[go: up one dir, main page]

WO2024245371A1 - 一种组合产品、盐及其用于治疗神经退行性疾病或病症的用途 - Google Patents

一种组合产品、盐及其用于治疗神经退行性疾病或病症的用途 Download PDF

Info

Publication number
WO2024245371A1
WO2024245371A1 PCT/CN2024/096520 CN2024096520W WO2024245371A1 WO 2024245371 A1 WO2024245371 A1 WO 2024245371A1 CN 2024096520 W CN2024096520 W CN 2024096520W WO 2024245371 A1 WO2024245371 A1 WO 2024245371A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
disease
compound
carbon atoms
heterocyclic ring
Prior art date
Application number
PCT/CN2024/096520
Other languages
English (en)
French (fr)
Inventor
单永强
吕志良
冯腾
Original Assignee
上海复宏汉霖生物技术股份有限公司
上海复宏汉霖生物医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海复宏汉霖生物技术股份有限公司, 上海复宏汉霖生物医药有限公司 filed Critical 上海复宏汉霖生物技术股份有限公司
Publication of WO2024245371A1 publication Critical patent/WO2024245371A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • AMX0035 is designed to target the endoplasmic reticulum (ER) and mitochondria of motor neurons in ALS. The endoplasmic reticulum and mitochondria are connected by mitochondrial membranes, and both play a key role in maintaining neuronal survival.
  • Parkinson’s disease is multifactorial, caused by genetics, environment, or a combination of both (Bloem, Okun, and Klein, “Parkinson’s Disease.”).
  • Parkinson’s disease is classified into two forms: sporadic (late-onset) and familial (early-onset) (Ryan et al., “Mitochondrial Dysfunction and Mitophagy in Parkinson’s.”). Epidemiological studies have shown that familial Parkinson’s disease accounts for only a minority of Parkinson’s disease patients, while the vast majority of Parkinson’s disease patients are sporadic Parkinson’s disease patients (Zeng, Geng, and Jia, “Neurotoxin-Induced Animal Models of Parkinson’s Disease.”).
  • PD treatments include levodopa, dopamine agonists, monoamine oxidase (MAO) inhibitors, and amantadine, which aim to improve symptoms and slow disease progression.
  • MAO monoamine oxidase
  • amantadine which aim to improve symptoms and slow disease progression.
  • none of these treatments can completely cure the disease and they also have some side effects.
  • the present invention relates to the following technical solutions:
  • the present application relates to a combination product comprising:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy, wherein the hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl and phenyl;
  • R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
  • R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
  • the molar ratio of component (a) to component (b) is 1:1000-1000:1.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein;
  • the molar ratio of component (a) to component (b) is 1:1000-1000:1.
  • the present invention relates to an acid-base addition salt of formula (II):
  • a + is a cationic portion of a compound of formula (I);
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein;
  • B- is an anionic moiety of a bile acid or a derivative or an analog thereof.
  • the invention relates to a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any of the preceding embodiments, for use in improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by active oxidative metabolites in the cells, regulating redox homeostasis in the cells or reducing mitochondrial dysfunction in the cells.
  • the invention relates to a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments for use in treating, alleviating and/or preventing neurodegenerative diseases or disorders.
  • the present invention relates to a method for improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by active oxidative metabolites in the cells, regulating redox homeostasis in the cells or reducing mitochondrial dysfunction in the cells, comprising contacting the cells with a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present invention relates to a method for treating, alleviating and/or preventing a neurodegenerative disease or disorder, comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present invention relates to a kit comprising:
  • the kit is used for treating and/or preventing neurodegenerative diseases or disorders.
  • Figure 1 Describes the effects of compound Y, compound T, compound B, compound N, compound combination Y+T, compound combination B+N, compound combination PB+T and new salt of YT on the viability of SH-sy5y cells induced by hydrogen peroxide.
  • the control group is a cell culture group without any drug or H 2 O 2 stimulation; the model group is a cell culture group without any drug but stimulated by H 2 O 2.
  • DMSO is a cell culture group without any drug or H 2 O 2 stimulation but only DMSO is added.
  • the concentration of compound Y was 100 ⁇ M; the concentration of compound T was 100 ⁇ M; the concentration of compound B was 100 ⁇ M; the concentration of compound N was 100 ⁇ M; the concentration of compound combination Y+T was 100 ⁇ M (compound Y) + 100 ⁇ M (compound T); the concentration of compound combination B+N was 100 ⁇ M (compound B) + 100 ⁇ M (compound N); the concentration of compound combination PB+T was 500 ⁇ M (compound T) + 200 ⁇ M (compound PB); the concentration of YT salt was 100 ⁇ M. All drug administration groups were stimulated and induced with H 2 O 2. Data are presented as mean ⁇ SEM.
  • Figure 2 Describes the effects of compound Y, compound T, compound combination Y+T, YT salt and compound UDCA (U) on CD4 positive T cell proliferation.
  • concentration of YT salt is 100 ⁇ M, which is equivalent to the same proportion of compound Y concentration of 100 ⁇ M, compound T concentration of 100 ⁇ M, compound combination Y+T concentration of 100 ⁇ M (compound Y) + 100 ⁇ M (compound T), and compound U concentration of 100 ⁇ M.
  • Figure 3 Describes the effects of compound Y, compound T, compound combination Y+T, YT salt and compound UDCA (U) on CD8 positive T cell proliferation.
  • concentration of YT salt is 100 ⁇ M, which is equivalent to the same proportion of compound Y concentration of 100 ⁇ M, compound T concentration of 100 ⁇ M, compound combination Y+T concentration of 100 ⁇ M (compound Y) + 100 ⁇ M (compound T), and compound U concentration of 100 ⁇ M.
  • Figure 4 describes the effect of YT salt on the pathogenesis of ALS model mice with SOD1 G93A mutation.
  • the model group was not given any drug treatment, and the YT salt group was given a dose of 496 mg/kg (administered intragastrically once a day). Log-rank test was used for data analysis, and P ⁇ 0.05 indicated statistical differences between different groups.
  • Figure 5 Describes the effect of YT salt on the occurrence of severe disease in ALS model mice with SOD1 G93A mutation.
  • the model group was not given any drug treatment, and the YT salt group was given a dose of 496 mg/kg (administered once a day by gavage). Log-rank test was used for data analysis, and P ⁇ 0.05 indicated statistical differences between different groups.
  • Figure 6 Describes the effect of YT salt on the survival of ALS model mice with SOD1 G93A mutation.
  • the model group was not given any drug treatment, and the YT salt group was given a dose of 496 mg/kg (administered once a day by oral gavage). Log-rank test was used for data analysis, and P ⁇ 0.05 indicated statistical differences between different groups.
  • Figure 7 Describes the effect of YT salt on the grip strength of MPTP-induced Parkinson's mouse model.
  • the sham operation group was C57BL/6 mice intraperitoneally injected with 10mL/kg normal saline; the model group was C57BL/6 mice intraperitoneally injected with 30mg/kg of MPTP, and no drug treatment was given;
  • the L-DOPA group was the positive drug control group, and the model mice were given 40mg/kg L-DOPA (gavage twice a day) for treatment;
  • the low-dose YT salt group was given 167.5mg/kg YT salt (gavage twice a day) in the model mice;
  • the high-dose YT salt group was given 248mg/kg YT salt (gavage twice a day) in the model mice.
  • the data in the figure are expressed as mean ⁇ standard error.
  • P ⁇ 0.05 indicates statistical significance, * indicates P ⁇ 0.05, ** indicates P ⁇ 0.01, *** indicates P
  • Figure 8 Describes the effect of YT salt on the MPTP-induced Parkinson's mouse model rotarod test, evaluating the time it takes for the animal to maintain balance on the rotarod until it falls to the ground.
  • the sham operation group was C57BL/6 mice injected intraperitoneally with 10 mL/kg normal saline; the model group was C57BL/6 mice injected intraperitoneally with 30 mg/kg of MPTP, and no drug treatment was given; the L-DOPA group was the positive drug control group, and the model mice were given 40 mg/kg L-DOPA (gavage twice a day) for treatment; the low-dose YT salt group was given 167.5 mg/kg YT salt (gavage twice a day) in the model mice; the high-dose YT salt group was given 248 mg/kg YT salt (gavage twice a day) in the model mice.
  • the data in the figure are expressed as mean ⁇ standard error.
  • P ⁇ 0.05 indicates statistical significance
  • Figure 9 Describes the effect of YT salt on the number of TH-positive cells in the substantia nigra of the MPTP-induced Parkinson's mouse model.
  • the sham operation group was C57BL/6 mice intraperitoneally injected with 10 mL/kg saline; the model group was C57BL/6 mice intraperitoneally injected with 30 mg/kg of MPTP, and no drug treatment was given; the L-DOPA group was the positive drug control group, and the model mice were given 40 mg/kg L-DOPA (gavage twice a day) for treatment; the low-dose YT salt group was given 167.5 mg/kg YT salt (gavage twice a day) in the model mice; the high-dose YT salt group was given 248 mg/kg YT salt (gavage twice a day) in the model mice.
  • the data in the figure are expressed as mean ⁇ standard error. P ⁇ 0.05 indicates statistical significance, **** indicates P ⁇ 0.0001.
  • Figure 10 Describes the effect of YT salt on the percentage of TH-positive cells in the striatum of the MPTP-induced Parkinson's mouse model.
  • the sham operation group was C57BL/6 mice intraperitoneally injected with 10 mL/kg saline; the model group was C57BL/6 mice intraperitoneally injected with 30 mg/kg of MPTP, and no drug treatment was given; the L-DOPA group was the positive drug control group, and the model mice were given 40 mg/kg L-DOPA (gavage twice a day) for treatment; the low-dose YT salt group was given 167.5 mg/kg YT salt (gavage twice a day) in the model mice; the high-dose YT salt group was given 248 mg/kg YT salt (gavage twice a day) in the model mice.
  • the data in the figure are expressed as mean ⁇ standard error.
  • P ⁇ 0.05 indicates statistical significance, ** indicates P ⁇ 0.01, and **** indicates P ⁇ 0.0001.
  • Figure 11 Describes the effect of YT salt on the number of wrong steps in the grid walking test of 6-OHDA-induced Parkinson's rats.
  • the sham operation group is SD rats without modeling treatment;
  • the model group is SD rats injected with 4 ⁇ L 6-OHDA (5 ⁇ g/ ⁇ L) into the right cranial (medial forebrain bundle, MFB) and no drug treatment is given;
  • the Istradefylline group is the positive drug control group, and the model rats are given 10mg/kg Istradefylline (administered orally once a day) for treatment;
  • the YT salt administration group is the model rats given 248mg/kg YT salt (administered orally once a day).
  • the data in the figure are expressed as mean ⁇ standard error (SEM).
  • P ⁇ 0.05 indicates statistical significance, and * indicates P ⁇ 0.05.
  • Figure 12 Describes the effect of YT salt on the wrong step rate in the grid walking test of 6-OHDA-induced Parkinson's rats.
  • the sham operation group was injected with 4 ⁇ L (0.2mg/mL) ascorbic acid solution into the right cranial (medial forebrain bundle, MFB) of SD rats;
  • the model group was injected with 4 ⁇ L 6-OHDA (5 ⁇ g/ ⁇ L) into the right cranial MFB of SD rats to establish the model, and no drug treatment was given;
  • the Istradefylline group was the positive drug control group, and the model rats were given 10mg/kg Istradefylline (administered once a day by gavage) for treatment;
  • the YT salt administration group was given 248mg/kg YT salt (administered once a day by gavage) in the model rats.
  • the data in the figure are expressed as mean ⁇ standard error.
  • P ⁇ 0.05 indicates statistical significance
  • * indicates P ⁇
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 10 carbon atoms, and most preferably an alkyl group containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • lower alkyl groups having 1 to 6 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.
  • alkoxy refers to -O-(alkyl) and -O-(cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.
  • groups which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio,
  • halo and halogen refer to fluoro, chloro, bromo, and iodo.
  • haloalkyl by itself or as part of another substituent refers to an alkyl group in which some or all of the hydrogen atoms are replaced by halogen atoms.
  • alkyl haloalkyl can have any suitable number of carbon atoms, such as C1-6.
  • haloalkyl includes trifluoromethyl, fluoromethyl, etc.
  • perfluoro can be used to define a compound or group in which all hydrogens are replaced by fluorine.
  • perfluoromethyl refers to 1,1,1-trifluoromethyl.
  • hydroxy refers to an -OH moiety
  • the present invention also includes various deuterated forms of formula (I). Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated forms of formula (I), or they can be synthesized using deuterated reagents using conventional techniques, and non-limiting examples of deuterated reagents include: deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • “Pharmaceutically acceptable” means that the components are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the term "pharmaceutically acceptable salt” refers to a pharmaceutically acceptable organic or inorganic salt of a compound when used herein.
  • Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, hydrochlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisates, fumarates, gluconates, glucuronates, sugarates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., s
  • Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as acetate ions, succinate ions, or other counterions.
  • Counterions may be any organic or inorganic module that stabilizes the charge of the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. In the case where multiple charged atoms are components of a pharmaceutically acceptable salt, multiple counterions may be present.
  • a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.
  • acid anion refers to an anion produced when an acid is ionized.
  • Common acid anions include chloride, bromide, iodide, carbonate, bicarbonate, sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, formate, acetate, and the like.
  • the acid anion can be -1, -2, -3, -4, and the like.
  • the term "pharmaceutically acceptable carrier” refers to a conventional non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation adjuvant or carrier in the art used with a therapeutic agent, which together constitutes a "pharmaceutical composition" for administration to an individual.
  • a pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration employed and is compatible with the other ingredients of the formulation.
  • a pharmaceutically acceptable carrier is suitable for the formulation employed.
  • pharmaceutically acceptable excipient refers to a substance that facilitates administration of an active agent to an individual.
  • useful pharmaceutical excipients include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coating agents, sweeteners, flavoring agents, and coloring agents.
  • the compounds of the present invention may contain one or more asymmetric centers.
  • Asymmetric carbon atoms may exist in (R)- and/or (S)- configurations, resulting in racemic mixtures in the case of a single asymmetric center, and in the case of multiple asymmetric centers, resulting in diastereomeric mixtures.
  • the substituents on the ring may also exist in cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention.
  • Preferred compounds are those that produce more desired biological activity.
  • the separation, pure or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures are included within the scope of the present invention.
  • the purification and separation of such substances can be achieved by standard techniques known in the art.
  • Tautomers sometimes called proton-shift tautomers, are two or more compounds related by the migration of a hydrogen atom, accompanied by a switch of one or more single bonds and one or more adjacent double bonds.
  • the compounds of the present invention may exist in one or more tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the present invention.
  • Isotopic variants of the compounds of the present invention are defined as compounds of the present invention in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass commonly or primarily found in nature.
  • Certain isotopic variants of the compounds of the present invention for example, those in which one or more radioactive isotopes (e.g., 3 H or 14 C) are introduced, can be used for drug and/or substrate tissue distribution studies.
  • Isotopic variants of the compounds of the invention can generally be prepared using conventional methods known to those skilled in the art, for example, using the preparation methods described in the illustrative methods or in the examples below, using suitable isotopic variants of suitable reagents.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers or any mixture of said stereoisomers in any ratio.
  • the separation of single stereoisomers, such as single enantiomers or single diastereomers, of the compounds of the present invention can be achieved by any suitable prior art method, such as chromatography, in particular, such as chiral chromatography.
  • the present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers in any ratio.
  • solvate refers to a compound of the present invention that forms a pharmaceutically acceptable solvate with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate, etc. Hydrate is a specific form of solvate in which the solvent is water.
  • the terms "effective amount” and “therapeutically effective amount” refer to a dosage of a compound, such as a compound, compound combination, or salt form of the present invention, that produces the therapeutic effect for which it is administered.
  • the exact dosage will depend on the purpose of the treatment, and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.
  • treatment is a method for obtaining beneficial or desired results (including clinical results).
  • beneficial or desired clinical results include but are not limited to one or more of the following: alleviating one or more symptoms caused by the disease, reducing the degree of the disease, stabilizing the disease (for example, preventing or delaying the deterioration of the disease), preventing or delaying the spread of the disease (for example, metastasis), preventing or delaying the recurrence of the disease, delaying or slowing down the progress of the disease, improving the disease state, providing the alleviation of the disease (partial or complete), reducing the dosage of one or more other drugs required for the treatment of the disease, delaying the progress of the disease, increasing or improving the quality of life, increasing weight gain and/or prolonging survival.”
  • treatment also encompasses the pathological consequences (such as, for example, tumor volume) of reducing cancer.
  • the method of the present application takes into account any one or more of these treatment aspects.
  • prevention includes providing protection against the occurrence or recurrence of a disease in an individual who may be susceptible to the disease but has not yet been diagnosed with the disease.
  • subject refers to mammals, including but not limited to humans, cows, horses, cats, dogs, rodents, or primates.
  • the individual is a human.
  • an “effective amount” of an agent is an amount effective to achieve the desired therapeutic or preventive result, at dosages and for periods of time necessary.
  • the specific dosage may vary depending on one or more of the following: the particular agent selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.
  • the term “synergistic” or “synergistic” is used to refer to a combination of two compounds, components, or targeting agents that results in a greater than the sum of the individual agents together.
  • the term “synergistic” or “synergistic” means that the disease condition or disorder being treated is improved compared to the use of each compound, component, or targeting agent alone. This improvement in the disease condition or disorder being treated is a “synergistic effect.”
  • a “synergistic amount” is the amount of a combination of two compounds, components, or targeting agents that results in a synergistic effect (“synergistic" as defined herein).
  • Determining the synergistic interaction between one or both components, the optimal range of the effect, and the absolute dosage range of each component for the effect can be explicitly measured by administering the components within different w/w ratio ranges and dosages to patients in need of treatment.
  • observing synergy in in vitro or in vivo models can predict the effect in humans and other species and existing in vitro or in vivo models as described herein to measure synergistic effects, and the results of such studies can also be used to predict the effective dose and plasma concentration ratio range required in humans and other species, as well as absolute doses and plasma concentrations, by applying pharmacokinetic/pharmacodynamic methods.
  • references herein to "about” a value or parameter include (and describe) variations with respect to that value or parameter itself. For example, description referring to "about X” includes description of "X”.
  • the term "about” when modifying the quantity of an ingredient or reactant of the invention refers to variations in the numerical amount that may occur, for example, in typical measurements and liquid handling procedures used to prepare concentrates or actual use solutions; accidental errors in these procedures; differences in the manufacture, source, or purity of the ingredients used to prepare the composition or implement the method; etc.
  • the term “about” also includes amounts that differ due to different equilibrium conditions relative to the composition obtained from a particular starting mixture. Whether or not modified by the term “about”, the claims include equivalent amounts of the amount.
  • the term “about” means within 10% of the reported value, preferably within 5% of the reported value.
  • the present disclosure provides a combination product comprising:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy, wherein the hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl and phenyl;
  • R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
  • R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
  • component (b) bile acid or its derivative or analogue or its pharmaceutically acceptable salt, solvate, hydrate or stereoisomer; wherein the molar ratio of component (a) to component (b) is 1:1000-1000:1.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxy, methoxy and benzyloxy, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.
  • one or two of R 1 , R 2 and R 3 are hydrogen, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 5 membered heterocyclic ring containing one or more oxygen atoms.
  • one of R 1 , R 2 and R 3 is hydrogen, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 5 membered heterocyclic ring containing two oxygen atoms.
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxyl and methoxy, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.
  • one or two of R 4 , R 5 and R 6 are hydrogen, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.
  • one of R 4 , R 5 and R 6 is hydrogen, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.
  • the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate.
  • 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.
  • the compound of formula (I) is selected from:
  • the bile acid or its derivative or analogue is selected from: cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid and tauroursodeoxycholic acid, etc.
  • the molar ratio of component (a) to component (b) is 1:100-100: 1.
  • the molar ratio of component (a) to component (b) is 1:90-90: 1, 1:80-80: 1, 1:70-70: 1, 1:60-60: 1, 1:50-50: 1, 1:40-40: 1, 1:30-30: 1, 1:20-20: 1, 1:10-10: 1.
  • 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 a value between any two thereof.
  • the combination product is used to improve cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by reactive oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.
  • the combination product is used to treat, alleviate and/or prevent neurodegenerative diseases or disorders.
  • 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).
  • the neurodegenerative disease or condition is selected from Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).
  • the present disclosure provides a pharmaceutical composition comprising:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy, wherein the hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl and phenyl;
  • R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
  • R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
  • the molar ratio of component (a) to component (b) is 1:1000-1000:1.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxy, methoxy and benzyloxy, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.
  • one or two of R 1 , R 2 and R 3 are hydrogen, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 5 membered heterocyclic ring containing one or more oxygen atoms.
  • one of R 1 , R 2 and R 3 is hydrogen, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 5 membered heterocyclic ring containing two oxygen atoms.
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxyl and methoxy, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.
  • one or two of R 4 , R 5 and R 6 are hydrogen, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.
  • one of R 4 , R 5 and R 6 is hydrogen, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.
  • the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate.
  • 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.
  • the compound of formula (I) is selected from:
  • the bile acid or its derivative or analogue is selected from: cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid and tauroursodeoxycholic acid, etc.
  • the molar ratio of component (a) to component (b) is 1:100-100: 1.
