Compounds and Uses Thereof

Abstract

The present invention provides a compound represented by Formula I or its pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite, and its use in the pharmaceutical field. The above compound, particularly propafenone, can be used to treat and / or prevent psoriasis-related diseases. The present invention also found that, at the same dosage, topical application of the drug is more effective than injection in treating psoriasis-related diseases. The propafenone ointment of the present invention has a superior effect in treating psoriasis-related diseases compared to flecainide ointment, which has a similar antiarrhythmic effect.

Description

[Technical Field]

[0001] The present invention relates to the field of biomedicine, and in particular to compounds of formula I or pharmaceutically acceptable salts, stereoisomers, isotopic derivatives, solvates (e.g., hydrates), prodrugs, metal chelates, crystalline forms, or metabolites thereof, and their use in the treatment and / or prevention of psoriasis-related diseases. [Background technology]

[0002] Psoriasis is a skin condition caused by an abnormality in the body's immune system. Currently, clinical treatments mainly rely on ultraviolet light irradiation, oral immunosuppressants, and topical immunosuppressants.

[0003] Patent CA2950727A1 discloses the preparation of β-d-nicotinamide riboside in the niacin pathway, which can be used to prepare various drugs and treat various diseases, including psoriasis. Patent CA2618360C discloses benzothiazoles and thiazolopyridines as modulators of the sirtuin pathway, which can be used to prepare various drugs and treat various diseases, including psoriasis.

[0004] However, the prior art does not report the activity of compounds of formula I in the treatment and / or prevention of psoriasis-related diseases. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides compounds of formula I or pharmaceutically acceptable salts, stereoisomers, hydrates, prodrugs, solvates, metabolites or isotopic derivatives thereof, and their use in the treatment or prevention of psoriasis-related disorders. [Means for solving the problem]

[0006] In a first aspect of the present invention, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof, in the preparation of a product for treating and / or preventing psoriasis-related diseases, wherein the compound has the structure: [ka] (I) (where X is a single bond, -O-(C0-C 10 Alkylene)-, -S-(C0-C 10 Alkylene)-, -N(C0-C 10 Alkyl)-(C0-C 10 Alkylene)-, C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 alkynylene, R0 is H, -CO(C 1~10 alkyl), -CO(C 6~10 aryl), R1 and R1' are independently H, C1 to C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Haloalkyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -N(C 0~10 Alkyl)(C 0~10 alkyl), -O(C 0~10 alkyl), or R and R together with the nitrogen atom to which they are attached form a heterocycle, wherein H in said heterocycle is selected from halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -N(C 0~10 Alkyl)(C 0~10 alkyl), -O(C 0~10 alkyl), -S(C0~10 alkyl), R2, R3, R4, R5, R6, R7, R8, R9, R 10 are independently H, halogen, cyano, nitro, azide, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -N(C 0~10 Alkyl)(C 0~10 alkyl), -O(C 0~10 alkyl), -S(C 0~10 alkyl).

[0007] Furthermore, X is selected from C1 to C6 alkylene (e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-), C2 to C6 alkenylene (e.g., -CH=CH-, -CH=CH-CH=CH-, -CH=CH-CH=CH-CH=CH-).

[0008] In some embodiments of the invention, X is -CH2CH2- or -CH=CH-.

[0009] Furthermore, R0 can be H, -CO(C 1~6 alkyl) (e.g., —COCH3, —COCH2CH3, —COCH2CH2CH3, —COCH2CH2CH2CH3).

[0010] In some embodiments of the invention, R0 is H.

[0011] In some embodiments of the present invention, R0 is -COCH3.

[0012] Furthermore, R1 and R1' are independently H, C1-C6 alkyl (e.g., -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2), -(C0-C6 alkylene)-(C6-C 10 aryl) (e.g., [ka] ) is selected.

[0013] In some embodiments of the present invention, R 1 ' is H.

[0014] In some embodiments of the present invention, R 1 is —CH 2 CH 2 CH 3 and R 1′ is H.

[0015] In some embodiments of the present invention, R1 is -CH(CH3)2 and R1' is H.

[0016] In some embodiments of the present invention, R1 is -CH2CH3 and R1' is -CH3.

[0017] In some embodiments of the invention, R1 is [ka] and R1' is H, or R1 is H and R1' is [ka] is.

[0018] Furthermore, R1 and R1' together with the nitrogen atom to which they are linked form a 4- to 6-membered nitrogen-containing heterocycle, wherein H in the 4- to 6-membered nitrogen-containing heterocycle is optionally substituted with one or more groups selected from C1 to C6 alkyl.

[0019] Furthermore, the 4- to 6-membered nitrogen-containing heterocycle is [ka] is selected from, preferably [ka] is.

[0020] In some embodiments of the present invention, R1 and R1' together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen-containing heterocycle. [ka] Form.

[0021] In addition, R2, R3, R4, R5, R6, R7, R8, R9, R 10 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O(C 0~6 alkyl).

[0022] In some embodiments of the invention, R2 is H.

[0023] In some embodiments of the invention, R3 is H.

[0024] In some embodiments of the invention, R4 is H, halogen (eg, F, Cl, Br, I), C1-C6 haloalkyl (eg, -CF3).

[0025] In some embodiments of the present invention, R5 is H.

[0026] In some embodiments of the present invention, R6 is H.

[0027] In some embodiments of the invention, R7 is H or -OH.

[0028] In some embodiments of the present invention, R8 is H.

[0029] In some embodiments of the present invention, R9 is H or -OH.

[0030] In some embodiments of the present invention, R 10 is H.

[0031] In some embodiments of the invention, the compound has the following structure: [ka] (II)

[0032] In some embodiments of the invention, the compound has the following structure: [ka] (III)

[0033] In some embodiments of the invention, the compound has the following structure: [ka] (IV) (wherein X is selected from a single bond, —O—, —S—, or alkylene).

[0034] Preferably, in formula IV, X is a single bond or a C1-C 10 More preferably, X is selected from C1 to C4 alkylene.

[0035] In formula IV, R1 is selected from H, alkyl, alkoxy, alkenyl, or alkynyl. Preferably, R1 is C1-C 10 More preferably, R1 is selected from C1 to C4 alkyl.

[0036] In Formula IV, R2, R3, R4, R5, and R6 are independently selected from H, alkyl, or halogen atoms. Preferably, R2, R3, R4, R5, and R6 are independently selected from H, F, Cl, Br, I, methyl, or ethyl. More preferably, R2, R3, R4, R5, and R6 are independently selected from H, F, Cl, Br, I, methyl, or ethyl.

[0037] In some embodiments of the present invention, in Formula IV, X is selected from C1-C4 alkylene, R1 is selected from C1-C4 alkyl, and R2, R3, R4, R5, R6 are independently selected from H, F, Cl, Br, I, methyl, or ethyl.

[0038] In some embodiments of the present invention, in Formula IV, X is —CHCH—, R is selected from C-C alkyl, and R, R, R, R, and R are independently selected from H, F, Cl, Br, I, methyl, or ethyl.

[0039] In some embodiments of the invention, in Formula IV, X is selected from C1-C4 alkylene; R1 is selected from -CH2CH2CH3; and R2, R3, R4, R5, and R6 are independently selected from H, F, Cl, Br, I, methyl, or ethyl.

[0040] In some embodiments of the present invention, in formula IV, X is selected from C1-C4 alkylene; R1 is selected from C1-C4 alkyl; and R2, R3, R4, R5, R6 are all H.

[0041] In some embodiments of the invention, the compound has the following structure: [ka]

[0042] In some other embodiments of the invention, the compound has the structure: [ka]

[0043] Furthermore, said stereoisomer has the following structure: [ka]

[0044] In some embodiments of the invention, the stereoisomer has the following structure: [ka]

[0045] In some embodiments of the invention, the stereoisomer has the following structure: [ka]

[0046] In one specific embodiment of the invention, the stereoisomer of the compound has the following structure: [ka] especially [ka]

[0047] In some other embodiments of the present invention, the stereoisomer has the following structure: [ka]

[0048] Preferably, the stereoisomer has the following structure: [ka]

[0049] Furthermore, the isotope derivatives include compounds in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass, and include stable isotopes of hydrogen, carbon, oxygen, etc., and radioactive isotopes, specifically 2H (deuterium, D), 3H (tritium, T), 11C, 13C, 14C, 17O, 18O, etc., with deuterium being preferred.

