Combination products, salts, and their use in treating neurodegenerative diseases or conditions

Abstract

The present invention relates to novel combination products, pharmaceutical compositions, salt forms, methods for producing the same, and their use in the treatment, mitigation, and / or prevention of neurodegenerative diseases or conditions.

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical field and relates to novel combination products, pharmaceutical compositions, salt forms, methods for producing the same, and their use in the treatment, mitigation, and / or prevention of neurodegenerative diseases or conditions. [Background technology]

[0002] Alzheimer's disease (AD) is a chronic neurodegenerative disease 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, it is the fourth leading cause of death, after heart disease, cancer, and stroke. ARICEPT® is an acetylcholinesterase inhibitor approved by the FDA to slow the progression of Alzheimer's disease. However, this drug is only effective for a limited time and in specific patients. To date, there is no definitive drug that can treat or cure this devastating disease.

[0003] Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease affecting the superior and inferior motor neurons of the brainstem and spinal cord. ALS patients develop widespread muscular dystrophy 3 to 5 years after onset, leading to paralysis and death. Its pathological features include the aggregation and accumulation of ubiquitinated protein inclusions in motor neurons. ALS is classified into familial ALS (fALS), accounting for approximately 10% of cases, and sporadic ALS (sALS), without a family history, accounting for approximately 90%. The main causative factors of ALS include genetics, environment, and lifestyle, or the interaction of both (PARALS Registry et al., "Genome-Wide Association Analyses Identify New Risk Variants and the Genetic Architecture of Amyotrophic Lateral Sclerosis"). Regarding the pathogenesis of ALS, it is still not fully understood, as it involves various 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 metabolic disorders, and abnormal RNA-binding proteins (Donnelly, Grima, and Sattler, "Aberrant RNA Homeostasis in Amyotrophic Lateral Sclerosis.").

[0004] The incidence and prevalence of ALS increase with age. To date, there are no treatments or drugs that can stop or reverse the disease, and the identified drugs are intended to alleviate symptoms or slow disease progression. Since its approval by the U.S. Food and Drug Administration (FDA) in 1995, riluzole has been the only widely recognized treatment that can extend the survival of ALS patients by three months (Miller, Mitchell, and Moore, "Riluzole for Amyotrophic Lateral Sclerosis (ALS) / Motor Neuron Disease (MND)"). Evadarone, approved by the U.S. Food and Drug Administration (FDA) in 2017, tends to improve ALS Functional Rating Scale (ALSFRS-R) scores and slow 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 experiment, the median survival time (medianOS) was extended by 4.8 months, and after adjusting for two types of post-hoc analyses, it was extended by 9.7 months after RPSFTM adjustment. Using a survival prediction algorithm created with natural history data, The survival benefit is extended by 9.9 months. AMX0035 is an oral fixed-dose compound of sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA) developed by Amyyx Pharmaceuticals. Sodium phenylbutyrate is a histone deacetylase inhibitor that can inhibit the endoplasmic reticulum stress response, and tauroursodeoxycholic acid can inhibit mitochondrial-associated apoptosis (Mead et al., "Amyotrophic Lateral Sclerosis"). AMX0035 is intended to target the endoplasmic reticulum (ER) and mitochondria of motor neurons in ALS, which are linked by the mitochondrial membrane and play important roles in maintaining neuronal survival.

[0005] Parkinson's disease (PD) is a chronic neurodegenerative disease that primarily affects older adults. The most common clinical features are motor tremor (rhythmic shaking), muscle rigidity, and bradykinesia (slowness of movement), but non-motor symptoms, including sleep disturbances, constipation, anxiety, depression, and fatigue, are also present. Its main pathological features are the loss of dopaminergic neurons in the substantia nigra (SN) of the midbrain and dopaminergic nerve fibers in the striatal region, as well as the formation of intraneuronal protein inclusions, called Lewy bodies (LBs), which are mainly composed of alpha-synuclein (John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, UK et al., "Parkinson's Disease"). Parkinson's disease is a multifactorial disease resulting from genetics, environment, or the interaction of both (Bloem, Okun, and Klein, "Parkinson's Disease"). Parkinson's disease is classified into two forms: sporadic (delayed type) and familial (early type) (Ryan et al., "Mitochondrial Dysfunction and Mitophagy in Parkinson's"). Epidemiological studies indicate that familial Parkinson's disease accounts for only a small fraction of Parkinson's disease cases, with the majority of patients having sporadic Parkinson's disease (Zeng, Geng, and Jia, "Neurotoxin-Induced Animal Models of Parkinson Disease").From 1990 to 2016, the total number of Parkinson's disease (PD) patients exceeded 6 million (Dorsey et al., "Global, Regional, and National Burden of Parkinson's Disease, 1990-2016."), and is projected to more than double to over 12 million by 2040 (Rossi et al., "Projection of the Prevalence of Parkinson's Disease in the Coming Decades."). The etiology of Parkinson's disease is still unclear, but it may be associated with various risk factors such as excitotoxicity, oxidative stress, and neuroinflammation.

[0006] Currently, Parkinson's disease (PD) is treated with levodopa, dopamine agonists, monoamine oxidase (MAO) inhibitors, and amantadine, all of which aim to improve symptoms and slow disease progression. However, none of these treatments can completely cure the disease, and they also have several side effects.

[0007] Existing therapies for neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) have many problems. ARICEPT® is effective only for a limited period and in specific patients with AD. Treatment for ALS is usually costly and partially ineffective, and improvement with current drugs or treatments is limited, leaving a very large unmet clinical need. Parkinson's disease has a significant social impact and is currently the leading cause of the fastest-growing neurological disease and disorder worldwide. Current drugs or treatments aim to improve symptoms and slow disease progression, but they also have many side effects, leaving a large gap in clinical needs.

[0008] Therefore, in this field, there is an urgent need for novel therapies for neurodegenerative diseases or conditions that are more effective and safer than conventional therapies, given the complex pathogenesis of these conditions. [Overview of the Initiative]

[0009] The inventor of the present application solves the above needs through creative efforts.

[0010] Specifically, the present invention relates to the following technical solutions.

[0011] In one embodiment, the present application relates to (a) a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and [Chemical formula] (I) Here, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each independently selected from hydrogen, halogen, hydroxy group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group, and the above hydroxy group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl group and phenyl group, or any two adjacent ones of R 1 , R 2 and R 3 form a 4- to 7-membered heterocyclic ring containing one or more heteroatoms together with the carbon atom to which they are attached, and the above heteroatoms are selected from O, S or N, or any two adjacent ones of R 4 , R 5 and R 6 form a 4- to 7-membered heterocyclic ring containing one or more heteroatoms together with the carbon atom to which they are attached, and the above heteroatoms are selected from O, S or N, (b) a combination product comprising a bile acid or a derivative or an analog thereof or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. Here, the molar ratio of component (a) to component (b) is 1:1000 to 1000:1.

[0012] In another embodiment, the present invention is (a) A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, [ka] (I) Here, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 This is as defined herein, (b) Bile acids or their derivatives or analogs or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, (c) With respect to pharmaceutical compositions comprising pharmaceutically acceptable carriers, excipients and / or diluents, Here, the molar ratio of component (a) to component (b) is 1:1000 to 1000:1.

[0013] In yet another embodiment, the present invention relates to an acid-base addition salt of formula (II), (A + ) m (B - ) n (C - ) p (II) Here, (a)A + This is the cation moiety of the compound of formula (I), [ka] (I) Here, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 This is as defined herein, (b)B - is an anionic moiety which is a bile acid or a derivative or analog thereof, and (c)C - It is a rhizal anion, Here, m, n, and p are integers independently chosen from 1 to 6 such that the salt composition reaches charge equilibrium, and when m=n, p is 0.

[0014] In further embodiments, the present invention relates to combination products, pharmaceutical compositions, acid-base addition salts, or compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers thereof, used to improve cell viability, particularly neuronal cell viability, and in particular to improve cell viability by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells, as described in any one of the above embodiments.

[0015] In further embodiments, the present invention relates to combination products, pharmaceutical compositions, acid-base addition salts, or compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers thereof, as described in any one of the above embodiments, used for treating, alleviating, and / or preventing neurodegenerative diseases or conditions.

[0016] In further embodiments, the present invention relates to a method for improving cell viability, particularly neuronal cell viability, by 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, as described in any one of the above embodiments, and in particular by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells.

[0017] In another embodiment, the present invention relates to a method for treating, alleviating and / or preventing neurodegenerative diseases or conditions, comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof described in any one of the above embodiments.

[0018] In another embodiment, the present invention is The present invention relates to a reagent kit comprising a combination product, acid-base addition salt, pharmaceutical composition, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and instructions for use, as described in any one of the above embodiments. Herein, the reagent kit is used to treat and / or prevent neurodegenerative diseases or conditions.

[0019] Details of this application are described in the attached description below. Similar or equivalent methods and materials described herein may be used in the practice or testing of this application, but illustrative methods and materials are described here. Other features, purposes and advantages of this application will be apparent from the specification and claims. In the specification and the attached claims, singular nouns also include plural nouns unless otherwise specified in the context. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they would be commonly understood by those skilled in the art. All patents and publications referenced herein are incorporated herein by whole by reference.