  • the molar ratio of component (a) to component (b) is 1:90-90: 1, 1:80-80: 1, 1:70-70: 1, 1:60-60: 1, 1:50-50: 1, 1:40-40: 1, 1:30-30: 1, 1:20-20: 1, 1:10-10: 1.
  • 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 a value between any two thereof.
  • the pharmaceutical composition is used to improve cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by active oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.
  • the pharmaceutical composition is used to treat, alleviate and/or prevent neurodegenerative diseases or disorders.
  • the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular atrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia.
  • the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).
  • the present disclosure provides an acid-base addition salt of formula (II):
  • a + is a cationic portion of a compound of formula (I);
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy, wherein the hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy are optionally substituted with one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl and phenyl,
  • R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N,
  • R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
  • B- is an anionic moiety of a bile acid or a derivative or an analog thereof.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxy, methoxy and benzyloxy, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.
  • one or two of R 1 , R 2 and R 3 are hydrogen, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 5 membered heterocyclic ring containing one or more oxygen atoms.
  • one of R 1 , R 2 and R 3 is hydrogen, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 5 membered heterocyclic ring containing two oxygen atoms.
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxyl and methoxy, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.
  • one or two of R 4 , R 5 and R 6 are hydrogen, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.
  • one of R 4 , R 5 and R 6 is hydrogen, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.
  • the cationic portion of the compound of formula (I) is selected from the group consisting of:
  • component (b) is an anionic portion selected from the group consisting of cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid and tauroursodeoxycholic acid, etc.
  • C - is a monovalent, divalent, trivalent, tetravalent acid anion or a mixture thereof.
  • C - is a monovalent, divalent or trivalent acid anion or a mixture thereof. More preferably, C - is a monovalent or divalent acid anion or a mixture thereof. Most preferably, C - is a monovalent acid anion or a mixture thereof.
  • n is 1, and p is 0, or m is 2, n is 1, and p is 1.
  • the pharmaceutical composition is used to improve cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by active oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.
  • the pharmaceutical composition is used to treat, alleviate and/or prevent neurodegenerative diseases or disorders.
  • the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular atrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia and frontotemporal dementia.
  • the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS).
  • the present disclosure provides a method for treating, alleviating and/or preventing a neurodegenerative disease or condition.
  • the method for treating, alleviating and/or preventing a neurodegenerative disease or condition comprises administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the foregoing embodiments.
  • the present disclosure provides a method for treating, alleviating and/or preventing Alzheimer's disease (AD), comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • AD Alzheimer's disease
  • the present disclosure provides a method for treating, alleviating and/or preventing Huntington's disease (HD), comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • a method for treating, alleviating and/or preventing Huntington's disease (HD) comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present disclosure provides a method for treating, alleviating and/or preventing Parkinson's disease (PD), comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • PD Parkinson's disease
  • the present disclosure provides a method for treating, alleviating and/or preventing amyotrophic lateral sclerosis (ALS), comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • ALS amyotrophic lateral sclerosis
  • the present disclosure provides a method for treating, alleviating and/or preventing Pick's disease, comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present disclosure provides a method for treating, alleviating and/or preventing multi-infarct dementia, comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present disclosure provides a method for treating, alleviating and/or preventing Creutzfeldt-Jakob disease, comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present disclosure provides a method for treating, alleviating and/or preventing dementia with Lewy bodies (DLB), comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • DLB dementia with Lewy bodies
  • the present disclosure provides a method for treating, alleviating and/or preventing mixed dementia, comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present disclosure provides a method for treating, alleviating and/or preventing frontotemporal dementia, comprising administering to a patient in need thereof a combination product, a pharmaceutical composition, an acid-base addition salt, or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present disclosure provides a method of treating and/or preventing a neurodegenerative disease or disorder, comprising: Scheme 1, administering to a patient in need thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy, wherein the hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy are optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl and phenyl, or any two adjacent ones of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N,
  • R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N; or,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy, wherein the hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy are optionally substituted by one or more groups selected from the group consisting of halogen, C 1 -C 6 alkyl and phenyl, or any two adjacent ones of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N,
  • R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more heteroatoms selected from O, S or N;
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, hydroxy, methoxy and benzyloxy, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.
  • one or two of R 1 , R 2 and R 3 are hydrogen, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 5 membered heterocyclic ring containing one or more oxygen atoms.
  • one of R 1 , R 2 and R 3 is hydrogen, or any two adjacent groups of R 1 , R 2 and R 3 together with the carbon atoms to which they are attached form a 5 membered heterocyclic ring containing two oxygen atoms.
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxyl and methoxy, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 4-7 membered heterocyclic ring containing one or more oxygen atoms.
  • one or two of R 4 , R 5 and R 6 are hydrogen, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing one or more oxygen atoms.
  • one of R 4 , R 5 and R 6 is hydrogen, or any two adjacent groups of R 4 , R 5 and R 6 together with the carbon atoms to which they are attached form a 5-membered heterocyclic ring containing two oxygen atoms.
  • the pharmaceutically acceptable salt of the compound of formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate.
  • 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.
  • the compound of formula (I) is selected from:
  • the bile acid or its derivative or analogue is selected from: cholic acid, obeticholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iodocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, 24-demethylursodeoxycholic acid and tauroursodeoxycholic acid, etc.
  • the molar ratio of component (a) to component (b) is 1:100-100: 1.
  • the molar ratio of component (a) to component (b) is 1:90-90: 1, 1:80-80: 1, 1:70-70: 1, 1:60-60: 1, 1:50-50: 1, 1:40-40: 1, 1:30-30: 1, 1:20-20: 1, 1:10-10: 1.
  • 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 a value between any two thereof.
  • the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.
  • AD Alzheimer's disease
  • HD Huntington's disease
  • PD Parkinson's disease
  • ALS amyotrophic lateral sclerosis
  • sarcopenia muscular dystrophy
  • Pick's disease multi-infarct dementia
  • Creutzfeldt-Jakob disease dementia with Lewy bodies (DLB)
  • mixed dementia dementia with Lewy bodies
  • frontotemporal dementia preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS).
  • the present disclosure provides a method for improving cell viability, in particular neuronal cell viability, in particular by reducing oxidative damage mediated by active oxidative metabolites in the cells, regulating redox homeostasis in the cells, or reducing mitochondrial dysfunction in the cells, comprising contacting the cells with a combination product, pharmaceutical composition, acid-base addition salt, or compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof according to any one of the preceding embodiments.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, which is used to improve cell viability, especially neuronal cell viability, especially by reducing oxidative damage mediated by active oxidative metabolites in cells, regulating redox homeostasis in cells or reducing mitochondrial dysfunction in cells.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof for use in treating, ameliorating and/or preventing a neurodegenerative disease or disorder.
  • the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.
  • AD Alzheimer's disease
  • HD Huntington's disease
  • PD Parkinson's disease
  • ALS amyotrophic lateral sclerosis
  • sarcopenia muscular dystrophy
  • Pick's disease multi-infarct dementia
  • Creutzfeldt-Jakob disease dementia with Lewy bodies (DLB)
  • mixed dementia dementia with Lewy bodies
  • frontotemporal dementia frontotemporal dementia
  • Administration of the compounds or salt forms of the combinations of the present invention may be effected by any method capable of delivering the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.
  • the compound or salt form of the method or combination of the present invention can be formulated before administration.
  • the preparation will be suitable for a specific mode of administration.
  • These compounds can be formulated with pharmaceutically acceptable carriers known in the art and administered in a variety of dosage forms known in the art.
  • the active ingredient is usually mixed with a pharmaceutically acceptable carrier, or diluted or encapsulated in a carrier with a carrier.
  • Such carriers include, but are not limited to, solid diluents or fillers, excipients, sterile aqueous media, and various non-toxic organic solvents.
  • Dosage unit forms or pharmaceutical compositions include tablets, capsules such as gelatin capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, lozenges, lozenges, hard candies, sprays, creams, ointments, suppositories, pectins, gels, pastes, lotions, ointments, injections, elixirs, syrups, and parenteral solutions packaged in containers suitable for subdividing into individual doses.
  • Parenteral formulations include pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, emulsions and sterile powders (for their preparation).
  • carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils and injectable organic esters, such as ethyl oleate. Fluidity can be maintained by using a coating such as lecithin, a surfactant or maintaining an appropriate particle size.
  • Exemplary parenteral administration forms include solutions or suspensions of the compounds of the invention in sterile aqueous solutions, such as propylene glycol aqueous solutions or dextrose solutions. Such dosage forms may be appropriately buffered if necessary.
  • lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of similar type may also be used in soft and hard-filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compounds therein may be combined with various sweeteners or flavorings, colorants or dyes, and, if desired, emulsifiers or suspending agents, and diluents such as water, ethanol, propylene glycol, glycerol or a combination thereof.
  • the present disclosure provides a kit for treating, alleviating and/or preventing a neurodegenerative disease or disorder, comprising a combination product according to any one of the foregoing embodiments, an acid-base addition salt, a pharmaceutical composition or a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof and instructions for use of the therapeutic agent.
  • the instructions for use detail and define the mode of administration of the therapeutic agent, for example, for simultaneous, joint, separate or sequential administration of the therapeutic agent of the present invention.
  • the instructions for use detail and define the mode of administration of the therapeutic agent for example, by specifying the number of days for administration of each therapeutic agent during a specific period of time to detail and define the mode of administration of the therapeutic agent.
  • the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), sarcopenia, muscular dystrophy, Pick's disease, multi-infarct dementia, Creutzfeldt-Jakob disease, dementia with Lewy bodies (DLB), mixed dementia, and frontotemporal dementia.
  • AD Alzheimer's disease
  • HD Huntington's disease
  • PD Parkinson's disease
  • ALS amyotrophic lateral sclerosis
  • sarcopenia muscular dystrophy
  • Pick's disease multi-infarct dementia
  • Creutzfeldt-Jakob disease dementia with Lewy bodies (DLB)
  • mixed dementia dementia with Lewy bodies
  • frontotemporal dementia preferably, the neurodegenerative disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS).
  • berberine hydrochloride compound B
  • ursodeoxycholic acid compound U
  • tauroursodeoxycholic acid compound T
  • Neuroblastoma SH-sy5y cells were purchased from the Cell Bank of the Chinese Academy of Sciences.
  • LC-MS Unless otherwise stated, the analytical LC-MS system used consisted of a Shimadzu LCMS-2020 with electrospray ionization (ESI) in positive ion detection mode, with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20APDA detector, and an LCMS2020MS detector.
  • the column was HALO, i.e., C18 30 mm ⁇ 5.0 mm, 2.7 ⁇ m.
  • Mobile phase A was water containing 0.05% TFA
  • mobile phase B was acetonitrile containing 0.05% TFA.
  • the gradient was set as follows: from 5% mobile phase B to 100% (95%) in 2.0 minutes, held for 0.7 minutes, then returned to 5% mobile phase B in 0.05 minutes and held for 0.25 minutes.
  • the column oven (CTO-20AC) was operated at 40.0°C.
  • the flow rate was 1.5 mL/min and the injection volume was 1 ⁇ L.
  • the PDA (SPD-M20A) detection range was 190 nm to 400 nm.
  • MS detector which was configured with electrospray ionization as the ionizable source; acquisition mode: scanning; nebulizing gas flow rate: 1.5 L/min; drying gas flow rate: 15 L/min; detector voltage: tuning voltage ⁇ 0.2 kv; DL temperature: 250°C; heating block temperature: 250°C; scanning range: 90.00 m/z to 900.00 m/z.
  • ELSD Alltech 3300 detector parameters: drift tube temperature: 60 ⁇ 5°C; N2 flow rate: 1.8 ⁇ 0.2 L/min. The mobile phase gradient was optimized for each compound. The calculated mass corresponds to the exact mass.
  • Preparative HPLC Unless otherwise stated, preparative HPLC purification was performed with a Waters Auto purification system (2545-2767) with a 2489 UV detector.
  • the column was selected from one of the following: Waters C18, 19 mm ⁇ 150 mm, 5 ⁇ m; XBridge Prep OBD C18 column, 30 mm ⁇ 150 mm, 5 ⁇ m; XSelect CSH Prep C18 OBD column, 5 ⁇ m, 19 mm ⁇ 150 mm; XBridge Shield RP18 OBD column, 30 mm ⁇ 150 mm, 5 ⁇ m; Xselect CSH fluorophenyl, 30 mm ⁇ 150 mm, 5 ⁇ m; or YMC-Actus Triart C18, 30 mm ⁇ 150 mm, 5 ⁇ m.
  • the mobile phase consisted of a mixture of acetonitrile (5%-95%) in an aqueous solution containing 0.1% FA or 10 mmol/L NH 4 HCO 3 .
  • the flow rate was maintained at 25 mL/min, the injection volume was 1200 ⁇ L, and the UV detector used two channels, 254 nm and 220 nm.
  • the mobile phase gradient was optimized for each compound.
  • Chiral analytical chromatography was performed on one of the following items: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.), (R, R)-Whelk-O1, (S, S)-Whelk-O1 columns (Regis technologies, Inc.), CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.); different column sizes (50mm ⁇ 4.6mm, 100mm ⁇ 4.6mm, 150mm ⁇ 4.6mm, 250mm ⁇ 4.6mm, 50mm ⁇ 3.0mm, 100mm ⁇ 3.0mm), ethanol percentage in hexane (%Et/Hex) or isopropanol percentage in hexane (%IPA/Hex) as an isocratic solvent system, or using supercritical fluid (SFC) conditions.
  • SFC supercritical fluid
  • Normal phase flash chromatography Unless otherwise stated, normal phase flash column chromatography (FCC) was performed on silica gel with prepacked silica gel columns using EtOAc/hexane, EtOAc/petroleum ether (bp 60-90°C), CH2Cl2 / MeOH or CH2Cl2 /10% 2N NH3 in MeOH as eluents.
  • FCC normal phase flash column chromatography
  • 1H NMR spectra were obtained using a 400 MHz spectrometer (or 300 MHz spectrometer) in DMSO-d 6 solution.
  • Nuclear magnetic resonance (NMR) spectral features refer to chemical shifts ( ⁇ ) expressed in parts per million (ppm).
  • Tetramethylsilane (TMS) was used as an internal standard in DMSO-d 6 solution, and residual CH 3 OH peak or TMS was used as an internal standard in CD 3 OD solution.
  • Coupling constants (J) are reported in Hertz (Hz).
  • LAH (2.5M, 1.00L) was added dropwise to a solution of 1,3-Benzodioxole-5-acetic acid (500g, 2.78mol) in THF (200mL) at 0°C, and the mixture was stirred at 25°C for 12 hours under N2 atmosphere.
  • the mixture was cooled to -10-0°C, and then H2O (95..0mL), NaOH (15%, 95.0mL), and H2O (285mL) were added in sequence.
  • Na2SO4 500g was added to the mixture, and stirred at 25°C for 0.5 hours.
  • the mixture was filtered, and the filter cake was washed with THF (5.00L). The filtrate was collected and concentrated.
  • the title compound (460g, 2.77mol, 99.7% yield) was obtained as a yellow oil.
  • YT salt Compound Y and compound T were suspended in a mixed solvent of methanol/ethyl acetate (isopropyl acetate) (v/v: 1/9) and stirred for 24 hours, and more solids were suspended in the system. The solids were obtained by filtration and dried to obtain the YT salt form.
  • Characterization of YT salt The ion ratio of Y and T in YT salt is 1:1.
  • Example 3 Effects of compound Y alone (Y), compound T alone (T), compound B alone (B), compound N alone (N), compound combination Y+T, compound combination B+N, compound combination PB+T, and new salt YT on the viability of the cell line SH-sy5y induced by hydrogen peroxide.
  • Neuroblastoma SH-sy5y cells purchased from the Cell Bank of the Chinese Academy of Sciences were cultured in a complete medium DMEM + 10% FBS + 1% PS in a cell culture incubator at 37°C and 5% CO 2. The experiment was divided into 11 groups:
  • Group 3 SH-sy5y cells + hydrogen peroxide + compound Y (100 ⁇ M)
  • Group 8 SH-sy5y cells + hydrogen peroxide + compound combination B + N (100 ⁇ M + 100 ⁇ M)
  • Neuroblastoma SH-sy5y cells were plated at 1 ⁇ 10 4 cells/well in complete medium DMEM+10% FBS+1% PS and cultured in a cell culture incubator at 37°C and 5% CO 2 for 24 hours, and then the corresponding compounds were added. After incubation for 24 hours, hydrogen peroxide was added for stimulation for 1 hour, and the final concentration of hydrogen peroxide was 350 ⁇ M. Then, 50 (CTG) reagent, shake for 2 minutes, and then detect its luminescent signal value, and its luminescent signal value can represent the cell viability.
  • CCG 50
  • compound Y alone (column 3) has an excellent effect on improving cell viability (P ⁇ 0.0001), and the effect of compound Y alone (column 3) is better than that of compound B alone (column 5);
  • compound T alone (column 4), compound B alone (column 5), compound combination B+N (column 8), and compound combination PB+T (column 9), compound combination Y+T (column 7) and YT salt (column 10) have significantly excellent effects in improving cell viability, indicating that the effects of compound combination Y+T and YT salt on the repair of oxidative stress damage of nerve cells are significantly better than compound T alone, compound B alone, compound combination B+N and compound combination PB+T, among which compound combination PB+T refers to the concentrations of compound PB and compound T in the data of the marketed drug AMX0035 (David L.
  • Example 4 Effects of Compound Y alone, Compound T alone, Compound combination Y+T, and YT salt on the proliferation of CD4-positive and CD8-positive T cells
  • ALS Th cells have been described as major players in inflammation and disease progression.
  • CD4 T cell infiltration was observed in the spinal cord adjacent to degenerative areas of ALS patients.
  • CD8 T cell infiltration was observed in the spinal cord and brain of ALS patients.
  • PBMCs peripheral blood mononuclear cells
  • CD4 positive T cells refer to positive cells stained with anti-CD45-PerCPCy5.5 and anti-CD4-AF700 dyes
  • CD8 positive T cells refer to positive cells stained with anti-CD45-PerCPCy5.5 and anti-CD8-FITC dyes.
  • the proliferation of CD4-positive and CD8-positive T cells was determined by fluorescence of Celltrace dye.
  • YT salt and compound combination Y+T have a significant inhibitory effect on the proliferation of CD4-positive and CD8-positive T cells derived from human PBMC induced by Anti-CD3/CD28, and their effects are significantly better than compound T and compound U (UDCA); indicating that YT salt and compound combination Y+T have the potential to inhibit the infiltration or proliferation of immune cells in neurodegenerative diseases.
  • YT salt The therapeutic effect of YT salt on the survival status of ALS animals was evaluated in SOD1 G93A transgenic mice (B6SJL-Tg(SOD1*G93A)1/cyagen). 16 female and 14 male B6SJL-Tg(SOD1*G93A)1/cyagen mice were selected and randomly divided into 2 groups (7 males + 8 females/group) according to gender and weight, namely the model group (control) and the YT salt group (drug group). The YT salt was administered at a dose of 496 mg/kg, once a day by gavage. Drug administration began on the 66th day of mouse age, and weight changes were monitored, animal status and symptom severity were evaluated, and individual survival time was counted.
  • Statistics of animal symptom severity include the time of the first onset of the animal and the time when severe symptoms were first discovered.
  • first onset is defined as the starting point of ALS onset when the mouse shows circling, abnormal gait, or weakness and tremor of the front and rear limbs.
  • severe was defined as a state in which the animal was completely paralyzed and unable to move freely, but still alive; if the animal died directly after the onset of the disease without the "paralysis” stage, the death was considered to be a severe case.
  • the survival statistics were the time the animal survived at the end of the trial (day 130). The hazard ratio was calculated using the Log-rank test method.
  • YT salt has a tendency to delay the onset of disease, significantly reduce the incidence of severe disease, and prolong their survival compared with the model group. This suggests that YT salt has a potential preventive, alleviating or therapeutic effect on ALS.
  • mice Sixty C57BL/6 male mice were selected and randomly divided into 5 groups (12 mice/group), namely sham operation group (normal control), model group (model control), L-DOPA group (positive drug control, 40 mg/kg), YT salt low-dose group (167.5 mg/kg) and YT salt high-dose group (248 mg/kg).
  • MPTP was used to intraperitoneally inject mice with a dose of 30 mg/kg for 5 consecutive days.
  • YT salt was administered orally twice a day (7-8h interval between two administrations) for 13 consecutive days.
  • L-DOPA was administered twice a day (7-8h interval between two administrations) for 8 consecutive days.
  • the improvement effect of YT salt on the motor function of MPTP-induced Parkinson's mice was evaluated by behavioral indicators such as grip strength test and rotarod test.
  • the animals were subjected to histopathological examination to evaluate the protective effect of YT salt on dopaminergic neurons in MPTP-induced Parkinson's mice.
  • the results of the gripping force test showed that the gripping force of animals was significantly reduced after MPTP modeling (model group vs sham operation group, P ⁇ 0.0001), as shown in Figure 7.
  • the L-DOPA group and the high-dose YT salt group could significantly improve the MPTP-induced reduction in animal gripping force under the set treatment plan (L-DOPA group vs model group, P ⁇ 0.001; high-dose YT salt group vs model group, P ⁇ 0.01).
  • the results of the rotarod test showed that, as shown in Figure 8, after MPTP modeling, the median time on the rod in the rotarod test was reduced in the model group compared with the sham group.
  • the high-dose YT salt group had a significant improvement on the MPTP-induced reduction in the rod time of animals under the set treatment plan (high-dose YT salt group vs model group, P ⁇ 0.05).
  • TH tissue immunostaining in the substantia nigra region showed that, as shown in Figure 9, compared with the sham operation group, the number of TH-positive cells in the substantia nigra region of the model group was significantly reduced (P ⁇ 0.05).
  • the L-DOPA group, the low-dose YT salt group and the high-dose YT salt group could significantly inhibit the decrease in TH-positive cells in the substantia nigra region of the model animals at the set dose (P ⁇ 0.0001).
  • YT salt can significantly inhibit apoptosis of dopaminergic neurons in the substantia nigra and striatum of model animals at a dose of 167.5 mg/kg, and can not only significantly inhibit apoptosis of dopaminergic neurons in the substantia nigra of model animals at a dose of 248 mg/kg, but also significantly improve behavioral indicators such as grip strength and rotarod of model animals. This suggests that YT salt has potential preventive, alleviating or therapeutic effects on Parkinson's disease.
  • Example 7 Effects of Compound YT salt on 6-OHDA-induced Parkinson's disease rat model.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种新型组合产品、药物组合物、盐型、其制备方法及其在治疗、缓解和/或预防神经退行性疾病或病症中的用途。