[0050] In some embodiments of the invention, the isotopic derivative has the following structure: [ka]

[0051] Further, the product is a drug comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof; The drug is a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof in an amount of 0.01 to 99.5% by weight (specifically, 0.01% by weight, 0.02% by weight, 0.025% by weight, 0.03% by weight, 0.04% by weight, 0.05% by weight, 0.06% by weight, 0.07% by weight, 0.08% by weight, 0.09% by weight, 0.10% by weight, 0.11% by weight, 0.12% by weight, 0.13% by weight, 0.14% by weight, 0.15% by weight, 0.16% by weight, 0.17% by weight, 0.18% by weight, 0.19% 6% by weight, 0.07% by weight, 0.08% by weight, 0.09% by weight, 0.1% by weight, 0.12% by weight, 0.14% by weight, 0.16% by weight, 0.18% by weight, 0.2% by weight, 0.22 Weight%, 0.24% by weight, 0.26% by weight, 0.28% by weight, 0.3% by weight, 0.32% by weight, 0.34% by weight, 0.36% by weight, 0.38% by weight, 0.4% by weight, 0.42% by weight Amount%, 0.44% by weight, 0.46% by weight, 0.48% by weight, 0.5% by weight, 0.52% by weight, 0.54% by weight, 0.56% by weight, 0.58% by weight, 0.6% by weight, 0.62% by weight %, 0.64 wt%, 0.66 wt%, 0.68 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, 1 wt%, 2 wt. %, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 20 wt%, 30 wt%, 40 wt%, 50 wt%, 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt%, 99 wt%, or 99.5 wt%, preferably 0.02 to 0.5 wt%, and more preferably 0.1 to 0.5 wt%.

[0052] Furthermore, the drug can be administered by any suitable route, such as gastrointestinal administration (e.g., oral administration) or non-gastrointestinal administration (e.g., intravenous, intramuscular, subcutaneous, intradermal, intraorgan, intranasal, intraocular, infusion, intracerebral, intrathecal, transdermal, rectal, etc.), preferably by a non-gastrointestinal administration route.

[0053] In some embodiments of the invention, the route of administration is subcutaneous, intradermal, or transdermal, in particular transdermal.

[0054] Furthermore, the drug may be in any suitable dosage form, such as a dosage form for gastrointestinal administration or a dosage form for non-gastrointestinal administration. Preferably, the drug is in a dosage form for non-gastrointestinal administration.

[0055] Furthermore, the dosage form of the drug is an external preparation, an injection, or an oral preparation; the topical preparation is selected from a solution, a tincture, a spirit, a paste, an oil, an ointment, a cream, a gel, a film coating, a liniment, a detergent, a spray, a suspension, a solution, an emulsion, a microemulsion, a suspension, a plaster, a gel, a patch, a powder aerosol, a suppository, an eye drop, or a nose drop; The injection is selected from a solution, a suspension, an emulsion, or a powder injection; The oral formulation is selected from tablets, pills, pellets, powders, granules, capsules, troches, syrups, suspensions, emulsions, microemulsions, powder aerosols, pastes, sublingual tablets or suppositories.

[0056] In some embodiments of the present invention, the dosage form of the drug is an external preparation.

[0057] In some embodiments of the invention, the topical formulation is an ointment, patch or gel, particularly an ointment.

[0058] Furthermore, the drug may be a human drug or a veterinary drug.

[0059] Furthermore, the drugs can be used alone or in combination with other types of active ingredients.

[0060] In a second aspect of the present invention, there is provided a topical formulation for treating and / or preventing psoriasis-related disorders, said topical formulation comprising a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof; Preferably, the topical formulation further comprises a pharmaceutically acceptable auxiliary material.

[0061] Further, the topical formulation is selected from a solution, a tincture, a spirit, a paste, an oil, an ointment, a cream, a gel, a film coating, a liniment, a detergent, a spray, a suspension, a solution, an emulsion, a microemulsion, a suspension, a plaster, a gel, a patch, a powder aerosol, a suppository, an eye drop, or a nose drop; Preferably, all of the ancillary materials are of pharmaceutical grade.

[0062] More preferably, the topical formulation is an ointment, patch or gel.

[0063] In some embodiments of the invention, the topical formulation is an ointment or patch, particularly an ointment.

[0064] Furthermore, the auxiliary materials include one or more of carriers, excipients, diluents, wetting agents, fillers, adhesives, lubricants, disintegrants, antioxidants, buffers, suspension aids, solubilizers, thickeners, stabilizers, flavoring agents, preservatives, etc.

[0065] Additionally, the auxiliary materials include one or more of a solubilizer, an oil phase, a water phase, and an additive.

[0066] Preferably, the solubilizer comprises one or more of aliphatic alcohol polyoxyethylene ethers, fatty acid polyoxyethylene esters, castor oil polyoxyethylene ethers, alkylphenol polyoxyethylene ethers, aliphatic amine polyoxyethylene ethers, polyoxyethylene polyoxypropylene copolymers, polyethylene glycol, polyethylene glycol stearate, sorbitol ester polyoxyethylene ethers, sorbitan esters.

[0067] Preferably, the oil phase comprises one or more of liquid paraffin, solid paraffin, stearic acid, white petrolatum, cetyl alcohol, stearyl alcohol, glyceryl monostearate, isopropyl myristate, dimethicone, silicone, beeswax, lanolin, spermaceti, glyceryl caprylate / caprate, isooctyl palmitate, isopropyl palmitate, PEG-100 stearate, vegetable oils, and animal oils.

[0068] Preferably, the aqueous phase comprises one or more of water, ethanol, glycerin, cetyl alcohol, stearyl alcohol, hexanediol, propylene glycol, glycerin, dipropylene glycol, ethylene glycol, pentylene glycol.

[0069] Preferably, the additives include one or more of an emulsifier, a transdermal penetration enhancer, a pH adjuster, and a preservative.

[0070] More preferably, the transdermal penetration enhancer comprises one or more of azone, dimethyl sulfoxide, decyl methyl sulfoxide, menthol, borneol, clove oil, ethanol, bay leaf oil, urea, capsaicin, oleic acid, urea.

[0071] More preferably, the pH adjuster comprises one or more of citric acid, salicylic acid, boric acid, fatty acid, sodium hydroxide, potassium hydroxide.

[0072] More preferably, the emulsifier is one or more selected from triethanolamine, fatty acid soap, sodium lauryl sulfate, polyoxyethylene ether, polyoxypropylene ether, ethylene oxide, lecithin, and gum arabic.

[0073] More preferably, the preservative comprises one or more of imidazolidinyl urea, diazolidinyl urea, DMDMH, quaternium-15, benzoic acid and its derivative preservatives, phenoxyethanol, benzyl alcohol, polyol preservatives, chlorphenesin, bronopol, cathon, benzalkonium bromide, benzalkonium chloride, ethylparaben, methylparaben, isopropyl alcohol, salicylic acid, and sorbic acid.

[0074] And / or the additive further comprises one or more of vitamin E, dextran, betaine, butylated hydroxyanisole, ascorbic acid, propionic acid basic compounds, ethanol, benzalkonium bromide, hydroxyphenylpropionamidobenzoic acid.

[0075] Furthermore, when the drug dosage form is a gel, the auxiliary materials further include one or more of gelatin, carbomer, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, glycerin, propylene glycol, dipropylene glycol, and water.

[0076] Furthermore, the external preparation is preferably in unit dosage form.In this form, the preparation is further divided into unit doses that contain appropriate amounts of active ingredients.The unit dosage form can be ointment, patch or any dosage form.The unit dosage form can also be a packaged preparation, such as the ointment or patch that is packaged in a vial or box.

