Compound and application thereof

Abstract

The invention provides a compound shown in a formula I or pharmaceutically acceptable salts, stereoisomers, isotope derivatives, solvates (such as hydrates), prodrugs, metal chelates, crystal forms or metabolites of the compound and application of the compound in the field of medicine. The compound can be used for treating and / or preventing psoriasis diseases, especially propafenone. The invention also finds that under the condition of the same administration dosage, the effect of smearing administration on treating psoriasis diseases is better than that of injection administration. Compared with a flecainib ointment with a similar anti-arrhythmia function, the propafenone ointment disclosed by the invention has a better effect on treating psoriasis diseases.

Description

A compound and its application Technical Field

[0001] The present invention relates to the field of biopharmaceutical technology, and specifically to a compound represented by Formula I or a pharmaceutically acceptable salt, stereoisomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form or metabolite thereof, and its use in treating and / or preventing psoriasis-related diseases. Background Art

[0002] Psoriasis is a skin symptom caused by an abnormal immune system. Currently, clinical treatment methods mainly include ultraviolet radiation, 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 a variety of 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 a variety of drugs and treat various diseases including psoriasis.

[0004] However, the prior art has not reported on the effects of the compound represented by Formula I in treating and / or preventing psoriasis-related diseases.

[0005] Summary of the Invention

[0006] The present invention provides a compound represented by Formula I or a pharmaceutically acceptable salt, stereoisomer, hydrate, prodrug, solvate, metabolite or isotope derivative thereof, as well as use thereof in treating or preventing psoriasis-related diseases.

[0007] In a first aspect, the present invention provides 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 for use in preparing a product for treating and / or preventing psoriasis-related diseases, wherein the compound has the following structure:

[0008] Wherein, X is selected from: 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 Alkynylidene;

[0009] R0 is selected from: H, -CO(C 1-10 alkyl), -CO(C 6-10 aryl);

[0010] R1, R1' are independently selected from: H, C1-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 heterocyclic group), -N(C 0-10 Alkyl)(C 0-10 alkyl), -O(C 0-10 or, R1 and R1' together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein the H on the heterocyclic ring is optionally substituted by one or more groups selected from the following: 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(C 0-10 alkyl);

[0011] R2, R3, R4, R5, R6, R7, R8, R9, R 10 Independently selected from: H, halogen, cyano, nitro, azido, 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 heterocyclic group), -N(C 0-10 Alkyl)(C 0-10 alkyl), -O(C 0- 10 Alkyl), -S(C 0-10 alkyl).

[0012] Further, X is selected from: C1-C6 alkylene (such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-), C2-C6 alkenylene (such as -CH=CH-, -CH=CH-CH=CH-, -CH=CH-CH=CH-CH=CH-).

[0013] In some embodiments of the present invention, X is -CH2CH2- or -CH=CH-.

[0014] Further, R0 is selected from: H, -CO(C 1-6 alkyl) (e.g., -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH2CH2CH2CH3).

[0015] In some embodiments of the present invention, R0 is H.

[0016] In some embodiments of the present invention, R0 is -COCH3.

[0017] Furthermore, R1 and R1' are independently selected from the group consisting of: H, C1-C6 alkyl (such as -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2), -(C0-C6 alkylene)-(C6-C 10 Aryl) (such as ).

[0018] In some embodiments of the present invention, R1' is H.

[0019] In some embodiments of the present invention, R1 is -CH2CH2CH3 and R1' is H.

[0020] In some embodiments of the present invention, R1 is -CH(CH3)2 and R1' is H.

[0021] In some embodiments of the present invention, R1 is -CH2CH3 and R1' is -CH3.

[0022] In some embodiments of the present invention, R1 is R1' is H; or, R1 is H, R1' is

[0023] Furthermore, R1 and R1' together with the nitrogen atom to which they are connected form a 4-6 membered nitrogen-containing heterocyclic ring, wherein the H on the 4-6 membered nitrogen-containing heterocyclic ring is optionally substituted with one or more groups selected from the following: C1-C6 alkyl.

[0024] Furthermore, the 4-6 membered nitrogen-containing heterocycle is selected from: Preferably

[0025] In some embodiments of the present invention, R1 and R1' together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring.

[0026] Furthermore, R2, R3, R4, R5, R6, R7, R8, R9, R 10 Independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O(C 0-6 alkyl).

[0027] In some embodiments of the present invention, R2 is H.

[0028] In some embodiments of the present invention, R3 is H.

[0029] In some embodiments of the present invention, R4 is H, halogen (such as F, Cl, Br, I), C1-C6 haloalkyl (such as -CF3).

[0030] In some embodiments of the present invention, R5 is H.

[0031] In some embodiments of the present invention, R6 is H.

[0032] In some embodiments of the present invention, R7 is H or -OH.

[0033] In some embodiments of the present invention, R8 is H.

[0034] In some embodiments of the present invention, R9 is H or -OH.