Description

一种组合产品、盐及其用于治疗神经退行性疾病或病症的用途 技术领域
本发明属于医药领域，且涉及一种新型组合产品、药物组合物、盐型、其制备方法及其在治疗、缓解和/或预防神经退行性疾病或病症中的用途。
 背景技术
阿尔兹海默氏病(AD)是一种慢性神经退行性疾病，其特征表现为神经元细胞死亡、患者丧失认知能力并具有严重的行为异常，从而导致患者的最终死亡。目前在美国有250万到400万AD患者，全世界有1700万到2500万AD患者。该病在西方国家已经成为继心脏病、癌症和中风之后第四位导致死亡的疾病。是一种乙酰胆碱酯酶抑制剂，已被FDA批准用于减缓阿尔兹海默氏病患者的恶化速率。然而，该药仅对限定的时期和某些患者有效。至今还没有明确的药物能够治疗或治愈该破坏性疾病。
肌萎缩侧索硬化症(Amyotropyic Lateral Sclerosis,ALS)是一种严重的神经退行性疾病，影响脑干和脊髓的上下运动神经元。ALS患者在发病3-5年后出现广泛的肌肉萎缩，从而导致瘫痪和死亡；其病理特征为运动神经元中泛素化蛋白质内含物的聚集和积累。ALS可分为家族性ALS(fALS)，约占10％和不存在家族性疾病史的散发ALS(sALS)约占90％。ALS的主要发病因素有基因、环境和生活方式等，或者两者相互影响(PARALS Registry et al.,“Genome-Wide Association Analyses Identify New Risk Variants and the Genetic Architecture of Amyotrophic Lateral Sclerosis.”)。发病机制方面，ALS涉及多种病理生理途径，包括谷氨酸兴奋性毒性(Van Den Bosch et al.,“The Role of Excitotoxicity in the Pathogenesis of Amyotrophic Lateral Sclerosis.”)，神经炎症(Liu and Wang,“Role of Neuroinflammation in Amyotrophic Lateral Sclerosis.”)，铁积累(Ndayisaba,Kaindlstorfer,and Wenning,“Iron in Neurodegeneration-Cause or Consequence？”)，microRNA代谢失调和异常RNA结合蛋白(Donnelly,Grima,and Sattler,“Aberrant RNA Homeostasis in Amyotrophic Lateral Sclerosis.”)等，其发病机制尚未完全阐明。
ALS发病率和患病率随年龄增加而增加。至今，没有任何治疗措施或药物可以阻止或逆转疾病，已获批药物旨在减轻症状或延缓疾病恶化。自从1995年利鲁唑经美国食品药品监督管理局(FDA)获批以来利鲁唑治疗一直是唯一一种被广泛认可的治疗药物，可以延长ALS患者3个月的生存(Miller,Mitchell,and Moore,“Riluzole for Amyotrophic Lateral Sclerosis(ALS)/Motor Neuron Disease(MND).”)。2017年，美国食品药品监督管理局(FDA)批准的Evadarone,改善ALS功能评定量表(ALSFRS-R)评分，有延缓疾病进展的趋势(Al-Chalabi et al.,“July 2017ENCALS Statement on Edaravone.”)。2022年9月，AMX0035被FDA批准用于ALS的治疗。在ITT实验中，中位生存时间(medianOS)延长4.8个月，分别经两种事后分析矫正，RPSFTM矫正后延长9.7个月，自然历史数据创建的生存预测算法为延长9.9个月的生存获益。AMX0035是Amyyx Pharmaceuticals开发的苯基丁酸钠(PB)和牛磺熊去氧胆酸(TUDCA)的口服固定剂量复方。苯基丁酸钠是一种组蛋白去乙酰化酶抑制剂，可抑制内质网应激反应；牛磺熊去氧胆酸可抑制线粒体相关凋亡(Mead et al.,“Amyotrophic Lateral Sclerosis.”)。AMX0035旨在靶向ALS中运动神经元的内质网(ER)和线粒体，内质网和线粒体通过线粒体膜相连，两者在维持神经元存活方面起着关键作用。
帕金森病(Parkinson’s disease，PD)是一种慢性神经退行性疾病，主要影响老年人。最常见的临床特征为运动震颤(一种有节奏的抖动)、肌肉僵硬以及运动缓慢(称为运动迟缓)；但也表现为非运动症状，包括睡眠障碍、便秘、焦虑、抑郁和疲劳等。其主要病理特征为中脑的黑质致密部(substantia nigra,SN)多巴胺能神经元和纹状体区域多巴胺能神经纤维的丢失，以及神经元内蛋白质包涵体的形成，称为路易小体(Lewy bodies，LBs)，主要由α-突触核蛋白(alpha-synuclein)组成(John van Geest Centre for Brain Repair,Department of Clinical Neurosciences,University of Cambridge,UK et al.,“Parkinson’s Disease.”)。帕金森病是多因素的，由遗传、环境或者两者相互影响所导致(Bloem,Okun,and Klein,“Parkinson’s Disease.”)。帕金森病分为两种形式：散发性(迟发性)和家族性(早发性)(Ryan et al.,“Mitochondrial Dysfunction and Mitophagy in Parkinson’s.”)。流行病学研究表明，家族性帕金森病仅占少数帕金森病患者的比例，而绝大多数帕金森病患者为散发性帕金森病患者(Zeng,Geng,and Jia,“Neurotoxin-Induced Animal Models of Parkinson Disease.”)。1990年到2016年期间，PD患者总人数超过600万(Dorsey et al.,“Global,Regional,and National Burden of Parkinson’s Disease,1990-2016.”)，预计到2040年，将翻一番达到1200万以上(Rossi et al.,“Projection of the Prevalence of Parkinson’s Disease in the Coming Decades.”)。帕金森病的病因尚不清楚，但可能与各种危险因素有关，如兴奋毒性、氧化应激和神经炎症。
目前，PD的治疗包括左旋多巴、多巴胺激动剂、单胺氧化酶(MAO)抑制剂和金刚烷胺，这些药物旨在改善症状和减缓疾病进展。然而，这些治疗方法都不能完全治愈疾病，而且还有一些副作用。
神经退行性疾病诸如阿尔兹海默氏病(Alzheimer’s Disease,AD)、肌萎缩侧索硬化症(ALS)和帕金森病(PD)的现有疗法存在诸多问题。仅对AD的限定的时期和某些患者有效。ALS的治疗通常成本高昂，且部分无效，目前的治疗药物或措施只能实现有限的改善，具有巨大的未满足的临床需求。帕金森病具有很大的社会影响，是目前全球增长最快的神经系统疾病和导致残疾的主要原因。目前的治疗药物或措施旨在改善症状和减缓疾病进展，而且还存在多种副作用，因而临床需求仍存在巨大的缺口。
因此，对于神经退行性疾病或病症的复杂发病机制，本领域亟需一种神经退行性疾病或病症的新型疗法，相对于现有疗法，其效果更佳且安全性更高。
发明内容
本申请的发明人通过创造性的工作，解决了上述需求。
具体而言，本发明涉及如下技术方案：
在一个实施方案中，本申请涉及一种组合产品，其包含：
(a)式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基；
或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
(b)胆汁酸或其衍生物或其类似物或其药学上可接受的盐、溶剂化物、水合物或立体异构体；
其中所述组分(a)与组分(b)的摩尔比为1:1000-1000:1。
在另一个实施方案中，本发明涉及一种药物组合物，其包含：
(a)式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
其中R1、R2、R3、R4、R5和R6如本文中所定义；
(b)胆汁酸或其衍生物或其类似物或其药学上可接受的盐、溶剂化物、水合物或立体异构体；
(c)药学上可接受的载体、赋形剂和/或稀释剂；
其中所述组分(a)与组分(b)的摩尔比为1:1000-1000:1。
在又一个实施方案中，本发明涉及一种式(II)的酸-碱加成盐：
(A+)m(B-)n(C-)p
(II)
其中，
(a)A+是式(I)的化合物的阳离子部分；
其中R1、R2、R3、R4、R5和R6如本文中所定义；
(b)B-是胆汁酸或其衍生物或其类似物的阴离子部分；且
(c)C-是酸根阴离子；
其中m、n和p各自独立地是选自1-6的整数，使得盐构型达到电荷平衡，且当m＝n时，p为0。
在又一个实施方案中，本发明涉及前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体，其用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。
在又一个实施方案中，本发明涉及前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体，其用于治疗、缓解和/或预防神经退行性疾病或病症。
在又一个实施方案中，本发明涉及一种提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力的方法，其包括使根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体与所述细胞接触。
在又另一个实施方案中，本发明涉及一种治疗、缓解和/或预防神经退行性疾病或病症的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在还有一个实施方案中，本发明涉及一种试剂盒，其包含：
根据前述实施方案中任一项所述的组合产品、酸-碱加成盐、药物组合物或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体以及使用说明书，
其中所述试剂盒用于治疗和/或预防神经退行性疾病或病症。
本申请的细节在下面随附的说明中阐述。尽管与本文所述类似或等同的方法和材料可用于本申请的实践或测试中，但现在描述说明性方法和材料。根据说明书和权利要求书，本申请的其他特征、目的和优点将是显而易见的。在说明书和所附权利要求书中，单数形式也包括复数形式，除非上下文另有明确规定。除非另有定义，本文所用的所有技术和科学术语具有与本申请所属领域的普通技术人员通常理解的相同含义。本说明书中引用的所有专利和出版物通过引用整体并入本文。
在整个本申请中引用的所有参考文献(包括文献参考文献、授权的专利、公开的专利申请和共同未决的专利申请)的内容在此明确地通过引用整体并入本文。除非另有定义，否则本文所用的所有技术和科学术语均符合本领域普通技术人员通常已知的含义。
 附图说明
图1.描述了化合物Y、化合物T、化合物B、化合物N、化合物组合Y+T、化合物组合B+N、化合物组合PB+T以及YT新型盐的对双氧水诱导SH-sy5y细胞的活力的影响。其中，对照为不加任何药物不做H2O2刺激处理的细胞培养组；模型(Model)为不加任何药物但给予H2O2刺激的细胞培养组。DMSO为不加任何药物不做H2O2刺激处理但只加入DMSO的细胞培养组。在给药组中，化合物Y浓度为100μM；化合物T浓度为100μM；化合物B的浓度为100μM；化合物N浓度为100μM；化合物组合Y+T的浓度分别为100μM(化合物Y)+100μM(化合物T)；化合物组合B+N的浓度为100μM(化合物B)+100μM(化合物N)；化合物组合PB+T的浓度分别为500μM(化合物T)+200μM(化合物PB)；YT盐的浓度为100μM。所有给药组均使用H2O2刺激诱导。数据呈现为平均值±S.E.M。使用单因素方差分析(One-Way ANOVA)，****为P＜0.0001,***为P＜0.001,**为P<0.01,*P为＜0.05,vs YT；####为P＜0.0001,#为P＜0.05,vs模型。
图2.描述了化合物Y、化合物T、化合物组合Y+T、YT盐及化合物UDCA(U)对CD4阳性T细胞增殖的影响。其中YT盐浓度为100μM，换算为同比例化合物Y浓度为100μM，化合物T浓度为100μM，化合物组合Y+T浓度为100μM(化合物Y)+100μM(化合物T),化合物U浓度为100μM。
图3.描述了化合物Y、化合物T、化合物组合Y+T、YT盐及化合物UDCA(U)对CD8阳性T细胞增殖的影响。其中YT盐浓度为100μM，换算为同比例化合物Y浓度为100μM，化合物T浓度为100μM，化合物组合Y+T浓度为100μM(化合物Y)+100μM(化合物T),化合物U浓度为100μM。
[根据细则91更正 21.06.2024]
图4.描述了YT盐对SOD1G93A突变的ALS模型小鼠发病的影响。其中，模型组不给予任何药物处理，YT盐组给药剂量为496mg/kg(每天灌胃给药胃1次)。数据分析采用Log-rank检验，P<0.05表示不同组之间具有统计学差异。
图5.描述了YT盐对SOD1G93A突变的ALS模型小鼠重症发生的影响。其中，模型组不给予任何药物处理，YT盐组给药剂量为496mg/kg(每天灌胃给药1次)。数据分析采用Log-rank检验，P<0.05表示不同组之间具有统计学差异。
图6.描述了YT盐对SOD1G93A突变的ALS模型小鼠生存期的影响。其中，模型组不给予任何药物处理，YT盐组给药剂量为496mg/kg(每天灌胃给药1次)。数据分析采用Log-rank检验，P<0.05表示不同组之间具有统计学差异。
图7.描述了YT盐对MPTP诱导的帕金森小鼠模型抓握力量的影响。其中，假手术组为C57BL/6小鼠腹腔注射10mL/kg生理盐水；模型组为C57BL/6小鼠腹腔注射30mg/kg剂量的MPTP造模，且不给予任何药物处理；L-DOPA组为阳性药对照组，在模型小鼠中给予40mg/kg L-DOPA(每天灌胃给药2次)治疗；YT盐低剂量组为在模型小鼠中给予167.5mg/kg YT盐(每天灌胃给药2次)；YT盐高剂量组为在模型小鼠中给予248mg/kg YT盐(每天灌胃给药2次)。图中数据均以平均值(Mean)±标准误(SEM)表示。P<0.05表示具有统计学意义，*表示P<0.05，**表示P<0.01，***表示P<0.001，****表示P<0.0001。
图8.描述了YT盐对MPTP诱导的帕金森小鼠模型转棒测试的影响，评估动物在转棒上维持平衡至跌落地面的时间。其中，假手术组为C57BL/6小鼠腹腔注射10mL/kg生理盐水；模型组为C57BL/6小鼠腹腔注射30mg/kg剂量的MPTP造模，且不给予任何药物处理；L-DOPA组为阳性药对照组，在模型小鼠中给予40mg/kg L-DOPA(每天灌胃给药2次)治疗；YT盐低剂量组为在模型小鼠中给予167.5mg/kg YT盐(每天灌胃给药2次)；YT盐高剂量组为在模型小鼠中给予248mg/kg YT盐(每天灌胃给药2次)。图中数据均以平均值(Mean)±标准误(SEM)表示。P<0.05表示具有统计学意义，*表示P<0.05，**表示P<0.01。
图9.描述了YT盐对MPTP诱导的帕金森小鼠模型脑黑质区TH阳性细胞数量的影响。其中，假手术组为C57BL/6小鼠腹腔注射10mL/kg生理盐水；模型组为C57BL/6小鼠腹腔注射30mg/kg剂量的MPTP造模，且不给予任何药物处理；L-DOPA组为阳性药对照组，在模型小鼠中给予40mg/kg L-DOPA(每天灌胃给药2次)治疗；YT盐低剂量组为在模型小鼠中给予167.5mg/kg YT盐(每天灌胃给药2次)；YT盐高剂量组为在模型小鼠中给予248mg/kg YT盐(每天灌胃给药2次)。图中数据均以平均值(Mean)±标准误(SEM)表示。P<0.05表示具有统计学意义，****表示P<0.0001。
图10.描述了YT盐对MPTP诱导的帕金森小鼠模型脑纹状体区TH阳性细胞占比的影响。其中，假手术组为C57BL/6小鼠腹腔注射10mL/kg生理盐水；模型组为C57BL/6小鼠腹腔注射30mg/kg剂量的MPTP造模，且不给予任何药物处理；L-DOPA组为阳性药对照组，在模型小鼠中给予40mg/kg L-DOPA(每天灌胃给药2次)治疗；YT盐低剂量组为在模型小鼠中给予167.5mg/kg YT盐(每天灌胃给药2次)；YT盐高剂量组为在模型小鼠中给予248mg/kg YT盐(每天灌胃给药2次)。图中数据均以平均值(Mean)±标准误(SEM)表示。P<0.05表示具有统计学意义，**表示P<0.01，****表示P<0.0001。
图11.描述了YT盐对6-OHDA诱导的帕金森大鼠网格行走测试中错步次数的影响。其中，假手术组为SD大鼠不做造模处理；模型组为SD大鼠右侧颅内(内侧前脑束，MFB)注射4μL6-OHDA(5μg/μL)造模，且不给予任何药物处理；Istradefylline组为阳性药对照组，在模型大鼠中给予10mg/kg Istradefylline(每天灌胃给药1次)治疗；YT盐给药组为在模型大鼠中给予248mg/kg YT盐(每天灌胃给药1次)。图中数据均以平均值(Mean)±标准误(SEM)表示。P<0.05表示具有统计学意义，*表示P<0.05。
图12.描述了YT盐对6-OHDA诱导的帕金森大鼠网格行走测试中错步率的影响。其中，假手术组为给予SD大鼠右侧颅内(内侧前脑束，MFB)注射4μL(0.2mg/mL)抗坏血酸溶液；模型组为SD大鼠右侧颅内MFB注射4μL6-OHDA(5μg/μL)造模，且不给予任何药物处理；Istradefylline组为阳性药对照组，在模型大鼠中给予10mg/kg Istradefylline(每天灌胃给药1次)治疗；YT盐给药组为在模型大鼠中给予248mg/kg YT盐(每天灌胃给药1次)。图中数据均以平均值(Mean)±标准误(SEM)表示。P<0.05表示具有统计学意义，*表示P<0.05。
 具体实施方式
定义
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
如本文所用，术语“卤素”是指氟、氯、溴或碘。
如本文所用，术语“烷基”是指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至10个碳原子的烷基，最优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氨基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基。
如本文所用，术语“烷氧基”是指-O-(烷基)和-O-(环烷基)，其中烷基或环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
如本文所用，术语“卤代”和“卤素”是指氟、氯、溴和碘。
如本文所用，术语“卤代烷基”本身或作为另一取代基的一部分，是指其中一些氢原子或所有氢原子被卤素原子替代的烷基。对于烷基，卤代烷基可以具有任何合适数目的碳原子，例如C1-6。例如，卤代烷基包括三氟甲基、氟甲基等。在一些情况下，术语“全氟”可用于定义其中所有氢被氟替代的化合物或基团。例如，全氟甲基是指1,1,1-三氟甲基。
如本文所用，术语“羟基”是指-OH部分。
本发明还包括各种氘化形式的式(I)。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)。在制备氘代形式的式(I)时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂的非限制性实例包括：氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“药学上可接受的”是指所述组分与制剂的其它组分相容并且对其接受者无毒害。
如本文所用，术语“药学上可接受的盐”在用于本文时指化合物的药学上可接受的有机或无机盐。例示性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、盐酸盐、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和扑酸盐(即1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐))。药学上可接受的盐可能牵涉包含另一种分子，诸如乙酸盐离子、琥珀酸盐离子或其他抗衡离子。抗衡离子可以是稳定母体化合物电荷的任何有机或无机模块。另外，药学上可接受的盐可以在其结构中具有超过一种带电荷原子。在多种带电荷原子作为药学上可接受的盐的组成部分的情况中可以具有多种抗衡离子。因此，药学上可接受的盐可具有一种或多种带电荷原子和/或一种或多种抗衡离子。
如本文所用，术语“酸根阴离子”是指酸电离时产生的阴离子。常见的酸根阴离子包括氯离子、溴离子、碘离子、碳酸根离子、碳酸氢根离子、硫酸根离子、磷酸根离子、磷酸氢根离子、磷酸二氢根离子、甲酸根离子、乙酸根离子等等。所述酸根阴离子可以为-1价、-2价、-3价、-4价等等。
如本文所用，术语“药学上可接受的载体”是指与治疗剂一起使用的本领域常规的无毒固体、半固体、或液体填充剂、稀释剂、包封材料、配制品助剂或载体，二者共同组成用于向个体施用的“药物组合物”。药学上可接受的载体在所采用的剂量和浓度下对接受者无毒，并且与配制品的其他成分兼容。药学上可接受的载体适用于所采用的配制品。
如本文所用，术语“药学上可接受的赋形剂”是指有助于向个体施用活性剂的物质。有用的药物赋形剂包括但不限于粘合剂、填充剂、崩解剂、润滑剂、助流剂、包衣剂、甜味剂、矫味剂和着色剂。
根据期望的各种取代基的位置和性质，本发明的化合物可以含有一个或多个不对称中心。不对称的碳原子可以以(R)-和/或(S)-构型存在，在单一不对称中心的情况下导致外消旋混合物，并且在多个不对称中心的情况下导致非对映异构体混合物。在某些情况下，由于围绕特定键的旋转受阻还可能存在不对称性，例如该中心键连接特定化合物的两个被取代的芳环。环上的取代基还可以顺式或反式形式存在。意图所有的此类构型(包括对映体和非对映体)均包括于本发明的范围内。优选的化合物是产生更多所需生物活性的那些。本发明化合物的分离的、纯净的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映体混合物均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
互变异构体，有时被称为质子-移位互变异构体，是通过氢原子的迁移、伴随一个或多个单键和一个或多个相邻双键的转换关联的两种或更多种化合物。本发明的化合物可以以一种或多种互变异构形式存在。
本发明还包括本发明化合物的所有合适的同位素变体。本发明化合物的同位素变体定义为：其中至少一个原子被原子序数相同但原子量不同于自然界中通常或主要发现的原子量的原子替代的本发明的化合物。可以掺入本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素，例如分别为2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明化合物的某些同位素变体，例如，其中引入一个或多个放射性同位素(例如，3H或14C)的那些变体可用于药物和/或底物组织分布研究。尤其优选氚和碳-14(即，14C)同位素，这是由于它们的容易制备和可检测性。进一步，用同位素诸如氘取代可以提供由更好的代谢稳定性导致的确定的治疗优点，例如增加的体内半衰期或减小的剂量需求，并且因此在一些情况下可以是优选的。通常可以利用本领域技术人员已知的常规方法，例如，利用说明性方法或下文实施例所描述的制备方法，使用合适试剂的合适的同位素变体来制备本发明化合物的同位素变体。