[0020] The contents of all references cited throughout this application (including references to documents, granted patents, published patent applications and concurrently pending patent applications) are hereby incorporated expressly by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly known to those skilled in the art. [Brief explanation of the drawing]

[0021] [Figure 1]This study demonstrates the effects of compound Y, compound T, compound B, compound N, combinations of compound Y+T, combinations of compound B+N, combinations of compound PB+T, and a novel salt of YT on the activity of hydrogen peroxide-induced SH-sy5y cells. The control group consisted of cells cultured without any drug addition or H2O2 stimulation, while the model group consisted of cells cultured with H2O2 stimulation but without any drug addition. The DMSO group consisted of cells cultured with DMSO only, without any drug addition or H2O2 stimulation. In the treatment groups, the concentrations of compound Y, compound T, compound B, and compound N were 100 μM, respectively. The concentrations of compound Y and T were 100 μM (compound Y) + 100 μM (compound T), compound B and N were 100 μM (compound B) + 100 μM (compound N), compound PB and T were 500 μM (compound T) + 200 μM (compound PB), and the concentration of the YT salt was 100 μM. All treatment groups were induced by H2O2 stimulation. Data are expressed as mean ± SEM. One-way ANOVA was used, and **** represents P<0.0001, *** represents P<0.001, ** represents P<0.01, * represents P<0.05, vs YT, #### represents P<0.0001, # represents P<0.05, vs Model.

[0022] [Figure 2] The effects of compound Y, compound T, the combination of compound Y+T, YT salt, and compound UDCA(U) on CD4-positive T cell proliferation are shown. Here, the YT salt concentration is 100 μM, the compound Y concentration converted to the same ratio is 100 μM, the compound T concentration is 100 μM, the compound Y+T combination concentration is 100 μM (compound Y) + 100 μM (compound T), and the compound U concentration is 100 μM.

[0023] [Figure 3]The effects of compound Y, compound T, the combination of compound Y+T, YT salt, and compound UDCA(U) on CD8-positive T cell proliferation are shown. Here, the YT salt concentration is 100 μM, and converted to the same ratio, the compound Y concentration is 100 μM, the compound T concentration is 100 μM, the compound Y+T combination concentration is 100 μM (compound Y) + 100 μM (compound T), and the compound U concentration is 100 μM.

[0024] [Figure 4] This study demonstrates the effect of YT salt on the development of ALS in SOD1G93A mutant mice. The model group received no drug treatment, while the YT salt group received a dose of 496 mg / kg (intragastric administration once daily). Log-rank tests were used for data analysis, with P<0.05 indicating a statistically significant difference between the groups.

[0025] [Figure 5] This study demonstrates the effect of YT salt on the development of severe ALS in SOD1G93A mutant mice. The model group received no drug treatment, while the YT salt group received a dose of 496 mg / kg (administered intragastricly once daily). Log-rank tests were used for data analysis, with P<0.05 indicating a statistically significant difference between the groups.

[0026] [Figure 6] This study demonstrates the effect of YT salt on the survival time of ALS model mice with the SOD1G93A mutation. The model group received no drug treatment, while the YT salt group received a dose of 496 mg / kg (once daily intragastric administration). Log-rank tests were used for data analysis, with P<0.05 indicating a statistically significant difference between the groups.

[0027] [Figure 7]This study demonstrates the effect of YT salt on grip strength in MPTP-induced Parkinson's mouse models. The sham surgery group consisted of C57BL / 6 mice intraperitoneally injected with 10 mL / kg of saline. The model group consisted of C57BL / 6 mice intraperitoneally injected with 30 mg / kg of MPTP, without any other drug treatments. The L-DOPA group served as a positive drug control, treating model mice with 40 mg / kg of L-DOPA (administered intragastricly twice daily). The low-dose YT salt group administered 167.5 mg / kg of YT salt (administered intragastricly twice daily), and the high-dose YT salt group administered 248 mg / kg of YT salt (administered intragastricly twice daily). All data in the figures are expressed as mean ± standard error (SEM). P<0.05 indicates that it has statistical significance, * indicates P<0.05, ** indicates P<0.01, *** indicates P<0.001, and **** indicates P<0.0001.

[0028] [Figure 8] This study demonstrates the effects of YT salt on the rotarod test in MPTP-induced Parkinson's mouse models, evaluating the time it takes for animals to maintain balance on the rotarod and fall to the ground. The sham surgery group consisted of C57BL / 6 mice intraperitoneally injected with 10 mL / kg of saline. The model group consisted of C57BL / 6 mice intraperitoneally injected with 30 mg / kg of MPTP, without any other drug treatments. The L-DOPA group served as a positive drug control, treating model mice with 40 mg / kg of L-DOPA (administered intragastricly twice daily). The low-dose YT salt group administered 167.5 mg / kg of YT salt (administered intragastricly twice daily), and the high-dose YT salt group administered 248 mg / kg of YT salt (administered intragastricly twice daily). All data in the figures are expressed as mean ± standard error (SEM). P<0.05 indicates that the result has statistical significance, * indicates P<0.05, and ** indicates P<0.01.

[0029] [Figure 9]This study shows the effect of YT salt on the number of TH-positive cells in the substantia nigra region of the brain in MPTP-induced Parkinson's mouse models. The sham surgery group consisted of C57BL / 6 mice intraperitoneally injected with 10 mL / kg of saline, while the model group consisted of C57BL / 6 mice intraperitoneally injected with MPTP at a dose of 30 mg / kg without any other drug treatments. The L-DOPA group was the positive drug control group, treated with 40 mg / kg of L-DOPA (administered intragastricly twice daily) in the model mice. The low-dose YT salt group received 167.5 mg / kg of YT salt (administered intragastricly twice daily), and the high-dose YT salt group received 248 mg / kg of YT salt (administered intragastricly twice daily). All data in the figures are expressed as mean ± standard error (SEM). P<0.05 indicates that it has statistical significance, and **** indicates P<0.0001.

[0030] [Figure 10] This study shows the effect of YT salt on the proportion of TH-positive cells in the striatal region of an MPTP-induced Parkinson's mouse model. The sham surgery group consisted of C57BL / 6 mice intraperitoneally injected with 10 mL / kg of saline, while the model group consisted of C57BL / 6 mice intraperitoneally injected with 30 mg / kg of MPTP without any other drug treatments. The L-DOPA group was a positive drug control group, treated with 40 mg / kg of L-DOPA (administered intragastricly twice daily) in the model mice. The low-dose YT salt group received 167.5 mg / kg of YT salt (administered intragastricly twice daily), and the high-dose YT salt group received 248 mg / kg of YT salt (administered intragastricly twice daily). All data in the figures are expressed as mean ± standard error (SEM). P<0.05 indicates that it has statistical significance, ** indicates P<0.01, and **** indicates P<0.0001.

[0031] [Figure 11]This figure shows the effect of YT salt on the number of missed steps in the grid walking test in 6-OHDA-induced Parkinson's rats. The sham surgery group was SD rats that did not undergo modeling treatment, while the model group was modeled by injecting 4 μL of 6-OHDA (5 μg / μL) into the right intracranial region (medial forebrain bundle, MFB) of SD rats, without any drug treatment. The istradefylline group was the positive drug control group, treated with 10 mg / kg of istradefylline (administered intragastricly once daily) in the model rats, and the YT salt group was administered 248 mg / kg of YT salt (administered intragastricly once daily) in the model rats. All data in the figure are expressed as mean ± standard error (SEM). P<0.05 indicates statistical significance, and * indicates P<0.05.

[0032] [Figure 12] This figure shows the effect of YT salt on the rate of foot missteps in the grid gait test in 6-OHDA-induced Parkinson's rats. The sham surgery group received 4 μL (0.2 mg / mL) of ascorbic acid solution into the right intracranial (medial forebrain bundle, MFB) of SD rats, while the model group received 4 μL of 6-OHDA (5 μg / μL) into the right intracranial MFB of SD rats, without any other drug treatment. The Istradefylline group was the positive drug control group, treated with 10 mg / kg of Istradefylline (administered intragastricly once daily) in model rats, and the YT salt group received 248 mg / kg of YT salt (administered intragastricly once daily) in model rats. All data in the figure are expressed as mean ± standard error (SEM). P<0.05 indicates statistical significance, and * indicates P<0.05. [Modes for carrying out the invention]

[0033] definition In this invention, unless otherwise specified, the scientific and technical terms used herein have meanings that are commonly understood by those skilled in the art. Furthermore, the terms and laboratory procedures used herein relating to protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology are all commonly used terms and procedures in their respective fields. At the same time, to better understand this invention, definitions and interpretations of the relevant terms are provided below.

[0034] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0035] As used herein, the term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a linear or branched 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 group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl This includes groups such as 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.More preferably, it includes a lower alkyl group containing 1 to 6 carbon atoms, and non-limiting examples include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, and the like. The alkyl group may be substituted or not, and if substituted, the substituent may be substituted at any available linking point, and preferably the substituent is one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0036] As used herein, the term "alkoxy group" refers to -O-(alkyl group) and -O-(cycloalkyl group), where the definitions of alkyl group and cycloalkyl group are as given above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups. Alkoxy groups may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0037] As used herein, the terms "halo" and "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0038] As used herein, the term “haloalkyl group” refers to an alkyl group in which some or all of its hydrogen atoms are substituted with halogen atoms, either by itself or as part of another substituent. In the case of alkyl groups, a haloalkyl group may have any suitable number of carbon atoms, such as C1-C6. For example, haloalkyl groups include trifluoromethyl groups, fluoromethyl groups, and so on. In some cases, the term “perfluoro” may be used to define a compound or group in which all hydrogens are substituted with fluorine. For example, a perfluoromethyl group refers to a 1,1,1-trifluoromethyl group.

[0039] As used herein, the term "hydroxyl group" refers to the -OH moiety.

