomers, sometimes called proton-shift tautomers, are two or more compounds related by the migration of a hydrogen atom accompanied by a switch of one or more single bonds and one or more adjacent double bonds. The compounds of the present invention may exist in one or more tautomeric forms.

[0071] The present invention also includes all suitable isotopic variations of the compounds of the present invention. An isotopic variation of a compound of the present invention is defined as a compound of the present invention in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 129 I and 131 I. Certain isotopic variations of the compounds of the present invention, for example, wherein one or more radioactive isotopes (e.g., 3 H or 14C) can be used for drug and / or substrate tissue distribution studies. Tritium and carbon-14 (i.e., 14 C) isotopes, due to their ease of preparation and detectability. Further, substitution with isotopes such as deuterium can provide definite therapeutic advantages resulting from better metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some cases. Isotopic variants of the compounds of the invention can generally be prepared using conventional methods known to those skilled in the art, for example, using the illustrative methods or the preparation methods described in the Examples below, using suitable isotopic variants of suitable reagents.

[0072] The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers or any mixture of said stereoisomers in any ratio. The separation of single stereoisomers, such as single enantiomers or single diastereomers, of the compounds of the present invention can be achieved by any suitable prior art method, such as chromatography, in particular, such as chiral chromatography.

[0073] The present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers in any ratio.

[0074] As used herein, the term "solvate" or "solvate" refers to a compound of the present invention that forms a pharmaceutically acceptable solvate with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate, etc. Hydrates are a specific form of solvate in which the solvent is water.

[0075] As used herein, the terms "effective amount" and "therapeutically effective amount" refer to the dosage of a compound, such as a compound of the invention, a combination of compounds, or a salt form, that produces the therapeutic effect for which it is administered. The exact dosage will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition, 2006, Brunton, Ed., McGraw-Hill; and Remington: The Science and Practice of Pharmacy, 21st Edition, 2005, Hendrickson, Ed., Lippincott, Williams & Wilkins).

[0076] As used herein, " treatment (treatment or treating) " is the method for obtaining beneficial or desired result (including clinical outcome).For the purpose of the application, beneficial or desired clinical outcome includes but is not limited to one or more of the following: alleviate one or more symptoms caused by the disease, reduce the degree of the disease, stabilize the disease (for example, prevent or delay the deterioration of the disease), prevent or delay the spread of the disease (for example, metastasis), prevent or delay the recurrence of the disease, delay or slow down the progress of the disease, improve the disease state, provide the alleviation (partial or complete) of the disease, reduce the dosage of one or more other drugs required for the treatment of the disease, delay the progress of the disease, increase or improve the quality of life, increase weight gain and / or prolong survival." treatment " also encompasses the pathological consequences (such as, tumor volume) that reduce cancer. The method of the application contemplates any one or more of these treatment aspects.

[0077] As used herein, "prevention" or "preventing" includes providing protection against the occurrence or recurrence of a disease in an individual who may be susceptible to the disease but has not yet been diagnosed with the disease.

[0078] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to mammals, including but not limited to humans, cows, horses, cats, dogs, rodents, or primates. In some embodiments, the individual is a human.

[0079] An "effective amount" of an agent is an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or preventive result. The specific dosage may vary depending on one or more of the following: the particular agent selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0080] As used herein, the term "synergistic" or "synergistic" is used to refer to the result of the combination of two compounds, components, or targeting agents being greater than the sum of the individual agents together. The term "synergistic" or "synergistic" means that the disease condition or condition being treated is improved compared to when each compound, component, or targeting agent is used alone. This improvement in the disease condition or condition being treated is a "synergistic effect." A "synergistic amount" is the amount of a combination of two compounds, components, or targeting agents that results in a synergistic effect ("synergistic" as defined herein).

[0081] Determining the synergistic interaction between one or both components, the optimal range of the effect, and the absolute dose range of each component for the effect can be clearly measured by administering the components within different w / w ratios and dosages to patients in need of treatment. However, observing synergy in in vitro or in vivo models can predict the effect in humans and other species, as well as existing in vitro or in vivo models as described herein to measure synergistic effects, and the results of such studies can also be used to predict the desired effective dose and plasma concentration ratio range in humans and other species, as well as absolute doses and plasma concentrations, by applying pharmacokinetic / pharmacodynamic methods.

[0082] It should be understood that embodiments of the application described herein include "consisting of" and / or "consisting essentially of.

[0083] Reference herein to "about" a value or parameter includes (and describes) variations with respect to that value or parameter itself. For example, description referring to "about X" includes description of "X."

[0084] As used herein, the term "about XY" has the same meaning as "about X to about Y."

[0085] As used herein, the term "about" when used to modify an amount of an ingredient or reactant of the invention refers to variations in the numerical amount that may occur, for example, in typical measurements and liquid handling procedures used to prepare concentrates or actual use solutions; accidental errors in such procedures; differences in the manufacture, source, or purity of ingredients used to prepare the compositions or practice the methods; etc. The term "about" also includes amounts that vary due to different equilibrium conditions relative to the composition obtained from a particular starting mixture. Whether or not modified by the term "about," the claims include equivalent amounts of the amounts. In one embodiment, the term "about" means within 10% of the reported value, preferably within 5% of the reported value.

[0086] Those skilled in the art will understand that when a numerical value is stated in a claim, whether or not it is preceded by "about," the actual value of the numerical value may fluctuate by 10% (±10%) above or below the stated value, preferably by 5% (±5%) above or below the stated value.

[0087] As used herein and in the appended claims, the singular forms "a," "an," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0088] Implementation Plan Description

[0089] Combination products

[0090] In some aspects, the present disclosure provides a combination product comprising:

[0091] (a) a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof:

[0092] where R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, wherein the hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl and phenyl;

[0093] or R 1 、R 2 and R 3Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;

[0094] or R 4 、R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;

[0095] (b) bile acid or a derivative or analogue thereof or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof; wherein the molar ratio of component (a) to component (b) is 1:1000-1000:1.

[0096] In a further embodiment, R 1 、R 2 and R 3 are independently selected from hydrogen, hydroxy, methoxy and benzyloxy, or R 1 、R 2 and R 3 Any two adjacent ones of the R-1-2-1 ... 1 、R 2 and R 3 One or both of them are hydrogen, or R 1 、R 2 and R 3 Any two adjacent ones of the R-1-2-1-2-1-1-1-1 and the carbon atoms to which they are attached together form a 5-membered heterocyclic ring containing one or more oxygen atoms. In yet a further embodiment, R 1 、R 2 and R 3 One of them is hydrogen, or R 1 、R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.

[0097] In a further embodiment, R 4 、R 5 and R 6 are independently selected from hydrogen, hydroxy and methoxy, or R 4 、R 5 and R 6 Any two adjacent ones of the R-1-2-1 ... 4 、R 5 and R 6One or both of them are hydrogen, or R 4 、R 5 and R 6 Any two adjacent ones of the R-1-2-1-2-1-1-1-1 and the carbon atoms to which they are attached together form a 5-membered heterocyclic ring containing one or more oxygen atoms. In yet a further embodiment, R 4 、R 5 and R 6 One of them is hydrogen, or R 4 、R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.