本发明包括作为单一立体异构体或呈任何比率的所述立体异构体的任何混合物的本发明的化合物的所有可能的立体异构体。可通过任意适合的现有技术方法例如色谱法，特别是例如手性色谱法实现本发明化合物的单一立体异构体例如单一对映体或单一非对映体的分离。
本发明包括本发明化合物的所有可能的互变异构体，其是单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。
如本文所用，术语“溶剂化物”或“溶剂合物”是指本发明的化合物与一种或多种溶剂分子形成可药用的溶剂化物，溶剂分子的非限制性实例包括水、乙醇、乙腈、异丙醇、DMSO、乙酸乙酯等。水合物是其中溶剂为水的溶剂化物的具体形式。
如本文所用，术语“有效量”和“治疗有效量”是指产生其施用的治疗效果的化合物如本发明的化合物、化合物组合或盐型的剂量。确切剂量将取决于治疗的目的，并且将由本领域技术人员使用已知技术确定(参见，例如，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；和Remington:The Science and Practice of Pharmacy,21st Edition,2005,Hendrickson,Ed.,Lippincott,Williams&Wilkins)。
如本文所用，“治疗(treatment或treating)”是用于获得有益的或所希望的结果(包括临床结果)的方法。出于本申请的目的，有益的或所希望的临床结果包括但不限于以下中的一种或多种：缓解由疾病引起的一种或多种症状、减少疾病的程度、稳定疾病(例如，预防或延迟疾病的恶化)、预防或延迟疾病的传播(例如，转移)、预防或延迟疾病的重现、延迟或减缓疾病的进展，改善疾病状态、提供疾病的缓解(部分或全部)、减少治疗疾病所需的一种或多种其他药物的剂量、延迟疾病的进展、增加或改善生活质量、增加体重增长和/或延长存活。“治疗”还涵盖减少癌症的病理后果(像例如，肿瘤体积)。本申请的方法考虑了这些治疗方面中的任何一个或多个。
如本文所用，“预防(prevention或preventing)”包括针对可能易患疾病但尚未被诊断出患有所述疾病的个体中所述疾病的发生或复发提供预防。
术语“受试者”、“个体”和“患者”在本文可互换使用，是指哺乳动物，包括但不限于人、牛、马、猫、犬、啮齿动物或灵长类动物。在一些实施方案中，个体是人。
药剂的“有效量”是指在必要的剂量和时间段内有效达到所需治疗或预防结果的量。具体的剂量可取决于以下中的一个或多个而变化：选择的特定药剂、要遵循的给药方案、是否与其他化合物组合施用、施用时间、要成像的组织以及携带其的物理传递系统。
如本文所用，术语“协同”或“协同的”用于指两种化合物、组分或靶向剂的组合的结果大于各药剂一起的总和。术语“协同”或“协同的”是指与单独使用每种化合物、组分或靶向剂相比，所治疗的疾病状况或病症得到改善。所治疗的疾病状况或病症的这种改善为“协同效果”。“协同量”为导致协同效果(“协同的”如本文所定义)的两种化合物、组分或靶向剂的组合的量。
确定一种或两种组分之间的协同相互作用、所述效果的最佳范围和所述效果的各组分的绝对剂量范围可通过向需要治疗的患者施用在不同w/w比范围和剂量内的组分来明确测量。然而，在体外模型或体内模型中观察协同可预测在人类和其他物种及如本文所述的现有的体外模型或体内模型中的效果以测量协同效果，且此类研究的结果也可通过应用药代动力学/药效学方法来用于预测人类和其他物种中所需的有效剂量和血浆浓度比范围，以及绝对剂量和血浆浓度。
应当理解，本文所述的申请的实施方案包括“由……组成”和/或“基本上由……组成”。
本文对“约”值或参数的引用包括(并描述)针对该值或参数本身的变化。例如，涉及“约X”的描述包括“X”的描述。
如本文所用，术语“约X-Y”具有与“约X至约Y”相同的含义。
如本文所用，用术语“约”修饰本发明的成分或反应物的数量时是指数值量的变化，它们可能发生在例如，典型的测量和用于制备浓缩液或实际使用溶液的液体处理程序中；这些程序中的偶然误差中；制造、来源、或用于制备组合物或实施方法的成分的纯度的差异中；等。术语“约”还包括由于相对于由特定起始混合物所得组合物的不同平衡条件而不同的量。无论是否通过术语“约”来修饰，权利要求包括量的等同量。在一个实施方案中，术语“约”是指在报告数值10％范围内，优选地在报告数值5％范围内。
本领域技术人员应理解，当在权利要求中记载数值时，无论其是否有前缀“约”，该数值的实际值可以在记载值上下浮动10％(±10％)，优选上下浮动5％(±5％)。
当在本文和附带的权利要求中使用时，单数形式“一个/种(a)”、“一个/种(an)”、“或(or)”和“这些/该(the)”包括复数指代物，除非上下文明确地指示其他的情况。
实施方案描述
组合产品
在一些方面，本公开提供了一种组合产品，其包含：
(a)式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基；
或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
(b)胆汁酸或其衍生物或其类似物或其药学上可接受的盐、溶剂化物、水合物或立体异构体；其中所述组分(a)与组分(b)的摩尔比为1:1000-1000:1。
在进一步实施方案中，R1、R2和R3各自独立地选自：氢、羟基、甲氧基和苄氧基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。在更进一步实施方案中，R1、R2和R3中的一个或两个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。在又进一步实施方案中，R1、R2和R3中的一个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有两个氧原子的5元杂环。
在进一步实施方案中，R4、R5和R6各自独立地选自：氢、羟基和甲氧基，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。在更进一步实施方案中，R4、R5和R6中的一个或两个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。在又进一步实施方案中，R4、R5和R6中的一个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有两个氧原子的5元杂环。
在进一步实施方案中，式(I)的化合物的药学上可接受的盐选自马来酸盐、盐酸盐、草酸盐、酒石酸盐、富马酸盐、柠檬酸盐、苹果酸盐、己二酸盐、甲磺酸盐、磷酸盐、乙酸盐、扁桃酸盐或硫酸盐。优选地，式(I)的化合物的药学上可接受的盐选自马来酸盐或盐酸盐。更优选地，式(I)的化合物的药学上可接受的盐为盐酸盐。
在进一步实施方案中，式(I)的化合物选自：
在进一步实施方案中，所述胆汁酸或其衍生物或其类似物选自：胆酸、奥贝胆酸、熊去氧胆酸、鹅去氧胆酸、猪去氧胆酸、7-氧代石胆酸、石胆酸、碘代去氧胆酸、碘胆酸、牛磺鹅去氧胆酸、牛磺去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、甘氨胆酸、24-去甲熊去氧胆酸和牛磺熊去氧胆酸等。
在进一步实施方案中，组分(a)与组分(b)的摩尔比为1:100-100:1。优选地，组分(a)与组分(b)的摩尔比为1:90-90:1、1:80-80:1、1:70-70:1、1:60-60:1、1:50-50:1、1:40-40:1、1:30-30:1、1:20-20:1、1:10-10:1。更优选地，组分(a)与组分(b)的摩尔比为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或10:1或其任意两者之间的数值。
在进一步实施方案中，所述组合产品用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。优选地，所述组合产品用于治疗、缓解和/或预防神经退行性疾病或病症。更优选地，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(Huntington’s Disease,HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症(Sarcopenia)、肌肉萎缩(Muscular Dystrophy,MD)、皮克病(Pick's Disease,PID)、多发梗塞性痴呆(Multi Infarct Dementia,MID)、克-雅二氏病(Creutzfeldt-Jakob Disease,CJD)、具有雷维小体的痴呆症(Dementia with Lewy Bodies,DLB)、混合型痴呆症(Mixed Dementia)和额颞痴呆症(Frontotemporal Dementia,FTD)。优选地，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、帕金森氏病(PD)或肌萎缩侧索硬化症(ALS)。
药物组合物
在一些方面，本公开提供了一种药物组合物，其包含：
(a)式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基；
或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
(b)胆汁酸或其衍生物或其类似物或其药学上可接受的盐、溶剂化物、水合物或立体异构体；
(c)药学上可接受的载体、赋形剂和/或稀释剂；
其中所述组分(a)与组分(b)的摩尔比为1:1000-1000:1。
在进一步实施方案中，R1、R2和R3各自独立地选自：氢、羟基、甲氧基和苄氧基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。在更进一步实施方案中，R1、R2和R3中的一个或两个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。在又进一步实施方案中，R1、R2和R3中的一个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有两个氧原子的5元杂环。
在进一步实施方案中，R4、R5和R6各自独立地选自：氢、羟基和甲氧基，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。在更进一步实施方案中，R4、R5和R6中的一个或两个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。在又进一步实施方案中，R4、R5和R6中的一个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有两个氧原子的5元杂环。
在进一步实施方案中，式(I)的化合物的药学上可接受的盐选自马来酸盐、盐酸盐、草酸盐、酒石酸盐、富马酸盐、柠檬酸盐、苹果酸盐、己二酸盐、甲磺酸盐、磷酸盐、乙酸盐、扁桃酸盐或硫酸盐。优选地，式(I)的化合物的药学上可接受的盐选自马来酸盐或盐酸盐。更优选地，式(I)的化合物的药学上可接受的盐为盐酸盐。
在进一步实施方案中，式(I)的化合物选自：
在进一步实施方案中，所述胆汁酸或其衍生物或其类似物选自：胆酸、奥贝胆酸、熊去氧胆酸、鹅去氧胆酸、猪去氧胆酸、7-氧代石胆酸、石胆酸、碘代去氧胆酸、碘胆酸、牛磺鹅去氧胆酸、牛磺去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、甘氨胆酸、24-去甲熊去氧胆酸和牛磺熊去氧胆酸等。
在进一步实施方案中，组分(a)与组分(b)的摩尔比为1:100-100:1。优选地，组分(a)与组分(b)的摩尔比为1:90-90:1、1:80-80:1、1:70-70:1、1:60-60:1、1:50-50:1、1:40-40:1、1:30-30:1、1:20-20:1、1:10-10:1。更优选地，组分(a)与组分(b)的摩尔比为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或10:1或其任意两者之间的数值。
在进一步实施方案中，所述药物组合物用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。优选地，所述药物组合物用于治疗、缓解和/或预防神经退行性疾病或病症。更优选地，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。优选地，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、帕金森氏病(PD)或肌萎缩侧索硬化症(ALS)。
酸-碱加成盐
在一些方面，本公开提供了一种式(II)的酸-碱加成盐：
(A+)m(B-)n(C-)p
(II)
其中，
(a)A+是式(I)的化合物的阳离子部分；
其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基，
或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N，
或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
(b)B-是胆汁酸或其衍生物或其类似物的阴离子部分；且
(c)C-是酸根阴离子；
其中m、n和p各自独立地是选自1-6的整数，使得盐构型达到电荷平衡，且当m＝n时，p为0。
在进一步实施方案中，R1、R2和R3各自独立地选自：氢、羟基、甲氧基和苄氧基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。在更进一步实施方案中，R1、R2和R3中的一个或两个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。在又进一步实施方案中，R1、R2和R3中的一个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有两个氧原子的5元杂环。
在进一步实施方案中，R4、R5和R6各自独立地选自：氢、羟基和甲氧基，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。在更进一步实施方案中，R4、R5和R6中的一个或两个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。在又进一步实施方案中，R4、R5和R6中的一个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有两个氧原子的5元杂环。
在进一步实施方案中，式(I)的化合物选自下组的阳离子部分：
在进一步实施方案中，组分(b)选自下组的阴离子部分：胆酸、奥贝胆酸、熊去氧胆酸、鹅去氧胆酸、猪去氧胆酸、7-氧代石胆酸、石胆酸、碘代去氧胆酸、碘胆酸、牛磺鹅去氧胆酸、牛磺去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、甘氨胆酸、24-去甲熊去氧胆酸和牛磺熊去氧胆酸等。
在进一步实施方案中，C-是一价、二价、三价、四价酸根阴离子或它们的混合物。优选地，C-是一价、二价或三价酸根阴离子或它们的混合物。更优选地，C-是一价或二价酸根阴离子或它们的混合物。最优选地，C-是一价酸根阴离子或其混合物。
在进一步实施方案中，m为1，n为1，p为0，或者m为2，n为1且p为1。
在进一步实施方案中，所述药物组合物用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。优选地，所述药物组合物用于治疗、缓解和/或预防神经退行性疾病或病症。更优选地，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。优选地，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、帕金森氏病(PD)或肌萎缩侧索硬化症(ALS)。
治疗和/或预防
在一些方面，本公开提供了一种治疗、缓解和/或预防神经退行性疾病或病症的方法。在一些方面，所述治疗、缓解和/或预防神经退行性疾病或病症的方法包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防阿尔茨海默氏病(AD)的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防亨廷顿氏病(HD)的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防帕金森氏病(PD)的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防肌萎缩侧索硬化症(ALS)的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防皮克病的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防多发梗塞性痴呆的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防克-雅二氏病的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防具有雷维小体的痴呆症(DLB)的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防混合型痴呆症的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗、缓解和/或预防额颞痴呆症的方法，其包括向有此需要的患者施用根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在一些方面，本公开提供了一种治疗和/或预防神经退行性疾病或病症的方法，其包括：方案1，向有此需要的患者施用：
(a)治疗和/或预防有效量的式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N，
或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；或者，
方案2，向有此需要的患者同时、共同、分开或依次施用：
(a)治疗和/或预防有效量的式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N，
或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；和
(b)治疗和/或预防有效量的胆汁酸或其衍生物或其类似物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
在进一步实施方案中，R1、R2和R3各自独立地选自：氢、羟基、甲氧基和苄氧基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。在更进一步实施方案中，R1、R2和R3中的一个或两个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。在又进一步实施方案中，R1、R2和R3中的一个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有两个氧原子的5元杂环。
在进一步实施方案中，R4、R5和R6各自独立地选自：氢、羟基和甲氧基，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。在更进一步实施方案中，R4、R5和R6中的一个或两个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。在又进一步实施方案中，R4、R5和R6中的一个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有两个氧原子的5元杂环。
在进一步实施方案中，式(I)的化合物的药学上可接受的盐选自马来酸盐、盐酸盐、草酸盐、酒石酸盐、富马酸盐、柠檬酸盐、苹果酸盐、己二酸盐、甲磺酸盐、磷酸盐、乙酸盐、扁桃酸盐或硫酸盐。优选地，式(I)的化合物的药学上可接受的盐选自马来酸盐或盐酸盐。更优选地，式(I)的化合物的药学上可接受的盐为盐酸盐。
在进一步实施方案中，式(I)的化合物选自：
在进一步实施方案中，所述胆汁酸或其衍生物或其类似物选自：胆酸、奥贝胆酸、熊去氧胆酸、鹅去氧胆酸、猪去氧胆酸、7-氧代石胆酸、石胆酸、碘代去氧胆酸、碘胆酸、牛磺鹅去氧胆酸、牛磺去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、甘氨胆酸、24-去甲熊去氧胆酸和牛磺熊去氧胆酸等。
在进一步实施方案中，组分(a)与组分(b)的摩尔比为1:100-100:1。优选地，组分(a)与组分(b)的摩尔比为1:90-90:1、1:80-80:1、1:70-70:1、1:60-60:1、1:50-50:1、1:40-40:1、1:30-30:1、1:20-20:1、1:10-10:1。更优选地，组分(a)与组分(b)的摩尔比为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或10:1或其任意两者之间的数值。
在进一步实施方案中，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。优选地，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、帕金森氏病(PD)或肌萎缩侧索硬化症(ALS)。
在一些方面，本公开提供了一种提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力的方法，其包括使根据前述实施方案中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体与所述细胞接触。
在一些方面，本公开提供了式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体，其用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。
在一些方面，本公开提供了式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体，其用于治疗、缓解和/或预防神经退行性疾病或病症。
在进一步实施方案中，其中所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。
施用方式
施用本发明的组合的化合物或盐型可能被任何能够将所述化合物递送至作用部位的方法影响。这些方法包括口服途径、十二指肠内途径、肠胃外注射(包括静脉内、皮下、肌肉内、血管内或输注)、局部和直肠施用。
本发明的方法或组合的化合物或盐型可在施用前配制。优选地，所述制剂将适合特定的施用模式。这些化合物可与本领域已知的药学上可接受的载体一起配制并以本领域已知的多种剂型施用。在制备本发明的药物组合物时，通常将活性成分与药学上可接受的载体混合，或以载体稀释或包封在载体中。此类载体包括但不限于固体稀释剂或填充剂、赋形剂、无菌水性介质和各种非毒性有机溶剂。剂量单位形式或药物组合物包括包装在适合细分为单独剂量的容器中的片剂、胶囊如明胶胶囊、丸剂、粉剂、颗粒、水性和非水性口服溶液和悬浮液、锭剂、糖锭、硬糖、喷雾剂、乳膏、药膏、栓剂、果胶、凝胶、糊剂、洗剂、软膏、注射液、酏剂、糖浆和肠胃外溶液。