[0077] Furthermore, the topical formulations can be used alone or in combination with other types of active ingredients.

[0078] Furthermore, the amount of the active ingredient in the unit dose formulation can be varied or adjusted between 10 ng and 10 mg (specifically, 10 ng, 20 ng, 50 ng, 100 ng, 200 ng, 500 ng, 1 μg, 2 μg, 5 μg, 10 μg, 20 μg, 50 μg, 100 μg, 200 μg, 500 μg, 1 mg, 2 mg, 5 mg, or 10 mg), and is determined according to the specific use and effect of the active ingredient, and the formulation may further contain other appropriate therapeutic agents, if necessary.

[0079] Preferably, the amount of the active ingredient in the unit dose preparation is 10 μg to 10 mg.

[0080] Various dosage forms of the drug of the present invention can be prepared according to conventional production methods in the pharmaceutical field.

[0081] Furthermore, the topical formulation contains 0.01 to 99.5% by weight (specifically, 0.01% by weight, 0.02% by weight, 0.025% by weight, 0.03% by weight, 0.04% by weight, 0.05% by weight, 0.06% by weight, 0.07% by weight, 0.08% by weight, 0.09% by weight, 0.10% by weight, 0.11% by weight, 0.12% by weight, 0.13% by weight, 0.14% by weight, 0.15% by weight, 0.16% by weight, 0.17% by weight, 0.18% by weight, 0.19 ... Weight%, 0.05% by weight, 0.06% by weight, 0.07% by weight, 0.08% by weight, 0.09% by weight, 0.1% by weight, 0.12% by weight, 0.14% by weight, 0.16% by weight, 0.18% by weight %, 0.2% by weight, 0.22% by weight, 0.24% by weight, 0.26% by weight, 0.28% by weight, 0.3% by weight, 0.32% by weight, 0.34% by weight, 0.36% by weight, 0.38% by weight, 0. 4% by weight, 0.42% by weight, 0.44% by weight, 0.46% by weight, 0.48% by weight, 0.5% by weight, 0.52% by weight, 0.54% by weight, 0.56% by weight, 0.58% by weight, 0.6% by weight %, 0.62 wt%, 0.64 wt%, 0.66 wt%, 0.68 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, 1 wt. %, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 20 wt%, 30 wt%, 40 wt%, 50 wt%, 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt%, 99 wt%, or 99.5 wt%, preferably 0.02 to 0.5 wt%, and more preferably 0.1 to 0.5 wt%.

[0082] Furthermore, the topical formulations may be for human or animal use.

[0083] In one specific embodiment of the invention, the topical formulation comprises a compound according to the first and / or second aspect of the invention or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof, an oil phase, an aqueous phase, an additive, the oil phase comprises paraffin, glyceryl monostearate, white petrolatum, and lanolin; The aqueous phase contains glycerin and water, The additives include emulsifiers and preservatives.

[0084] In one specific embodiment of the invention, the preservative is ethylparaben.

[0085] In one specific embodiment of the invention, the emulsifier is triethanolamine.

[0086] In a third aspect of the present invention, a method for producing a pharmaceutical composition for pharmaceutical preparations includes the steps of: (1) mixing and heating an aqueous phase, a preservative, and an emulsifier, followed by adding an active ingredient and stirring until dissolved, to obtain an aqueous phase mixture, wherein the active ingredient is a compound according to the first and / or second aspects of the present invention, or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof; and (2) mixing, heating, and stirring the oil phase components until dissolved, and adding the aqueous phase mixture obtained in step (1) to the oil phase, followed by stirring to solidify the mixture into an ointment.

[0087] Furthermore, the oil phase, the water phase, the preservatives, the emulsifiers have the definitions as set out in the third aspect of the present invention.

[0088] Furthermore, in the oil phase, the mass ratio of liquid paraffin, glyceryl monostearate, white petrolatum, and lanolin is 1-3:3-5:2-4:1-3.

[0089] In some embodiments of the present invention, the mass ratio of liquid paraffin, glyceryl monostearate, white petrolatum, and lanolin in the oil phase is 2:4:3:2.

[0090] Furthermore, in the aqueous phase, the mass ratio of glycerin to water is 2-4:10-18.

[0091] In some embodiments of the present invention, the weight ratio of glycerin to water in the aqueous phase is 3:14.11.

[0092] Furthermore, the mass ratio of the glycerin, ethylparaben, water, triethanolamine, and active ingredient is 2-4:0.05-0.13:10-18:0.1-0.4:0.01-0.05.

[0093] In some embodiments of the present invention, the weight ratio of glycerin, ethylparaben, water, triethanolamine, and active ingredient is 3:0.09:14.11:0.3:0.0285.

[0094] Furthermore, in the step (1), the heating temperature is 50 to 100°C (specifically, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100°C), preferably 70 to 90°C, and more preferably 75 to 80°C.

[0095] Furthermore, in the step (1), the rotation speed of the stirring is 200 to 500 r / min (specifically, 200, 250, 300, 350, 400, 450, 500 r / min), and preferably 350 r / min.

[0096] Furthermore, the step (1) includes mixing an aqueous phase, a preservative, and an emulsifier, heating the mixture in a water bath, and when the temperature reaches 75 to 80°C, adding the active ingredient and stirring until dissolved to obtain an aqueous phase mixture.

[0097] Furthermore, in the step (2), the heating temperature is 50 to 100°C (specifically, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100°C), preferably 70 to 90°C, and more preferably 80°C.

[0098] Furthermore, in the step (2), the rotation speed of the stirring is 200 to 500 r / min (specifically, 200, 250, 300, 350, 400, 450, or 500 r / min), and preferably 250 r / min.

[0099] Furthermore, step (2) includes mixing the oil phase components, heating to 80°C in a water bath, stirring until dissolved, slowly adding the aqueous phase mixture obtained in step (1) to the oil phase, stirring, and then leaving it at room temperature until it solidifies into an ointment while stirring.

[0100] In a fourth aspect of the present invention, there is provided a method of treating and / or preventing a psoriasis-related disorder, comprising administering to an individual a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof, or a topical formulation according to the second aspect.

[0101] Furthermore, the administration may be via a gastrointestinal (e.g., oral) or non-gastrointestinal (e.g., intravenous, intramuscular, subcutaneous, intradermal, intraorgan, intranasal, intraocular, infusion, intracerebral, intrathecal, transdermal, rectal, etc.) route.

[0102] In some embodiments of the present invention, the administration may be by injection or transdermal administration (such as topical or microneedle administration).

[0103] Furthermore, the above-mentioned drug or topical preparation is preferably in unit dosage form.In this form, the preparation is further divided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be capsules, tablets or any dosage form.The unit dosage form can also be packaged preparations such as tablets, capsules and powders packaged in vials or ampoules.

[0104] Furthermore, the drugs or topical preparations can be used alone or in combination with other types of active ingredients.

[0105] Furthermore, the amount of the active ingredient in the unit dose preparation can be varied or adjusted between 10 ng and 10 mg (specifically, 10 ng, 20 ng, 50 ng, 100 ng, 200 ng, 500 ng, 1 μg, 2 μg, 5 μg, 10 μg, 20 μg, 50 μg, 100 μg, 200 μg, 500 μg, 1 mg, 2 mg, 5 mg, or 10 mg), and is determined according to the specific use and effect of the active ingredient; if necessary, the drug or topical preparation may further contain other suitable therapeutic agents.

[0106] Preferably, the amount of active ingredient in said unit dose preparation is 10 μg to 10 mg. [Effects of the Invention]

[0107] The present invention has the following beneficial effects:

[0108] (1) The present invention has discovered that compounds 1, 2, and 5, especially compound 1, can be used to treat psoriasis-related diseases.

[0109] (2) The present invention has found that topical application of drugs is more effective than drug injection in treating psoriasis-related diseases when the dosage is the same.