[0040] The present invention further includes various deuterated forms of formula (I). Each available hydrogen atom bonded to a carbon atom may be independently substituted with a deuterium atom. Those skilled in the art can synthesize compounds of the deuterated form of formula (I) by referring to relevant literature. When preparing the deuterated form of formula (I), commercially available deuterated starting materials may be used, or they may be synthesized using deuterating reagents by the prior art. Non-limiting examples of deuterating reagents include deuterated borane, trihydrobolanetetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0041] "Pharmacologically acceptable" means that the above-mentioned component is compatible with the other components of the formulation and is not toxic to the recipient.

[0042] As used herein, the term “pharmaceutically acceptable salt” means, as used herein, a pharmaceutically acceptable organic or inorganic salt of a compound. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, hydrochlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bistartrates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, glucurons, sugarates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylenebis(2-hydroxy-3-naphthoate)). A pharmaceutically acceptable salt may contain other molecules such as acetate ions, succinate ions, or other counterions. The counterion may be any organic or inorganic module that stabilizes the charge of the parent compound. A pharmaceutically acceptable salt may also have two or more charged atoms in its structure. If multiple charged atoms constitute the components of a pharmaceutically acceptable salt, it may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0043] As used herein, the term “acid anion” refers to the anion produced when an acid is ionized. Common acid anions include chloride ions, bromide ions, iodide ions, carbonate ions, bicarbonate ions, sulfate ions, phosphate ions, hydrogen phosphate ions, dihydrogen phosphate ions, formate ions, acetate ions, and the like. The above acid anions may be -1-valent, -2-valent, -3-valent, -4-valent, etc.

[0044] As used herein, the term “pharmaceutically acceptable carrier” refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation aid, or carrier common in the art, used in conjunction with a therapeutic agent to jointly constitute a “pharmaceutical composition” for administration to an individual. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dose and concentration used and is compatible with other components of the formulation. A pharmaceutically acceptable carrier is suitable for the formulation in which it is used.

[0045] As used herein, the term “pharmaceutically acceptable excipient” refers to a substance that helps to administer an activator to an organism. Useful pharmaceutical excipients include, but are not limited to, binders, fillers, disintegrants, lubricants, flow enhancers, coatings, sweeteners, flavorings, and colorants.

[0046] Depending on the position and nature of the desired substituents, the compounds of the present invention may contain one or more chiral centers. The chiral carbon atom can exist in (R)- and / or (S)- configurations, resulting in a racemic mixture in the case of a single chiral center and a diastereomerized mixture in the case of multiple chiral centers. In some cases, chirality may arise because rotation around a particular bond is hindered, for example, when the central bond is bonded to two substituted aromatic rings of a particular compound. Substituents on the rings may exist in cis or trans form. All such configurations (including enantiomers and diastereomers) are intended to be within the scope of the present invention. Preferred compounds are those that yield more desired biological activity. Isolated, pure, or partially purified isomers and stereoisomers, or racemic or diastereomerized mixtures of the compounds of the present invention are all within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0047] Tautomers, sometimes called proton-shift tautomers, are related compounds of two or more types that undergo exchange of one or more single bonds and one or more adjacent double bonds through the movement of hydrogen atoms. The compounds of the present invention may exist in one or more tautomer forms.

[0048] The present invention further comprises all suitable isotopic variants of the compounds of the present invention. An isotopic variant of a compound of the present invention is defined as a compound of the present invention in which at least one of its atoms is replaced by an atom having the same atomic number but with an atomic weight different from the atomic weight commonly or primarily found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 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 Includes I. Some isotopic variants of the compound of the present invention, for example, one or more radioactive isotopes (e.g., 3 H or 14 Mutants incorporating C) may be used in studies of the tissue distribution of drugs and / or substrates. For ease of manufacture and detectability, tritium and carbon-14 (i.e., 14 C) Isotopes are particularly preferred. Furthermore, substitution with isotopes such as deuterium can provide determined therapeutic benefits resulting from better metabolic stability, such as increased in vivo half-life or reduced dose needs, and are therefore preferred in some cases. Isotope variants of the compounds of the present invention can usually be produced using appropriate isotope variants of appropriate reagents by utilizing conventional methods known to those skilled in the art, for example, by utilizing exemplary methods or the production methods described in the following examples.

[0049] The present invention comprises all possible stereoisomers of the compounds of the present invention, either as single stereoisomers or as any mixture of the above stereoisomers exhibiting any ratio. Separation of single stereoisomers of the compounds of the present invention, such as single enantiomers or single diastereoisomers, can be achieved by any suitable prior art method, such as chromatography, particularly by chiral chromatography.

[0050] The present invention comprises all possible tautomers of the compounds of the present invention, in the form of a single tautomer or any mixture of the above tautomers in any proportion.

[0051] As used herein, the terms “solvate” or “solvent compound” refer to pharmaceutically acceptable solvates formed by the compounds of the present invention with one or more solvent molecules, non-limiting examples of solvent molecules include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate, and the like. A hydrate is a specific form of a solvate in which the solvent is water.

[0052] As used herein, the terms “effective dose” and “therapeutic dose” refer to the dose of a compound, combination of compounds, or salt form of the present invention that produces a therapeutic effect when administered. The exact dose depends on the therapeutic purpose and is determined using techniques known to those skilled in the art (see, for example, 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).

[0053] As used herein, “treatment” or “treating” is a method for obtaining a beneficial or desired outcome (including clinical outcomes). For the purposes of this application, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by the disease; reducing the severity of the disease; stabilizing the disease (e.g., preventing or delaying disease progression); preventing or delaying disease transmission (e.g., metastasis); preventing or delaying disease recurrence; delaying or suppressing disease progression; improving the disease state; providing some or all relief of the disease; reducing the dose of one or more other drugs necessary for the treatment of the disease; delaying disease progression; improving or enhancing quality of life; increasing weight gain; and / or extending survival. “Treatment” further encompasses reducing the pathological outcomes of cancer (e.g., tumor volume). The methods of this application consider one or more of these aspects of treatment.

[0054] As used herein, “prevention (or preventing)” includes providing prevention against the onset or recurrence of the disease in an individual who is susceptible to the disease but has not yet been diagnosed with the disease.

[0055] The terms “subject,” “individual,” and “patient” are used interchangeably herein and refer to mammals, including but not limited to humans, cattle, horses, cats, dogs, rodents, or primates. In some embodiments, the individual is a human.

[0056] The “effective dose” of a drug refers to the amount that effectively achieves the desired therapeutic or preventive outcome within the required dosage and duration. The specific dose may vary depending on one or more of the following: the chosen drug, the method of administration to be followed, whether or not it is used in combination with other compounds, the time of administration, the tissue to be imaged, and the physical delivery system carrying it.

[0057] As used herein, the terms “synergistic” or “synergistic” refer to a result of a combination of two compounds, components, or targeting agents that is greater than the sum of the individual agents combined. The terms “synergistic” or “synergistic” refer to an improvement in the state or symptom of a disease being treated compared to when each compound, component, or targeting agent is used alone. Such improvement in the state or symptom of a disease being treated is a “synergistic effect.” “Synergistic amount” is the amount of a combination of two compounds, components, or targeting agents that produces a synergistic effect ("synergistic" as defined herein).

[0058] To determine the synergistic interactions between one or two components, the optimal range of the above effects, and the absolute dose range of each component for the above effects, these can be clearly measured by administering components within different w / w ratio ranges and doses to patients requiring treatment. However, observing synergies in in vitro or in vivo models can predict the effects in humans and other species, as well as in existing in vitro or in vivo models described herein, in order to measure synergistic effects, and the results of such studies can also be used to predict the required effective dose and plasma concentration ratio range, as well as absolute dose and plasma concentration, in humans and other species by applying pharmacokinetic / pharmacodynamic methods.

[0059] It should be understood that the embodiments of the present application described herein include "...consisting of..." and / or "basically consisting of...".

[0060] In this specification, references to values ​​or parameters "about" include (and should be described) changes to the value or parameter itself. For example, a description of "about X" includes a description of "X".

[0061] As used herein, the term "approximately X to Y" has the same meaning as "approximately X to approximately Y".

[0062] Where used herein, the term “about” modifies the number of components or reactants of the present invention, meaning that the numerical variation may result from, for example, typical measurement and liquid handling procedures for producing a concentrate or actual working solution, accidental errors in such procedures, differences in the production, source, or purity of the components used in the production of the composition or the implementation of the method. The term “about” further includes different amounts due to different equilibrium conditions for the composition obtained from a particular starting mixture. Whether modified by the term “about” or not, a claim includes equal amounts of quantity. In one embodiment, the term “about” means within 10% of the reported value, preferably within 5% of the reported value.

[0063] Those skilled in the art should understand that, when a claim contains a numerical value, the actual value of that numerical value may vary by 10% (±10%), preferably 5% (±5%), from the stated value, regardless of whether or not the prefix "approximately" is present.

[0064] As used herein and in the appended claims, the singular forms “a,” “an,” “or,” and “the” include multiple referents unless the context explicitly indicates otherwise.

[0065] Description of the Embodiment Combination products In some embodiments, this disclosure is, (a) A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, [ka] (I) Here, R 1 , R 2 , R 3 , R 4 , R 5 and R 6These are homologous or different and each is independently selected from hydrogen, halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group, and the above hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl group and phenyl group. Or R 1 , R 2 and R 3 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R 4 , R 5 and R 6 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) With respect to combination products containing bile acids or their derivatives or analogs or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, Here, the molar ratio of component (a) to component (b) is 1:1000 to 1000:1.

