Application of 1-(3-aminopropyl) substituted cyclic amine compound

Abstract

The invention relates to medical application of a 1-(3-aminopropyl) substituted cyclic amine compound. Specifically, the invention relates to application of the 1-(3-aminopropyl) substituted cyclic amine compound shown in a general formula (I) or pharmaceutically acceptable salts, solvates, optically pure isomers, stereoisomers or mixtures thereof in preparation of medicines for treating and / or preventing multiple sclerosis and related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to the use of 1-(3-aminopropyl) substituted cyclic amine compounds in the preparation of drugs for treating and / or preventing multiple sclerosis and related diseases. Background Art

[0002] Multiple sclerosis (MS) is a disease characterized by chronic inflammatory demyelination of the central nervous system mediated by the immune system. It mainly affects the spinal cord and the white matter of the brain, and is accompanied by inflammatory infiltration, myelin loss, and glial cell lesions. According to the different disease progressions, multiple sclerosis can be divided into relapsing remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). The clinical symptoms of multiple sclerosis are mostly manifested as limb weakness, visual impairment, dizziness, etc., and can reach the peak of onset within a few days, leading to paralysis or blindness in severe cases. When multiple sclerosis enters the late stage, cognitive dysfunction and mental abnormalities will also occur. At present, the global number of cases of multiple sclerosis is about 2.3 million, and the incidence rate in China is about 50 / 1 million person-times, and there is an obvious upward trend in recent years. The average survival time of multiple sclerosis patients is 40 years, and they are deeply affected by the disease and treatment. Patients are faced with a series of problems such as progressive disability and psychosocial adaptation for a long time, which not only brings great pain to patients, but also causes an extremely heavy economic burden to society.

[0003] At present, the pathogenesis of multiple sclerosis is not yet clear, and the involved factors include the central nervous system, immune system, nutrition, and environment. Demyelination, as the main pathological hallmark of multiple sclerosis, may be caused by immune responses mediated by T cells and B cells. During the occurrence of multiple sclerosis, the peripheral immune system mediated by T cells and B cells is activated, releasing a large number of inflammatory factors, attacking the blood brain barrier (BBB), and infiltrating into the central nervous system. The change of the inflammatory microenvironment in the central nervous system causes gliosis and excessive secretion of inflammatory factors, thereby damaging oligodendrocytes, leading to their necrosis and apoptosis, and triggering the shedding of myelin sheaths. Currently, the drugs for treating multiple sclerosis only play a role in repair treatment. More than 10 disease-modifying therapies for multiple sclerosis have been marketed abroad, mainly by inhibiting the peripheral immune response to reduce disease recurrence and delay disability. Among them, fingolimod, as a receptor agonist of sphingosine-1-phosphate, binds to the S1P receptor on lymphocytes to prevent their release from lymphoid tissues, reducing their infiltration into the central nervous system and causing multiple sclerosis. However, due to the diversity of S1P distribution in the human body, adverse reactions are prone to occur after the use of fingolimod, such as lymphopenia, bradycardia, atrioventricular block, and retinal macular edema. Currently, only interferon β-1a, β-1b, and teriflunomide are approved in China. Among them, teriflunomide is the main active metabolite of the anti-rheumatic drug leflunomide, which inhibits the key mitochondrial enzyme in the de novo pyrimidine synthesis pathway - dihydroorotate dehydrogenase, reducing the proliferation of activated T cells and B cells, lymphocyte infiltration in the central system, and axonal loss, thereby protecting the nervous system function. Due to the limited drugs for preventing the recurrence of multiple sclerosis in the Chinese market and the lack of effective treatment methods to prevent nerve axon damage or myelin repair, patients with multiple sclerosis face great treatment difficulties.

[0004] It has been reported that CCR5 antagonists can be used to inhibit multiple sclerosis. However, the current CCR5 antagonists for treating multiple sclerosis have problems such as a long administration cycle and slow onset, making it difficult for CCR5 antagonists to be practically applied in the preparation of drugs for treating multiple sclerosis.

[0005] Therefore, there is an urgent need in the art to develop novel drugs that can effectively treat and / or prevent multiple sclerosis and related diseases. Summary of the Invention

[0006] The object of the present invention is to provide the use of 1-(3-aminopropyl) substituted cyclic amine compounds in the preparation of drugs for treating and / or preventing multiple sclerosis and related diseases.

[0007] In a first aspect of the present invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof, for the preparation of a medicament for the treatment and / or prevention of multiple sclerosis and related diseases;

[0008] The compound of formula (I) has the following structure:

[0009]

[0010] wherein,

[0011] W is absent or is -CH 2 CH 2 -; X is N or CR 6 ;

[0012] R 1 is selected from a 5- to 7-membered heteroaryl which is unsubstituted or substituted with 1 to 3 substituents, the heteroaryl containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, and the substituents are each independently selected from halogen, C1-C4 straight-chain or branched-chain alkyl, C1-C4 straight-chain or branched-chain haloalkyl, C1-C4 straight-chain or branched-chain alkoxy, C1-C4 straight-chain or branched-chain haloalkoxy, -NR 10 R 11 、-C(=O)R 12 、C1-C4 straight-chain or branched-chain alkanoyloxy, cyano, nitro and hydroxy, or two adjacent substituents together with the carbon atom to which they are attached form a 5- to 7-membered ring;

[0013] R 10 and R 11 are each independently selected from H, C1-C4 straight-chain or branched-chain alkyl and -C(=O)R 13 ;

[0014] R 12 is selected from C1-C4 straight-chain or branched-chain alkyl, C1-C4 straight-chain or branched-chain alkoxy, hydroxy, amino (NH 2 ) and C1-C4 straight-chain or branched-chain alkylamino;

[0015] R 13 is selected from H and C1-C4 straight-chain or branched-chain alkyl;

[0016] R 2Selected from the following groups which are unsubstituted or substituted by 1 - 3 substituents: C1 - C6 straight or branched chain alkyl, C3 - C7 cycloalkyl, 4 - 7 - membered heterocyclic group, C6 - C12 aryl or 5 - 7 - membered heteroaryl; wherein, the substituents are selected from halogen, hydroxy, C1 - C4 straight or branched chain alkyl, C1 - C4 straight or branched chain haloalkyl, C1 - C4 straight or branched chain alkoxy, C1 - C4 straight or branched chain alkylcarbonyl, C1 - C4 straight or branched chain haloalkoxy, C1 - C4 straight or branched chain alkylsulfonyl, C1 - C4 straight or branched chain alkylsulfonylcarbamoyl, tetrazolyl, cyano, nitro, amino, carboxyl, phenyl and phenoxy;

[0017] R 3 、R 4 and R 5 are each independently selected from hydrogen, C1 - C6 straight or branched chain alkyl, C1 - C6 straight or branched chain haloalkyl and C3 - C7 cycloalkyl;

[0018] R 6 is selected from hydrogen and C1 - C6 straight or branched chain alkyl;