肠胃外制剂包括药学上可接受的水性或非水性溶液、分散体、悬浮液、乳液和无菌粉末(用于它们的制备)。载体的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇)、植物油和可注射的有机酯，诸如油酸乙酯。流动性可通过使用涂层，诸如卵磷脂、表面活性剂或保持适当的粒度维持。示例性肠胃外施用形式包括在无菌水溶液，例如丙二醇水溶液或右旋糖溶液中的本发明化合物的溶液或悬浮液。如果需要的话，可适当地缓冲此类剂型。
此外，润滑剂，诸如硬脂酸镁、月桂基硫酸钠和滑石通常可用于压片目的。相似类型的固体组合物也可用于软和硬填充明胶胶囊中。因此，优选的材料包括乳糖(lactose或milk sugar)和高分子量聚乙二醇。当需要水性悬浮液或酏剂以用于口服施用时，其中的活性化合物可与各种甜味剂或调味剂、着色剂或染料，并且如果需要的话，乳化剂或悬浮剂，以及稀释剂如水、乙醇、丙二醇、甘油或其组合合并。
使用特定量的活性化合物制备各种药物组合物的方法是本领域技术人员已知的或显而易见的。例如，参见Remington's Pharmaceutical Sciences,Mack PublishingCompany,Easter,Pa.,第15版(1975)。
试剂盒
在一些方面，本公开提供了用于治疗、缓解和/或预防神经退行性疾病或病症的试剂盒，其包含根据前述实施方案中任一项所述的组合产品、酸-碱加成盐、药物组合物或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体和用于施用所述治疗剂的使用说明书。在一个实施方案中，所述使用说明书详述和限定所述治疗剂的施用模式，例如以用于同时、共同、分开或依次施用本发明的治疗剂。在一个实施方案中，所述使用说明书详述和限定所述治疗剂的施用模式，例如通过指定在特定时段期间各治疗剂的施用天数来详述和限定所述治疗剂的施用模式。
在一些方面，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。优选地，所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、帕金森氏病(PD)或肌萎缩侧索硬化症(ALS)。
实施例
以下通过实施例对本发明进行进一步的详细说明，不应理解为对本发明的限制。
材料和试剂：除非另有说明，否则本发明的实验部分涉及的试剂均为市售产品。例如，盐酸小檗碱(化合物B)、熊去氧胆酸(化合物U)和牛磺熊去氧胆酸(化合物T)购自安耐吉化学(Energy Chemical)。神经母细胞瘤SH-sy5y细胞购自中国科学院细胞库。
在获得下文实施例中描述的化合物和相应的分析数据时，除非另外指明，否则遵循以下实验和分析方案。
LC-MS：除非另有说明，否则所使用的分析型LC-MS系统由具有正离子检测模式的电喷雾电离(ESI)的岛津(Shimadzu)LCMS-2020组成，其具有20ADXR泵、SIL-20ACXR自动进样器、CTO-20AC柱温箱、M20APDA检测器和LCMS2020MS检测器。柱为HALO，即C18 30mm×5.0mm，2.7μm。流动相A为含有0.05％TFA的水，并且流动相B为含有0.05％TFA的乙腈。梯度设置如下：在2.0分钟内从5％流动相B变为100％(95％)，保持0.7分钟，然后在0.05分钟内恢复至5％流动相B并保持0.25分钟。柱温箱(CTO-20AC)在40.0℃运行。流速为1.5mL/分钟，并且注射体积为1μL。PDA(SPD-M20A)检测范围为190nm至400nm。MS检测器，其配置有电喷雾电离作为可电离源；获取方式：扫描；雾化气体流速：1.5L/分钟；干燥气体流速：15L/分钟；检测器电压：调谐电压±0.2kv；DL温度：250℃；加热块温度：250℃；扫描范围：90.00m/z至900.00m/z。ELSD(Alltech 3300)检测器参数：漂移管温度：60±5℃；N2流速：1.8±0.2L/分钟。针对各个化合物优化流动相梯度。计算的质量对应于精确质量。
制备型HPLC：除非另有说明，否则用具有2489UV检测器的沃特世自动(WatersAuto)纯化系统(2545-2767)进行制备型HPLC纯化。柱选自以下项中的一种：Waters C18，19mm×150mm，5μm；XBridge Prep OBD C18柱，30mm×150mm，5μm；XSelect CSH Prep C18OBD柱，5μm，19mm×150mm；XBridge Shield RP18 OBD柱，30mm×150mm，5μm；Xselect CSH氟苯基，30mm×150mm，5μm；或YMC-Actus Triart C18，30mm×150mm，5μm。流动相由乙腈(5％-95％)在含有0.1％FA或10mmol/L NH4HCO3的水溶液中的混合物组成。流速保持在25mL/分钟，注射体积为1200μL，并且UV检测器使用两个通道，即254nm和220nm。针对各个化合物优化流动相梯度。
手性色谱法：手性分析色谱法在以下项中的一者上进行：所述的Chiralpak AS、AD，Chiralcel OD、OJ，Chiralpak IA、IB、IC、ID、IE、IF、IG、IH柱(Daicel ChemicalIndustries，Ltd.)，(R，R)-Whelk-O1、(S，S)-Whelk-O1柱(Regis technologies，Inc.)，CHIRAL Cellulose-SB、SC、SA柱(YMC Co.，Ltd.)；不同柱尺寸(50mm×4.6mm、100mm×4.6mm、150mm×4.6mm、250mm×4.6mm、50mm×3.0mm、100mm×3.0mm)，己烷中的乙醇百分比(％Et/Hex)或己烷中的异丙醇百分比(％IPA/Hex)作为等度溶剂体系，或使用超临界流体(SFC)条件。
正相快速色谱法：除非另有说明，否则正相快速柱色谱法(FCC)在硅胶上用预包装的硅胶柱进行，使用乙酸乙酯(EtOAc)/己烷、乙酸乙酯(EtOAc)/石油醚(b.p.60℃至90℃)、CH2Cl2/MeOH或CH2Cl2/10％2N NH3的MeOH溶液作为洗脱液。
1 H NMR：除非另有说明，否则1H NMR光谱是使用400MHz光谱仪(或300MHz光谱仪)在DMSO-d6溶液中获得的。核磁共振(NMR)光谱特征是指以百万分率(ppm)表示的化学位移(δ)。四甲基硅烷(TMS)在DMSO-d6溶液中用作内标，并且残留的CH3OH峰或TMS在CD3OD溶液中用作内标。偶合常数(J)以赫兹(Hz)为单位进行报告。关于多重性的位移的性质被报告为s(单峰)、d(二重峰)、t(三重峰)、q(四重峰)、dd(双二重峰)、dt(双三重峰)、m(多重峰)、br(宽峰)。
用于本说明书、特别是实施例中的缩写列于下表中：
实施例1.化合物Y的合成
步骤1. 2-(苯并[d][1,3]二氧环戊基-5-基)乙烷-1-醇的合成
在0℃下向1,3-苯并二氧环戊烷-5-乙酸(1,3-Benzodioxole-5-acetic acid)(500g，2.78mol)的THF(200mL)溶液中滴加LAH(2.5M，1.00L)，然后在N2气氛下在25℃下将混合物搅拌12小时。将混合物冷却至-10～0℃，然后依次加入H2O(95..0mL)、NaOH(15％，95.0mL)、H2O(285mL)。0.5小时后，向混合物中加入Na2SO4(500g)，并在25℃下搅拌0.5小时。过滤混合物，并用THF(5.00L)洗涤滤饼。收集滤液并浓缩。获得作为黄色油状物的标题化合物(460g，2.77mol，99.7％产率)。
步骤2. 2-(苯并[d][1,3]二氧环戊基-5-基)乙烷-1-特戊酸酯的合成
将2-(苯并[d][1,3]二氧环戊基-5-基)乙烷-1-醇(455g)和吡啶(435g)溶解在DCM(2.00L)中，在0℃和N2保护下逐滴加入化合物b(664g)，并继续搅拌8小时。将残留物倒入水中，并用DCM萃取水相。合并的有机相用盐水洗涤，干燥，并浓缩。残留物通过硅胶色谱法纯化以获得作为黄色油状物的标题化合物(670g)。
HNMR(CDCl3):δ6.78-6.70(m,2H),6.68-6.64(m,1H),6.10-5.58(m,2H),4.22(t,J＝6.94Hz,2H),2.84(t,J＝6.94Hz,2H),1.20-1.16(m,9H)。
步骤3. 2-(6-乙酰基-苯并[d][1,3]二氧环戊基-5-基)乙烷-1-特戊酸酯的合成
在0℃下，向2-(苯并[d][1,3]二氧环戊基-5-基)乙烷-1-特戊酸酯(620g)的Ac2O(3.00L)溶液中，在N2下一次加入ZnCl2(1.01kg)，然后将混合物室温下继续搅拌8小时。将反应物倒入水中，然后用乙酸乙酯萃取，用盐水洗涤合并有机相，干燥，浓缩。硅胶色谱法纯化以获得作为黄色油状物的标题化合物(467g)。
HNMR(CDCl3):δ7.23(s,1H),6.75(s,1H),6.78-6.70(m,1H),6.02(s,2H),4.26(t,J＝6.63Hz,1H),4.35-4.21(m,1H),3.17(t,J＝6.63Hz,2H),2.54(s,3H),1.16(s,9H)。
步骤4. 2-(6-(2-(2-(1,3-二氧戊环-2-基)-4,5-二甲氧基苯基)乙酰基)苯并[d][1,3]二氧戊环-5-基)特戊酸乙酯的合成
在室温和N2保护下将Cs2CO3(451g)和(Ahphos)2PdCl2(58.8g)一次性加入到2-(6-乙酰基-苯并[d][1,3]二氧环戊基-5-基)乙烷-1-特戊酸酯(284g)和化合物a(200g)的DCE溶液中。将混合物在90℃下维温反应10小时。反应结束后将反应体系缓慢滴加至水中并用乙酸乙酯萃取，有机相用盐水洗涤，干燥，浓缩。硅胶色谱法纯化以获得作为黄色固体的标题化合物(310g)。
步骤5.化合物Y的合成
在室温N2保护下，向2-(6-(2-(2-(1,3-二氧戊环-2-基)-4,5-二甲氧基苯基)乙酰基)苯并[d][1,3]二氧戊环-5-基)特戊酸乙酯(310g)的EtOH中，一次性加入NH4Cl溶液(3M，3.38eq)，然后将混合物在120℃下高压反应24小时。反应结束后将混合物冷却至25℃，过滤，滤饼用MTBE洗涤。通过硅胶色谱法纯化，得到标题化合物190g。
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)。
实施例2.YT盐的制备和表征
YT盐的制备：将化合物Y和化合物T在甲醇/乙酸乙酯(乙酸异丙酯)(v/v:1/9)混合溶剂中悬浮并持续搅拌24小时，较多固体悬浮于体系中。通过过滤获得固体，烘干，得到YT盐型。
YT盐的表征：YT盐中Y和T的离子比例为1:1。
HNMR(DMSO-d6):δ9.60(s,1H),8.77(s,1H),7.73～7.71(d,1H),7.70～7.69(t,2H),7.60(s,1H),7.09(s,1H),6.17(s,2H),4.79～4.77(t,2H),4.47～4.46(d,1H),4.07(s,3H),4.05～4.01(q,1H),4.00(s,3H),3.89～3.88(d,1H),3.31～3.25(m,4H),3.21～3.18(t,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)。
实施例3.化合物Y单药(Y)、化合物T单药(T)、化合物B单药(B)、化合物N单药(N)、化合物组合Y+T、化合物组合B+N、化合物组合PB+T、新型盐YT对双氧水诱导的细胞系SH-sy5y细胞活力的影响。
神经母细胞瘤SH-sy5y细胞(购自中国科学院细胞库)用完全培养基DMEM+10％FBS+1％PS于37℃，5％CO2的细胞培养箱中进行培养。实验总共分成11组：
组1(对照)：SH-sy5y细胞
组2(模型)：SH-sy5y细胞+双氧水
组3：SH-sy5y细胞+双氧水+化合物Y(100μM)
组4：SH-sy5y细胞+双氧水+化合物T(100μM)
组5：SH-sy5y细胞+双氧水+化合物B(100μM)
组6：SH-sy5y细胞+双氧水+化合物N(100μM)
组7：SH-sy5y细胞+双氧水+化合物组合Y+T(100μM+100μM)
组8：SH-sy5y细胞+双氧水+化合物组合B+N(100μM+100μM)
组9：SH-sy5y细胞+双氧水+化合物组合PB+T(500μM+200μM)
组10：SH-sy5y细胞+双氧水+YT盐(100μM)
组11：SH-sy5y细胞+DMSO
将神经母细胞瘤SH-sy5y细胞在完全培养基DMEM+10％FBS+1％PS中按照1×104个细胞/孔铺板，在37℃、5％CO2的细胞培养箱中培养24小时，然后加入相应的化合物。孵育24小时，然后加入双氧水刺激1h，双氧水的终浓度为350μM。然后，加入50(CTG)试剂，震荡2min，然后检测其发光信号值，其光信号值可表征细胞存活力。
如图1中所示，与模型(柱2)相比，化合物Y单药(柱3)具有优异的提高细胞存活力的效果(P＜0.0001)，且化合物Y单药(柱3)的效果优于化合物B单药(柱5)；与化合物T单药(柱4)、化合物B单药(柱5)、化合物组合B+N(柱8)、化合物组合PB+T(柱9)相比，化合物组合Y+T(柱7)以及YT盐(柱10)在提高细胞存活力的方面具有显著性优异的效果，表明化合物组合Y+T以及YT盐对神经细胞的氧化应激后损伤修复的效果显著优于化合物T单药、化合物B单药、化合物组合B+N和化合物组合PB+T，其中化合物组合PB+T参考的是已上市药物AMX0035资料中化合物PB与化合物T的浓度(DavidL.Carbone. Pharmacology/toxicologyNDAreviewandevaluation,Application number:216660Orig1s000,Food and Drug Administration.doi:pink.pharmaintelligence.informa.com/-/media/supporting-documents/pink-sheet/2022/11/relyvrio_nonclinical.pdf？rev＝d27109bf35c040d4a78f73144d132917&has h＝414BB5B4473A21ECE0231375EB1C0341)。
以上结果表明，化合物Y单药、化合物组合Y+T和YT盐在提高细胞存活力以及对神经细胞的氧化应激后损伤修复的效果的方面具有显著性优异的效果，表明其具有作为治疗、缓解和/或预防神经退行性疾病或病症的药物的潜力。
实施例4.化合物Y单药、化合物T单药、化合物组合Y+T及YT盐抑制CD4阳性及CD8阳性T细胞增殖的作用
据报道，在ALS中，Th细胞被描述为炎症和疾病进展的主要参与者。20世纪90年代，在ALS患者的邻近退行性区域的脊髓中观察到CD4 T细胞浸润。类似地，在ALS患者的脊髓和脑中也观察到CD8 T细胞浸润。(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.)为了观察本发明的化合物、化合物组合或盐对免疫细胞浸润或增殖的抑制，进一步分析它们抑制CD4阳性及CD8阳性T细胞增殖的作用。
首先将一定数量人外周血单核细胞(PBMC)与5μMCellTrace细胞增殖检测试剂于37℃，5％CO2的培养箱中避光孵育20分钟。然后将1.5*105个经CellTrace染色的PBMC接种于96孔U底板，并按照1:1(细胞数量：磁珠数量)的比例用Anti-CD3/CD28抗体偶联磁珠处理上述PBMC，以刺激PBMC向T细胞分化。然后使各种化合物以相应的浓度(化合物Y 100μM，化合物T 100μM，化合物组合Y+T(100μM化合物Y+100μM化合物T),YT盐100μM，对照组UDCA(100μM))与上述处理过的细胞在37℃与5％CO2的培养箱的条件下共同孵育72小时，然后通过流式细胞仪进行分析。具体而言，首先用Live/dead染料(633nm，1:1000稀释)于4℃处理待测细胞30分钟，以区分死细胞与活细胞。随后在室温条件下，上述待测细胞同时与波长染料anti-CD45-PerCPCy5.5、anti-CD4-AF700、anti-CD8-FITC共同孵育30分钟，以区分不同系列的T细胞(CD4阳性T细胞，CD8阳性T细胞)。经过适当的清洗后，将上述经染色的细胞进行在不同波长下通过流式细胞仪进行分析。后续细胞分析指的是通过Live/dead染料染色后呈现阳性的活细胞。CD4阳性T细胞指的是经anti-CD45-PerCPCy5.5及anti-CD4-AF700染料染色的阳性细胞；CD8阳性T细胞指的是经anti-CD45-PerCPCy5.5及anti-CD8-FITC染料染色的阳性细胞。CD4阳性及CD8阳性T细胞的增殖通过Celltrace染料的荧光确定。
如图2中所示，与对照组DMSO相比(波形图1，从上往下依次为波形图1-6)，YT盐(波形图2)、对应剂量的化合物Y(波形图3)及化合物组合Y+T(波形图5)的CD4阳性T细胞增殖波峰整体向右偏移，说明上述组别显著抑制了CD4阳性T细胞的增殖。类似地，如图3中所示，与对照组DMSO相比(波形图1)，YT盐(波形图2)、对应剂量的化合物Y(波形图3)及化合物组合Y+T(波形图5)CD8阳性T细胞增殖波峰整体向右偏移，说明上述组别显著抑制了CD8阳性T细胞的增殖。
以上结果表明，针对Anti-CD3/CD28诱导分化人源PBMC来源的CD4阳性及CD8阳性T细胞，YT盐及化合物组合Y+T具有显著地抑制CD4阳性及CD8阳性T细胞的增殖作用，其作用显著优于化合物T及化合物U(UDCA)；表明YT盐及化合物组合Y+T具有潜在抑制神经退行性疾病中的免疫细胞浸润或增殖的作用。
实施例5：化合物YT盐对SOD1G93AALS小鼠模型发病、重症及生存的影响
在SOD1G93A转基因小鼠(B6SJL-Tg(SOD1*G93A)1/cyagen)中，评价YT盐对于ALS动物的生存状态的治疗效应。选取16只雌性和14只雄性B6SJL-Tg(SOD1*G93A)1/cyagen小鼠，按性别、体重随机分为2组(7雄+8雌/组)，分别为模型组(对照)和YT盐组(给药组)，YT盐给药剂量为496mg/kg，每天灌胃1次。从鼠龄第66天开始给药，监控体重变化，评估动物状态、症状程度，并统计个体生存期。动物症状程度统计包括动物首次发病时间和首次发现重症的时间。本研究中“首次发病”定义为以小鼠出现转圈、步态异常或前后肢虚弱、震颤等表现视为ALS发病的起始点。本研究中“重症”定义为动物完全瘫痪，无法自由移动，但仍然存活的状态；若动物发病后未经“瘫痪”阶段直接死亡，则将死亡视为重症发生。生存期统计为试验终点时(第130天)动物存活的时间。风险比采用Log-rank检验法计算得到。
动物状态观察统计如图4，从发病分析来看，YT盐组与模型组相比，在首次发病时间上未见统计学差异(P＝0.0802)，但从总体发病情况来看，YT盐组发病时间在鼠龄90天之后，均不早于模型组，且中位发病时间(109天)比模型组(102天)多7天；YT盐组发病风险比(0.5716)较模型组(1.749)减少约3倍。试验结果表明YT盐具有延缓ALS模型小鼠的发病时间和降低发病风险比的效果。
从动物重症发生的结果来看，如图5，YT盐组的动物重症发生率显著低于模型组(P<0.05)，YT盐组的终点重症率为66.667％；YT盐组的中位重症发生时间也明显晚于模型组，YT盐组中位重症发生时间(117天)相对于模型对照组(109天)约增加8天；YT盐组重症风险比(0.45)较之模型组(2.222)减少约5倍。试验结果表明YT盐具有有效降低ALS模型小鼠的重症发生的效果。
在生存期统计中，如图6，YT盐组的动物生存期显著优于模型组(P<0.01)，YT盐组的终点存活率为53.333％，模型组的终点存活率仅为7.143％；模型组的中位生存期为115.5天，而YT盐组截至试验终点死亡个体却未超过半数，未达到计算中位生存期的条件；YT盐组的死亡风险比(0.3212)比模型组(3.113)低了近10倍。试验结果表明YT盐具有显著延长ALS模型小鼠的生存期和降低死亡风险的效果。
综上，在SOD1 G93A突变的ALS模型小鼠中，与模型组相比，YT盐具有延缓发病的趋势，能显著减少重症的发生率，并延长其生存期。这提示YT盐对于ALS具有潜在的预防、缓解或治疗的效果。
实施例6：化合物YT盐对MPTP诱导的帕金森病小鼠模型的影响
选择C57BL/6雄性小鼠60只，随机分为5组(12只/组)，分别为假手术组(正常对照)、模型组(模型对照)、L-DOPA组(阳性药对照，40mg/kg)、YT盐低剂量给药组(167.5mg/kg)和YT盐高剂量给药组(248mg/kg)。使用MPTP连续5天对小鼠腹腔注射造模，剂量为30mg/kg。YT盐每天灌胃给药2次(两次给药间隔7～8h)，连续给药13天。L-DOPA每天给药2次(两次给药间隔7～8h)，连续给药8天。通过抓力测试、转棒试验等行为学指标评价YT盐对MPTP诱导的帕金森小鼠的运动功能的改善效果。对动物做组织病理学检查，评价YT盐对MPTP诱导的帕金森小鼠的多巴胺能神经元的保护作用。
抓力测试结果显示，如图7，MPTP造模后动物抓力显著减小(模型组vs假手术组，P<0.0001)。L-DOPA组、YT盐高剂量给药组在设定治疗方案下，可显著改善MPTP引起的动物抓力减小(L-DOPA组vs模型组，P<0.001；YT盐高剂量给药组vs模型组，P<0.01)。
转棒试验结果显示，如图8，MPTP造模后，模型组动物相比假手术组在转棒试验中的在棒时长中位数降低。YT盐高剂量给药组在设定治疗方案下，对MPTP引起的动物在棒时长减小具有显著改善作用(YT盐高剂量给药组vs模型组，P<0.05)。
黑质区TH组织免疫染色结果显示，见图9，相较于假手术组，模型组的黑质区TH阳性细胞数显著减少(P<0.05)，L-DOPA组、YT盐低剂量给药组和YT盐高剂量给药组在设定剂量下可显著抑制模型动物黑质区TH阳性细胞减少变化(P<0.0001)。
纹状体TH组织免疫染色结果显示，见图10，相较于假手术组，模型组的TH阳性神经元丢失极为显著(P<0.0001)，YT盐高剂量给药组在设定治疗方案下可显著抑制黑质区TH阳性神经元丢失(P<0.01)。
本实施例的评估结果表明，YT盐在167.5mg/kg剂量下可显著抑制模型动物黑质区及纹状体区多巴胺能神经元凋亡，在248mg/kg剂量下不仅可显著抑制模型动物黑质区多巴胺能神经元凋亡，并对模型动物抓力、转棒等行为学指标具有明显改善作用。这提示YT盐对于帕金森病具有潜在的预防、缓解或治疗的效果。
实施例7：化合物YT盐对6-OHDA诱导的帕金森病大鼠模型的影响。
选择雄性SD大鼠48只，分为4组(12只/组)，分别为假手术组(正常对照)、模型组(模型对照)、Istradefylline组(伊曲茶碱，作为阳性药对照，10mg/kg)和YT盐给药组(248mg/kg)。使用6-OHDA对大鼠右侧颅内(内侧前脑束，MFB)注射20μg6-OHDA构建帕金森模型。造模后使用Istradefylline和YT盐每天灌胃给药1次，连续给药6周，并在给药6周时进行网格行走实验来评价大鼠疾病进展情况。
结果显示，如图11和图12，经6-OHDA构建帕金森模型后，在网格行走实验中模型组动物的错步次数和错步率均显著上升(P<0.05)。与模型组相比，YT盐给药组在设定剂量下，可显著减少错步次数和错步率(P<0.05)。
本实施例的评估结果表明，YT盐对6-OHDA诱导的大鼠帕金森病模型的运动行为能力损伤具有显著的改善作用。这提示YT盐对于帕金森病具有潜在的缓解或治疗的效果。
应理解，在阅读了本发明的上述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (54)