[0110] (3) Compound 1 is a conventional antiarrhythmic drug, and the present invention has found that not all compounds with antiarrhythmic activity have the effect of treating psoriasis-related diseases.Compared with flecainide ointment, which has a similar antiarrhythmic activity, the compound of the present invention has a particularly significant therapeutic effect, although flecainide ointment is ineffective in treating psoriasis.

[0111] (4) The present inventors have experimentally discovered that compound 3 (i.e., R-propafenone) has a better therapeutic effect on psoriasis-related diseases than compound 1 (i.e., R / S-propafenone). Based on the above experimental results, the inventors speculate that at the same mass concentration, compound 1 contains compound 2 (i.e., S-propafenone), so the relative concentration of compound 3 in compound 1 is lower than that of compound 3 alone, which may be the main reason why the therapeutic effect of compound 1 is slightly lower than that of compound 3.

[0112] "Comprising" or "having" as used herein is an open description that includes the specified components or steps described and other specified components or steps that are not substantially affected.

[0113] "Treatment" according to the present invention means slowing, interrupting, preventing, controlling, halting, mitigating, or reversing the signs, symptoms, disorders, conditions, or progression or severity of a disease after the disease has begun to develop, but does not necessarily mean completely eliminating all signs, symptoms, conditions, or disorders associated with the disease.

[0114] "Prevention" according to the present invention refers to a method carried out to prevent or delay the occurrence of a disease, condition, or symptom in an organism.

[0115] The "product" according to the present invention may be a drug, a device, a kit, or the like.

[0116] "Pharmaceutically acceptable" according to the present invention refers to a substance that does not significantly irritate an organism and does not inhibit the biological activity and properties of the active ingredients of the administered product.

[0117] According to the present invention, a "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, including inorganic or organic acids or bases. The inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, hydroiodic acid, or sulfuric acid. The inorganic base is selected from calcium, magnesium, lithium, sodium, zinc, aluminum, or potassium. The organic acid is selected from formic acid, glycolic acid, propionic acid, acetic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, glutamic acid, benzoic acid, stearic acid, alginic acid, benzenesulfonic acid, glucuronic acid, pamoic acid, or galacturonic acid. The organic base is selected from diethanolamine, choline, procaine, lysine, or 1,2-ethylenediamine.

[0118] "Stereoisomers" according to the present invention include those existing in the form of enantiomers, diastereomers and geometric isomers.

[0119] According to the present invention, a "hydrate" refers to a compound containing water, which may be bound to the compound by coordinate, covalent, or hydrogen bonds. For example, when a compound crystallizes from an aqueous solution of its constituent ions, the formed crystal is called a hydrate.

[0120] The term "prodrug" as used herein refers to a compound obtained by chemically modifying a drug, which has no or low activity in vitro or at a non-specific target site, but releases an active drug (e.g., the compound of the present invention) by enzymatic or non-enzymatic conversion in vivo, thereby exerting its medicinal effect.

[0121] "Solvate" according to the present invention refers to a physical combination of the compound of the present invention with one or more solvent molecules. This physical combination may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution-phase solvates and isolable solvates. Representative solvates include hydrates, ethanolates, methanolates, etc.

[0122] The term "metabolite" as used herein refers to a product generated when the compound of the present invention is chemically decomposed under physiological conditions in vivo.

[0123] The term "derivative" as used herein refers to a product in which a certain atom or atomic group in a compound molecule is substituted with another atom or atomic group, or a product produced by hydrolysis of a compound.

[0124] The "individual" according to the present invention may be either a human or a non-human mammal, and the non-human mammal may be a wild animal, a zoo animal, an economic animal, a pet, a laboratory animal, etc. Preferably, the non-human mammal includes, but is not limited to, a pig, a cow, a sheep, a horse, a donkey, a fox, a raccoon dog, a mink, a camel, a dog, a cat, a rabbit, a mouse (e.g., a rat, a mouse, a guinea pig, a hamster, a gerbil, a chinchilla, a squirrel), or a monkey.

[0125] "Intradermal injection" according to the present invention means that the drug is injected below the epidermis of the skin, generally above the dermis, but not into the subcutaneous tissue.

[0126] "Alkyl" according to the present invention refers to a straight or branched hydrocarbon chain group that does not contain unsaturated bonds, and the hydrocarbon chain group is connected to other parts of the molecule via a single bond. Typical alkyl groups include 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, nonyl, decyl, undecyl, 1-methylundecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl. In the present invention, CO alkyl refers to H, i.e., C 0~10 Alkyl (or C0-C 10 alkyl) contains H and C 1~10 Alkyl (or C1-C 10 alkyl).

[0127] "Alkylene" as used herein refers to a hydrocarbon group (divalent alkyl) formed by the loss of two hydrogen atoms from an alkane molecule, and may be linear or branched, and is connected to the rest of the molecule by a single bond. Typical alkylenes have 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, C0 alkylene refers to a single bond, i.e., C 0~10 Alkylene (or C0-C 10 Alkylene) contains a single bond and C 1~10 Alkylene (or C1-C 10 alkylene).

[0128] The "alkoxy" described in the present invention is an alkyl group bonded to an oxygen atom, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, 2-ethylbutoxy, n-pentyloxy, isopentyloxy, 1-methylpentyloxy, 1,3-dimethylbutoxy, n-hexyloxy, 1-methylhexyloxy, n-heptyloxy, isoheptyloxy, 1,1,3,3-tetramethylbutoxy, and 1-methylheptyl. oxy, 3-methylheptyloxy, n-octyloxy, 2-ethylhexyloxy, 1,1,3-trimethylhexyloxy, 1,1,3,3-tetramethylpentyloxy, nonyloxy, decyloxy, undecyloxy, 1-methylundecyloxy, dodecyloxy, 1,1,3,3,5,5-hexamethylhexyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, and eicosyloxy.

[0129] In the present invention, "alkenyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one unsaturated bond, and the hydrocarbon chain radical is connected to the rest of the molecule by a single bond. Typical alkenyls contain 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as ethenyl, 1-methyl-ethenyl, 1-propenyl, 2-propenyl, or butenyl.

[0130] In the present invention, "alkynyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one carbon-carbon triple bond, and the hydrocarbon chain radical is connected to the rest of the molecule by a single bond. Typical alkynyl groups include 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), butynyl (e.g., 1-butynyl, 2-butynyl, 3-butynyl), pentynyl (e.g., 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, or 2-methyl-3-butynyl), etc.

[0131] The "halogen atom" according to the present invention includes fluorine, chlorine, bromine and iodine.

[0132] The term "cycloalkyl" as used herein refers to an alicyclic hydrocarbon having 1 to 4 monocyclic and / or fused rings and 3 to 18, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.

[0133] According to the present invention, "haloalkyl" refers to a group in which one or more hydrogen atoms in an alkyl are replaced by a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), such as -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0134] "Aryl" according to the present invention refers to a monocyclic or polycyclic radical, including monocyclic aryl groups and / or polycyclic radicals containing fused aryl groups, for example, radicals containing 1 to 3 monocyclic or fused rings and 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, and is a C6-C6 radical according to the present invention. 12 Aryl refers to aryl groups containing 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, and the like.

[0135] According to the present invention, "heterocyclyl" refers to a 3-18-membered non-aromatic ring group containing 2-17 carbon atoms and 1-10 heteroatoms. Heterocyclyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused, spirocyclic, or bridged ring systems. Heterocyclyl may be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryls in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O, S and P atoms and include, for example, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl.Suitable heterocycloalkyls in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, thiiranyl, azepinyl, oxazepanyl. , diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiolanyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolidinyl. In the present invention, the substitution position in an optionally substituted heterocyclyl may be at any suitable carbon atom or heteroatom. For example, [ka] In the formula, the substitution position of R can be any suitable carbon or nitrogen atom, for example, [ka] or [ka] may be.

[0136] In the present invention, "D" refers to deuterium. "Substituted with deuterium" means replacing one or more hydrogen atoms with the corresponding number of deuterium atoms.