[0019] Alternatively, R 5 and R 6 can be linked together with to form

[0020] R 7 is selected from hydrogen, C(=O)R 8 、C(=O)OR 8 、C(=O)NR 8 R 9 、SO 2 R 8 and the following groups which are substituted by 1 - 3 substituents: C1 - C6 straight or branched chain alkyl, C3 - C7 cycloalkyl, 4 - 7 - membered heterocyclic group, benzyl, C6 - C12 aryl and 5 - 7 - membered heteroaryl; wherein, the substituents are selected from halogen, hydroxy, C1 - C4 straight or branched chain alkoxy, C1 - C4 straight or branched chain alkyl, C1 - C4 straight or branched chain haloalkyl, C1 - C4 straight or branched chain haloalkoxy, cyano, nitro, amino, carboxyl;

[0021] R 8 and R 9Each independently selected from hydrogen and the following groups which are unsubstituted or substituted with 1 - 3 substituents: C1 - C6 straight-chain or branched-chain alkyl, C3 - C7 cycloalkyl, 4 - 7-membered heterocyclic group, benzyl, C6 - C12 aryl, and 5 - 7-membered heteroaryl; wherein, the substituents are selected from halogen, hydroxy, C1 - C4 straight-chain or branched-chain alkoxy, C1 - C4 straight-chain or branched-chain alkyl, C1 - C4 straight-chain or branched-chain haloalkyl, C1 - C4 straight-chain or branched-chain haloalkoxy, cyano, nitro, amino, carboxyl.

[0022] In another preferred example, the compound is selected from the group consisting of:

[0023]

[0024] In another preferred example, multiple sclerosis is selected from the group consisting of: relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, progressive-relapsing multiple sclerosis, or a combination thereof.

[0025] In another preferred example, multiple sclerosis-related diseases are diseases selected from the group consisting of: neuromyelitis optica, acute disseminated encephalomyelitis, stroke, craniocerebral injury, epilepsy, Alzheimer's disease, Parkinson's disease, immune inflammatory response, demyelinating injury.

[0026] In another preferred example, multiple sclerosis and its related diseases: relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, stroke, craniocerebral injury, epilepsy, immune inflammatory response, demyelinating injury.

[0027] In another preferred example, the compound is used for:

[0028] (1) Repairing demyelination in the spinal cord of multiple sclerosis;

[0029] (2) Reducing infiltrating immune cells in the spinal cord of multiple sclerosis;

[0030] (3) Reducing myeloid deviation in the spinal cord of multiple sclerosis.

[0031] In another preferred embodiment, the pharmaceutically acceptable salts include salts formed by reacting the compounds of the present invention with inorganic acids or organic acids to form conventional pharmaceutically acceptable salts. For example, conventional pharmaceutically acceptable salts can be prepared by reacting the compounds of the present invention with inorganic acids or organic acids. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid, etc., and the organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, hydroxy-14-ethanesulfonic acid, etc.; or sodium salts, potassium salts, calcium salts, aluminum salts or ammonium salts formed by reacting the compounds of the present invention with inorganic bases; or methylamine salts, ethylamine salts or ethanolamine salts formed by reacting the compounds of the present invention with organic bases.

[0032] In another preferred embodiment, the administration route of the compound is selected from the group consisting of: oral, rectal, parenteral.

[0033] In another preferred embodiment, the parenteral administration route is selected from the group consisting of: intravenous, intramuscular or subcutaneous administration.

[0034] In another preferred embodiment, the oral preparations are selected from the group consisting of: capsules, tablets, pills, powders, granules, emulsions, solutions, suspensions, syrups and tinctures.

[0035] The second aspect of the present invention provides the use of a pharmaceutical composition for the preparation of a medicament for treating and / or preventing multiple sclerosis and related diseases;

[0036] And the pharmaceutical composition comprises:

[0037] (i) A first active ingredient selected from the group consisting of: a compound of formula (I), or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer thereof;

[0038] (ii) Optionally a second active ingredient selected from the group consisting of: interferon β-1a, interferon β-1b, teriflunomide, fingolimod, copaxone, ofatumumab, or a combination thereof;

[0039] (iii) A pharmaceutically acceptable carrier;

[0040] The compound of formula (I) is as defined in the first aspect of the present invention.

[0041] In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0042]

[0043] In another preferred embodiment, in the pharmaceutical composition, the content of the first active ingredient is 0.01 - 99 wt%, preferably 0.1 - 90 wt%, based on the total weight of the pharmaceutical composition.

[0044] In another preferred embodiment, the use of the compound of formula (I) as a single ingredient in combination with other effective methods for the treatment of multiple sclerosis (such as surgical treatment, radiotherapy, etc.) in the comprehensive treatment of multiple sclerosis.

[0045] The third aspect of the present invention provides a method for treating and / or preventing multiple sclerosis and its related diseases, comprising administering to a subject in need a medically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or a mixture thereof;

[0046] The compound of formula (I) is as defined in the first aspect of the present invention.

[0047] In another preferred embodiment, the subject is a primate mammal, such as a human.

[0048] The present invention relates to a drug for treating and / or preventing multiple sclerosis, which contains as an active ingredient a 1-(3-aminopropyl)-substituted cyclic amine compound represented by the general formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, prodrug and a mixture thereof.

[0049] The drug can be introduced into the body, such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue, by injection, spraying, nasal dropping, eye dropping, osmosis, absorption, physical or chemical mediated methods; or it can be mixed or encapsulated with other substances and then introduced into the body. If necessary, one or more pharmaceutically acceptable carriers can be added to the above drug.

[0050] The carriers include conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

[0051] Using the 1-(3-aminopropyl)-substituted cyclic amine compound represented by the general formula (I) or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, prodrug as an active ingredient, alone or in combination or formulated with other drugs, excipients, etc. into various dosage forms, including but not limited to tablets, powders, pills, injections, capsules, films, suppositories, ointments, granules, etc. The drugs of the above various dosage forms can be prepared according to the conventional methods in the pharmaceutical field.

[0052] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or technical solutions in another preferred example. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent or similar purpose. Due to space limitations, they will not be elaborated one by one here. Brief Description of the Drawings

[0053] Figure 1 Respectively show the neurological deficit scores and body weight changes of mice in the model group drug administration group (EAE + DC521022) and the model group control group (EAE + Vehicle) after immunization; Figure 1 A shows that on the day of modeling, 50 mg / kg of DC521022 and normal saline (Saline) were intraperitoneally injected; Figure 1 B shows that after the mice showed symptoms, 50 mg / kg of DC521022 and normal saline (Saline) were intraperitoneally injected; Figure 1 C shows that on the day of modeling, 50 mg / kg of DC521022 and normal saline (Saline) were given by gavage; Figure 1 D shows that after the mice showed symptoms, 50 mg / kg of DC521022 and normal saline (Saline) were given by gavage.

[0054] Figure 2 Shows the H&E and Luxol fast blue staining of spinal cord tissue sections of mice in the DC521022 treatment group and the normal saline treatment group after 14 days and 28 days of drug administration respectively.