[0066] In a further embodiment, R 1 , R 2 and R 3 Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R 1 , R 2 and R 3 Any two adjacent atoms in R form a 4- to 7-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 1 , R 2 and R 3 One or two of them are hydrogen, or R 1 , R 2 and R 3Any two adjacent ones in form a 5-membered heterocyclic ring containing one or more oxygen atoms together with the carbon atoms to which they are attached. In a further embodiment, R 1 R 2 and R 3 one of is hydrogen, or any two adjacent ones in R 1 R 2 and R 3 form a 5-membered heterocyclic ring containing two oxygen atoms together with the carbon atoms to which they are attached.

[0067] In a further embodiment, R 4 R 5 and R 6 are each independently selected from hydrogen, a hydroxy group, and a methoxy group, or any two adjacent ones in R 4 R 5 and R 6 form a 4- to 7-membered heterocyclic ring containing one or more oxygen atoms together with the carbon atoms to which they are attached. In a further embodiment, one or two of R 4 R 5 and R 6 are hydrogen, or any two adjacent ones in R 4 R 5 and R 6 form a 5-membered heterocyclic ring containing one or more oxygen atoms together with the carbon atoms to which they are attached. In a further embodiment, one of R 4 R 5 and R 6 is hydrogen, or any two adjacent ones in R 4 R 5 and R 6 form a 5-membered heterocyclic ring containing two oxygen atoms together with the carbon atoms to which they are attached.

[0068] In further embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipine, 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.

[0069] In further embodiments, the compound of formula (I) is [ka] They are selected from among them.

[0070] In further embodiments, the above bile acid or its derivative or analog is selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid.

[0071] In further embodiments, the molar ratio of component (a) to component (b) is 1:100 to 100:1. Preferably, the molar ratio of component (a) to component (b) is 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, or 1:10 to 10:1. More preferably, the molar ratio of component (a) to component (b) is 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 two of these values.

[0072] In further embodiments, the combination product is used to improve cell viability, particularly neuronal cell viability, by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells. Preferably, the combination product is used to treat, alleviate, and / or prevent neurodegenerative diseases or conditions. More preferably, the neurodegenerative disease or condition 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). More preferably, the neurodegenerative disease or condition is selected from Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS).

[0073] Pharmaceutical composition In some embodiments, this disclosure is, (a) A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, [ka] (I) Here, R 1 , R 2 , R 3 , R 4 , R 5 and R 6These are homologous or different and each is independently selected from hydrogen, halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group, and the above hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl group and phenyl group. Or R 1 , R 2 and R 3 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R 4 , R 5 and R 6 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) Bile acids or their derivatives or analogs or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, (c) Provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient and / or diluent, Here, the molar ratio of component (a) to component (b) is 1:1000 to 1000:1.

[0074] In a further embodiment, R 1 , R 2 and R 3 Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R 1 , R 2 and R 3 Any two adjacent atoms in R form a 4- to 7-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 1 , R 2 and R 3 One or two of them are hydrogen, or R 1, R 2 and R 3 Any two adjacent atoms in R form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 1 , R 2 and R 3 One of them is hydrogen, or R 1 , R 2 and R 3 Any two adjacent atoms in the compound form a five-membered heterocycle containing two oxygen atoms, along with the carbon atoms to which they are bonded.

[0075] In a further embodiment, R 4 , R 5 and R 6 Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R 4 , R 5 and R 6 Any two adjacent atoms in R form a 4- to 7-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 4 , R 5 and R 6 One or two of them are hydrogen, or R 4 , R 5 and R 6 Any two adjacent atoms in R form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 4 , R 5 and R 6 One of them is hydrogen, or R 4 , R 5 and R 6 Any two adjacent atoms in the compound form a five-membered heterocycle containing two oxygen atoms, along with the carbon atoms to which they are bonded.

[0076] In further embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipine, 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.

[0077] In further embodiments, the compound of formula (I) is [ka] They are selected from among them.

[0078] In further embodiments, the above bile acid or its derivative or analog is selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid.

[0079] In further embodiments, the molar ratio of component (a) to component (b) is 1:100 to 100:1. Preferably, the molar ratio of component (a) to component (b) is 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, or 1:10 to 10:1. More preferably, the molar ratio of component (a) to component (b) is 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 two of these values.

[0080] In further embodiments, the pharmaceutical composition is used to improve cell viability, particularly neuronal cell viability, and in particular to improve cell viability by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells. Preferably, the pharmaceutical composition is used to treat, alleviate and / or prevent neurodegenerative diseases or conditions. More preferably, the neurodegenerative disease or condition 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, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. Preferably, the neurodegenerative disease or condition is selected from Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS).

[0081] Acid-base addition salts In some embodiments, the present disclosure provides an acid-base addition salt of formula (II), (A + ) m (B - ) n (C - ) p (II) Here, (a)A + This is the cation moiety of the compound of formula (I), [ka] (I) Here, R 1 , R 2 , R 3 , R 4 , R 5 and R 6These are homologous or different and each is independently selected from hydrogen, halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group, and the above hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl group and phenyl group. Or R 1 , R 2 and R 3 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R 4 , R 5 and R 6 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b)B - is an anionic moiety which is a bile acid or a derivative or analog thereof, and (c)C - It is a rhizal anion, Here, m, n, and p are integers independently chosen from 1 to 6 such that the salt composition reaches charge equilibrium, and when m=n, p is 0.

[0082] In a further embodiment, R 1 , R 2 and R 3 Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R 1 , R 2 and R 3 Any two adjacent atoms in R form a 4- to 7-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 1 , R 2 and R 3One or two of them are hydrogen, or R 1 , R 2 and R 3 Any two adjacent atoms in R form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 1 , R 2 and R 3 One of them is hydrogen, or R 1 , R 2 and R 3 Any two adjacent atoms in the compound form a five-membered heterocycle containing two oxygen atoms, along with the carbon atoms to which they are bonded.

[0083] In a further embodiment, R 4 , R 5 and R 6 Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R 4 , R 5 and R 6 Any two adjacent atoms in R form a 4- to 7-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 4 , R 5 and R 6 One or two of them are hydrogen, or R 4 , R 5 and R 6 Any two adjacent atoms in R form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 4 , R 5 and R 6 One of them is hydrogen, or R 4 , R 5 and R 6 Any two adjacent atoms in the compound form a five-membered heterocycle containing two oxygen atoms, along with the carbon atoms to which they are bonded.

[0084] In further embodiments, the compound of formula (I) is [ka] This is a cation moiety selected from the group consisting of the following:

[0085] In a further embodiment, component (b) is an anionic moiety selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid.

[0086] In a further embodiment, C - is a monovalent, divalent, trivalent, or tetravalent acid root anion or a mixture thereof. Preferably, C - is a monovalent, divalent, or trivalent acid root anion or a mixture thereof. More preferably, C - is a monovalent or divalent acid root anion or a mixture thereof. Most preferably, C - This is a monovalent acid root anion or a mixture thereof.

[0087] In a further embodiment, m is 1, n is 1, and p is 0, or m is 2, n is 1, and p is 1.

[0088] In further embodiments, the pharmaceutical composition is used to improve cell viability, particularly neuronal cell viability, and in particular to improve cell viability by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells. Preferably, the pharmaceutical composition is used to treat, alleviate and / or prevent neurodegenerative diseases or conditions. More preferably, the neurodegenerative disease or condition 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, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. Preferably, the neurodegenerative disease or condition is selected from Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS).

[0089] Treatment and / or prevention In some embodiments, the Disclosure provides methods for treating, alleviating and / or preventing neurodegenerative diseases or conditions. In some embodiments, the methods for treating, alleviating and / or preventing such neurodegenerative diseases or conditions include administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof described in any one of the embodiments.

[0090] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing Alzheimer's disease (AD), comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, as described in any one of the above embodiments.

[0091] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing Huntington's disease (HD), comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, as described in any one of the above embodiments.

[0092] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing Parkinson's disease (PD), comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, as described in any one of the above embodiments.

[0093] In some embodiments, the Disclosure provides a method for treating, alleviating and / or preventing amyotrophic lateral sclerosis (ALS), comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof described in any one of the above embodiments.

[0094] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing Pick's disease, comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, as described in any one of the above embodiments.

[0095] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing multiple infarct dementia, comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, as described in any one of the above embodiments.

[0096] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing Creutzfeldt-Jakob disease, comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof described in any one of the above embodiments.

[0097] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing Lewy body dementia (DLB), comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof described in any one of the above embodiments.

[0098] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing mixed dementia, comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof described in any one of the above embodiments.

[0099] In some embodiments, the Disclosure provides a method for treating, alleviating, and / or preventing frontotemporal dementia, comprising administering to a patient in need a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof described in any one of the above embodiments.

[0100] In some embodiments, the present disclosure provides methods for treating and / or preventing neurodegenerative diseases or conditions, including Method 1 and Method 2, wherein in Method 1, a patient in need of the treatment is provided. (a) Administer a therapeutic and / or prophylactic effective dose of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, [ka] (I) Here, R1 , R 2 , R 3 , R 4 , R 5 and R 6 These are homologous or different and each is independently selected from hydrogen, halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group, and the above hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl group and phenyl group. Or R 1 , R 2 and R 3 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R 4 , R 5 and R 6 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. In Method 2, for patients who require it, (a) A therapeutic and / or prophylactic effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, [ka] (I) Here, R 1 , R 2 , R 3 , R 4 , R 5 and R 6These are homologous or different and each is independently selected from hydrogen, halogen, hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group, and the above hydroxyl group, C1-C6 alkyl group, C1-C6 haloalkyl group, C1-C6 alkoxy group and C1-C6 haloalkoxy group are optionally substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl group and phenyl group. Or R 1 , R 2 and R 3 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R 4 , R 5 and R 6 Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) Administer therapeutic and / or prophylactic effective amounts of bile acids or their derivatives or analogs or their pharmaceutically acceptable salts, solvates, hydrates or stereoisomers simultaneously, together, individually or sequentially.