[0098] In further embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate. Preferably, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate or hydrochloride. More preferably, the pharmaceutically acceptable salt of the compound of formula (I) is hydrochloride.

[0099] In a further embodiment, the compound of formula (I) is selected from:

[0100] In a further embodiment, the bile acid or its derivative or analogue is selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid and tauroursodeoxycholic acid, etc.

[0101] In a further embodiment, the molar ratio of component (a) to component (b) is from 1:100 to 100: 1. Preferably, the molar ratio of component (a) to component (b) is from 1:90 to 90: 1, 1:80 to 80: 1, 1:70 to 70: 1, 1:60 to 60: 1, 1:50 to 50: 1, 1:40 to 40: 1, 1:30 to 30: 1, 1:20 to 20: 1, 1:10 to 10: 1. More preferably, the molar ratio of component (a) to component (b) is from 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, or any value therebetween.

[0102] In a further embodiment, the combination product is used to improve cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by reactive oxidative metabolites in the cells, regulating redox homeostasis in the cells, or reducing mitochondrial dysfunction in the cells. Preferably, the combination product is used to treat, alleviate and / or prevent neurodegenerative diseases or disorders. More preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy (MD), Pick's disease (PID), multi-infarct dementia (MID), Creutzfeldt-Jakob disease (CJD), dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia (FTD). Preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).

[0103] Pharmaceutical composition

[0104] In some aspects, the present disclosure provides a pharmaceutical composition comprising:

[0105] (a) a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof:

[0106] where R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, wherein the hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl and phenyl;

[0107] or R 1 、R 2 and R 3Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;

[0108] or R 4 、R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;

[0109] (b) bile acid or its derivative or analogue or its pharmaceutically acceptable salt, solvate, hydrate or stereoisomer;

[0110] (c) pharmaceutically acceptable carriers, excipients and / or diluents;

[0111] The molar ratio of the component (a) to the component (b) is 1:1000-1000:1.

[0112] In a further embodiment, R 1 、R 2 and R 3 are independently selected from hydrogen, hydroxy, methoxy and benzyloxy, or R 1 、R 2 and R 3 Any two adjacent ones of the R-1-2-1 ... 1 、R 2 and R 3 One or both of them are hydrogen, or R 1 、R 2 and R 3 Any two adjacent ones of the R-1-2-1-2-1-1-1-1 and the carbon atoms to which they are attached together form a 5-membered heterocyclic ring containing one or more oxygen atoms. In yet a further embodiment, R 1 、R 2 and R 3 One of them is hydrogen, or R 1 、R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.

[0113] In a further embodiment, R 4 、R 5 and R 6 are independently selected from hydrogen, hydroxy and methoxy, or R 4 、R 5 and R 6Any two adjacent ones of the R-1-2-1 ... 4 、R 5 and R 6 One or both of them are hydrogen, or R 4 、R 5 and R 6 Any two adjacent ones of the R-1-2-1-2-1-1-1-1 and the carbon atoms to which they are attached together form a 5-membered heterocyclic ring containing one or more oxygen atoms. In yet a further embodiment, R 4 、R 5 and R 6 One of them is hydrogen, or R 4 、R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.

[0114] In further embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate. Preferably, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate or hydrochloride. More preferably, the pharmaceutically acceptable salt of the compound of formula (I) is hydrochloride.

[0115] In a further embodiment, the compound of formula (I) is selected from:

[0116] In a further embodiment, the bile acid or its derivative or analogue is selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid and tauroursodeoxycholic acid, etc.

[0117] In a further embodiment, the molar ratio of component (a) to component (b) is from 1:100 to 100: 1. Preferably, the molar ratio of component (a) to component (b) is from 1:90 to 90: 1, 1:80 to 80: 1, 1:70 to 70: 1, 1:60 to 60: 1, 1:50 to 50: 1, 1:40 to 40: 1, 1:30 to 30: 1, 1:20 to 20: 1, 1:10 to 10: 1. More preferably, the molar ratio of component (a) to component (b) is from 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, or any value therebetween.

[0118] In a further embodiment, the pharmaceutical composition is used to improve cell viability, in particular neuronal cell viability, especially by reducing oxidative damage mediated by active oxidative metabolites in the cell, regulating redox homeostasis in the cell or reducing mitochondrial dysfunction in the cell. Preferably, the pharmaceutical composition is used to treat, alleviate and / or prevent neurodegenerative diseases or disorders. More preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscle atrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia. Preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).

[0119] Acid-base addition salts

[0120] In some aspects, the present disclosure provides an acid-base addition salt of formula (II):

[0121] (A + ) m (B - ) n (C - ) p

[0122] (II)

[0123] in,

[0124] (a)A + is the cationic portion of the compound of formula (I);

[0125] where R 1 、R 2 、R 3 、R4 、R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, wherein the hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl and phenyl,

[0126] or R 1 、R 2 and R 3 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N,

[0127] or R 4 、R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;

[0128] (b)B - is the anionic portion of a bile acid, a derivative thereof, or an analog thereof; and

[0129] (c)C - It is an acid anion;

[0130] wherein m, n and p are each independently an integer selected from 1-6 such that the salt configuration achieves charge balance, and when m=n, p is 0.

[0131] In a further embodiment, R 1 、R 2 and R 3 are independently selected from hydrogen, hydroxy, methoxy and benzyloxy, or R 1 、R 2 and R 3 Any two adjacent ones of the R-1-2-1 ... 1 、R 2 and R 3 One or both of them are hydrogen, or R 1 、R 2 and R 3 Any two adjacent ones of the R-1-2-1-2-1-1-1-1 and the carbon atoms to which they are attached together form a 5-membered heterocyclic ring containing one or more oxygen atoms. In yet a further embodiment, R 1 、R 2 and R3 One of them is hydrogen, or R 1 、R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.

[0132] In a further embodiment, R 4 、R 5 and R 6 are independently selected from hydrogen, hydroxy and methoxy, or R 4 、R 5 and R 6 Any two adjacent ones of the R-1-2-1 ... 4 、R 5 and R 6 One or both of them are hydrogen, or R 4 、R 5 and R 6 Any two adjacent ones of the R-1-2-1-2-1-1-1-1 and the carbon atoms to which they are attached together form a 5-membered heterocyclic ring containing one or more oxygen atoms. In yet a further embodiment, R 4 、R 5 and R 6 One of them is hydrogen, or R 4 、R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.

[0133] In a further embodiment, the cationic portion of the compound of formula (I) is selected from the group consisting of:

[0134] In a further embodiment, component (b) is an anionic moiety selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid, and tauroursodeoxycholic acid, and the like.

[0135] In a further embodiment, C - is a monovalent, divalent, trivalent, tetravalent acid anion or a mixture thereof. - is a monovalent, divalent or trivalent acid anion or a mixture thereof. More preferably, C - is a monovalent or divalent acid anion or a mixture thereof. Most preferably, C - It is a monovalent acid anion or a mixture thereof.