  1. 一种组合产品，其包含：
    (a)式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
    其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基；
    或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
    或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
    (b)胆汁酸或其衍生物或其类似物或其药学上可接受的盐、溶剂化物、水合物或立体异构体；
    其中所述组分(a)与组分(b)的摩尔比为1:1000-1000:1。
  2. 根据权利要求1所述的组合产品，其中R1、R2和R3各自独立地选自：氢、羟基、甲氧基和苄氧基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。
  3. 根据权利要求1或2所述的组合产品，其中R4、R5和R6各自独立地选自：氢、羟基和甲氧基，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。
  4. 根据权利要求1-3中任一项所述的组合产品，其中R1、R2和R3中的一个或两个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。
  5. 根据权利要求1-4中任一项所述的组合产品，其中R4、R5和R6中的一个或两个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。
  6. 根据权利要求1-5中任一项所述的组合产品，其中式(I)的化合物的药学上可接受的盐选自马来酸盐、盐酸盐、草酸盐、酒石酸盐、富马酸盐、柠檬酸盐、苹果酸盐、己二酸盐、甲磺酸盐、磷酸盐、乙酸盐、扁桃酸盐或硫酸盐；优选马来酸盐或盐酸盐，更优选盐酸盐。
  7. 根据权利要求1-6中任一项所述的组合产品，其中式(I)的化合物选自：
  8. 根据权利要求1-7中任一项所述的组合产品，其中所述胆汁酸或其衍生物或其类似物选自：胆酸、奥贝胆酸、熊去氧胆酸、鹅去氧胆酸、猪去氧胆酸、7-氧代石胆酸、石胆酸、碘代去氧胆酸、碘胆酸、牛磺鹅去氧胆酸、牛磺去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、甘氨胆酸、24-去甲熊去氧胆酸和牛磺熊去氧胆酸。
  9. 根据权利要求1-8中任一项所述的组合产品，其中组分(a)与组分(b)的摩尔比为1:1或2:1。
  10. 根据权利要求1-9中任一项所述的组合产品，其用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。
  11. 根据权利要求1-10中任一项所述的组合产品，其用于治疗、缓解和/或预防神经退行性疾病或病症。
  12. 根据权利要求1-11所述的组合产品，其中所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。
  13. 一种药物组合物，其包含：
    (a)式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
    其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基；
    或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
    或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
    (b)胆汁酸或其衍生物或其类似物或其药学上可接受的盐、溶剂化物、水合物或立体异构体；
    (c)药学上可接受的载体、赋形剂和/或稀释剂；
    其中所述组分(a)与组分(b)的摩尔比为1:1000-1000:1。
  14. 根据权利要求13所述的药物组合物，其中R1、R2和R3各自独立地选自：氢、羟基、甲氧基和苄氧基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。
  15. 根据权利要求13或14所述的药物组合物，其中R4、R5和R6各自独立地选自：氢、羟基和甲氧基，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。
  16. 根据权利要求13-15中任一项所述的药物组合物，其中R1、R2和R3中的一个或两个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。
  17. 根据权利要求13-16中任一项所述的药物组合物，其中R4、R5和R6中的一个或两个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。
  18. 根据权利要求13-17中任一项所述的药物组合物，其中式(I)的化合物的药学上可接受的盐选自马来酸盐、盐酸盐、草酸盐、酒石酸盐、富马酸盐、柠檬酸盐、苹果酸盐、己二酸盐、甲磺酸盐、磷酸盐、乙酸盐、扁桃酸盐或硫酸盐；优选马来酸盐或盐酸盐，更优选盐酸盐。
  19. 根据权利要求13-18中任一项所述的药物组合物，其中式(I)的化合物选自：
  20. 根据权利要求13-19中任一项所述的药物组合物，其中所述胆汁酸或其衍生物或其类似物选自：胆酸、奥贝胆酸、熊去氧胆酸、鹅去氧胆酸、猪去氧胆酸、7-氧代石胆酸、石胆酸、碘代去氧胆酸、碘胆酸、牛磺鹅去氧胆酸、牛磺去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、甘氨胆酸、24-去甲熊去氧胆酸和牛磺熊去氧胆酸。
  21. 根据权利要求13-20中任一项所述的药物组合物，其中组分(a)与组分(b)的摩尔比为1:1或2:1。
  22. 根据权利要求13-21中任一项所述的药物组合物，其用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。
  23. 根据权利要求13-22中任一项所述的药物组合物，其用于治疗、缓解和/或预防神经退行性疾病或病症。
  24. 根据权利要求23所述的药物组合物，其中所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。
  25. 一种式(II)的酸-碱加成盐：
    (A+)m(B-)n(C-)p
    (II)
    其中，(a)A+是式(I)的化合物的阳离子部分；
    其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基，
    或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N，
    或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；
    (b)B-是胆汁酸或其衍生物或其类似物的阴离子部分；且
    (c)C-是酸根阴离子；
    其中m、n和p各自独立地是选自1-6的整数，使得盐构型达到电荷平衡，且当m＝n时，p为0。
  26. 根据权利要求25所述的酸-碱加成盐，其中R1、R2和R3各自独立地选自：氢、羟基、甲氧基和苄氧基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。
  27. 根据权利要求25或26所述的酸-碱加成盐，其中R4、R5和R6各自独立地选自：氢、羟基和甲氧基，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。
  28. 根据权利要求25-27中任一项所述的酸-碱加成盐，其中R1、R2和R3中的一个或两个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。
  29. 根据权利要求25-28中任一项所述的酸-碱加成盐，其中R4、R5和R6中的一个或两个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。
  30. 根据权利要求25-29中任一项所述的酸-碱加成盐，其中式(I)的化合物选自下组的阳离子部分：
  31. 根据权利要求25-30中任一项所述的酸-碱加成盐，其中所述组分(b)选自下组的阴离子部分：胆酸、奥贝胆酸、熊去氧胆酸、鹅去氧胆酸、猪去氧胆酸、7-氧代石胆酸、石胆酸、碘代去氧胆酸、碘胆酸、牛磺鹅去氧胆酸、牛磺去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、甘氨胆酸、24-去甲熊去氧胆酸和牛磺熊去氧胆酸。
  32. 根据权利要求25-31中任一项的酸-碱加成盐，其中m为1，n为1，p为0，或者m为2，n为1且p为1。
  33. 根据权利要求25-32中任一项所述的酸-碱加成盐，其用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。
  34. 根据实施方案25-33中任一项所述的酸-碱加成盐，其用于治疗、缓解和/或预防神经退行性疾病或病症。
  35. 根据权利要求34所述的酸-碱加成盐，其中所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。
  36. 一种药物组合物，其包含根据权利要求1-12中任一项所述的组合产品或根据权利要求25-35中任一项所述的酸-碱加成盐。
  37. 一种治疗、缓解和/或预防神经退行性疾病或病症的方法，其包括向有此需要的患者施用根据权利要求1-36中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
  38. 根据权利要求37所述的方法，其中所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。
  39. 一种治疗和/或预防神经退行性疾病或病症的方法，其包括：
    方案1，向有此需要的患者施用：
    (a)治疗和/或预防有效量的式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
    其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、C1-C6烷基和苯基，
    或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N，
    或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；或者，
    方案2，向有此需要的患者同时、共同、分开或依次施用：
    (a)治疗和/或预防有效量的式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体：
    其中R1、R2、R3、R4、R5和R6相同或不同，且各自独立地选自：氢、卤素、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基，所述羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基和C1-C6卤代烷氧基任选地被一个或多个选自以下组的基团取代：卤素、 C1-C6烷基和苯基，
    或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N，
    或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个杂原子的4-7元杂环，所述杂原子选自O、S或N；和
    (b)治疗和/或预防有效量的胆汁酸或其衍生物或其类似物或其药学上可接受的盐、溶剂化物、水合物或立体异构体。
  40. 根据权利要求39所述的方法，其中R1、R2和R3各自独立地选自：氢、羟基、甲氧基和苄氧基，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。
  41. 根据权利要求39或40所述的方法，其中R4、R5和R6各自独立地选自：氢、羟基和甲氧基，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的4-7元杂环。
  42. 根据权利要求39-41中任一项所述的方法，其中R1、R2和R3中的一个或两个为氢，或者R1、R2和R3中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。
  43. 根据权利要求39-42中任一项所述的方法，其中R4、R5和R6中的一个或两个为氢，或者R4、R5和R6中任意相邻的两者与它们所连接的碳原子一起形成含有一个或多个氧原子的5元杂环。
  44. 根据权利要求39-43中任一项所述的方法，其中式(I)的化合物的药学上可接受的盐选自马来酸盐、盐酸盐、草酸盐、酒石酸盐、富马酸盐、柠檬酸盐、苹果酸盐、己二酸盐、甲磺酸盐、磷酸盐、乙酸盐、扁桃酸盐或硫酸盐；优选马来酸盐或盐酸盐，更优选盐酸盐。
  45. 根据权利要求39-44中任一项所述的方法，其中式(I)的化合物选自：