[0055] Figure 3 Shows the percentages of demyelination and inflammatory cell infiltration in the spinal cords of mice in the DC521022 treatment group and the normal saline treatment group.

[0056] Figure 4 Shows the results of analyzing the myeloid deviation of the bone marrow of mice on the 14th day and 28th day after DC521022 administration by flow cytometry. Figure 4 A shows the analysis of myeloid deviation of mouse bone marrow by flow cytometry; Figure 4 B shows a schematic diagram of the changes in the proportion and number of femoral hematopoietic stem cells (HSCs) after 14 days; Figure 4 C shows a schematic diagram of the changes in the proportion and number of hematopoietic stem cells after 14 days.

[0057] Figure 5 Shows the clinical score results of the EAE model group administered with the CCR5 antagonist DAPTA. Detailed Embodiments

[0058] Through extensive and in-depth research and a large number of screenings, the present inventors unexpectedly developed for the first time a class of active ingredients that can effectively inhibit multiple sclerosis and its related diseases, namely the compounds represented by the general formula (I) or their pharmaceutically acceptable salts, enantiomers, diastereomers or racemates. Tests have shown that the active ingredients of the present invention can efficiently repair demyelination in the spinal cord of multiple sclerosis, reduce infiltrating immune cells and myeloid deviation in the spinal cord, thereby treating and / or preventing multiple sclerosis. On this basis, the present invention has been completed.

[0059] The term

[0060] "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group. For example, "C1-8 alkyl" refers to straight-chain alkyls and branched-chain alkyls containing 1 to 8 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, etc.

[0061] "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. For example, "C3-8 cycloalkyl" refers to cycloalkyls containing 3 to 8 carbon atoms, divided into monocyclic cycloalkyls and polycyclic cycloalkyls, where: monocyclic cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls.

[0062] "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where one or more ring atoms are selected from nitrogen, oxygen or S.

[0063] "aryl" refers to a fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic group with a conjugated π-electron system (i.e., its rings with adjacent pairs of carbon atoms), including but not limited to phenyl and naphthyl.

[0064] "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, said heteroatoms including nitrogen, oxygen and S. For example, 5-7 membered heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, and 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.

[0065] "alkoxy" refers to -O-(alkyl), where alkyl is defined as above. For example, "C1-8 alkoxy" refers to an alkyloxy containing 1-8 carbons, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc. The present invention will be further described below with specific examples.

[0066] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be admixed with the compound of general formula (I) of the present invention, its pharmaceutically acceptable salts or its solvates, and with each other, without significantly reducing the efficacy of the active ingredient. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0067] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0068] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweetening agents, flavoring agents and fragrances.

[0069] In addition to the active ingredient, suspensions may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum monostearate and agar or mixtures of these substances, etc.

[0070] There is no particular limitation on the mode of administration of the compound of formula (I) or the pharmaceutical composition of the present invention. Representative modes of administration include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0071] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyhydric alcohols and their suitable mixtures.

[0072] Active ingredient

[0073] The compound of formula (I) according to the present invention has the following structure:

[0074]

[0075] Wherein, each group is as defined above.

[0076] In another preferred embodiment, the compound is in the S configuration or the R configuration, preferably, in the S configuration.

[0077] In another preferred embodiment, R 1 is selected from the following groups which are unsubstituted or substituted with 1-3 substituents:

[0078]

[0079] The substituents are selected from halogen, C1-C4 straight-chain or branched-chain alkyl, C1-C4 straight-chain or branched-chain haloalkyl, C1-C4 straight-chain or branched-chain alkoxy, -NR 10 R 11 , -C(=O)R 12 , C1-C4 straight-chain or branched-chain alkylcarbonyloxy, C1-C4 straight-chain or branched-chain haloalkoxy, cyano, nitro and hydroxy, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring; preferably, the substituents are selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, NR 10 R 11 , -C(=O)R 12 , C1-C2 alkylcarbonyloxy, C1-C2 haloalkoxy, cyano, nitro and hydroxy, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring, 5-7 membered heteroaryl ring or 5-7 membered heterocyclic ring; preferably, the substituents are selected from halogen, methyl, methoxy, ethyl, amino, hydroxy, cyano, nitro, acetyl, formamido, acetamido, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, formyloxy, acetyloxy, methoxycarbonyl, trifluoromethyl and trifluoromethoxy, or two adjacent substituents together with the carbon atom to which they are attached form a benzene ring, cyclopentene ring or dioxolene ring.

[0080] In another preferred embodiment, R 10 and R 11 each independently selected from H, C1-C2 alkyl and -C(=O)R 13 .

[0081] In another preferred embodiment, R 12 is selected from C1-C2 alkyl, C1-C2 alkoxy, hydroxy, amino (NH 2 ) and C1-C2 alkylamino.

[0082] In another preferred example, R 13 is selected from H and C1-C2 straight-chain or branched-chain alkyl groups.

[0083] In another preferred example, R 2 is selected from the following groups which are unsubstituted or substituted by 1-3 substituents: C1-C4 straight-chain or branched-chain alkyl groups, C3-C7 cycloalkyl groups, 4-7-membered heterocyclic groups, and phenyl groups, wherein the substituents are selected from halogen, hydroxyl, C1-C4 straight-chain or branched-chain alkyl groups, C1-C4 straight-chain or branched-chain haloalkyl groups, C1-C4 straight-chain or branched-chain alkoxy groups, C1-C4 straight-chain or branched-chain alkylcarbonyl groups, C1-C4 straight-chain or branched-chain haloalkoxy groups, C1-C4 straight-chain or branched-chain alkylsulfonyl groups, C1-C4 straight-chain or branched-chain alkylsulfonylcarbamoyl groups, tetrazolyl groups, cyano groups, nitro groups, amino groups, carboxyl groups, phenyl groups, halophenyl groups, phenoxy groups, and halophenoxy groups.

[0084] In another preferred example, R 2 is selected from C1-C4 straight-chain or branched-chain alkyl groups, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methanesulfonylpiperidin-4-yl, 4-fluorobenzyl, phenyl, difluorocyclohexyl (such as 4,4-difluorocyclohexyl), ethylcyclohexyl, and phenoxymethyl.

[0085] In another preferred example, R 3 , R 4 and R 5 are each independently selected from hydrogen, C1-C4 straight-chain or branched-chain alkyl groups, and C3-C7 cycloalkyl groups.

[0086] In another preferred example, R 3 , R 4 and R 5 are each independently selected from hydrogen, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0087] In another preferred example, R 3 , R 4 and R 5 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and cyclopropyl.

[0088] In another preferred example, R 6 is selected from hydrogen and C1-C4 straight-chain or branched-chain alkyl groups, and more preferably selected from hydrogen, methyl, and ethyl.