[0035] In some embodiments of the present invention, R 10 For H.

[0036] In some embodiments of the present invention, the compound has the following structure:

[0037] In some embodiments of the present invention, the compound has the following structure:

[0038] In some embodiments of the present invention, the compound has the following structure:

[0039] Wherein, X is selected from a single bond, -O-, -S- or an alkylene group.

[0040] Preferably, in formula IV, X is selected from a single bond or a C1-C 10 Further preferably, X is selected from C1-C4 alkylene.

[0041] In formula IV, R1 is selected from H, alkyl, alkoxy, alkenyl or alkynyl. Preferably, R1 is selected from C1-C 10 Further preferably, R1 is selected from a C1-C4 alkyl group.

[0042] In Formula IV, R2, R3, R4, R5, and R6 are independently selected from H, an alkyl group, or a halogen atom. Preferably, R2, R3, R4, R5, and R6 are independently selected from H, F, Cl, Br, I, a methyl group, or an ethyl group. Further preferably, R2, R3, R4, R5, and R6 are independently selected from H, F, Cl, Br, I, a methyl group, or an ethyl group.

[0043] In some embodiments of the present invention, in Formula IV, X is selected from C1-C4 alkylene; R1 is selected from C1-C4 alkyl; R2, R3, R4, R5, and R6 are independently selected from H, F, Cl, Br, I, methyl, or ethyl.

[0044] In some embodiments of the present invention, in Formula IV, X is -CH2CH2-, R1 is selected from C1-C4 alkyl; R2, R3, R4, R5, and R6 are independently selected from H, F, Cl, Br, I, methyl, or ethyl.

[0045] In some embodiments of the present invention, in Formula IV, X is selected from C1-C4 alkylene; R1 is selected from -CH2CH2CH3; R2, R3, R4, R5, R6 are independently selected from H, F, Cl, Br, I, methyl or ethyl.

[0046] In some embodiments of the present invention, in Formula IV, X is selected from C1-C4 alkylene; R1 is selected from C1-C4 alkyl; R2, R3, R4, R5, and R6 are all H.

[0047] In some embodiments of the present invention, the compound has the following structure:

[0048] In other embodiments of the present invention, the compound has the following structure:

[0049] Furthermore, the stereoisomer has the following structure:

[0050] In some embodiments of the present invention, the stereoisomer has the following structure:

[0051] In some embodiments of the present invention, the stereoisomer has the following structure:

[0052] In one embodiment of the present invention, the stereoisomers of the compound have the following structures:

[0053] in particular

[0054] In other embodiments of the present invention, the stereoisomer has the following structure:

[0055] Preferably, the stereoisomer has the following structure:

[0056] Furthermore, the isotope derivative includes a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass, such as stable and radioactive isotopes of hydrogen, carbon, oxygen, etc., specifically 2H (deuterium, D), 3H (tritium, T), 11C, 13C, 14C, 17O, 18O, etc., preferably deuterium.

[0057] In some embodiments of the present invention, the isotopic derivative has the following structure:

[0058] Furthermore, the product is a drug comprising the compound of Formula I or its pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form or metabolite;

[0059] The drug may contain 0.01-99.5% by weight (specifically, 0.01%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.12%, 0.14%, 0.16%, 0.18%, 0.2%, 0.22%, 0.24%, 0.26%, 0.28%, 0.3%, 0.32%, 0.34%, 0.36%, 0.38%, 0.4%, 0.42%, 0.44%, 0.46%, 0.48%, 0.5%, 0.52%, 0.54%, 0.56%, 0.58%). %, 0.6%, 0.62%, 0.64%, 0.66%, 0.68%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%) of the compound of Formula I or its pharmaceutically acceptable salt, stereoisomer, isotope derivative, solvate (such as hydrate), prodrug, metal chelate, crystalline form or metabolite, preferably 0.02-0.5%, more preferably 0.1%-0.5%.

[0060] Furthermore, the drug can be administered by any suitable route, such as enteral administration (e.g., oral) or parenteral administration (e.g., intravenous, intramuscular, subcutaneous, intradermal, intraorgan, intranasal, intraocular, instillation, intracerebral, intrathecal, transdermal, rectal, etc.), preferably parenteral administration.

[0061] In some embodiments of the present invention, the administration route is a subcutaneous administration route, an intradermal administration route or a transdermal administration route, in particular a transdermal administration route.

[0062] Furthermore, the drug can be in any suitable dosage form, such as a dosage form for enteral administration or a dosage form for parenteral administration. Preferably, the drug is a dosage form for parenteral administration.