[0136] In further embodiments, m is 1, n is 1, and p is 0, or m is 2, n is 1, and p is 1.

[0137] In a further embodiment, the pharmaceutical composition is used to improve cell viability, in particular neuronal cell viability, especially by reducing oxidative damage mediated by active oxidative metabolites in the cell, regulating redox homeostasis in the cell or reducing mitochondrial dysfunction in the cell. Preferably, the pharmaceutical composition is used to treat, alleviate and / or prevent neurodegenerative diseases or disorders. More preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscle atrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia. Preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).

[0138] Treatment and / or prevention

[0139] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing a neurodegenerative disease or condition. In some aspects, the method for treating, alleviating and / or preventing a neurodegenerative disease or condition comprises administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof according to any one of the aforementioned embodiments.

[0140] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing Alzheimer's disease (AD), comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0141] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing Huntington's disease (HD), comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0142] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing Parkinson's disease (PD), comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0143] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing amyotrophic lateral sclerosis (ALS), comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0144] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing Pick's disease, comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0145] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing multi-infarct dementia, comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt according to any one of the preceding embodiments, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

[0146] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing Creutzfeldt-Jakob disease, comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0147] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing dementia with Lewy bodies (DLB), comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0148] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing mixed dementia, comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0149] In some aspects, the present disclosure provides a method for treating, alleviating and / or preventing frontotemporal dementia, comprising administering to a patient in need thereof a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0150] In some aspects, the present disclosure provides a method of treating and / or preventing a neurodegenerative disease or disorder, comprising: Scheme 1, administering to a patient in need thereof:

[0151] (a) a therapeutically and / or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof:

[0152] where R 1 、R 2 、R 3 、R 4 、R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, wherein the hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl and phenyl, or R 1 、R 2 and R 3 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N,

[0153] or R 4 、R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; or

[0154] Option 2, administering simultaneously, concurrently, separately or sequentially to a patient in need thereof:

[0155] (a) a therapeutically and / or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof:

[0156] where R 1 、R 2 、R 3 、R 4、R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, wherein the hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl and phenyl, or R 1 、R 2 and R 3 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N,

[0157] or R 4 、R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; and

[0158] (b) a therapeutically and / or prophylactically effective amount of bile acid, a derivative or an analog thereof, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

[0159] In a further embodiment, R 1 、R 2 and R 3 are independently selected from hydrogen, hydroxy, methoxy and benzyloxy, or R 1 、R 2 and R 3 Any two adjacent ones of the R-1-2-1 ... 1 、R 2 and R 3 One or both of them are hydrogen, or R 1 、R 2 and R 3 Any two adjacent ones of the R-1-2-1-2-1-1-1-1 and the carbon atoms to which they are attached together form a 5-membered heterocyclic ring containing one or more oxygen atoms. In yet a further embodiment, R 1 、R 2 and R 3 One of them is hydrogen, or R 1 、R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.

[0160] In a further embodiment, R 4、R 5 and R 6 are independently selected from hydrogen, hydroxy and methoxy, or R 4 、R 5 and R 6 Any two adjacent ones of the R-1-2-1 ... 4 、R 5 and R 6 One or both of them are hydrogen, or R 4 、R 5 and R 6 Any two adjacent ones of the R-1-2-1-2-1-1-1-1 and the carbon atoms to which they are attached together form a 5-membered heterocyclic ring containing one or more oxygen atoms. In yet a further embodiment, R 4 、R 5 and R 6 One of them is hydrogen, or R 4 、R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.

[0161] In further embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate. Preferably, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate or hydrochloride. More preferably, the pharmaceutically acceptable salt of the compound of formula (I) is hydrochloride.

[0162] In a further embodiment, the compound of formula (I) is selected from:

[0163] In a further embodiment, the bile acid or its derivative or analogue is selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid and tauroursodeoxycholic acid, etc.

[0164] In a further embodiment, the molar ratio of component (a) to component (b) is from 1:100 to 100: 1. Preferably, the molar ratio of component (a) to component (b) is from 1:90 to 90: 1, 1:80 to 80: 1, 1:70 to 70: 1, 1:60 to 60: 1, 1:50 to 50: 1, 1:40 to 40: 1, 1:30 to 30: 1, 1:20 to 20: 1, 1:10 to 10: 1. More preferably, the molar ratio of component (a) to component (b) is from 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1, or any value therebetween.

[0165] In a further embodiment, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscle atrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia. Preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).

[0166] In some aspects, the present disclosure provides a method for improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by reactive oxidative metabolites in the cells, regulating redox homeostasis in the cells, or reducing mitochondrial dysfunction in the cells, comprising contacting the cells with a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.

[0167] In some aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, which is used to improve cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by active oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.

[0168] In some aspects, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof for use in treating, ameliorating and / or preventing a neurodegenerative disease or disorder.

[0169] In a further embodiment, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.

[0170] Administration

[0171] Administration of the compounds or salt forms of the combinations of the present invention may be effected by any method capable of delivering the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

[0172] The compound or salt form of the method or combination of the present invention can be formulated before administration. Preferably, the formulation will be suitable for a specific mode of administration. These compounds can be formulated together with pharmaceutically acceptable carriers known in the art and administered in a variety of dosage forms known in the art. When preparing the pharmaceutical composition of the present invention, the active ingredient is usually mixed with a pharmaceutically acceptable carrier, or diluted with a carrier or encapsulated in a carrier. Such carriers include, but are not limited to, solid diluents or fillers, excipients, sterile aqueous media, and various non-toxic organic solvents. Dosage unit forms or pharmaceutical compositions include tablets, capsules such as gelatin capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, lozenges, troches, hard candies, sprays, creams, ointments, suppositories, pectins, gels, pastes, lotions, ointments, injections, elixirs, syrups, and parenteral solutions packaged in containers suitable for subdividing into individual doses.

[0173] Parenteral formulations include pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, emulsions and sterile powders (for their preparation). Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils and injectable organic esters, such as ethyl oleate. Flowability can be maintained by using a coating such as lecithin, a surfactant or maintaining an appropriate particle size. Exemplary parenteral administration forms include solutions or suspensions of the compounds of the present invention in sterile aqueous solutions, such as propylene glycol aqueous solutions or dextrose solutions. If necessary, such dosage forms can be appropriately buffered.

[0174] In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be generally used for tableting purposes. Similar types of solid compositions can also be used in soft and hard filled gelatin capsules. Therefore, preferred materials include lactose (lactose or milk sugar) and high molecular weight polyethylene glycol. When aqueous suspensions or elixirs are needed for oral administration, the active compound therein can be combined with various sweeteners or flavorings, coloring agents or dyes, and if necessary, emulsifiers or suspending agents, and diluents such as water, ethanol, propylene glycol, glycerol or a combination thereof.

[0175] Methods of preparing various pharmaceutical compositions using specific amounts of active compounds are known or apparent to those skilled in the art. For example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th edition (1975).