[0089] Or R 5 and R 6 can be linked together with form together

[0090] In another preferred embodiment, R 7 is selected from hydrogen, C(=O)R 8 C(=O)OR 8 C(=O)NR 8 R 9 SO 2 R 8 and the following groups substituted with 1 to 3 substituents: C1-C4 straight or branched alkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocyclic group, benzyl and phenyl, wherein the substituents are selected from halogen, hydroxy, C1-C4 straight or branched alkoxy, C1-C4 straight or branched alkyl, C1-C4 straight or branched haloalkyl, C1-C4 straight or branched haloalkoxy, cyano, nitro, amino and carboxyl.

[0091] In another preferred embodiment, R 7 is selected from C(=O)R 8 C(=O)OR 8 and SO 2 R 8 ;

[0092] R 8 and R 9 are each independently selected from hydrogen and the following groups which are unsubstituted or substituted with 1 to 3 substituents: C1-C4 straight or branched alkyl, C1-C4 straight or branched haloalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocyclic group, benzyl, phenyl and 5- to 7-membered heteroaryl, wherein the substituents are selected from halogen, hydroxy, C1-C4 straight or branched alkoxy, C1-C4 straight or branched alkyl, C1-C4 straight or branched haloalkyl, C1-C4 straight or branched haloalkoxy, cyano, nitro, amino and carboxyl, preferably selected from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino and carboxyl.

[0093] In another preferred embodiment, R 8 and R 9 are each independently selected from hydrogen, C1-C4 straight or branched alkyl, C1-C4 straight or branched haloalkyl, C3-C7 cycloalkyl, benzyl and phenyl.

[0094] In another preferred embodiment, R 8 and R 9 are each independently selected from methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, sec-butyl and tert-butyl.

[0095] In another preferred embodiment, there is provided a 1-(3-aminopropyl) substituted cyclic amine compound represented by the general formula (II), its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or a mixture thereof:

[0096]

[0097] wherein R 1 , R 2 , R 3 , R 4 , R 5 , and W are as defined in the general formula (I).

[0098] In another preferred embodiment, in the general formula (II), R 1 is selected from the following groups which are unsubstituted or substituted with 1 to 3 substituents: The substituents are selected from halogen, C1-C4 straight-chain or branched-chain alkyl, C1-C4 straight-chain or branched-chain haloalkyl, C1-C4 straight-chain or branched-chain alkoxy, C1-C4 straight-chain or branched-chain alkylcarbonyloxy, C1-C4 straight-chain or branched-chain haloalkoxy, NR 10 R 11 , -C(=O)R 12 , cyano, nitro and hydroxyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring; preferably, the substituents are selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkylcarbonyloxy, C1-C2 alkoxy, C1-C2 haloalkoxy, NR 10 R 11 , -C(=O)R 12 , cyano, nitro and hydroxyl, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered carbocyclic ring, 5-7 membered heteroaryl ring or 5-7 membered heterocyclic ring; preferably, the substituents are selected from halogen, methyl, trifluoromethyl, trifluoromethoxy, methoxy, ethyl, amino, cyano, nitro, acetyl, formamido, acetamido, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetoxy, formyloxy and methoxycarbonyl, or two adjacent substituents together with the carbon atom to which they are attached form a benzene ring, cyclopentene ring or dioxolene ring;

[0099] R 10 and R 11 are each independently selected from H, C1-C4 straight-chain or branched-chain alkyl and -C(=O)R 13 ; preferably, R 10 and R 11 are each independently selected from H, C1-C2 alkyl and -C(=O)R 13 ;

[0100] R 12 is selected from C1-C4 linear or branched alkyl groups, C1-C4 linear or branched alkoxy groups, hydroxyl groups, amino groups (NH 2 ), and C1-C4 linear or branched alkylamino groups; preferably, R 12 is selected from C1-C2 alkyl groups, C1-C2 alkoxy groups, hydroxyl groups, amino groups (NH 2 ), and C1-C2 alkylamino groups;

[0101] R 13 is selected from H and C1-C4 linear or branched alkyl groups; preferably, R 13 is selected from H and C1-C2 linear or branched alkyl groups;

[0102] R 2 is selected from unsubstituted or 1-3 substituent-substituted phenyl groups, C1-C4 linear or branched alkyl groups, and C3-C7 cycloalkyl groups, wherein the substituents are selected from halogen, hydroxyl, C1-C4 linear or branched alkyl groups, C1-C4 linear or branched haloalkyl groups, C1-C4 linear or branched alkoxy groups, C1-C4 linear or branched alkylcarbonyl groups, C1-C4 linear or branched haloalkoxy groups, C1-C4 linear or branched alkylsulfonyl groups, C1-C4 linear or branched alkylsulfonylcarbamoyl groups, tetrazolyl groups, amino groups, phenyl groups, halophenyl groups, phenoxy groups, and halophenoxy groups.

[0103] In another preferred example, R 2 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methanesulfonylpiperidin-4-yl, 4-fluorobenzyl, phenyl, ethylcyclohexyl, and difluoro-substituted cyclohexyl;

[0104] R 3 , R 4 and R 5 are each independently selected from hydrogen and C1-C4 linear or branched alkyl groups.

[0105] In another preferred example, R 3 , R 4 and R 5 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

[0106] In another preferred example, R 3 , R 4 and R 5 are each independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl.

[0107] In another preferred embodiment, there is provided a 1-(3-aminopropyl) substituted cyclic amine compound represented by the general formula (III), its pharmaceutically acceptable salt, enantiomer, diastereomer, racemate or a mixture thereof:

[0108]

[0109] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and W are as defined in the general formula (I).

[0110] In the general formula (III), preferably, R 1 is selected from the following groups which are unsubstituted or substituted by 1-3 substituents: The substituents are selected from halogen, C1-C4 straight-chain or branched-chain alkyl, C1-C4 straight-chain or branched-chain haloalkyl, C1-C4 straight-chain or branched-chain alkylcarbonyloxy, C1-C4 straight-chain or branched-chain alkoxy, C1-C4 straight-chain or branched-chain haloalkoxy, NR 10 R 11 , -C(=O)R 12 , cyano, nitro and hydroxyl, or two adjacent substituents together with the carbon atom to which the substituents are attached form a 5-7 membered ring; preferably, the substituents are selected from halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, C1-C2 alkylcarbonyloxy, C1-C2 haloalkoxy, NR 10 R 11 , -C(=O)R 12 , cyano, nitro and hydroxyl, or two adjacent substituents together with the carbon atom to which the substituents are attached form a 5-7 membered carbocyclic ring, 5-7 membered heteroaryl ring or 5-7 membered heterocyclic ring; preferably, the substituents are selected from halogen, methyl, trifluoromethyl, trifluoromethoxy, methoxy, ethyl, amino, cyano, nitro, acetyl, formamido, acetamido, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, formyloxy, acetyloxy and methoxycarbonyl, or two adjacent substituents together with the carbon atom to which the substituents are attached form a benzene ring, cyclopentene ring or dioxolene ring;

[0111] R 10 and R 11 are each independently selected from H, C1-C4 straight-chain or branched-chain alkyl and -C(=O)R 13 ; preferably, R 10 and R 11 are each independently selected from H, C1-C2 alkyl and -C(=O)R 13;