[0137] It is recognized that the natural isotopic abundance of synthesized compounds may vary to some extent depending on the source of chemical materials used in synthesis.Therefore, the compounds of the present invention will inherently contain a small amount of deuterated isotopes.Despite this variation, the concentration of stable hydrogen and carbon isotopes present at such natural abundances is low and insignificant compared to the degree of stable isotope substitution in the compounds of the present invention.See, for example, Wada, E et al., Seikagaku, 1994, 66: 15;Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

[0138] In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," it is understood that the position is hydrogen with natural abundance isotopic composition. Similarly, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," it is understood that the position has a deuterium abundance (i.e., at least 45% deuterium incorporation) that is at least 3000 times greater than the natural abundance of deuterium (0.015%).

[0139] The term "isotopic enrichment factor," as used herein, refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0140] In other embodiments, compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0141] The term "isotopomer" as used herein refers to a substance having a chemical structure that differs from the specific compound of the present invention only in its isotopic composition.

[0142] The "psoriasis-related disease" according to the present invention includes, for example, diseases such as psoriasis (e.g., plaque psoriasis (e.g., generalized pustular psoriasis (Zumbusch)), localized pustular psoriasis (also called Barber type or palmoplantar pustular psoriasis)), psoriatic arthritis, erythrodermic psoriasis), parapsoriasis (e.g., guttate parapsoriasis, plaque parapsoriasis, lichenoid parapsoriasis, varioliform parapsoriasis), pityriasis rubra pilaris, pityriasis rosea Gibertii, lichen planus, lichen sclerosus, lichen pilaris, chronic eczema, parapsoriasis (e.g., guttate parapsoriasis, plaque parapsoriasis, lichenoid parapsoriasis, varioliform parapsoriasis), or seborrheic dermatitis. In particular, the psoriasis-related disease according to the present invention is preferably psoriasis. [Brief explanation of the drawings]

[0143] Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. [Figure 1] This is an HPLC chart before separation. [Figure 2] 1 is an HPLC chart of a standard sample of Compound 2. [Figure 3] 1 is an HPLC chart of a standard sample of Compound 3. [Figure 4]1 shows the results of scoring the treatment of psoriasis using various administration methods of Compound 1. [Figure 5] This study compares the efficacy of compound 1 and flecainide in treating psoriasis. [Figure 6] 1 is a dose-effect study of Compound 1 for the treatment of psoriasis. [Figure 7] 1 shows the evaluation of the efficacy of compounds 2 and 3 in treating psoriasis by PASI scoring. [Figure 8] 1 shows the evaluation of the efficacy of compounds 4 and 5 in treating psoriasis by PASI scoring. DETAILED DESCRIPTION OF THE INVENTION

[0144] The technical solutions in the embodiments of the present invention will be described below clearly and completely with reference to the drawings in the embodiments of the present invention, but it is clear that the described embodiments are only some of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative work fall within the protection scope of the present invention.

[0145] Sources of animals and reagents used in the examples Mice used: purchased from Charles River, female, weighing 18-20g Recombinant IL-23: Purchased from Novoprotein, Catalog Number: CS31 Flecainide: Purchased from MedChem Express, catalog number: HY-17429 Compound 1: Molecular formula C 21 H 27 NO3, CAS number: 54063-53-5, molar mass: 341.444 g / mol, boiling point: 519.6 °C, structural formula: [ka] Compound 1 injection: purchased from Shanghai Xin Yi Co., Ltd., catalog number: 0114006. Compound 1 powdered drug substance: purchased from Henan Qixin Co., Ltd., catalog number: H22091. Compounds 4-1, 4-2, 4-4, 5-4, and n-propylamine were purchased from Shanghai Bidepharm Co., Ltd. Catalog numbers: Compound 4-1: BD20230110, Compound 4-2: BD20221219, Compound 4-4: BD20221118, Compound 5-4: BD20230511, and n-propylamine: BD20231015.

[0146] Example 1 Preparation of Compound 2 and Compound 3 [ka] A sample solution was prepared by dissolving 150 mg of the free base of compound 1 (R / S-propafenone) in 2 mL of ethanol. Compound 1 was separated by high-performance liquid chromatography (HPLC). The chromatogram, shown in Figure 1, demonstrates high resolution between the two peaks. The resulting solutions, with retention times of 3.1 min (Peak 1) and 5.8 min (Peak 2), were concentrated under reduced pressure to yield 50 mg (Peak 1) and 60 mg (Peak 2) of white powder. The compounds corresponding to Peak 1 and Peak 2 were characterized by HPLC. Comparison of the HPLC charts with those of authentic Compound 2 and authentic Compound 3 (see Figures 2 and 3) revealed that Peak 1 was S-propafenone (i.e., Compound 2) and Peak 2 was R-propafenone (i.e., Compound 3). The high performance liquid chromatography conditions were as follows. Liquid chromatograph: K-Prep LAB 100G (YMC CO., LTD.); column model: CHIRALPAK AY; column size: 2.5 cm ID × 25 cm L; packing material specification: 10 μm; mobile phase: n-hexane:ethanol = 40:60; flow rate: 50 mL / min; detection wavelength: UV 210 nm; column temperature: 40 °C.

[0147] Example 2 Synthesis of Compound 4 [ka] (1) Synthesis of Compound 4-3 Compound 4-1 (876 mg, 8.26 mmol) was dissolved in 80 mL of EtOH and then compound 4-2 (2.00 g, 8.26 mmol) was added. Sodium hydroxide (1.32 g, 33.02 mmol) dissolved in 13.2 mL of water was added dropwise. After the addition was complete, the reaction mixture was stirred at 25 °C for 16 h. After the target product was detected by LCMS, the reaction mixture was poured into ice water and slowly added with 1 M hydrochloric acid until the pH reached 4-5. The mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and compressed onto a silica gel sample. The sample was purified by flash column chromatography (eluent: ethyl acetate: petroleum ether = 0-30%) to give compound 4-3 (1.8 g, yield: 46.2%, purity: 70%). The structure was confirmed by LCMS. LCMS: MS=331.1 [M+H] + .

[0148] (2) Synthesis of Compound 4-5 Compound 4-3 (940 mg, 2.85 mmol) and compound 4-4 (1.32 g, 14.23 mmol) were dissolved in acetonitrile (20 mL) in a sealed container, and potassium carbonate (786.5 mg, 5.69 mmol) was added. After the dropwise addition, the mixture was stirred at 100 °C for 12 h. After the product was detected by LCMS, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and compressed to prepare a silica gel sample. The sample was purified using a flash column machine (ethyl acetate:petroleum ether = 0-50%) to obtain compound 4-5 (330 mg, yield: 30%). The structure was confirmed by LCMS. LCMS: MS=387.1 [M+H] + . (3) Synthesis of Compounds 4-6

[0149] Compound 4-5 (330 mg, 0.854 mmol) was added to a sealed vessel containing acetonitrile (6 mL) together with n-propylamine (101 mg, 1.71 mmol) and stirred at 60° C. for 2 h. After the product was detected by LCMS, the reaction mixture was directly passed through a Flash reverse-phase column to give compound 4-6 (160 mg, 42% yield), the structure of which was confirmed by LCMS. LCMS: MS=446.3 [M+H] + .

[0150] (4) Synthesis of Compound 4 Compound 4-6 (160 mg, 0.359 mmol) was dissolved in methanol (3 mL) and 10% palladium on carbon (76 mg, 0.072 mmol) was added. After the addition was complete, the mixture was purged with hydrogen gas three times and stirred under a hydrogen atmosphere for 1 h. When the reaction was complete by LCMS, the mixture was filtered through a filter head. The filtrate was collected and a silica gel sample was prepared. The sample was purified using a flash column machine (methanol:dichloromethane = 0-50%, 1% aqueous ammonia) to give compound 4 (39 mg, yield: 30%). The structure was confirmed by LCMS and HNMR. LCMS: M=358.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 7.29 - 7.20 (m, 4H), 7.17 (d, J = 6.8 Hz, 1H), 6.96 (dd, J = 15.8, 5.9 Hz, 2H), 6.90 (dd, J = 8.8, 3.1 Hz, 1H), 4.08 - 3.84 (m, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.68 (dt, J = 12.2, 6.7 Hz, 2H), 2.50 - 2.38 (m, 4H), 1.42 (dd, J = 14.6, 7.3 Hz, 2H), 1.23 (s, 2H), 0.84 (t, J = 7.4 Hz, 3H).