  46. 根据权利要求39-45中任一项所述的方法，其中所述胆汁酸或其衍生物或其类似物选自：胆酸、奥贝胆酸、熊去氧胆酸、鹅去氧胆酸、猪去氧胆酸、7-氧代石胆酸、石胆酸、碘代去氧胆酸、碘胆酸、牛磺鹅去氧胆酸、牛磺去氧胆酸、甘氨熊去氧胆酸、牛磺胆酸、甘氨胆酸、24-去甲熊去氧胆酸和牛磺熊去氧胆酸。
  47. 根据权利要求39-46中任一项所述的方法，其中组分(a)与组分(b)的摩尔比为1:1或2:1。
  48. 根据权利要求39-47中任一项所述的方法，其中所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。
  49. 一种试剂盒，其包含：
    根据权利要求1-36中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体以及使用说明书，
    其中所述试剂盒用于治疗、缓解或预防神经退行性疾病或病症。
  50. 根据实施方案49所述的试剂盒，其中所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。
  51. 一种提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力的方法，其包括使根据权利要求1-36中任一项所述的组合产品、药物组合物、酸-碱加成盐、或式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体与所述细胞接触。
  52. 式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体，其用于提高细胞存活力、特别是神经元细胞存活力，尤其是通过减少细胞中活性氧化代谢物介导的氧化损伤、调节细胞中的氧化还原稳态或减少细胞中的线粒体功能障碍而提高细胞存活力。
  53. 式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体，其用于治疗、缓解和/或预防神经退行性疾病或病症。
  54. 根据权利要求53所述的式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物或立体异构体，其中所述神经退行性疾病或病症选自阿尔茨海默氏病(AD)、亨廷顿氏病(HD)、帕金森氏病(PD)、肌萎缩侧索硬化症(ALS)、肌肉减少症、肌肉萎缩、皮克病、多发梗塞性痴呆、克-雅二氏病、具有雷维小体的痴呆症(DLB)、混合型痴呆症和额颞痴呆症。
PCT/CN2024/096520 2023-05-31 2024-05-31 一种组合产品、盐及其用于治疗神经退行性疾病或病症的用途 WO2024245371A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202310639549 2023-05-31
CN202310639549.4 2023-05-31
CN202410302178.5 2024-03-15
CN202410302178 2024-03-15