[0101] In a further embodiment, R 1 , R 2 and R 3 Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R 1 , R 2 and R 3 Any two adjacent atoms in R form a 4- to 7-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 1 , R 2 and R 3 One or two of them are hydrogen, or R 1 , R 2 and R 3Any two adjacent atoms in R form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 1 , R 2 and R 3 One of them is hydrogen, or R 1 , R 2 and R 3 Any two adjacent atoms in the compound form a five-membered heterocycle containing two oxygen atoms, along with the carbon atoms to which they are bonded.

[0102] In a further embodiment, R 4 , R 5 and R 6 Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R 4 , R 5 and R 6 Any two adjacent atoms in R form a 4- to 7-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 4 , R 5 and R 6 One or two of them are hydrogen, or R 4 , R 5 and R 6 Any two adjacent atoms in R form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. In further embodiments, R 4 , R 5 and R 6 One of them is hydrogen, or R 4 , R 5 and R 6 Any two adjacent atoms in the compound form a five-membered heterocycle containing two oxygen atoms, along with the carbon atoms to which they are bonded.

[0103] In further embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipine, 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.

[0104] In further embodiments, the compound of formula (I) is [ka] They are selected from among them.

[0105] In further embodiments, the above bile acid or its derivative or analog is selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid.

[0106] In further embodiments, the molar ratio of component (a) to component (b) is 1:100 to 100:1. Preferably, the molar ratio of component (a) to component (b) is 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, or 1:10 to 10:1. More preferably, the molar ratio of component (a) to component (b) is 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 two of these values.

[0107] In further embodiments, the neurodegenerative disease or condition 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, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. Preferably, the neurodegenerative disease or condition is selected from Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS).

[0108] In some embodiments, the Disclosure provides a method for improving cell viability, particularly neuronal cell viability, by 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 described in any one of the above embodiments, thereby improving cell viability, particularly neuronal cell viability, by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells.

[0109] In some embodiments, the disclosure provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof used to improve cell viability, particularly neuronal cell viability, and in particular by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells.

[0110] In some embodiments, the Disclosure provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, or stereoisomers thereof used to treat, alleviate, and / or prevent neurodegenerative diseases or conditions.

[0111] In a further embodiment, the neurodegenerative disease or condition 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, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia.

[0112] Administration method The administration of the combination compounds or salt forms of the present invention is influenced by any method that can deliver the compounds to the site of action. These methods include oral, intraduodenal, extra-enterogastric injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), topical, and rectal administration.

[0113] The methods, combination compounds, or salt forms of the present invention may be prepared before administration. Preferably, the formulations are suitable for a specific mode of administration. These compounds are prepared with pharmaceutically acceptable carriers known in the art and administered in various dosage forms known in the art. When preparing the pharmaceutical compositions of the present invention, the active ingredient is usually mixed with a pharmaceutically acceptable carrier, 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. Dose-unit forms or pharmaceutical compositions include tablets, capsules such as gelatin capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, lozenges, pastilles, hard candies, sprays, creams, ointments, suppositories, pectins, gels, pastes, lotions, ointments, injections, elixirs, syrups, and extra-gastrointestinal solutions, packaged in containers suitable for subdivision into separate doses.

[0114] Extra-gastrointestinal formulations include pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, and sterile powders (for their manufacture). Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of coatings such as lecithin and surfactants, or by maintaining an appropriate particle size. Exemplary extra-gastrointestinal administration forms include sterile aqueous solutions such as solutions or suspensions of the compound of the present invention in aqueous propylene glycol or dextrose solution. If necessary, such dosage forms may be appropriately buffered.

[0115] Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be commonly used for tableting purposes. Similar types of solid compositions may be used in soft gelatin capsules and hard gelatin capsules. Therefore, preferred materials include lactose (or milk sugar) and high molecular weight polyethylene glycol. If an aqueous suspension or elixir is required for oral administration, the active compound may be combined with various sweeteners or flavorings, colorants or dyes, emulsifiers or suspending agents as needed, and diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0116] Methods for preparing various pharmaceutical compositions using specific amounts of active compounds are known or obvious to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th edition (1975).

[0117] Reagent kit In some embodiments, the Disclosure provides a reagent kit for treating, alleviating and / or preventing neurodegenerative diseases or conditions, comprising a combination product, acid-base addition salt, pharmaceutical composition, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, as described in any one of the embodiments above, and instructions for administering the therapeutic agent. In one embodiment, the instructions describe and limit the modes of administration of the therapeutic agent, for example, by being used to administer the therapeutic agent of the present invention simultaneously, jointly, individually, or sequentially. In one embodiment, the instructions describe and limit the modes of administration of the therapeutic agent, for example, by specifying the number of days for which each therapeutic agent is administered over a specific period.

[0118] In some embodiments, the neurodegenerative disease or condition 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, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. Preferably, the neurodegenerative disease or condition is selected from Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS). [Examples]

[0119] The present invention will be described in more detail below with reference to examples, but this should not be understood as limiting the present invention.

[0120] Materials and Reagents: Unless otherwise specified, all reagents used in the experimental portion of this invention are 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.

[0121] When obtaining the compounds and corresponding analytical data described in the examples in the context, follow the experimental and analytical methods below unless otherwise specified.

[0122] LC-MS Unless otherwise specified, the analytical LC-MS system used is a Shimadzu LCMS-2020 with electrospray ionization (ESI) in positive ion detection mode, featuring a 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20APDA detector, and LCMS 2020MS detector. The column is HALO, i.e., C18 30mm × 5.0mm, 2.7μm. Mobile phase A is water containing 0.05% TFA, and mobile phase B is acetonitrile containing 0.05% TFA. The gradient is set to change from 5% mobile phase B to 100% (95%) within 2.0 minutes, hold for 0.7 minutes, then return to 5% mobile phase B within 0.05 minutes and hold for 0.25 minutes. The column oven (CTO-20AC) operates at 40.0°C. The flow rate is 1.5 mL / min, and the injection volume is 1 μL. The detection range of the PDA (SPD-M20A) is 190 nm to 400 nm. The MS detector is configured to have electrospray ionization as the ionization source, the acquisition method is scanning, the spray gas flow rate is 1.5 L / min, the dry gas flow rate is 15 L / min, the detector voltage is tuning voltage ±0.2 kV, the DL temperature is 250 °C, the heat block temperature is 250 °C, and the scanning range is 90.00 m / z to 900.00 m / z. ELSD (Alltech3300) detector parameters: drift tube temperature is 60 ± 5 °C, and N2 flow rate is 1.8 ± 0.2 L / min. The mobile phase gradient is optimized for each compound. The calculated mass corresponds to the accurate mass.

[0123] Preparative HPLCUnless otherwise specified, preparative HPLC purification is performed using a Waters Auto purification system (2545-2767) equipped with a 2489 UV detector. The column is one of the following selected from 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 group, 30 mm × 150 mm, 5 μm; or YMC-Actus Triart C18, 30 mm × 150 mm, 5 μm. The mobile phase consists of a mixture of acetonitrile (5% to 95%) in an aqueous solution containing 0.1% FA or 10 mmol / L NH4HCO3. The flow rate is maintained at 25 mL / min, the injection volume is 1200 μL, and the UV detector uses two channels, 254 nm and 220 nm. The mobile phase gradient is optimized for each compound.

[0124] Chiral chromatography Chiral analytical chromatography uses the following columns: 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 The experiment is conducted at one of the following locations (Co., Ltd.): with different column sizes (50mm × 4.6mm, 100mm × 4.6mm, 150mm × 4.6mm, 250mm × 4.6mm, 50mm × 3.0mm, 100mm × 3.0mm), using either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) as the isocratic solvent system, or using supercritical fluid (SFC) conditions.

[0125] Normal-phase flash chromatographyUnless otherwise specified, normal-phase flash chromatography (FCC) is performed in silica gel using a pre-packaged silica gel column, with ethyl(siRNA) / hexane, ethyl(siRNA) / petroleum ether (bp 60°C~90°C), CH2Cl2 / MeOH, or CH2Cl2 / 10% 2N NH3 MeOH solution used as the eluent.

[0126] 1 1H NMR: Unless otherwise specified, 1 ¹H NMR spectra are obtained in DMSO-d6 solution using a 400 MHz spectrometer (or 300 MHz spectrometer). Nuclear magnetic resonance (NMR) spectral features refer to chemical shifts (δ) expressed in parts per million (ppm). Tetramethylsilane (TMS) is used as an internal standard in DMSO-d6 solution, and the residual CH3OH peak or TMS is used as an internal standard in CD3OD solution. Coupling constants (J) are reported in Hertz (Hz). The properties of multiplicity shifts are reported as s (single peak), d (double peak), t (triple peak), q (quadruple peak), dd (double double peak), dt (double triple peak), m (multiple peak), and br (broad peak).

[0127] The abbreviations used in this specification, particularly in the examples, are listed in the table below.

[0128] [Table 1]

[0129] Example 1. Synthesis of compound Y Step 1.2 - Synthesis of (benzo[d][1,3]dioxocyclopentyl-5-yl)ethane-1-ol [ka] 1,3-Benzodioxole-5-acetic acid (500 g, 2.78 mol) was dissolved in THF (200 mL) at 0°C, to which LAH (2.5 M, 1.00 L) was added dropwise. The mixture was then stirred at 25°C under an 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 sequence. 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.