[0176] Reagent test kit

[0177] In some aspects, the present disclosure provides a kit for treating, alleviating and / or preventing a neurodegenerative disease or condition, comprising a combination product according to any one of the preceding embodiments, an acid-base addition salt, a pharmaceutical composition or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof and instructions for administering the therapeutic agent. In one embodiment, the instructions for use detail and define the mode of administration of the therapeutic agent, for example, for administering the therapeutic agent of the present invention simultaneously, jointly, separately or sequentially. In one embodiment, the instructions for use detail and define the mode of administration of the therapeutic agent, for example, by specifying the number of days for administration of each therapeutic agent during a specific period of time to detail and define the mode of administration of the therapeutic agent.

[0178] In some aspects, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscle atrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia. Preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).

[0179] Example

[0180] The present invention is further described in detail below by way of examples, which should not be construed as limiting the present invention.

[0181] Materials and Reagents: Unless otherwise specified, all reagents used in the experimental sections of this invention were commercially available. For example, berberine hydrochloride (Compound B), ursodeoxycholic acid (Compound U), and tauroursodeoxycholic acid (Compound T) were purchased from Energy Chemical. Neuroblastoma SH-sy5y cells were purchased from the Cell Bank of the Chinese Academy of Sciences.

[0182] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0183] LC-MS: Unless otherwise noted, the analytical LC-MS system used consisted of a Shimadzu LCMS-2020 electrospray ionization (ESI) system in positive ion detection mode, equipped with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20APDA detector, and an LCMS2020MS detector. The column was a HALO C18 30 mm × 5.0 mm, 2.7 μm column. Mobile phase A was water containing 0.05% TFA, and mobile phase B was acetonitrile containing 0.05% TFA. The gradient was as follows: 5% mobile phase B to 100% (95%) over 2.0 minutes, held for 0.7 minutes, then returned to 5% mobile phase B over 0.05 minutes and held for 0.25 minutes. The column oven (CTO-20AC) was operated at 40.0°C. The flow rate was 1.5 mL / min, and the injection volume was 1 μL. The PDA (SPD-M20A) detection range was 190 nm to 400 nm. The MS detector was configured with electrospray ionization as the ionizable source; acquisition mode: scan; nebulizing gas flow rate: 1.5 L / min; drying gas flow rate: 15 L / min; detector voltage: tuning voltage ± 0.2 kV; DL temperature: 250°C; heating block temperature: 250°C; scan range: 90.00 m / z to 900.00 m / z. ELSD (Alltech 3300) detector parameters: drift tube temperature: 60 ± 5°C; N2 flow rate: 1.8 ± 0.2 L / min. The mobile phase gradient was optimized for each compound. The calculated masses correspond to the exact masses.

[0184] Preparative HPLC: Unless otherwise stated, preparative HPLC purifications were performed using a Waters Auto purification system (2545-2767) with a 2489 UV detector. The column was selected from one of the following: Waters C18, 19 mm × 150 mm, 5 μm; XBridge Prep OBD C18 column, 30 mm × 150 mm, 5 μm; XSelect CSH Prep C18 OBD column, 5 μm, 19 mm × 150 mm; XBridge Shield RP18 OBD column, 30 mm × 150 mm, 5 μm; Xselect CSH Fluorophenyl, 30 mm × 150 mm, 5 μm; or YMC-Actus Triart C18, 30 mm × 150 mm, 5 μm. The mobile phase consisted of a mixture of acetonitrile (5%-95%) in water containing 0.1% FA or 10 mmol / L NH4HCO3. The flow rate was maintained at 25 mL / min, the injection volume was 1200 μL, and the UV detector used two channels, 254 nm and 220 nm.The mobile phase gradient was optimized for each compound.

[0185] Chiral chromatography: Chiral analytical chromatography was performed on one of the following: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.), (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc.), CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.); different column dimensions (50 mm × 4.6 mm, 100 mm × 4.6 mm, 150 mm × 4.6 mm, 250 mm × 4.6 mm, 50 mm × 3.0 mm, 100 mm × 3.0 mm), percentage of ethanol in hexane (% Et / Hex) or percentage of isopropanol in hexane (% IPA / Hex) as an isocratic solvent system, or using supercritical fluid (SFC) conditions.

[0186] Normal phase flash chromatography: Unless otherwise stated, normal phase flash column chromatography (FCC) was performed on silica gel using prepacked silica gel columns using ethyl acetate (EtOAc) / hexane, ethyl acetate (EtOAc) / petroleum ether (bp 60°C to 90°C), CH2Cl2 / MeOH, or CH2Cl2 / 10% 2N NH3 in MeOH as eluents.

[0187] 1H NMR: Unless otherwise stated, 1 H NMR spectra were obtained using a 400 MHz spectrometer (or a 300 MHz spectrometer) in DMSO-d6 solution. Nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) expressed in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal standard in DMSO-d6 solution, and the residual CH3OH peak or TMS was used as an internal standard in CD3OD solution. Coupling constants (J) were reported in Hertz (Hz). The properties of the shifts with respect to multiplicity were reported as s (singlet), d (doublet), t (triplet), q (quartet), dd (double of doublets), dt (double of triplets), m (multiplet), br (broad peak).

[0188] The abbreviations used in this specification, particularly in the examples, are listed in the table below:

[0189] Example 1. Synthesis of Compound Y

[0190] Step 1. Synthesis of 2-(Benzo[d][1,3]dioxolane-5-yl)ethan-1-ol

[0191] To a solution of 1,3-benzodioxole-5-acetic acid (500 g, 2.78 mol) in THF (200 mL) was added LAH (2.5 M, 1.00 L) dropwise at 0°C, and the mixture was stirred at 25°C under a N2 atmosphere for 12 hours. The mixture was cooled to -10 to 0°C, and then H2O (95.0 mL), NaOH (15%, 95.0 mL), and H2O (285 mL) were added in that order. After 0.5 hours, Na2SO4 (500 g) was added to the mixture, and the mixture was stirred at 25°C for 0.5 hours. The mixture was filtered, and the filter cake was washed with THF (5.00 L). The filtrate was collected and concentrated. The title compound (460 g, 2.77 mol, 99.7% yield) was obtained as a yellow oil.

[0192] Step 2. Synthesis of 2-(Benzo[d][1,3]dioxolan-5-yl)ethane-1-pivalate

[0193] 2-(Benzo[d][1,3]dioxolane-5-yl)ethane-1-ol (455 g) and pyridine (435 g) were dissolved in DCM (2.00 L), compound b (664 g) was added dropwise at 0 ° C. under N2 protection, and stirring was continued for 8 hours. The residue was poured into water, and the aqueous phase was extracted with DCM. The combined organic phase was washed with brine, dried, and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (670 g) as a yellow oil.

[0194] HNMR (CDCl3): δ 6.78-6.70 (m, 2H), 6.68-6.64 (m, 1H), 6.10-5.58 (m, 2H), 4.22 (t, J = 6.94Hz, 2H), 2.84 (t, J = 6.94Hz, 2H), 1.20-1.16 (m, 9H).