[0112] R 12 is selected from C1-C4 linear or branched alkyl, C1-C4 linear or branched alkoxy, hydroxy, amino (NH 2 ), and C1-C4 linear or branched alkylamino; preferably, R 12 is selected from C1-C2 alkyl, C1-C2 alkoxy, hydroxy, amino (NH 2 ), and C1-C2 alkylamino;

[0113] R 13 is selected from H and C1-C4 linear or branched alkyl; preferably, R 13 is selected from H and C1-C2 linear or branched alkyl;

[0114] R 2 is selected from unsubstituted or 1-3 substituent-substituted C1-C4 linear or branched alkyl and C3-C7 cycloalkyl, wherein the substituent is selected from halogen, hydroxy, C1-C4 linear or branched alkyl, C1-C4 linear or branched haloalkyl, C1-C4 linear or branched alkoxy, C1-C4 linear or branched alkylcarbonyl, C1-C4 linear or branched haloalkoxy, C1-C4 linear or branched alkylsulfonyl, C1-C4 linear or branched alkylsulfonylcarbamoyl, tetrazolyl, cyano, and amino; preferably, R 2 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methanesulfonylpiperidin-4-yl, and difluoro-substituted cyclohexyl;

[0115] R 3 and R 4 are each independently selected from hydrogen and C1-C4 linear or branched alkyl; preferably, R 3 and R 4 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl; preferably, R 3 and R 4 are each independently selected from hydrogen, methyl, and ethyl;

[0116] R 5 and R 6 can be linked together with fragment to form

[0117] R 7 is selected from hydrogen, C(=O)R 8 , C(=O)OR 8 , C(=O)NR 8 R 9and SO 2 R 8 ; Preferably, R 7 is selected from C(=O)R 8 , C(=O)OR 8 and SO 2 R 8 ;

[0118] R 8 and R 9 are each independently selected from hydrogen and the following groups which are unsubstituted or substituted by 1 - 3 substituents: C1 - C4 straight-chain or branched-chain alkyl, C1 - C4 straight-chain or branched-chain haloalkyl, C3 - C7 cycloalkyl, and benzyl, wherein the substituents are selected from halogen, hydroxy, C1 - C4 straight-chain or branched-chain alkoxy, C1 - C4 straight-chain or branched-chain alkyl, C1 - C4 straight-chain or branched-chain haloalkyl, C1 - C4 straight-chain or branched-chain haloalkoxy, and amino, preferably from halogen, hydroxy, methoxy, ethoxy, methyl, ethyl, trifluoromethyl, trifluoromethoxy, and amino; Preferably, R 8 and R 9 are each independently selected from hydrogen, C1 - C4 straight-chain or branched-chain alkyl, C1 - C4 straight-chain or branched-chain haloalkyl, and C3 - C7 cycloalkyl; Preferably, R 8 and R 9 are each independently selected from methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.

[0119] In another preferred embodiment, the active ingredient is a compound selected from the group consisting of, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer, or a mixture thereof:

[0120]

[0121] Indications

[0122] Multiple sclerosis (MS) is an immune-mediated chronic and disabling inflammatory demyelinating disease of the central nervous system, often involving the periventricular region, juxtacortical region, optic nerve, spinal cord, brainstem, and cerebellum. The lesions are characterized by multiple locations in space and multiple occurrences in time. Multiple locations in space mean multiple lesion sites, and the brain, brainstem, cerebellum, and spinal cord can be involved simultaneously or successively. Multiple occurrences in time refer to a relapsing-remitting course. Due to the extensive involvement of multiple sites and repeated attacks, it can eventually lead to disability or even death. The clinical manifestations are diverse, and common symptoms include visual impairment, diplopia, limb sensory disturbances, limb motor disorders, ataxia, bladder or rectal dysfunction, etc.

[0123] Relapsing-remitting multiple sclerosis (RRMS)

[0124] Relapsing-remitting multiple sclerosis is characterized by relapses, defined, for example, as an episode of new neurological deficit or neurological worsening lasting more than 24 hours, without fever or infection. During remission, there is no significant disease progression. At different time points, RRMS can be further characterized as active (evidence of relapses and / or new MRI activity) or inactive, and progressive (confirmed increase in disability within a specific time period after a relapse) or non-progressive.

[0125] The term RMS (relapsing multiple sclerosis) encompasses RRMS, secondary progressive multiple sclerosis (SPMS), and clinically isolated syndrome (CIS).

[0126] Primary progressive multiple sclerosis (PPMS)

[0127] PPMS is characterized by worsening neurological function (disability accumulation) from the onset of symptoms, without early relapses or remissions. PPMS can be further characterized at different time points as active (evidence of occasional relapses and / or new MRI activity) or inactive, and progressive (evidence of disease worsening by objective measures over time, with or without relapses or new MRI activity) or non-progressive.

[0128] Everyone's experience with PPMS is unique. PPMS can have periods of transient disease stability, with or without relapses or new MRI activity, and periods of increasing disability with or without new relapses or MRI lesions.

[0129] Secondary progressive multiple sclerosis (SPMS)

[0130] SPMS occurs after an initial relapsing-remitting course. Most people diagnosed with RRMS will eventually transition to a secondary progressive course, in which there is progressive worsening of neurological function (disability accumulation) over time. SPMS can be further characterized at different time points as active (evidence of relapses and / or new MRI activity) or inactive, and progressive (evidence of disease worsening by objective measures over time, with or without relapses) or non-progressive.

[0131] Everyone's experience with SPMS is unique. SPMS occurs after relapsing-remitting MS. Disability gradually increases over time, with or without evidence of disease activity (relapses or MRI changes). In SPMS, occasional relapses may occur, as well as periods of stability.

[0132] Clinically isolated syndrome (CIS):

[0133] Clinically Isolated Syndrome (CIS) can refer to a single clinical episode of inflammatory demyelinating symptoms in the central nervous system (CNS) that suggest multiple sclerosis (MS). The manifestations of CIS can be monofocal or multifocal and usually may involve the optic nerve, brainstem, cerebellum, spinal cord, or cerebral hemispheres.

[0134] The main advantages of the present invention include:

[0135] (a) The compounds of the present invention have excellent repair effects on spinal cord demyelination in multiple sclerosis.

[0136] (b) The compounds of the present invention can significantly reduce the infiltrating immune cells and myeloid deviation in the spinal cord of multiple sclerosis.

[0137] (c) The compounds of the present invention have a rapid onset of action in the treatment of multiple sclerosis and have a significant effect on relieving the onset symptoms.

[0138] (d) The compounds of the present invention can delay the onset process of multiple sclerosis.

[0139] (e) The compounds of the present invention have good drug-likeness and are suitable for long-term administration.

[0140] It should be understood that these examples are only for illustrating the present invention and not for limiting the scope of the present invention. The experimental methods without specific conditions noted in the following examples are generally carried out under conventional conditions (such as the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight percentage and weight parts.

[0141] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described herein are only for demonstration purposes.