[0151] Example 3 Synthesis of Compound 5 [ka]

[0152] (1) Synthesis of Compound 5-3 Compound 5-1 (876 mg, 8.26 mmol) was dissolved in ethanol (80 mL) and compound 5-2 (2.00 g, 8.26 mmol) was added. Sodium hydroxide solution (1.32 g, 33.02 mmol) dissolved in water (13.2 mL) was then added dropwise. After the addition was complete, the reaction mixture was stirred at 25 °C for 16 h. After the target product was detected by LCMS, the reaction mixture was poured into ice water and slowly added with 1 M hydrochloric acid until the pH reached 4-5. The mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and compressed to a silica gel sample. The sample was purified by automated column chromatography (eluent: ethyl acetate: petroleum ether = 0-30%) to obtain compound 5-1 (750 mg, yield: 27.5%). The structure was confirmed by LCMS. LCMS: MS=331.1 [M+H] + .

[0153] (2) Synthesis of Compound 5-5 Compound 5-3 (400 mg, 1.21 mmol) and compound 5-4 (118 mg, 4.84 mmol) were dissolved in acetonitrile (10 mL) in a sealed reaction vessel, and potassium carbonate (335 mg, 2.42 mmol) was added. After the dropwise addition, the reaction mixture was stirred at 100 °C for 12 h. After the product was detected by LCMS, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and compressed onto a silica gel sample. The sample was purified using a flash column machine (eluent: ethyl acetate: petroleum ether = 0-50%) to give compound 5-5 (330 mg, yield: 70%). The structure was confirmed by LCMS. LCMS: M=387.2 [M+H] + .

[0154] (3) Synthesis of Compound 5-6 Compound 5-5 (330 mg, 0.854 mmol) and n-propylamine (101 mg, 1.71 mmol) were added to a sealed reaction vessel containing acetonitrile (6 mL) and stirred at 60° C. for 2 h. After the product was detected by LCMS, the reaction mixture was directly purified using a reverse-phase column (packing material C18) to give compound 5-6 (160 mg, yield: 42%), the structure of which was confirmed by LCMS. LCMS: M=446.3 [M+H] + .

[0155] (4) Synthesis of Compound 5 Compound 5-6 (160 mg, 0.359 mmol) was dissolved in MeOH (3 mL) and 10% palladium on carbon (76 mg, 0.072 mmol) was added. After the addition was complete, the mixture was purged with hydrogen gas three times and stirred under hydrogen atmosphere for 1 h. When the reaction was complete by LCMS, the mixture was filtered through a filter head. The filtrate was collected and a silica gel sample was prepared. The sample was purified by flash column chromatography (eluent: MeOH:DCM = 0-50%, 1% aqueous ammonia) to give compound 5 (27.24 mg, yield: 21%). The structure was confirmed by LCMS and HNMR. LCMS: M=358.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 6.5 Hz, 4H), 7.12 (d, J = 7.4 Hz, 1H), 6.98 (s, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 3.90 (t, J = 24.6 Hz, 3H), 3.19 (s, 2H), 2.94 (t, J = 7.2 Hz, 2H), 2.80 - 2.16 (m, 4H), 1.47 (dd, J = 14.3, 6.9 Hz, 2H), 1.19 (s, 2H), 0.85 (t, J = 7.3 Hz, 3H).

[0156] Example 4 Preparation of Compound 1 Ointment The formulation of Compound 1 in ointment form is as follows: Oil phase: liquid paraffin 2g, glyceryl monostearate 4g, white petrolatum 3g, lanolin 2g Aqueous phase: glycerol 3g, ultrapure water 14.11g Main drug: Compound 1 0.0285 g (drug loading: 0.1%) Emulsifier: Triethanolamine 0.3g Preservative: Ethylparaben 0.09g Preparation method: The aqueous phase, preservative, and emulsifier were weighed into a 100 mL beaker according to the formula, placed in a 500 mL beaker equipped with a magnetic stirrer, and heated in a water bath. When the temperature reached 75°C, Compound 1 powder was added and stirred until dissolved (80°C, 350 r / min). The oil phase was weighed into another 100 mL beaker according to the formula, heated in a water bath, and stirred until dissolved (80°C, 250 r / min). The aqueous phase was slowly added to the oil phase and stirred for 10 min (80°C, 300 r / min). The mixture was then removed and placed at room temperature, with continuous stirring in the same direction until condensed into an ointment. The prepared ointment was placed in a 50 mL centrifuge tube, sealed with a sealing film, and stored. The mass concentration of Compound 1 in the ointment was 0.1%.

[0157] Example 5: Treatment of Psoriasis with Compounds of Formula I

[0158] 1. Construction of a Mouse Psoriasis Model A mouse psoriasis model was established by intradermal injection of recombinant IL-23 (1 ng / 20 μL PBS, one day per mouse, for four consecutive days) into mice with hair loss on the back.

[0159] 2. Testing steps On day 2 after modeling, the psoriasis model mice were randomly divided into three groups with equal numbers of mice in each group. They were divided into a model group and a treatment group (including subcutaneous and intradermal treatment groups). The model group served as a control. Starting on day 2, mice in the subcutaneous treatment group received subcutaneous injections of Compound 1 at 0.7 mg per mouse per day to simulate the effects of injection on psoriasis in mice. Mice in the intradermal treatment group received intradermal injections of Compound 1 at 0.07 mg per mouse per day to simulate the effects of topical administration on psoriasis in mice. The model group received intradermal injections of 20 μL of saline. All three groups received injections for four consecutive days. On day 6, mice in the model and treatment groups were scored for symptoms. The rule for calculating the number of days was to count the number of days from the completion of modeling, with the day on which modeling was completed being recorded as day 0, followed by day 1, day 2, and so on. The concentration of Compound 1 in the injection solution for the subcutaneous and intradermal treatment groups was 35 mg / 10 mL. Scoring scale: 0, no symptoms; 1, red rash on the skin; 2, scattered dandruff; 3, widespread dandruff; 4, scleroderma; 5, erythroderma or death.

[0160] 3. Test Results The results are shown in Figure 4. The model group and subcutaneous treatment group had scores close to 3, while the intradermal treatment group had a score of around 2. Compared with the model group and subcutaneous treatment group, the intradermal treatment group injected with Compound 1 injection showed a significant therapeutic effect. This demonstrated that Compound 1 is more effective in treating psoriasis by topical administration than by injection. Dose-finding studies showed that Compound 1 was therapeutically effective at intradermal injection doses of 10 μg, 20 μg, 50 μg, 100 μg, 200 μg, 500 μg, 1 mg, 2 mg, 5 mg, and 10 mg.

[0161] Example 6 Comparative efficacy test with flecainide

[0162] 1. Construction of a Mouse Psoriasis Model The same as in Example 5.

[0163] 2. Testing steps Compound 1 and flecainide are similar conventional antiarrhythmic drugs, but their target sites and mechanisms of action are different. To investigate whether antiarrhythmic drugs are effective in treating psoriasis, this experiment compared the effects of compound 1 and flecainide simultaneously in a mouse disease model. On the second day after modeling, the psoriasis model mice were divided equally into four groups: model group, ointment group, compound 1 ointment group, and flecainide ointment group. A different substance (see Table 1) was applied to the back of the mice in each group for four consecutive days, and the symptoms of the model mice and treatment group mice were scored from the first day.