[0195] Step 3. Synthesis of 2-(6-acetyl-benzo[d][1,3]dioxolan-5-yl)ethane-1-pivalate

[0196] To a solution of 2-(benzo[d][1,3]dioxolane-5-yl)ethane-1-pivalate (620 g) in AcO (3.00 L) at 0°C, ZnCl (1.01 kg) was added in one portion under N, and the mixture was stirred at room temperature for another 8 hours. The reaction was poured into water and extracted with ethyl acetate, and the combined organic phases were washed with brine, dried, and concentrated. Purification by silica gel chromatography afforded the title compound (467 g) as a yellow oil.

[0197] HNMR(CDCl3): δ7.23(s,1H),6.75(s,1H),6.78-6.70(m,1H),6.02(s,2H),4.26(t,J =6.63Hz,1H),4.35-4.21(m,1H),3.17(t,J=6.63Hz,2H),2.54(s,3H),1.16(s,9H).

[0198] Step 4. Synthesis of ethyl 2-(6-(2-(2-(1,3-dioxolan-2-yl)-4,5-dimethoxyphenyl)acetyl)benzo[d][1,3]dioxolan-5-yl)pivalate

[0199] CsCO (451 g) and (Ahphos)PdCl (58.8 g) were added to a DCE solution of 2-(6-acetyl-benzo[d][1,3]dioxolane-5-yl)ethane-1-pivalate (284 g) and compound a (200 g) at room temperature under N protection. The mixture was reacted at 90°C for 10 hours. After the reaction, the reaction system was slowly added dropwise to water and extracted with ethyl acetate. The organic phase was washed with brine, dried, and concentrated. Purification by silica gel chromatography afforded the title compound (310 g) as a yellow solid.

[0200] Step 5. Synthesis of Compound Y

[0201] Under N2 protection at room temperature, to a solution of ethyl 2-(6-(2-(2-(1,3-dioxolane-2-yl)-4,5-dimethoxyphenyl)acetyl)benzo[d][1,3]dioxolane-5-yl)pivalate (310 g) in EtOH was added a single NH4Cl solution (3 M, 3.38 eq), and the mixture was reacted at 120°C under high pressure for 24 hours. After the reaction, the mixture was cooled to 25°C, filtered, and the filter cake was washed with MTBE. Purification by silica gel chromatography gave 190 g of the title compound.

[0202] HNMR(DMSO-d6): δ9.73-9.41(s,1H),8.91-8.58(s,1H),7.79-7.66(s,2H),7.62-7.55(s,1H),7.15-7.0 4(s,1H),6.23-6.09(s,2H),4.86-4.69(m,2H),4.10-4.04(m,3H),4.02-3.97(s,3H),3.25-3.15(m,2H).

[0203] Example 2. Preparation and characterization of YT salt

[0204] Preparation of YT salt: Compound Y and Compound T were suspended in a methanol / ethyl acetate (isopropyl acetate) (v / v: 1 / 9) mixed solvent and stirred for 24 hours. A large amount of solid was suspended in the system. The solid was obtained by filtration and dried to obtain the YT salt.

[0205] Characterization of YT salt: The ion ratio of Y and T in YT salt is 1:1.

[0206] HNMR(DMSO-d6): δ9.60(s,1H),8.77(s,1H),7.73~7.71(d,1H),7.70~7.69(t,2H),7.60(s,1H),7.09(s,1H),6.17(s,2H),4.79~4 .77(t,2H),4.47~4.46(d,1H),4.07(s,3H),4.05~4.01(q,1H),4.00(s,3H),3.89~3.88(d,1H),3.31~3.25(m,4H),3.21~3.18(t,2 H),2.55~2.53(t,2H),2.07~2.02(m,1H),1.99(s,1H),1.94~1.89(m,2H),1.85~1.80(m,1H),1.75~1.71(m,1H),1.68~1.60(m,3H) ,1.49~1.44(m,3H),1.42~1.26(m,7H),1.22~1.06(m,7H),1.00~0.96(q,1H),0.93~0.88(dt,1H),0.88~0.86(m,6H),0.60(s,3H).

[0207] Example 3. Effects of compound Y alone (Y), compound T alone (T), compound B alone (B), compound N alone (N), compound combination Y+T, compound combination B+N, compound combination PB+T, and novel salt YT on the viability of the cell line SH-sy5y induced by hydrogen peroxide.

[0208] Neuroblastoma SH-sy5y cells (purchased from the Chinese Academy of Sciences Cell Bank) were cultured in complete medium DMEM + 10% FBS + 1% PS in a cell culture incubator at 37°C and 5% CO2. The experiment was divided into 11 groups:

[0209] Group 1 (control): SH-sy5y cells

[0210] Group 2 (model): SH-sy5y cells + hydrogen peroxide

[0211] Group 3: SH-sy5y cells + hydrogen peroxide + compound Y (100 μM)

[0212] Group 4: SH-sy5y cells + hydrogen peroxide + compound T (100 μM)

[0213] Group 5: SH-sy5y cells + hydrogen peroxide + compound B (100 μM)

[0214] Group 6: SH-sy5y cells + hydrogen peroxide + compound N (100 μM)

[0215] Group 7: SH-sy5y cells + hydrogen peroxide + compound combination Y + T (100 μM + 100 μM)

[0216] Group 8: SH-sy5y cells + hydrogen peroxide + compound combination B + N (100 μM + 100 μM)

[0217] Group 9: SH-sy5y cells + hydrogen peroxide + compound combination PB + T (500 μM + 200 μM)

[0218] Group 10: SH-sy5y cells + hydrogen peroxide + YT salt (100 μM)

[0219] Group 11: SH-sy5y cells + DMSO

[0220] Neuroblastoma SH-sy5y cells were cultured in complete medium DMEM+10% FBS+1% PS at a rate of 1×10 4 Cells / well were plated and cultured in a cell culture incubator at 37°C and 5% CO2 for 24 hours, and then the corresponding compounds were added. After incubation for 24 hours, hydrogen peroxide was added for stimulation for 1 hour, with a final concentration of hydrogen peroxide of 350 μM. Then, 50 (CTG) reagent, shake for 2 minutes, and then detect its luminescent signal value, which can represent the cell viability.

[0221] As shown in Figure 1, compared with the model (column 2), compound Y alone (column 3) has an excellent effect on improving cell viability (P < 0.0001), and the effect of compound Y alone (column 3) is better than that of compound B alone (column 5). Compared with compound T alone (column 4), compound B alone (column 5), compound combination B + N (column 8), and compound combination PB + T (column 9), compound combination Y + T (column 7) and YT salt (column 10) have significantly better effects on improving cell viability, indicating that the effects of compound combination Y + T and YT salt on the repair of oxidative stress-induced damage in neural cells are significantly better than those of compound T alone, compound B alone, compound combination B + N, and compound combination PB + T. The concentrations of compound combination PB + T are based on the data of the marketed drug AMX0035 (David L. Carbone, Pharmacology / toxicology NDA review and evaluation, Application number: 216660 Originally published, Food and Drug Administration). Administration.doi:pink.pharmaintelligence.informa.com / - / media / supporting-documents / pink-sheet / 2022 / 11 / relyvrio_nonclinical.pdf? rev=d27109bf35c040d4a78f73144d132917&has h=414BB5B4473A21ECE0231375EB1C0341).