[0142] Example 1. Preparation of Compound DC521022

[0143] The synthetic route of Compound DC521022 is shown as follows:

[0144]

[0145] Compound 1-9 was synthesized using the above route. Compound 1-9 (35.6 mg, 0.1 mmol) was dissolved in 5 mL of dichloromethane, and then triethylamine (28 μL, 0.2 mmol), 4,4-difluorocyclohexanecarboxylic acid (18 mg, 0.11 mmol), HOBt (14.8 mg, 0.11 mmol), and EDCI (21.1 mg, 0.11 mmol) were added successively. The mixture was stirred at room temperature for 12 hours, water was added, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (DCM:CH 3 OH = 10:1) to obtain the final product, compound DC521022.

[0146] 1 HNMR (500 MHz, CDCl 3 ): δ 7.31 (dd, J = 5.0, 2.9 Hz, 1H), 7.13 (d, J = 2.9 Hz, 1H), 7.01 (dd, J = 4.9, 1.4 Hz, 1H), 4.29 (tt, J = 12.0, 5.5 Hz, 1H), 3.41 (s, 2H), 2.98 (p, J = 6.8 Hz, 1H), 2.51 (s, 5H), 2.37 - 1.97 (m, 10H), 1.97 - 1.55 (m, 11H), 1.38 (dd, J = 6.8, 2.1 Hz, 6H). 13 CNMR (125 MHz, CDCl 3 ) δ 173.25, 159.11, 150.61, 142.95, 126.53, 126.12, 121.04, 77.23, 59.02, 58.40, 47.99, 47.63, 47.18, 42.93, 35.52, 35.34, 34.51, 33.02, 32.82, 26.72, 26.03, 25.96, 25.86, 21.67, 13.21. ESI-MS m / z: 520.3 [M + H] + . HRMS (ESI) calcd for C 27 H 39 F 2 N 5 OS ([M + H] + ): 520.2916; found: 520.2917.

[0147] Example 2. In vivo test of the onset of multiple sclerosis

[0148] Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis. In this experiment, the behavioral scores and body weights of two groups of mice were evaluated daily until the end of the experiment to investigate the effect of compound DC521022 on the onset of multiple sclerosis.

[0149] Experimental animals: C57 / BL6 mice, 10 weeks old, female, were randomly divided into an experimental group and a control group, namely: model group control group (EAE+Vehicle): saline was given after modeling; model group drug administration group (EAE+DC521022): DC521022 suspension was given after modeling. According to different administration times and administration methods, the model group control group and the model group drug administration group were each divided into four groups: 50 mg / kg of DC521022 was intraperitoneally injected after immunization, 50 mg / kg of DC521022 was given by gavage after immunization, 50 mg / kg of DC521022 was intraperitoneally injected when symptoms started, 50 mg / kg of DC521022 was given by gavage when symptoms started, and the control group was given the same dose of saline at the same time.

[0150] Preparation method of DC521022: Weigh an appropriate amount of DC521022 according to the preparation plan for standby. First, add an appropriate amount of solvent to a beaker marked with a certain volume, then add an appropriate amount of hydrochloric acid (the calculation formula for the amount of hydrochloric acid used: hydrochloric acid∶test substance = 1∶1 (molar ratio)) to the beaker. After slowly adding the test substance, at room temperature, shake vigorously and continuously for about 16 h until the test substance is completely dissolved and the solution is clear, and then add the solvent to the corresponding scale line.

[0151] Animal experiment method: The mouse polypeptide antigen MOG35-55 (purity > 95%) was repeatedly mixed with complete Freund's adjuvant containing inactivated Mycobacterium tuberculosis in a syringe for emulsification to form a water-in-oil state. The back skin at the midpoint of the connection of the upper and lower limbs on both sides of the mouse was selected as the injection site, and the emulsion was subcutaneously injected (MOG35-55 (CAS No.: 149635-73-4) 200 μg, inactivated Mycobacterium tuberculosis 500 μg), 100 μL each for the upper and lower parts, a total of 200 μL was injected. On the day of immunization and two days later, 200 ng of pertussis toxin was intraperitoneally injected. After the animal experiment was completed, the status of the mice was observed daily, clinical scores were made, and records were kept. According to the standard of 0-5 points: 0: asymptomatic; 1: weak tail; 2: weak hind limbs or unsteady gait; 3: complete hind limb paralysis; 4: complete hind limb paralysis accompanied by weak or paralyzed forelimbs; 5: death.

[0152] Explanation of successful modeling: After the above-mentioned modeling, the mice showed symptoms of drooping tails, indicating that the mice were successfully induced with experimental autoimmune encephalomyelitis (EAE) by MOG35-55 immunization.

[0153] Route of administration: Model group (EAE+DC521022): EAE was induced in C57 / BL6 mice by immunization with MOG35-55. On the day of modeling and the first day of onset, 50 mg / kg of DC521022 was injected by intraperitoneal injection and perfusion respectively; Model group control (EAE+Vehicle): EAE was induced in C57 / BL6 mice by immunization with MOG35-55. On the day of modeling and the first day of onset, the same dose of normal saline was injected by intraperitoneal injection and perfusion respectively.

[0154] Experimental method: After modeling, on the day of immunization and the first day of onset, DC521022 preparation suspension was immediately given by intraperitoneal injection and perfusion respectively, and the control group of mice was given normal saline. The drug was administered daily and the status of the mice was observed for clinical scoring until 14 days and 28 days after modeling. And at the peak of EAE and two weeks after treatment, the myeloid deviation in the bone marrow, spinal cord demyelination, and spinal cord inflammatory cell infiltration were analyzed.

[0155] The experimental results showed that after treatment with DC521022, the onset of the mice was later than that of the control group, and the score was lower. Treatment with DC521022 also had a certain improvement on the body weight of the mice. Compared with the control group, the body weight of the treated mice increased ( Figure 1 as shown), and this kind of compound had good application prospects for the treatment of multiple sclerosis, so it had good commercial value.

[0156] Example 3. Test of spinal cord demyelination level in multiple sclerosis in vivo

[0157] In this experiment, immunohistochemistry was used to perform fast blue staining of the spinal cord of mice to compare the spinal cord demyelination levels of the DC521022 treatment group and the normal saline treatment group 14 days and 28 days after the successful establishment of the EAE model.