[0164] [Table 1] The rule for calculating the number of days was to count the number of days from the completion of modeling, with the day on which modeling was completed being recorded as day 0, followed by day 1, day 2, and so on. The formulation and preparation method of the ointment group was the same as in Example 4, with the only difference being that no main drug was added. The formulation and preparation method of the Compound 1 ointment group refer to Example 4 (however, the mass concentration of Compound 1 in the Compound 1 ointment is 0.1%). The formulation and preparation method of flecainide ointment refer to Example 4, and the only difference from Example 4 is that the main drug is replaced with an equal amount of flecainide (the mass concentration of flecainide in flecainide ointment is 0.1%). Scoring scale: 0, no symptoms; 1, red rash on the skin; 2, scattered dandruff; 3, widespread dandruff; 4, scleroderma; 5, erythroderma or death.

[0165] 3. Test Results The results are shown in Figure 5. From day 1 to day 5, the score of the flecainide ointment group reached 3 points on day 2 and maintained 3 points from day 2 to day 7. The score of the compound 1 ointment group reached 2 points on day 2, 3 points from day 3 to day 4, decreased to 2 points or less from day 5, and decreased to 1 point on days 7 and 8. The above data indicate that the therapeutic effect of compound 1 is significantly stronger than that of flecainide at the same dosage.

[0166] Overall, compared with the model group, application of Compound 1 ointment had a significant therapeutic effect, whereas flecainide ointment and ointment alone had no therapeutic effect, indicating that Compound 1 has a significant effect in treating psoriasis compared with flecainide.

[0167] Example 7 Dose-effect relationship of Compound 1

[0168] 1. Construction of a Mouse Psoriasis Model The same as in Example 5.

[0169] 2. Testing steps On the second day after modeling, the psoriasis model mice were divided into seven groups: a model group, a plaster-only group, and five treatment groups with different doses. The model group served as a control, and each group had a different substance applied to their backs for four consecutive days (see Table 2). On the sixth day, the symptoms of the model mice and the treatment group mice were scored.

[0170] [Table 2] The rule for calculating the number of days was to count the number of days from the completion of modeling, with the day on which modeling was completed being recorded as day 0, followed by day 1, day 2, and so on. The formulation and preparation method of the plaster-only group was the same as in Example 4, with the only difference being that the main drug was not added. The formulation and preparation methods for 0.01%, 0.1%, 0.2%, 0.5%, and 1% ointments of Compound 1 were based on Example 4. The mass of the main drug in the formulation of Example 4 was adjusted to prepare ointments with mass fractions of Compound 1 of 0.01%, 0.1%, 0.2%, 0.5%, and 1%, respectively. Scoring scale: 0, no symptoms; 1, red rash on the skin; 2, scattered dandruff; 3, widespread dandruff; 4, scleroderma; 5, erythroderma or death.

[0171] 3. Test Results The results are shown in Figure 6. Compared with the model group, the effective dose window for Compound 1 ointment was 0.1% to 0.5%. Further dose investigation revealed that 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, and 0.1% were still effective, indicating that Compound 1 ointment has a clear therapeutic effect when the mass concentration of Compound 1 in Compound 1 ointment is 0.02% to 0.5%.

[0172] Example 8 Evaluation of the efficacy of Compound 2 and Compound 3

[0173] 1. Preparation of Compound 2 and 3 Ointments The results were the same as in Example 4.

[0174] 2. Construction of a Mouse Psoriasis Model The same as in Example 5.

[0175] 3. Testing steps On the second day after modeling, the psoriasis model mice were randomly and evenly divided into an ointment group, a compound 1 ointment treatment group, a compound 2 ointment treatment group, and a compound 3 ointment treatment group. A different substance (see Table 3) was applied to the back of the mice in each group for six consecutive days. Starting from the first day, the symptoms of the skin on the backs of the model mice and treatment group mice were scored every day.

[0176] [Table 3] The rule for calculating the number of days was to count the number of days from the completion of modeling, with the day on which modeling was completed being recorded as day 0, followed by day 1, day 2, and so on. The formulation and preparation method of the ointment group was the same as in Example 4, with the only difference being that no main drug was added. The formulation and preparation methods of Compound 1 ointment group, Compound 2 ointment group, and Compound 3 ointment are described in Example 4 (mass concentration: 0.025%).Scoring criteria: 0 points, no symptoms; 1 point, red skin rash; 2 points, scattered dandruff; 3 points, widespread dandruff; 4 points, sclerosis; 5 points, erythroderma or death.

[0177] 4. Test Results The PASI score results are shown in Figure 7. Over time, the skin scores of mice in each group initially increased and then decreased, demonstrating the typical trend of psoriasis. At the end of the experiment, compared with the ointment group, the skin scores of Compound 1 and Compound 3 ointments significantly decreased after treatment, effectively alleviating symptoms. Compound 3 had an even lower score, demonstrating a more pronounced therapeutic effect, while Compound 2 ointment showed no therapeutic effect. Because both Compound 3 and Compound 2 were isolated from Compound 1, the treatment results indicated that Compound 2 had no therapeutic effect, while Compound 3 did, proving that Compound 3 is the active ingredient of Compound 1. Because Compound 1 contains Compound 2 at the same mass concentration, the relative concentration of Compound 3 in Compound 1 was lower than that of the Compound 3 alone group. This is thought to be the main reason why the therapeutic effect of Compound 1 was slightly lower than that of the Compound 3 ointment group.

[0178] Example 9 Evaluation of the efficacy of Compound 4 and Compound 5

[0179] 1. Construction of a Mouse Psoriasis Model The same as in Example 5.

[0180] 2. Testing steps Because compounds 4 and 5 have poor transdermal efficacy, microneedle administration (MN) was used to verify their therapeutic efficacy. On the second day after modeling, psoriasis model mice were randomly and evenly divided into a model group, a compound 4 microneedle treatment group, and a compound 5 microneedle treatment group. After puncturing the mouse skin with a microneedle, 100 μL of compound 4 or 5 was dispensed onto the back of the mouse using a pipette and gently and evenly distributed (see Table 3). Treatment continued for 8 days. Starting from the first day, the symptoms on the back skin of the model mice and the treatment group mice were scored daily.

[0181] [Table 4] The rule for calculating the number of days was to count the number of days from the completion of modeling, with the day on which modeling was completed being recorded as day 0, followed by day 1, day 2, and so on. Scoring scale: 0, no symptoms; 1, red rash on the skin; 2, scattered dandruff; 3, widespread dandruff; 4, scleroderma; 5, erythroderma or death.

[0182] 3. Test Results The PASI score results are shown in Figure 8. Over time, the skin scores of mice in each group showed a typical trend of increasing and then decreasing, but the scores for each group varied. Compared to the model group treated with microneedles alone, after treatment with Compound 5, the skin scores rapidly decreased from the fifth day of treatment, effectively alleviating the symptoms.

[0183] Although the preferred embodiments of the present invention have been described in detail above, the present invention is not limited to the specific details in the above embodiments, and within the technical concept of the present invention, multiple simple modifications can be made to the technical solutions of the present invention, and all of these simple modifications fall within the protection scope of the present invention.

[0184] It should be noted that the specific technical features described in the above specific embodiments can be combined in any suitable manner as long as they are not contradictory, and in order to avoid unnecessary duplication, the present invention does not separately describe various possible combination methods.