[0222] The above results indicate that compound Y alone, compound combination Y+T, and YT salt have significantly superior effects in improving cell viability and repairing damage after oxidative stress in nerve cells, indicating that they have the potential to be used as drugs for the treatment, alleviation, and / or prevention of neurodegenerative diseases or disorders.

[0223] Example 4. Effects of Compound Y alone, Compound T alone, Compound Y+T combination, and YT salt on the proliferation of CD4-positive and CD8-positive T cells

[0224] It has been reported that in ALS, Th cells are described as the main players in inflammation and disease progression. In the 1990s, CD4 T cell infiltration was observed in the spinal cord adjacent to the degenerative area of ​​ALS patients. Similarly, CD8 T cell infiltration was also observed in the spinal cord and brain of ALS patients. (Elise Liu, et al, Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons, Front Mol Neurosci. 2021 Dec 14; 14: 767041. doi: 10.3389 / fnmol.2021.767041.) In order to observe the inhibition of immune cell infiltration or proliferation by the compounds, compound combinations or salts of the present invention, their effects on inhibiting the proliferation of CD4-positive and CD8-positive T cells were further analyzed.

[0225] First, a certain number of human peripheral blood mononuclear cells (PBMCs) were incubated with 5 μM CellTrace cell proliferation detection reagent in a 37°C, 5% CO2 incubator in the dark for 20 minutes. 5CellTrace-stained PBMCs were seeded into 96-well U-bottom plates and treated with anti-CD3 / CD28 antibody-coupled magnetic beads at a 1:1 ratio (cell number: bead number) to stimulate T cell differentiation. The treated cells were then incubated with various compounds at corresponding concentrations (Compound Y 100μM, Compound T 100μM, Compound Y+T combination (100μM Compound Y + 100μM Compound T), YT salt 100μM, and UDCA (100μM) as a control) for 72 hours at 37°C in a 5% CO2 incubator and analyzed by flow cytometry. Specifically, the cells were first treated with Live / Dead dye (633nm, 1:1000 dilution) at 4°C for 30 minutes to distinguish live from dead cells. Subsequently, at room temperature, the above-mentioned cells to be tested were incubated with wavelength dyes anti-CD45-PerCPCy5.5, anti-CD4-AF700, and anti-CD8-FITC for 30 minutes to distinguish different series of T cells (CD4 positive T cells, CD8 positive T cells). After appropriate washing, the above-mentioned stained cells were analyzed by flow cytometry at different wavelengths. Subsequent cell analysis refers to live cells that appear positive after staining with Live / dead dyes. CD4-positive T cells refer to positive cells stained with anti-CD45-PerCPCy5.5 and anti-CD4-AF700 dyes; CD8-positive T cells refer to positive cells stained with anti-CD45-PerCPCy5.5 and anti-CD8-FITC dyes. The proliferation of CD4-positive and CD8-positive T cells is determined by the fluorescence of Celltrace dyes.

[0226] As shown in Figure 2, compared with the DMSO control group (waveform 1, waveforms 1-6 from top to bottom), the CD4-positive T cell proliferation peaks of YT salt (waveform 2), the corresponding dose of compound Y (waveform 3) and the compound combination Y+T (waveform 5) are shifted to the right as a whole, indicating that the above groups significantly inhibit the proliferation of CD4-positive T cells. Similarly, as shown in Figure 3, compared with the DMSO control group (waveform 1), the CD8-positive T cell proliferation peaks of YT salt (waveform 2), the corresponding dose of compound Y (waveform 3) and the compound combination Y+T (waveform 5) are shifted to the right as a whole, indicating that the above groups significantly inhibit the proliferation of CD8-positive T cells.

[0227] The above results show that YT salt and compound combination Y+T have a significant inhibitory effect on the proliferation of CD4-positive and CD8-positive T cells derived from human PBMC induced by Anti-CD3 / CD28, and its effect is significantly better than compound T and compound U (UDCA); indicating that YT salt and compound combination Y+T have the potential to inhibit the infiltration or proliferation of immune cells in neurodegenerative diseases.

[0228] Example 5: Effect of Compound YT Salt on SOD1 G93A Effects of onset, severity and survival on ALS mouse model

[0229] In SOD1 G93A The therapeutic effect of YT salt on the survival status of ALS animals was evaluated in transgenic mice (B6SJL-Tg(SOD1*G93A)1 / cyagen). 16 female and 14 male B6SJL-Tg(SOD1*G93A)1 / cyagen mice were selected and randomly divided into 2 groups (7 males + 8 females / group) according to sex and weight, namely the model group (control) and the YT salt group (drug group). The dosage of YT salt was 496 mg / kg, and it was gavaged once a day. Drug administration started on the 66th day of mouse age, and the weight changes were monitored, the animal status and symptom severity were evaluated, and the individual survival time was counted. The statistics of the animal symptom severity included the time of the first onset of the animal and the time when severe symptoms were first discovered. In this study, "first onset" was defined as the starting point of ALS onset when the mouse showed circling, abnormal gait, or weakness and tremor of the front and back limbs. In this study, "severe" disease was defined as complete paralysis and inability to move freely, but still surviving. Animals that died without reaching the paralysis stage were considered severe. Survival was calculated as the time the animal was alive at the end of the study (Day 130). Hazard ratios were calculated using the log-rank test.

[0230] Figure 4 shows the animal status observations. No statistical difference was observed in the time to first onset of disease between the YT salt group and the model group (P = 0.0802). However, overall onset was observed in the YT salt group after 90 days of age, no earlier than the model group. The median onset time (109 days) was 7 days longer than the model group (102 days). The hazard ratio (HR) for disease onset in the YT salt group (0.5716) was approximately 3 times lower than that in the model group (1.749). These results suggest that YT salt has the effect of delaying the onset of ALS in mice and reducing the HR.

[0231] Judging from the results of severe disease in animals, as shown in Figure 5, the incidence of severe disease in the YT salt group was significantly lower than that in the model group (P<0.05), with the endpoint severe disease rate in the YT salt group being 66.667%. The median time to severe disease in the YT salt group was also significantly later than that in the model group, with the median time to severe disease in the YT salt group (117 days) increasing by approximately 8 days relative to the model control group (109 days). The hazard ratio for severe disease in the YT salt group (0.45) was approximately 5 times lower than that in the model group (2.222). The experimental results indicate that YT salt effectively reduces the incidence of severe disease in ALS model mice.