[0158] Preparation of paraffin sections: On the first day after successful induction of the EAE model, the mice were divided into an experimental group and a control group. In the experimental group, two groups were intraperitoneally or intragastrically injected with DC521022 on the day of modeling, and the other two groups were intraperitoneally or intragastrically injected with DC521022 at the onset of EAE in mice. The control group was injected with the same dose of normal saline by the same injection method as the control. For those administered on the day of immunization, they were observed for 2 weeks, and for those administered at the onset of symptoms, they were treated for 2 weeks. Then, the mice were anesthetized and sacrificed. The spinal cord was fixed after perfusion with phosphate buffer and 4% paraformaldehyde in sequence. First, the mice were deeply anesthetized with 20 μg / g tribromoethanol and properly fixed. The skin was longitudinally incised along the chest-abdominal connection line. After exposing the thoracic and abdominal cavities, the heart was freed and the liver was cut. The venous channel was opened, and 20 mL of PBS and 20 mL of 4% paraformaldehyde were sequentially administered through the left ventricle for perfusion. The criterion for successful perfusion was that abdominal organs such as the liver turned white. After perfusion, the back was incised along the midline, the spine was dissected, and the spinal cord was dissected, extending from the thoracic vertebra to the caudal vertebra. Then, it was incised along one side of the spine to expose the spinal cord. The lumbar spinal cord segments were taken and immersed in 4% paraformaldehyde at 4 °C for more than 16 h for fixation. After fixation, the brain tissue was taken out of the formaldehyde, placed in a tissue embedding cassette and marked, and placed in 50% ethanol, 75% ethanol, 85% ethanol, 95% ethanol, absolute ethanol (twice) for 1 h each, xylene for 20 min (twice), soft wax (52 - 54 °C) and hard wax (56 - 58 °C) for 1.5 h each. The specimens were dehydrated, cleared, and infiltrated with wax in the above solutions in sequence and then embedded. The specimens of the experimental group and the control group after embedding were taken, and the spinal cord tissue was cut into 5-μm-thick sections with a paraffin slicer. After being fully spread in distilled water at 40 °C, the sections were fished out and then dried in a drying oven at 60 °C for 2 h for standby. The paraffin sections were stored at room temperature.

[0159] Steps of immunohistochemical staining: The spinal cord sections were sequentially placed in xylene for 5 min (twice), absolute ethanol for 5 min (twice), 95% ethanol, 85% ethanol, 75% ethanol, 50% ethanol, and ultrapure water (DDW) for 2 min each. They were placed in a staining box containing Luxol Fast Blue Solution and incubated in an incubator at 60 °C for 2 h. They were thoroughly washed with distilled water for 5 min, soaked in lithium carbonate multiple times, with each time not exceeding 20 s at most. Then, they were continuously placed in Alcohol Reagent and observed under a microscope while being rinsed until the gray matter was colorless and the white matter remained blue. They were rinsed again with distilled water, placed in the Cresyl Echt Violet kit for 2 - 5 minutes, quickly rinsed in distilled water and then quickly dehydrated in absolute ethanol, and finally sealed with synthetic resin and photographed as soon as possible under an ordinary microscope. The staining results of the images were analyzed using the software imageJ. The demyelinated area and the white matter area of six layers of each lumbar spinal cord segment were averaged respectively to obtain the percentage of the demyelinated area in the total area.

[0160] The results showed that compared with the control group, the demyelination in the mice treated with DC521022 improved after 14 days and 28 days of drug administration, and it had an obvious repair effect on spinal cord demyelination.( Figure 2 as shown

[0161] Example 4. Testing the level of infiltrating immune cells in the spinal cord of multiple sclerosis in vivo

[0162] In this experiment, immunohistochemistry was used to perform HE staining of the mouse spinal cord, and the levels of infiltrating immune cells in the spinal cords of the DC521022 treatment group and the normal saline treatment group were compared 14 days and 28 days after the successful establishment of the EAE model.

[0163] The steps for preparing paraffin sections were the same as those for fast blue staining.

[0164] Steps for immunohistochemical staining: The spinal cord sections were successively placed in xylene for 5 minutes (twice), absolute ethanol for 5 minutes (twice), 95% ethanol, 85% ethanol, 75% ethanol, 50% ethanol, and DDW for 2 minutes each. Stained with hematoxylin solution for 5 minutes and rinsed with tap water for 5 seconds; differentiated with differentiating solution for 3 seconds, rinsed with tap water for 20 seconds to wash off the differentiating solution; blued with bluing solution for 30 seconds, rinsed with tap water for 20 seconds to wash off the bluing solution; stained with eosin for 30 seconds, rinsed with tap water for 5 seconds, dehydrated and cleared, and mounted.

[0165] The software ImageJ was used to analyze the staining results of the images. The inflammatory cell infiltration and white matter area of six layers in each lumbar spinal cord segment of the spinal cord were averaged respectively to obtain the percentage of the inflammatory cell infiltration area in the total area.

[0166] The experimental results showed that after long-term treatment with DC521022, the infiltrating immune cells in the spinal cord of the mice decreased, with statistical significance.( Figure 3 as shown

[0167] Example 5. Testing the myeloid shift in multiple sclerosis in vivo

[0168] In this experiment, flow cytometry was used to investigate the myeloid shift of the bone marrow of each group of mice in the model on the 14th day and 28th day of the experiment with compound DC521022.

[0169] Preparation of single-cell suspension of brain tissue: The mice were deeply anesthetized by intraperitoneal injection of tribromoethanol and properly fixed. The left femur of the mice was soaked in ice-cold PBS for later use; the bone marrow of the mouse femur was blown into a 15 mL centrifuge tube, centrifuged at 350G for 5 minutes, the supernatant was poured off, 1 mL of red blood cell lysate was added, after lysing for 6 minutes, 5 mL of PBS was added to terminate the lysis, centrifuged at 350G for 5 minutes. 1 mL of PBS was added to resuspend. Count.

[0170] For the fluorescent dye color matching of the flow antibodies, the following channels were selected: fluorescein isothiocyanate (FITC), phycoerythrin (PE), peridinin chlorophyll protein (PerCP-Cy5.5), allophycocyanin (APC), allophycocyanin-cyanine 7 (APC-Cy7), and phycoerythrin-cyanine 7 (PE-Cy7).

[0171] Specific flow antibodies against mouse target antigens: anti-mouse lin-antibody, anti-mouse sca-1 antibody, anti-mouse ckit antibody, anti-mouse CD48 antibody, anti-mouse CD150 antibody, anti-mouse CD127 antibody, anti-mouse CD135 antibody, anti-mouse CD34 antibody, anti-mouse 16 / 32 antibody, anti-mouse CD115 antibody, anti-mouse 7CD135 antibody.

[0172] Surface antibody staining: Add surface antibodies to a 100 μL single-cell suspension flow tube and vortex evenly (add them sequentially according to the instructions strictly). After adding, incubate at 4 °C in the dark for 30 min. Add 1 mL of PBS for washing, centrifuge at 1500 rpm for 5 min, discard the supernatant, add 400 μL of PBS to resuspend and blow evenly, and filter and load onto the machine.

[0173] In this experiment, the flow antibody staining adopted the settings of blank control, single-positive compensation, isotype control, and fluorescence minus one (FMO). Use FACS Aria II to collect flow cytometry data, and select the flow data analyzed by FlowJoV10 (Version 10, FlowJo, LLC).

[0174] The experimental results showed that on the 14th and 28th days, the proportion and quantity of bone marrow hematopoietic stem cells in EAE mice treated with DC521022 were significantly reduced, and the deviation towards the myeloid lineage was significantly reduced ( Figure 4 as shown).