Claims

1. 1. Use of a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof, in the preparation of a product for treating and / or preventing psoriasis-related conditions, wherein the compound has the structure: 【Chemistry 1】 (I) (wherein X is a single bond, —O—(C ０ ~C １０ alkylene)-, -S-(C ０ ~C １０ alkylene)-, -N(C ０ ~C １０ alkyl)-(C ０ ~C １０ alkylene)-, C １ ~C １０ Alkylene, C ２ ~C １０ Alkenylene, C ２ ~C １０ alkynylene, R ０ is H, -CO(C １～１０ alkyl), -CO(C ６～１０ aryl), R １ , R １ ' are independently H, C １ ~C １０ Alkyl, C ２ ~C １０ Alkenyl, C ２ ~C １０ Alkynyl, C １ ~C １０ Haloalkyl, -(C ０ ~C ６ alkylene)-(C ３ ~C １０ cycloalkyl), -(C ０ ~C ６ alkylene)-(C ６ ~C １０ aryl), -(C ０ ~C ６ alkylene)-(4- to 10-membered heterocyclyl), -N(C ０～１０ alkyl) (C ０～１０ alkyl), —O(C ０～１０ alkyl), or R １ and R １ ' form a heterocycle together with the nitrogen atom to which they are attached, wherein H in said heterocycle is selected from halogen, cyano, nitro, azido, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, —N(C ０～１０ alkyl) (C ０～１０ alkyl), —O(C ０～１０ alkyl), -S(C ０～１０ alkyl), R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ are independently H, halogen, cyano, nitro, azide, C １ ~C １０ Alkyl, C １ ~C １０ Haloalkyl, -(C ０ ~C ６ alkylene)-(C ３ ~C １０ cycloalkyl), -(C ０ ~C ６ alkylene)-(C ６ ~C １０ aryl), -(C ０ ~C ６ alkylene)-(4- to 10-membered heterocyclyl), -N(C ０～１０ alkyl) (C ０～１０ alkyl), —O(C ０～１０ alkyl), -S(C ０～１０ alkyl), Preferably, X is C １ ~C ６ Alkylene, C ２ ~C ６ alkenylene, more preferably -CH ２ CH ２ - or -CH=CH-, Preferably, R ０ is H, -CO(C １～６ alkyl), Preferably, R １ , R １ ' are independently H, C １ ~C ６ Alkyl, -(C ０ ~C ６ alkylene)-(C ６ ~C １０ aryl), or R １ and R １ ' form a 4- to 6-membered nitrogen-containing heterocycle together with the nitrogen atom to which they are attached, and H in the 4- to 6-membered nitrogen-containing heterocycle is C １ ~C ６ optionally substituted with one or more groups selected from alkyl; Preferably, R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ are independently H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ haloalkyl, —O(C ０～６ alkyl).

2. The compound has the following structure: 【Chemistry 2】 (II) 2. The use according to claim 1, characterized in that the compound preferably has the following structure: 【Transformation 3】 (III) (More preferably, R ４ is H, F, Cl, Br, I or —CF ３ and More preferably, R ７ , R ９ is H or —OH.)

3. 2. The use of claim 1, wherein the compound has the following structure: 【Chemistry 4】 (IV) wherein X is selected from a single bond, —O—, —S—, or alkylene; R １ is selected from H, alkyl, alkoxy, alkenyl or alkynyl; R ２ , R ３ , R ４ , R ５ , R ６ are independently selected from H, alkyl, or halogen atoms.

4. The X is a single bond or C １ ~C １０ 4. The use according to claim 3, characterized in that the alkylene is selected from the group consisting of alkylenes.

5. The R １ is C １ ~C １０ 5. The use according to claim 3 or 4, characterized in that the alkyl is selected from the group consisting of alkyl, methyl ...

6. The R ２ , R ３ , R ４ , R ５ , R ６ is independently selected from H, F, Cl, Br, I, methyl or ethyl.

7. X is C １ ~C ４ alkylene; R １ is C １ ~C ４ alkyl, R ２ , R ３ , R ４ , R ５ , R ６ is independently selected from H, F, Cl, Br, I, methyl or ethyl.

8. The use according to any one of claims 3 to 7, characterized in that the compound has the following structure: 【Transformation 5】

9. 9. The use according to claim 8, wherein the stereoisomer of the compound has the following structure: 【Transformation 6】 Preferably 【Transformation 7】

10. The compound has the following structure: 【Transformation 8】 Preferably, the stereoisomer has the structure: 【Chemistry 9】 More preferably, the stereoisomer has the structure: 【Chemistry 10】 2. The use according to claim 1, characterized in that the isotope derivative preferably has the following structure: 【Chemistry 11】

11. the product is a drug, The drug is an external preparation, an injection, or an oral preparation; the topical preparation is selected from a solution, a tincture, a spirit, a paste, an oil, an ointment, a cream, a gel, a film coating, a liniment, a detergent, a spray, a suspension, a solution, an emulsion, a microemulsion, a suspension, a plaster, a gel, a patch, a powder aerosol, a suppository, an eye drop, or a nose drop; The injection is selected from a solution, a suspension, an emulsion, or a powder injection; the oral formulation is selected from a tablet, a pill, a pellet, a powder, a granule, a capsule, a troche, a syrup, a suspension, an emulsion, a microemulsion, a powder aerosol, a paste, a sublingual tablet, or a suppository; The use according to any one of claims 1 to 10, characterized in that the dosage form of the drug is preferably an external preparation, in particular an ointment.

12. An external preparation for treating and / or preventing psoriasis-related diseases, comprising: The topical formulation comprises a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof; The topical preparation further comprises a pharmaceutically acceptable auxiliary material.

13. 13. The topical formulation according to claim 12, wherein the topical formulation is selected from the group consisting of waters, tinctures, spirits, pastes, oils, ointments, creams, gels, film coatings, liniments, detergents, sprays, suspensions, solutions, emulsions, microemulsions, suspensions, plasters, gels, patches, powder aerosols, suppositories, eye drops or nasal drops.

14. the auxiliary material comprises one or more of a solubilizer, an oil phase, an aqueous phase, and an additive; Preferably, the solubilizer comprises one or more of aliphatic alcohol polyoxyethylene ethers, fatty acid polyoxyethylene esters, castor oil polyoxyethylene ethers, alkylphenol polyoxyethylene ethers, aliphatic amine polyoxyethylene ethers, polyoxyethylene polyoxypropylene copolymers, polyethylene glycol, polyethylene glycol stearate, sorbitol ester polyoxyethylene ethers, sorbitan esters; Preferably, the oil phase comprises one or more of liquid paraffin, solid paraffin, stearic acid, white petrolatum, cetyl alcohol, stearyl alcohol, glyceryl monostearate, isopropyl myristate, dimethicone, silicone, beeswax, lanolin, spermaceti, glyceryl caprylate / caprate, isooctyl palmitate, isopropyl palmitate, PEG-100 stearate, vegetable oils, animal oils; Preferably, the aqueous phase comprises one or more of water, ethanol, glycerin, cetyl alcohol, stearyl alcohol, hexanediol, propylene glycol, glycerin, dipropylene glycol, ethylene glycol, pentylene glycol; Preferably, the additives include one or more of an emulsifier, a transdermal penetration enhancer, a pH adjuster, and a preservative; More preferably, the transdermal penetration enhancer comprises one or more of azone, dimethyl sulfoxide, decyl methyl sulfoxide, menthol, borneol, clove oil, ethanol, laurel oil, urea, capsaicin, oleic acid, urea; More preferably, the pH adjuster comprises one or more of citric acid, salicylic acid, boric acid, fatty acid, sodium hydroxide, potassium hydroxide; More preferably, the emulsifier is one or more selected from the group consisting of triethanolamine, fatty acid soap, sodium lauryl sulfate, polyoxyethylene ether, polyoxypropylene ether, ethylene oxide, lecithin, and gum arabic; More preferably, the preservative comprises one or more of imidazolidinyl urea, diazolidinyl urea, DMDMH, quaternium-15, benzoic acid and its derivative preservatives, phenoxyethanol, benzyl alcohol, polyol-based preservatives, chlorphenesin, bronopol, cathon, benzalkonium bromide, benzalkonium chloride, ethylparaben, methylparaben, isopropyl alcohol, salicylic acid, and sorbic acid; And / or the additives further comprise one or more of vitamin E, dextran, betaine, butylated hydroxyanisole, ascorbic acid, propionic acid basic compounds, ethanol, benzalkonium bromide, and hydroxyphenylpropionamidobenzoic acid.

15. 14. The topical formulation according to claim 13, wherein when the topical formulation is a gel, the auxiliary materials further comprise one or more of gelatin, carbomer, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, glycerin, propylene glycol, dipropylene glycol, and water.

16. 14. The topical formulation of claim 13, wherein the topical formulation comprises 0.01 to 99.5% by weight, preferably 0.02 to 0.5% by weight, more preferably 0.1% to 0.5% by weight, of the compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form, or metabolite thereof.

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