[0130] Step 2.2 - Synthesis of (benzo[d][1,3]dioxocyclopentyl-5-yl)ethane-1-pibarate [ka] 2-(benzo[d][1,3]dioxocyclopentyl-5-yl)ethane-1-ol (455 g) and pyridine (435 g) were dissolved in DCM (2.00 L), and compound b (664 g) was added dropwise at 0°C under N2 protection, with continuous stirring for 8 hours. The residue was poured into water, and the aqueous phase was extracted with DCM. The combined organic phase was washed with saline solution, dried, and concentrated. The residue was purified by silica gel chromatography to obtain the title compound (670 g) as a yellow oil.

[0131] HNMR (CDCl3): δ6.78-6.70 (m, 2H), 6.68-6.64 (m, 1H), 6.10-5.58 (m, 2H), 4.22 (t, J = 6.94 Hz, 2H), 2.84 (t, J = 6.94 Hz, 2H), 1.20- 1.16 (m, 9H).

[0132] Step 3.2 - Synthesis of (6-acetyl-benzo[d][1,3]dioxocyclopentyl-5-yl)ethane-1-pibarate [ka] At 0°C, 620 g of 2-(benzo[d][1,3]dioxocyclopentyl-5-yl)ethane-1-pivalate was dissolved in 3.00 L of Ac2O, to which 1.01 kg of ZnCl2 was added all at once with N2. The mixture was then stirred at room temperature for 8 hours. The reaction product was poured into water, extracted with ethyl acetate, washed with brine, the organic phases were combined, dried, and concentrated. The mixture was purified by silica gel chromatography to obtain the title compound (467 g) as a yellow oil.

[0133] HNMR (CDCl3): δ7.23 (s, 1H), 6.75 (s, 1H), 6.78-6.70 (m, 1H), 6.02 (s, 2H), 4.26 (t, J = 6.63 Hz, 1H), 4.35-4.21(m, 1H), 3.17 (t, J = 6.63 Hz, 2H), 2.54 (s, 3H), 1.16 (s, 9H).

[0134] Step 4. Synthesis of 2-(6-(2-(2-(1,3-dioxolan-2-yl)-4,5-dimethoxyphenyl)acetyl)benzo[d][1,3]dioxolan-5-yl)pivalate ethyl [ka] Cs2CO3 (451 g) and (Ahphos)2PdCl2 (58.8 g) were added simultaneously to a DCE solution of 2-(6-acetyl-benzo[d][1,3]dioxocyclopentyl-5-yl)ethane-1-pivalate (284 g) and compound a (200 g) at room temperature and under N2 protection. The mixture was reacted at 90°C for 10 hours while maintaining the temperature. After the reaction was complete, the reaction system was gradually added dropwise to water, extracted with ethyl acetate, washed the organic phase with brine, dried, and concentrated. The solution was purified by silica gel chromatography to obtain the title compound (310 g) as a yellow solid.

[0135] Step 5. Synthesis of Compound Y [ka] At room temperature and under N2 protection, 310 g of ethyl 2-(6-(2-(2-(1,3-dioxolan-2-yl)-4,5-dimethoxyphenyl)acetyl)benzo[d][1,3]dioxolan-5-yl)pivalate was added all at once to EtOH, and the mixture was then reacted at 120°C under high pressure for 24 hours. After the reaction was complete, the mixture was cooled to 25°C, filtered, and the filtered cake was washed with MTBE. The compound was purified by silica gel chromatography to obtain 190 g of the title compound.

[0136] 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), 7.15-7.04 (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).

[0137] Example 2. Production and Characterization of YT Salt [ka] Preparation of YT salt: Compounds Y and T were suspended in a methanol / ethyl acetate (isopropyl acetate) (v / v: 1 / 9) mixed solvent and continuously stirred for 24 hours, resulting in a relatively large amount of solid being suspended in the system. The solid was obtained by filtration and dried to obtain the YT salt form.

[0138] Characterization of YT salts: The ion ratio of Y to T in YT salts was 1:1.

[0139] 1H NMR (DMSO-d6): δ 9.60 (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, 2H), 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).

[0140] Example 3. Effects of single-agent compound Y (Y), single-agent compound T (T), single-agent compound B (B), single-agent compound N (N), combination of compound Y + T, combination of compound B + N, combination of compound PB + T, and novel salt YT on the activity of hydrogen peroxide-induced cell line SH-sy5y cells.

[0141] Neuroblastoma SH-sy5y cells (purchased from the Cell Bank of the Chinese Academy of Sciences) were cultured in a cell incubator at 37°C and 5% CO2 using complete medium DMEM + 10% FBS + 1% PS. The experiment was divided into a total of 11 groups.

[0142] Group 1 (control): SH-sy5y cells Group 2 (model): SH-sy5y cells + hydrogen peroxide solution Group 3: SH-sy5y cells + hydrogen peroxide solution + compound Y (100 μM) Group 4: SH-sy5y cells + hydrogen peroxide solution + compound T (100 μM) Group 5: SH-sy5y cells + hydrogen peroxide solution + compound B (100 μM) Group 6: SH-sy5y cells + hydrogen peroxide solution + compound N (100 μM) Group 7: SH-sy5y cells + hydrogen peroxide solution + compound Y + T combination (100 μM + 100 μM) Group 8: SH-sy5y cells + hydrogen peroxide solution + compound B + N combination (100 μM + 100 μM) Group 9: SH-sy5y cells + hydrogen peroxide solution + compound PB + T combination (500 μM + 200 μM) Group 10: SH-sy5y cells + hydrogen peroxide + YT salt (100 μM) Group 11: SH-sy5y cells + DMSO

[0143] Neuroblastoma SH-sy5y cells were raised to 1 × 10⁶ cells in complete medium DMEM + 10% FBS + 1% PS. 4 Cells were seeded in individual cells / well and cultured for 24 hours in a cell incubator at 37°C and 5% CO2, after which the corresponding compound was added. After incubation for 24 hours, hydrogen peroxide was added and stimulated for 1 hour, with a final concentration of 350 μM hydrogen peroxide. Next, 50 μM CellTiter-Glo® (CTG) reagent was added and shaken for 2 minutes, and then the luminescence signal value was detected, which can characterize cell viability.

[0144] As shown in Figure 1, compared to the model (column 2), compound Y alone (column 3) had a superior effect in improving cell viability (P<0.0001), and the effect of compound Y alone (column 3) was superior to that of compound B alone (column 5). Compared to compound T alone (column 4), compound B alone (column 5), the combination of compound B+N (column 8), and the combination of compound PB+T (column 9), the combination of compound Y+T (column 7) and the YT salt (column 10) showed a remarkably superior effect in improving cell viability. The effect of the compound Y+T combination and the YT salt on repairing neuronal damage after oxidative stress was remarkably superior to that of compound T alone, compound B alone, the combination of compound B+N, and the combination of compound PB+T. Here, the concentration of compound PB and compound T in the PB+T combination was referenced from the concentrations of compound PB and compound T in the commercially available drug AMX0035 data (David L. Carbone. Pharmacology / toxicology NDA review and evaluation, Application). number:216660Orig1s000,Food and Drug Administration.doi:pink.pharmaintelligence.informa.com / - / media / supporting-documents / pink-sheet / 2022 / 11 / relyvrio_nonclinical.pdf?rev=d27109bf35c040d4a78f73144d132917&hash=414BB5B4473A21ECE0231375EB1C0341).

[0145] The results above demonstrate that compound Y alone, the combination of compound Y and T, and the YT salt exhibit remarkably superior effects in improving cell viability and repairing damage to nerve cells after oxidative stress, indicating their potential as drugs for treating, alleviating, and / or preventing neurodegenerative diseases or conditions.

[0146] Example 4. Inhibitory effects of compound Y alone, compound T alone, combination of compound Y+T, and YT salt on CD4-positive and CD8-positive T cell proliferation. In ALS, Th cells have been reported to be the primary contributors to inflammation and disease progression. In the 1990s, CD4 T cell infiltration was observed in the spinal cord adjacent to degenerative areas in ALS patients. Similarly, CD8 T cell infiltration was 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.) To observe the inhibition of immune cell infiltration or proliferation by the compounds, combinations of compounds, or salts of the present invention, their inhibitory effects on CD4-positive and CD8-positive T cell proliferation were further analyzed.

[0147] 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 for 20 minutes in the dark. Next, 1.5 × 10⁶ cells stained with CellTrace were incubated. 5Individual PBMCs were seeded in a 96-well U-bottom plate, and the PBMCs were treated with Anti-CD3 / CD28 antibody coupled to magnetic beads in a 1:1 ratio (number of cells:number of magnetic beads) to stimulate differentiation of the PBMCs into T cells. Next, various compounds were treated with the cells described above at corresponding concentrations (100 μM compound Y, 100 μM compound T, combination of compound Y + T (100 μM compound Y + 100 μM compound T), 100 μM YT salt, control group UDCA (100 μM)) and co-incubated for 72 hours in an incubator at 37°C and 5% CO2, followed by analysis by flow cytometry. Specifically, live and dead cells were distinguished by first treating the cells awaiting measurement with a Live / dead dye (633 nm, diluted 1:1000) at 4°C for 30 minutes. Next, under room temperature conditions, the cells awaiting measurement were co-incubated for 30 minutes simultaneously with the wavelength dyes anti-CD45-PerCPCy5.5, anti-CD4-AF700, and anti-CD8-FITC to distinguish between different series of T cells (CD4-positive T cells and CD8-positive T cells). After appropriate washing, the stained cells were analyzed by flow cytometry at different wavelengths. Subsequent cell analysis refers to live cells that show positivity after staining with live / dead dyes. CD4-positive T cells refer to cells stained with anti-CD45-PerCPCy5.5 and anti-CD4-AF700 dyes, while CD8-positive T cells refer to cells stained with anti-CD45-PerCPCy5.5 and anti-CD8-FITC dyes. The proliferation of CD4-positive and CD8-positive T cells was determined by fluorescence of Celltrace dyes.