[0175] In summary, long-term administration of the test substance DC521022 can delay the onset time of multiple sclerosis in EAE model mice, has an obvious repair effect on mouse demyelination, and at the same time reduces the infiltrating immune cells and myeloid deviation in the spinal cord.

[0176] Compared with the effect of the reported selective CCR5 antagonist DAPTA (see Figure 5Or Sheikh et al., Cellular Immunology. 2022, 379, 104580, Figure 1), the drug was administered after the onset of the disease in mice on the 6th day, which did not delay the onset of the disease in mice and even aggravated the disease progression. The therapeutic effect was gradually manifested only when the drug was administered for 22 days.

[0177] The therapeutic effect of the present invention on EAE mice is significantly better than that of the research by Sheikh et al. The present invention uses two drug administration models for research. When the drug was administered on the day of modeling, the onset of EAE mice was significantly later than that of the control group, the behavioral score was lower than that of the control, and the body weight was better than that of the control (see Figure 1 Figures 1A and 1C); when the drug was administered after the mice showed symptoms, the development of the disease could be significantly delayed. At the same time, the behavioral score was lower and the body weight was significantly improved (see Figure 1 Figures 1B and 1D).

[0178] All the documents mentioned in the present invention are incorporated herein by reference as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present invention.

Claims

1. Use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof, characterized in that, for the preparation of a medicament for the treatment and / or prevention of multiple sclerosis and related diseases; The compound of formula (I) has the following structure: wherein, W does not exist or is -CH 2 CH 2 -; X is N or CR 6 ; R 1 Selected from unsubstituted or 1-3 substituted 5-7 membered heteroaryl groups, said heteroaryl group containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and said substituents being independently selected from halogen, C1-C4 straight or branched alkyl, C1-C4 straight or branched haloalkyl, C1-C4 straight or branched alkoxy, C1-C4 straight or branched haloalkoxy, -NR 10 R 11 , -C(=O)R 12 , C1-C4 straight or branched alkanoyloxy, cyano, nitro and hydroxy, or two adjacent substituents together with the carbon atom to which they are attached form a 5-7 membered ring; R 10 and R 11 each independently selected from H, C1-C4 linear or branched alkyl, and -C(=O)R 13 ; R 12 selected from C1-C4 linear or branched alkyl groups, C1-C4 linear or branched alkoxy groups, hydroxyl groups, amino groups (NH 2 ) and C1-C4 linear or branched alkylamino groups; R 13 selected from H and C1-C4 linear or branched alkyl groups; R 2 selected from the following groups which are unsubstituted or substituted by 1-3 substituents: C1-C6 straight-chain or branched-chain alkyl, C3-C7 cycloalkyl, 4-7-membered heterocyclic group, C6-C12 aryl or 5-7-membered heteroaryl; wherein, the substituents are selected from halogen, hydroxy, C1-C4 straight-chain or branched-chain alkyl, C1-C4 straight-chain or branched-chain haloalkyl, C1-C4 straight-chain or branched-chain alkoxy, C1-C4 straight-chain or branched-chain alkylcarbonyl, C1-C4 straight-chain or branched-chain haloalkoxy, C1-C4 straight-chain or branched-chain alkylsulfonyl, C1-C4 straight-chain or branched-chain alkylsulfonylcarbamoyl, tetrazolyl, cyano, nitro, amino, carboxyl, phenyl and phenoxy; R 3 、R 4 and R 5 are each independently selected from hydrogen, C1-C6 straight-chain or branched alkyl, C1-C6 straight-chain or branched haloalkyl, and C3-C7 cycloalkyl; R 6 selected from hydrogen and C1-C6 straight-chain or branched alkyl groups; Alternatively, R 5 and R 6 can be connected to to form together R 7 selected from hydrogen, C(=O)R 8 , C(=O)OR 8 , C(=O)NR 8 R 9 , SO 2 R 8 and the following groups substituted with 1 to 3 substituents: C1-C6 straight-chain or branched-chain alkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocyclic group, benzyl, C6-C12 aryl, and 5- to 7-membered heteroaryl; wherein the substituents are selected from halogen, hydroxy, C1-C4 straight-chain or branched-chain alkoxy, C1-C4 straight-chain or branched-chain alkyl, C1-C4 straight-chain or branched-chain haloalkyl, C1-C4 straight-chain or branched-chain haloalkoxy, cyano, nitro, amino, carboxyl; R 8 and R 9 each independently selected from hydrogen and the following groups which are unsubstituted or substituted with 1-3 substituents: C1-C6 straight-chain or branched-chain alkyl, C3-C7 cycloalkyl, 4-7-membered heterocyclic group, benzyl, C6-C12 aryl, and 5-7-membered heteroaryl; wherein, the substituents are selected from halogen, hydroxy, C1-C4 straight-chain or branched-chain alkoxy, C1-C4 straight-chain or branched-chain alkyl, C1-C4 straight-chain or branched-chain haloalkyl, C1-C4 straight-chain or branched-chain haloalkoxy, cyano, nitro, amino, and carboxyl.

2. The use according to claim 1, characterized in that, the multiple sclerosis is selected from the group consisting of: relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, progressive-relapsing multiple sclerosis, or a combination thereof.

3. The use according to claim 1, characterized in that, the related diseases are selected from the group consisting of: neuromyelitis optica, acute disseminated encephalomyelitis, stroke, craniocerebral injury, epilepsy, Alzheimer's disease, Parkinson's disease, immune inflammatory response, demyelinating injury.

4. The use according to claim 1, characterized in that, the multiple sclerosis and related diseases are selected from the group consisting of: relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, stroke, craniocerebral injury, epilepsy, immune inflammatory response, demyelinating injury.

5. The use according to claim 1, characterized in that, the compound is used for: (1) Repairing demyelination in the spinal cord of multiple sclerosis; (2) Reducing infiltrating immune cells in the spinal cord of multiple sclerosis; (3) Reducing myeloid deviation in the spinal cord of multiple sclerosis.

6. The use according to claim 1, characterized in that, the compound of formula (I) is selected from the group consisting of:

7. The use according to claims 1-6, characterized in that, the administration mode of the compound of formula (I) is selected from the group consisting of: oral, rectal, parenteral.

8. The use according to claim 7, characterized in that, the parenteral administration mode is selected from the group consisting of: intravenous, intramuscular or subcutaneous administration.

9. The use according to claim 7, characterized in that, the oral preparations are selected from the group consisting of: capsules, tablets, pills, powders, granules, emulsions, solutions, suspensions, syrups and tinctures.

10. Use of a pharmaceutical composition, characterized in that, the pharmaceutical composition is used for the preparation of a medicament for the treatment and / or prevention of multiple sclerosis and related diseases; and the pharmaceutical composition comprises: (i) A first active ingredient, which is selected from the group consisting of: a compound of formula (I), or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer thereof; (ii) Optionally a second active ingredient, which is selected from the group consisting of: interferon β-1a, interferon β-1b, teriflunomide, fingolimod, copaxone, ofatumumab, or a combination thereof; (iii) A pharmaceutically acceptable carrier; The compound of formula (I) is as defined in claim 1.

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