[0232] In survival statistics, as shown in Figure 6, the survival of animals in the YT salt group was significantly better than that in the model group (P<0.01). The endpoint survival rate in the YT salt group was 53.333%, while that in the model group was only 7.143%. The median survival in the model group was 115.5 days, while less than half of the individuals in the YT salt group had died by the end of the trial, failing to meet the criteria for calculating the median survival. The mortality hazard ratio in the YT salt group (0.3212) was nearly 10 times lower than that in the model group (3.113). These results demonstrate that YT salt significantly prolongs the survival of ALS model mice and reduces the risk of death.

[0233] In summary, in ALS model mice with the SOD1 G93A mutation, YT salt showed a tendency to delay onset, significantly reduced the incidence of severe disease, and prolonged survival compared to the model group. This suggests that YT salt has potential preventive, alleviating, or therapeutic effects for ALS.

[0234] Example 6: Effects of Compound YT Salt on MPTP-Induced Parkinson's Disease Mouse Model

[0235] Sixty C57BL / 6 male mice were randomly divided into five groups (12 mice / group): a sham-operated group (normal control), a model group (model control), an L-DOPA group (positive control, 40 mg / kg), a low-dose YT salt group (167.5 mg / kg), and a high-dose YT salt group (248 mg / kg). MPTP was injected intraperitoneally for 5 consecutive days to establish a model of the disease at a dose of 30 mg / kg. YT salt was administered orally twice daily (with a 7-8 hour interval between doses) for 13 consecutive days. L-DOPA was administered twice daily (with a 7-8 hour interval between doses) for 8 consecutive days. The improvement of motor function in MPTP-induced Parkinson's disease mice was evaluated using behavioral measures such as the grip strength test and the rotarod test. Histopathological examinations were performed to evaluate the protective effect of YT salt on dopaminergic neurons in MPTP-induced Parkinson's disease mice.

[0236] Grip strength test results, as shown in Figure 7, showed a significant decrease in grip strength after MPTP modeling (model group vs. sham group, P < 0.0001). L-DOPA and high-dose YT salt treatment groups, under the established treatment regimen, significantly improved MPTP-induced reduction in grip strength (L-DOPA group vs. model group, P < 0.001; high-dose YT salt group vs. model group, P < 0.01).

[0237] The results of the rotarod test, as shown in Figure 8, show that after MPTP modeling, the median time on the rod in the model group was reduced compared to the sham group. The high-dose YT salt group, under the established treatment regimen, significantly improved the MPTP-induced reduction in rod time (high-dose YT salt group vs. model group, P < 0.05).

[0238] The results of TH tissue immunostaining in the substantia nigra region showed that, as shown in Figure 9, compared with the sham operation group, the number of TH-positive cells in the substantia nigra region of the model group was significantly reduced (P<0.05). The L-DOPA group, the low-dose YT salt group and the high-dose YT salt group could significantly inhibit the decrease in TH-positive cells in the substantia nigra region of the model animals at the set dose (P<0.0001).

[0239] The results of immunostaining of striatal TH tissue showed, as shown in Figure 10, that compared with the sham operation group, the loss of TH-positive neurons in the model group was extremely significant (P<0.0001). The high-dose YT salt administration group could significantly inhibit the loss of TH-positive neurons in the substantia nigra under the set treatment regimen (P<0.01).

[0240] The evaluation results of this example show that YT salt significantly inhibited apoptosis of dopaminergic neurons in the substantia nigra and striatum of model animals at a dose of 167.5 mg / kg. At a dose of 248 mg / kg, it not only significantly inhibited apoptosis of dopaminergic neurons in the substantia nigra of model animals, but also significantly improved behavioral indicators such as grip strength and rotarod performance. This suggests that YT salt has the potential to prevent, alleviate, or treat Parkinson's disease.

[0241] Example 7: Effects of Compound YT Salt on 6-OHDA-induced Parkinson's disease rat model.

[0242] Forty-eight male Sprague-Dawley rats were divided into four groups (12 rats / group): a sham-operated group (normal control), a model group (model control), an istradefylline group (istradefylline, used as a positive control, 10 mg / kg), and a YT salt-treated group (248 mg / kg). A Parkinson's disease model was established by intracranial injection of 20 μg of 6-OHDA into the right medial forebrain bundle (MFB). Following model establishment, istradefylline and YT salt were administered orally once daily for 6 consecutive weeks. Disease progression was assessed by a grid walking test at week 6.

[0243] The results, as shown in Figures 11 and 12, showed that after the Parkinson's disease model was established with 6-OHDA, the number and rate of wrong steps in the model group significantly increased in the grid walking test (P<0.05). Compared with the model group, the YT salt-treated group significantly reduced the number and rate of wrong steps at the set dose (P<0.05).

[0244] The evaluation results of this example show that YT salt has a significant improvement effect on the motor behavior impairment of the 6-OHDA-induced Parkinson's disease rat model, which suggests that YT salt has a potential effect in alleviating or treating Parkinson's disease.

[0245] It should be understood that after reading the above content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A combination product comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof: Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are independently selected from: hydrogen, halogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 haloalkoxy, the hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 The haloalkoxy group is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 Alkyl and phenyl; or R 1 , R 2 and R 3 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; or R 4 , R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; (b) bile acid or its derivative or analogue or its pharmaceutically acceptable salt, solvate, hydrate or stereoisomer; The molar ratio of component (a) to component (b) is 1:1000-1000:

1.

2. The combination product according to claim 1, wherein R 1 , R 2 and R 3 are each independently selected from: hydrogen, hydroxy, methoxy and benzyloxy, or R 1 , R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.

3. The combination product according to claim 1 or 2, wherein R 4 , R 5 and R 6 are independently selected from: hydrogen, hydroxyl and methoxy, or R 4 , R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.

4. A combination product according to any one of claims 1 to 3, wherein R 1 , R 2 and R 3 One or both of them are hydrogen, or R 1 , R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.

5. A combination product according to any one of claims 1 to 4, wherein R 4 , R 5 and R 6 One or both of them are hydrogen, or R 4 , R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.

6. A combination product according to any one of claims 1 to 5, wherein a pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate; preferably maleate or hydrochloride, more preferably hydrochloride.

7. A combination product according to any one of claims 1 to 6, wherein the compound of formula (I) is selected from:

8. The combination product according to any one of claims 1 to 7, wherein the bile acid or its derivative or analogue is selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid and tauroursodeoxycholic acid.

9. The combination product according to any one of claims 1 to 8, wherein the molar ratio of component (a) to component (b) is 1:1 or 2:

1.

10. A combination product according to any one of claims 1 to 9 for use in improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by reactive oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.

11. A combination product according to any one of claims 1 to 10 for use in the treatment, alleviation and / or prevention of a neurodegenerative disease or disorder.

12. The combination product according to claims 1-11, wherein the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia.

13. A pharmaceutical composition comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof: Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are independently selected from: hydrogen, halogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 haloalkoxy, the hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 The haloalkoxy group is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 Alkyl and phenyl; or R 1 , R 2 and R 3 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; or R 4 , R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; (b) bile acid or its derivative or analogue or its pharmaceutically acceptable salt, solvate, hydrate or stereoisomer; (c) pharmaceutically acceptable carriers, excipients and / or diluents; The molar ratio of component (a) to component (b) is 1:1000-1000:

1.