[0148] As shown in Figure 2, compared to the control group DMSO (waveform 1, waveforms 1-6 from top to bottom), the CD4-positive T cell proliferation peaks for YT salt (waveform 2), compound Y at the corresponding dose (waveform 3), and the compound Y+T combination (waveform 5) were generally shifted to the right, indicating that these groups significantly inhibited the proliferation of CD4-positive T cells. Similarly, as shown in Figure 3, compared to the control group DMSO (waveform 1), the CD8-positive T cell proliferation peaks for YT salt (waveform 2), compound Y at the corresponding dose (waveform 3), and the compound Y+T combination (waveform 5) were generally shifted to the right, indicating that these groups significantly inhibited the proliferation of CD8-positive T cells.

[0149] The results above indicate that the combination of YT salt and compound Y+T has a significant inhibitory effect on CD4-positive and CD8-positive T cell proliferation in CD4-positive and CD8-positive T cells derived from Anti-CD3 / CD28-induced differentiated human PBMCs, and that this effect is significantly superior to that of compound T and compound U (UDCA). This suggests that the combination of YT salt and compound Y+T has potential inhibitory effects on immune cell infiltration or proliferation in neurodegenerative diseases.

[0150] Example 5: SOD1 by compound YT salt G93A Impact of ALS onset, severity, and survival in ALS mouse models SOD1 G93AThe therapeutic effect of YT salt on the survival status of ALS animals was evaluated in transgenic mice (B6SJL-Tg(SOD1*G93A)1 / cyagen). Sixteen female and fourteen male B6SJL-Tg(SOD1*G93A)1 / cyagen mice were selected and randomly divided into two groups (7 males + 8 females / group): a model group (control) and a YT salt group (treatment group), based on sex and body weight. YT salt was administered intragastricly once daily at a dose of 496 mg / kg. Administration began at 66 days postnatal, and body weight changes were monitored. The condition and severity of symptoms of the animals were evaluated, and the survival period of each individual was statistically recorded. The statistical severity of symptoms in the animals included the time of initial onset and the time when severe symptoms were first detected. In this study, "initial onset" was defined as the appearance of symptoms such as rotation, gait abnormalities, weakness of the fore and hind limbs, or tremors, which were considered the starting point of ALS onset. In this study, "critical condition" was defined as a state in which an animal is completely paralyzed and unable to move freely, but is still surviving. If an animal dies directly after the onset of symptoms without going through the "paralysis" stage, death is considered a critical condition. Survival statistics were calculated as the time the animal was alive at the study endpoint (day 130). Risk ratios were calculated using the log-rank test.

[0151] Regarding observational statistics of the animal condition, as shown in Figure 4, the onset analysis showed no statistically significant difference in the time of initial onset between the YT salt group and the model group (P=0.0802). However, the systemic onset status showed that the onset time in the YT salt group was 90 days after birth, which was later than in the model group. Furthermore, the median onset time (109 days) was 7 days longer than in the model group (102 days), and the onset risk ratio in the YT salt group (0.5716) was approximately three times lower than in the model group (1.749). The test results indicate that YT salt has the effect of delaying the onset time and reducing the onset risk ratio in ALS model mice.

[0152] As shown in Figure 5, the incidence of severe disease in the YT salt group was significantly lower than in the model group (P<0.05). The endpoint severity rate in the YT salt group was 66.667%, and the median time to severe disease was also significantly later in the YT salt group than in the model group. The median time to severe disease in the YT salt group (117 days) was approximately 8 days longer than in the model control group (109 days), and the severity risk ratio in the YT salt group (0.45) was approximately 5 times lower than in the model group (2.222). The test results showed that YT salt effectively reduces the incidence of severe disease in ALS model mice.

[0153] In survival statistics, as shown in Figure 6, the survival time of animals in the YT salt group was significantly better than that of the model group (P<0.01). The endpoint survival rate in the YT salt group was 53.333%, while the endpoint survival rate in the model group was only 7.143%. The median survival time in the model group was 115.5 days. On the other hand, in the YT salt group, less than half of the individuals died by the test endpoint, and the conditions for calculating the median survival time were not met. The mortality risk ratio in the YT salt group (0.3212) was nearly 10 times lower than that of the model group (3.113). The test results showed that YT salt significantly extends the survival time of ALS model mice and reduces the risk of death.

[0154] In summary, in ALS model mice with the SOD1 G93A mutation, YT salts tended to delay the onset of the disease, significantly reduced the incidence of severe cases, and extended survival compared to the model group. This suggests that YT salts may have potential preventive, mitigating, or therapeutic effects on ALS.

[0155] Example 6: Effects of compound YT salt on an MPTP-induced Parkinson's disease mouse model Sixty male mice from C57BL / 6 were selected and randomly assigned to five groups (12 mice / group): a sham surgery group (normal control), a model group (model control), an L-DOPA group (positive drug 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 administered intraperitoneally to the mice at a dose of 30 mg / kg for 5 consecutive days to model the condition. YT salt was administered intragastricly twice daily (7-8 hours between doses) for 13 consecutive days. L-DOPA was administered twice daily (7-8 hours between doses) for 8 consecutive days. The effect of YT salt on improving motor function in MPTP-induced Parkinson's mice was evaluated using behavioral indicators such as the grip strength test and the rotarod test. Animals were examined histopathologically to evaluate the protective effect of YT salt on dopaminergic neurons in MPTP-induced Parkinson's mice.

[0156] The gripping force test results, as shown in Figure 7, demonstrated a significant decrease in the animals' gripping force after MPTP modeling (model group vs. sham surgery group, P<0.0001). The L-DOPA group and the high-dose YT salt group were able to significantly improve the decrease in animal gripping force caused by MPTP in the set treatment plan (L-DOPA group vs. model group, P<0.001; high-dose YT salt group vs. model group, P<0.01).

[0157] As shown in Figure 8, the results of the rotorod test demonstrated that after MPTP modeling, the median rod gripping time in the model group decreased compared to the sham surgery group. The high-dose YT salt group showed a significant improvement in the reduction of rod gripping time in animals induced by MPTP in the set treatment plan (high-dose YT salt group vs. model group, P<0.05).

[0158] As shown in Figure 9, the immunohistochemical staining results for substantia nigra (TH) tissue showed a significant decrease in the number of TH-positive cells in the substantia nigra region of the model group compared to the sham surgery group (P<0.05). The L-DOPA group, the low-dose YT salt group, and the high-dose YT salt group significantly inhibited the decrease in TH-positive cells in the substantia nigra region of the model animals at the set doses (P<0.0001).

[0159] As shown in Figure 10, the results of TH tissue immunostaining of the striatum showed that the loss of TH-positive neurons in the model group was extremely significant compared with the sham operation group (P<0.0001), and the high-dose YT salt administration group significantly inhibited the loss of TH-positive neurons in the substantia nigra region in the set treatment plan (P<0.01).

[0160] The evaluation results of this example showed that YT salt at a dose of 167.5 mg / kg could significantly inhibit the apoptosis of dopaminergic neurons in the substantia nigra region and striatum region of model animals, and at a dose of 248 mg / kg could not only significantly inhibit the apoptosis of dopaminergic neurons in the substantia nigra region of model animals, but also had an obvious improvement effect on behavioral indicators such as the grasping force and rotarod of model animals. This suggested that YT salt had a potential preventive, alleviating or therapeutic effect on Parkinson's disease.

[0161] Example 7: Effect of compound YT salt on 6-OHDA-induced Parkinson's disease rat model Forty-eight male SD rats were selected and classified into four groups (12 rats / group): sham operation group (normal control), model group (model control), Istradefylline group (using Istradefylline as a positive drug control, 10 mg / kg), and YT salt administration group (248 mg / kg). 6-OHDA was used to inject 20 μg of 6-OHDA into the right intracranial cavity (medial forebrain bundle, MFB) of rats to construct a Parkinson's model. After modeling, Istradefylline and YT salt were administered intragastrically once a day for 6 consecutive weeks, and the progression of the rat disease was evaluated by a grid walking experiment 6 weeks after administration.

[0162] As shown in Figures 11 and 12, the results showed that after constructing a Parkinson's model with 6-OHDA, both the number of slips and the slip rate of the model group animals in the grid walking experiment were significantly improved (P<0.05). Compared with the model group, the YT salt administration group could significantly reduce the number of slips and the slip rate at the set dose (P<0.05).

[0163] The evaluation results of this example showed that YT salt had a significant improving effect on motor function impairment in a 6-OHDA-induced rat Parkinson's disease model. This suggests that YT salt may have potential mitigating or therapeutic effects on Parkinson's disease.

[0164] After reading the above description of the present invention, those skilled in the art may make various changes and modifications to the invention, but these equivalent forms should be understood to be similarly limited in scope by the claims attached to this application.