Publications (1)

Publication Number Publication Date
WO2024245371A1 true WO2024245371A1 (zh) 2024-12-05

Family

ID=93656743

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/096520 WO2024245371A1 (zh) 2023-05-31 2024-05-31 一种组合产品、盐及其用于治疗神经退行性疾病或病症的用途

Country Status (1)

Country Link
WO (1) WO2024245371A1 (zh)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105168228A (zh) * 2015-11-04 2015-12-23 北京凯因科技股份有限公司 奥贝胆酸和小檗碱的复方组合物及其应用
CN105693805A (zh) * 2016-03-15 2016-06-22 合肥华方医药科技有限公司 一种胆酸类小檗碱偶合物的制备及医药用途
CN106687460A (zh) * 2014-07-29 2017-05-17 深圳君圣泰生物技术有限公司 小檗碱盐、熊去氧胆酸盐、相关复方及其制备方法和应用
CN108137575A (zh) * 2015-04-06 2018-06-08 深圳君圣泰生物技术有限公司 熊去氧胆酸与小檗碱或左旋肉碱的共轭化合物和其组合物及其方法
EA201990883A1 (ru) * 2015-03-04 2019-12-30 Шэньчжэнь Хайтайд Биофармасьютикал, Лтд. Соли берберина, соли урсодезоксихолевой кислоты и их комбинации, способы получения и применения
WO2022185228A1 (en) * 2021-03-02 2022-09-09 S&R Farmaceutici S.P.A. Composition or formulation comprising one or more 5-alpha-reductase inhibitors and one or more bile acids
CN117618444A (zh) * 2023-11-27 2024-03-01 深圳君圣泰生物技术有限公司 一种药物组合物、酸碱加成盐或偶联物及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106687460A (zh) * 2014-07-29 2017-05-17 深圳君圣泰生物技术有限公司 小檗碱盐、熊去氧胆酸盐、相关复方及其制备方法和应用
EA201990883A1 (ru) * 2015-03-04 2019-12-30 Шэньчжэнь Хайтайд Биофармасьютикал, Лтд. Соли берберина, соли урсодезоксихолевой кислоты и их комбинации, способы получения и применения
CN108137575A (zh) * 2015-04-06 2018-06-08 深圳君圣泰生物技术有限公司 熊去氧胆酸与小檗碱或左旋肉碱的共轭化合物和其组合物及其方法
CN105168228A (zh) * 2015-11-04 2015-12-23 北京凯因科技股份有限公司 奥贝胆酸和小檗碱的复方组合物及其应用
CN105693805A (zh) * 2016-03-15 2016-06-22 合肥华方医药科技有限公司 一种胆酸类小檗碱偶合物的制备及医药用途
WO2022185228A1 (en) * 2021-03-02 2022-09-09 S&R Farmaceutici S.P.A. Composition or formulation comprising one or more 5-alpha-reductase inhibitors and one or more bile acids
CN117618444A (zh) * 2023-11-27 2024-03-01 深圳君圣泰生物技术有限公司 一种药物组合物、酸碱加成盐或偶联物及其应用

Similar Documents

Publication Publication Date Title
EP3573982B1 (en) Bis-heteroaryl derivatives as modulators of protein aggregation
JP6989505B2 (ja) Ｍａｌｔ１阻害剤およびその使用
JP7073385B2 (ja) タンパク質凝集のモジュレーターとしての二環式ビス－ヘテロアリール誘導体
EP2872143B1 (en) Di-and tri-heteroaryl derivatives as inhibitors of protein aggregation
CN110183461A (zh) 皮质抑素类似物及其合成和用途
EP3806958B1 (en) 6-aminopyridin-3-yl pyrazoles as modulators of roryt
KR102602998B1 (ko) 억제제 및 이의 사용
EP2967046A1 (en) Benzimidazole derivatives and uses thereof
EP2830608B1 (en) Phenyl-urea and phenyl-carbamate derivatives as inhibitors of protein aggregation
EP2320738A1 (en) Substituted aminothiazole derivatives, pharmaceutical compositions, and methods of use
IL291898A (en) Quinone-, hydroquinone- and naphthoquinone-analogues of vatiquinone for treatment of mitochondrial disorder diseases
WO2024245371A1 (zh) 一种组合产品、盐及其用于治疗神经退行性疾病或病症的用途
CN105218399B (zh) 一种取代乙酰肼类衍生物、其制备方法及用途
US6716857B2 (en) Tetrahydropyridine derivatives acting on muscarinic acetylcholine receptors
JP7295145B2 (ja) 神経変性疾患を治療するための医薬及びその使用
WO2024245370A1 (zh) 一种组合产品、盐及其用途
KR20220118483A (ko) Oga 억제제 화합물
RU2799454C2 (ru) Терапевтический препарат для лечения нейродегенеративных заболеваний и его применение
WO2020059841A1 (ja) プリオン病治療薬
WO2017098733A1 (ja) インドール酢酸誘導体
Montanari Cannabinoid system combined to classic targets for a new MTDL strategy: design and synthesis of natural inspired molecules for Alzheimer's disease
WO2017098731A1 (ja) ４－フェニル－４－オキソブタン酸誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24814566

Country of ref document: EP

Kind code of ref document: A1