14. The pharmaceutical composition according to claim 13, wherein R 1 , R 2 and R 3 are each independently selected from: hydrogen, hydroxy, methoxy and benzyloxy, or R 1 , R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.

15. The pharmaceutical composition according to claim 13 or 14, wherein R 4 , R 5 and R 6 are independently selected from: hydrogen, hydroxyl and methoxy, or R 4 , R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.

16. The pharmaceutical composition according to any one of claims 13 to 15, wherein R 1 , R 2 and R 3 One or both of them are hydrogen, or R 1 , R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.

17. The pharmaceutical composition according to any one of claims 13 to 16, wherein R 4 , R 5 and R 6 One or both of them are hydrogen, or R 4 , R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.

18. A pharmaceutical composition according to any one of claims 13 to 17, wherein a pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate; preferably maleate or hydrochloride, more preferably hydrochloride.

19. A pharmaceutical composition according to any one of claims 13 to 18, wherein the compound of formula (I) is selected from:

20. The pharmaceutical composition according to any one of claims 13 to 19, wherein the bile acid or its derivative or analogue is selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid and tauroursodeoxycholic acid.

21. The pharmaceutical composition according to any one of claims 13 to 20, wherein the molar ratio of component (a) to component (b) is 1:1 or 2:

1.

22. A pharmaceutical composition according to any one of claims 13 to 21, for improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by active oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.

23. The pharmaceutical composition according to any one of claims 13 to 22, for use in treating, alleviating and / or preventing neurodegenerative diseases or disorders.

24. The pharmaceutical composition of claim 23, wherein the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.

25. An acid-base addition salt of formula (II): (A + ) m (B - ) n (C - ) p (II) in, (a)A + is the cationic portion of the compound of formula (I); Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are independently selected from: hydrogen, halogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 haloalkoxy, the hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 The haloalkoxy group is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 Alkyl and phenyl, or R 1 , R 2 and R 3 Any two adjacent ones of the carbon atoms to which they are attached together form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N, or R 4 , R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; (b)B - is the anionic portion of a bile acid or a derivative or analog thereof; and (c)C - It is an acid anion; wherein m, n and p are each independently an integer selected from 1 to 6 such that the salt configuration achieves charge balance, and when m=n, p is 0.

26. The acid-base addition salt according to claim 25, wherein R 1 , R 2 and R 3 are each independently selected from: hydrogen, hydroxy, methoxy and benzyloxy, or R 1 , R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.

27. The acid-base addition salt according to claim 25 or 26, wherein R 4 , R 5 and R 6 are independently selected from: hydrogen, hydroxyl and methoxy, or R 4 , R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.

28. The acid-base addition salt according to any one of claims 25 to 27, wherein R 1 , R 2 and R 3 One or both of them are hydrogen, or R 1 , R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.

29. The acid-base addition salt according to any one of claims 25 to 28, wherein R 4 , R 5 and R 6 One or both of them are hydrogen, or R 4 , R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.

30. The acid-base addition salt according to any one of claims 25 to 29, wherein the cationic portion of the compound of formula (I) is selected from the group consisting of:

31. The acid-base addition salt according to any one of claims 25 to 30, wherein the component (b) is an anionic portion selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid and tauroursodeoxycholic acid.

32. The acid-base addition salt according to any one of claims 25 to 31, wherein m is 1, n is 1 and p is 0, or m is 2, n is 1 and p is 1.

33. The acid-base addition salt according to any one of claims 25 to 32, for use in improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by reactive oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.

34. The acid-base addition salt according to any one of embodiments 25-33, for use in treating, alleviating and / or preventing a neurodegenerative disease or disorder.

35. The acid-base addition salt of claim 34, wherein the neurodegenerative disease or disorder is selected from the group consisting of Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.

36. A pharmaceutical composition comprising a combination product according to any one of claims 1 to 12 or an acid-base addition salt according to any one of claims 25 to 35.

37. A method for treating, alleviating and / or preventing a neurodegenerative disease or disorder, comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of claims 1 to 36.

38. The method of claim 37, wherein the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.

39. A method for treating and / or preventing a neurodegenerative disease or condition, comprising: include: Scheme 1, administering to a patient in need thereof: (a) a therapeutically and / or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof: Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are independently selected from: hydrogen, halogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 haloalkoxy, the hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 The haloalkoxy group is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 Alkyl and phenyl, or R 1 , R 2 and R 3 Any two adjacent ones of the carbon atoms to which they are attached together form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N, or R 4 , R 5 and R 6 Any two adjacent ones of the carbon atoms to which they are attached together form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; or Scheme 2, administering simultaneously, concurrently, separately or sequentially to a patient in need thereof: (a) a therapeutically and / or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof: Where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are independently selected from: hydrogen, halogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 haloalkoxy, the hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy and C 1 -C 6 The haloalkoxy group is optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 Alkyl and phenyl, or R 1 , R 2 and R 3 Any two adjacent ones of the carbon atoms to which they are attached together form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N, or R 4 , R 5 and R 6 Any two adjacent ones of the group together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; and (b) a therapeutically and / or preventively effective amount of bile acid or a derivative or analog thereof or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

40. The method of claim 39, wherein R 1 , R 2 and R 3 are each independently selected from: hydrogen, hydroxy, methoxy and benzyloxy, or R 1 , R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.

41. The method according to claim 39 or 40, wherein R 4 , R 5 and R 6 are independently selected from: hydrogen, hydroxyl and methoxy, or R 4 , R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.

42. The method according to any one of claims 39-41, wherein R 1 , R 2 and R 3 One or both of them are hydrogen, or R 1 , R 2 and R 3 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.

43. The method according to any one of claims 39-42, wherein R 4 , R 5 and R 6 One or both of them are hydrogen, or R 4 , R 5 and R 6 Any two adjacent ones of the groups together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.

44. The method according to any one of claims 39-43, wherein the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate; preferably maleate or hydrochloride, more preferably hydrochloride.

45. The method according to any one of claims 39-44, wherein the compound of formula (I) is selected from:

46. ​​The method of any one of claims 39-45, wherein the bile acid or its derivative or analogue is selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid and tauroursodeoxycholic acid.

47. The method of any one of claims 39-46, wherein the molar ratio of component (a) to component (b) is 1:1 or 2:

1.

48. The method of any one of claims 39-47, wherein the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.

49. A kit comprising: A combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof and instructions for use according to any one of claims 1 to 36, The kit is used for treating, alleviating or preventing neurodegenerative diseases or disorders.

50. The kit of embodiment 49, wherein the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.

51. A method for improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by reactive oxidative metabolites in the cells, regulating redox homeostasis in the cells or reducing mitochondrial dysfunction in the cells, comprising contacting the cells with a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of claims 1 to 36.

52. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, for use in improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by active oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.

53. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof for use in treating, alleviating and / or preventing a neurodegenerative disease or disorder.

54. A compound of formula (I) according to claim 53, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia.

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