Claims

1. It is a combination product, (a) A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, 【Chemistry 1】 (I) Here, R １ 、R ２ 、R ３ 、R ４ 、R ５ and R ６ are the same or different and each independently is hydrogen, halogen, a hydroxy group, C １ to C ６ alkyl group, C １ to C ６ haloalkyl group, C １ to C ６ alkoxy group and C １ to C ６ haloalkoxy group, and the hydroxy group, C １ to C ６ alkyl group, C １ to C ６ haloalkyl group, C １ to C ６ alkoxy group and C １ to C ６ haloalkoxy group are optionally substituted with one or more groups selected from the group consisting of halogen, C １ to C ６ alkyl group and phenyl group, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) comprising bile acids or their derivatives or analogs or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, Here, the molar ratio of component (a) to component (b) is 1:1000 to 1000:

1. Combination product.

2. R １ , R ２ and R ３ Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R １ , R ２ and R ３ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The combination product according to claim 1.

3. R ４ , R ５ and R ６ Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R ４ , R ５ and R ６ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The combination product according to claim 1 or 2.

4. R １ , R ２ and R ３ One or two of them are hydrogen, or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. A combination product according to any one of claims 1 to 3.

5. R ４ , R ５ and R ６ One or two of them are hydrogen, or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. A combination product according to any one of claims 1 to 4.

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

7. The compound of formula (I) is 【Chemistry 2】 Selected from, A combination product according to any one of claims 1 to 6.

8. The aforementioned bile acids or their derivatives or analogs are selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid. A combination product according to any one of claims 1 to 7.

9. The molar ratio of component (a) to component (b) is 1:1 or 2:

1. A combination product according to any one of claims 1 to 8.

10. Used to improve cell viability, particularly neuronal cell viability, and especially by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells. A combination product according to any one of claims 1 to 9.

11. Used to treat, alleviate and / or prevent neurodegenerative diseases or conditions, A combination product according to any one of claims 1 to 10.

12. The aforementioned neurodegenerative diseases or conditions are selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. The combination product according to claims 1 to 11.

13. A pharmaceutical composition, (a) A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, 【Transformation 3】 (I) Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, a hydroxyl group, and C. １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Selected from haloalkoxy groups, the hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ The haloalkoxy group can optionally contain halogens and C １ ~C ６ Substituted with one or more groups selected from the group consisting of alkyl groups and phenyl groups, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) Bile acids or their derivatives or analogs or their pharmaceutically acceptable salts, solvates, hydrates or stereoisomers, (c) comprising a pharmaceutically acceptable carrier, excipient and / or diluent, Here, the molar ratio of component (a) to component (b) is 1:1000 to 1000:

1. Pharmaceutical composition.

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

15. R ４ , R ５ and R ６ Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R ４ , R ５ and R ６ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The pharmaceutical composition according to claim 13 or 14.

16. R １ 、 R ２ and R ３ one or two of which in are hydrogen, or R １ 、 R ２ and R ３ any two adjacent ones of which in form a 5-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are attached, A pharmaceutical composition according to any one of claims 13 to 15.

17. R ４ , R ５ and R ６ One or two of them are hydrogen, or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. A pharmaceutical composition according to any one of claims 13 to 16.

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

19. The compound of formula (I) is 【Chemistry 4】 Selected from, A pharmaceutical composition according to any one of claims 13 to 18.

20. The aforementioned bile acids or their derivatives or analogs are selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid. A pharmaceutical composition according to any one of claims 13 to 19.

21. The molar ratio of component (a) to component (b) is 1:1 or 2:

1. A pharmaceutical composition according to any one of claims 13 to 20.

22. Used to improve cell viability, particularly neuronal cell viability, and especially by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells. A pharmaceutical composition according to any one of claims 13 to 21.

23. Used to treat, alleviate and / or prevent neurodegenerative diseases or conditions, A pharmaceutical composition according to any one of claims 13 to 22.

24. The aforementioned neurodegenerative diseases or conditions are selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. The pharmaceutical composition according to claim 23.

25. The acid-base addition salt of formula (II), (A ＋ ) ｍ (B － ) ｎ (C － ) ｐ (II) Here, (a) A ＋ This is the cation moiety of the compound of formula (I), 【Transformation 5】 (I) Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, a hydroxyl group, and C. １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Selected from haloalkoxy groups, the hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ The haloalkoxy group can optionally contain halogens and C １ ~C ６ Substituted with one or more groups selected from the group consisting of alkyl groups and phenyl groups, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) B － is an anionic moiety which is a bile acid or a derivative or analog thereof, and (c) C － It is a rhizal anion, Here, m, n, and p are integers independently selected from 1 to 6 such that the salt composition reaches charge equilibrium, and when m = n, p is 0. Acid-base addition salt.

26. R １ , R ２ and R ３ Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R １ , R ２ and R ３ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The acid-base addition salt according to claim 25.

27. R ４ , R ５ and R ６ Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R ４ , R ５ and R ６ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The acid-base addition salt according to claim 25 or 26.

28. R １ , R ２ and R ３ One or two of them are hydrogen, or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The acid-base addition salt according to any one of claims 25 to 27.

29. R ４ , R ５ and R ６ One or two of them are hydrogen, or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The acid-base addition salt according to any one of claims 25 to 28.

30. The compound of formula (I) is 【Transformation 6】 A cation moiety selected from the group consisting of, The acid-base addition salt according to any one of claims 25 to 29.

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

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

33. Used to improve cell viability, particularly neuronal cell viability, and especially by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells. The acid-base addition salt according to any one of claims 25 to 32.

34. Used to treat, alleviate and / or prevent neurodegenerative diseases or conditions, An acid-base addition salt according to any one of Embodiments 25 to 33.

35. The aforementioned neurodegenerative diseases or conditions are selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. The acid-base addition salt according to claim 34.

36. A pharmaceutical composition, 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, Pharmaceutical composition.

37. A method for treating, alleviating and / or preventing neurodegenerative diseases or conditions, 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 claims 1 to 36. method.

38. The aforementioned neurodegenerative diseases or conditions are selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. The method according to claim 37.

39. A method for treating and / or preventing neurodegenerative diseases or conditions, comprising Method 1 and Method 2, In Method 1, for patients who require it, (a) Administer a therapeutic and / or prophylactic effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, 【Transformation 7】 (I) Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, a hydroxyl group, and C. １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Selected from haloalkoxy groups, the hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ The haloalkoxy group can optionally contain halogens and C １ ~C ６ Substituted with one or more groups selected from the group consisting of alkyl groups and phenyl groups, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. In Method 2, for patients who require it, (a) A therapeutic and / or prophylactic effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, 【Transformation 8】 (I) Here, R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are homologous or different, and each is independently a hydrogen atom, a halogen, a hydroxyl group, and C. １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ Selected from haloalkoxy groups, the hydroxyl group, C １ ~C ６ alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkoxy groups and C １ ~C ６ The haloalkoxy group can optionally contain halogens and C １ ~C ６ Substituted with one or more groups selected from the group consisting of alkyl groups and phenyl groups, Or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. Or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a 4- to 7-membered heterocycle containing one or more heteroatoms together with the carbon atoms to which they are bonded, and the heteroatoms are selected from O, S, or N. (b) Administer therapeutic and / or prophylactic effective amounts of bile acids or their derivatives or analogs or their pharmaceutically acceptable salts, solvates, hydrates or stereoisomers simultaneously, together, individually or sequentially. method.

40. R １ , R ２ and R ３ Each is independently selected from hydrogen, a hydroxyl group, a methoxy group, and a benzyloxy group, or R １ , R ２ and R ３ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The method according to claim 39.

41. R ４ , R ５ and R ６ Each is independently selected from hydrogen, a hydroxyl group, and a methoxy group, or R ４ , R ５ and R ６ Any two adjacent atoms in this compound, together with the carbon atoms to which they are bonded, form a 4- to 7-membered heterocycle containing one or more oxygen atoms. The method according to claim 39 or 40.

42. R １ , R ２ and R ３ One or two of them are hydrogen, or R １ , R ２ and R ３ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The method according to any one of claims 39 to 41.

43. R ４ , R ５ and R ６ One or two of them are hydrogen, or R ４ , R ５ and R ６ Any two adjacent atoms in the compound form a five-membered heterocycle containing one or more oxygen atoms together with the carbon atoms to which they are bonded. The method according to any one of claims 39 to 42.

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

45. The compound of formula (I) is 【Chemistry 9】 Selected from, The method according to any one of claims 39 to 44.

46. The aforementioned bile acids or their derivatives or analogs are selected from cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, butadeoxycholic acid, 7-oxolitocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-norursodeoxycholic acid, and tauroursodeoxycholic acid. The method according to any one of claims 39 to 45.

47. The molar ratio of component (a) to component (b) is 1:1 or 2:

1. The method according to any one of claims 39 to 46.

48. The aforementioned neurodegenerative diseases or conditions are selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. The method according to any one of claims 39 to 47.

49. A reagent 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. Here, the reagent kit is used to treat, alleviate, or prevent neurodegenerative diseases or conditions. Reagent kit.

50. The aforementioned neurodegenerative diseases or conditions are selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. The reagent kit described in Embodiment 49.

51. A method for improving cell viability, particularly neuronal cell viability, by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in 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 as described in any one of claims 1 to 36. method.

52. Used to improve cell viability, particularly neuronal cell viability, and especially by reducing active oxidative metabolite-mediated oxidative damage in cells, regulating redox homeostasis in cells, or reducing mitochondrial dysfunction in cells. The compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

53. Used to treat, alleviate and / or prevent neurodegenerative diseases or conditions, The compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

54. The aforementioned neurodegenerative diseases or conditions are selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multiple infarct dementia, Creutzfeldt-Jakob disease, Lewy body dementia (DLB), mixed dementia, and frontotemporal dementia. The compound of formula (I) described in claim 53, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

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