[0063] Furthermore, the dosage form of the drug is an external preparation, an injection or an oral preparation;

[0064] The topical preparation is selected from the group consisting of: aqueous solutions, tinctures, spirits, pastes, oils, ointments, creams, ointments, creams, gels, coatings, spreads, liniments, lotions, sprays, suspensions, solutions, emulsions, microemulsions, suspensions, plasters, gels, patches, powder sprays, suppositories, eye drops, or nasal drops;

[0065] The injection is selected from: aqueous solution, solution, suspension, emulsion or powder injection;

[0066] The oral preparation is selected from the group consisting of tablets, pills, drop pills, powders, granules, capsules, lozenges, syrups, suspensions, emulsions, microemulsions, powder sprays, pastes, sublingual tablets or suppositories.

[0067] In some embodiments of the present invention, the dosage form of the drug is an external preparation.

[0068] In some embodiments of the present invention, the external preparation is an ointment, a patch or a gel, in particular an ointment.

[0069] Furthermore, the drug can be a human drug or a veterinary drug.

[0070] Furthermore, the drug can be used alone or in combination with other types of active ingredients.

[0071] In a second aspect, the present invention provides an external preparation for treating and / or preventing psoriasis-related diseases, wherein the external preparation comprises the 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, crystal form, or metabolite thereof;

[0072] Preferably, the external preparation further comprises pharmaceutically acceptable excipients.

[0073] Furthermore, the topical preparation is selected from the group consisting of: aqueous solutions, tinctures, spirits, pastes, oils, ointments, creams, ointments, creams, gels, coatings, spreads, liniments, lotions, sprays, suspensions, solutions, emulsions, microemulsions, suspensions, plasters, gels, patches, powder sprays, suppositories, eye drops, or nasal drops;

[0074] Preferably, the excipients are all of pharmaceutical grade.

[0075] More preferably, the external preparation is an ointment, a patch or a gel.

[0076] In some embodiments of the present invention, the external preparation is an ointment or a patch, in particular an ointment.

[0077] Furthermore, the excipients include: one or more of: carriers, excipients, diluents, wetting agents, fillers, adhesives, lubricants, disintegrants, antioxidants, buffers, suspending agents, solubilizers, thickeners, stabilizers, flavoring agents, preservatives, etc.

[0078] Furthermore, the auxiliary materials include one or more of the following: a solubilizer, an oil phase, an aqueous phase, and an additive.

[0079] Preferably, the solubilizer includes one or more of: fatty alcohol polyoxyethylene ether, fatty acid polyoxyethylene ester, castor oil polyoxyethylene ether, alkylphenol polyoxyethylene ether, fatty amine polyoxyethylene ether, polyoxyethylene polyoxypropylene copolymer, polyethylene glycol, polyethylene glycol stearate, sorbitol ester polyoxyethylene ether, and sorbitan ester.

[0080] Preferably, the oil phase includes: 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, caprylic triglyceride, isooctyl palmitate, isopropyl palmitate, PEG-100 stearate, vegetable oil, and animal oil.

[0081] Preferably, the aqueous phase comprises one or more of water, ethanol, glycerol, hexadecanol, stearyl alcohol, hexylene glycol, propylene glycol, glycerol, dipropylene glycol, butylene glycol, and pentylene glycol.

[0082] Preferably, the additives include one or more of an emulsifier, a transdermal penetration enhancer, a pH regulator, and a preservative.

[0083] More preferably, the transdermal penetration enhancer is one or more of azone, dimethyl sulfoxide, decyl methyl sulfoxide, menthol, borneol, clove oil, ethanol, laurel oil, urea, capsaicin, oleic acid, and urea.

[0084] More preferably, the pH adjuster includes one or more of citric acid, salicylic acid, boric acid, fatty acid, sodium hydroxide, and potassium hydroxide.

[0085] More preferably, the emulsifier is selected from one or more of triethanolamine, fatty acid soap, sodium lauryl sulfate, polyoxyethylene ether, polyoxypropylene ether, ethylene oxide, lecithin, and gum arabic.

[0086] More preferably, the preservative includes: one or more of imidazolidinyl urea, diazolidinyl urea, DMDMH, quaternary ammonium salt-15, benzoic acid and its derivative preservatives, phenoxyethanol, benzyl alcohol, polyol preservatives, chlorphenesin, Bromopol, Kaisong, benzalkonium bromide, benzalkonium chloride, ethylparaben, methylparaben, isopropyl alcohol, salicylic acid, and sorbic acid.

[0087] And / or, the additive further comprises: one or more of vitamin E, dextran, betaine, butylated hydroxyanisole, ascorbic acid, dipropionic acid, ethanol, benzalkonium bromide, and hydroxyphenylpropionamide benzoic acid.

[0088] Furthermore, when the dosage form of the drug is a gel, the excipients also include: one or more of gelatin, carbomer, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, glycerol, propylene glycol, dipropylene glycol, and water.

[0089] Furthermore, the topical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be an ointment, patch, or any other dosage form; in addition, the unit dosage form can also be a packaged preparation, such as an ointment or patch packaged in a vial or box.

[0090] Furthermore, the external preparation can be used alone or in combination with other types of active ingredients.

[0091] Furthermore, the amount of the active ingredient in the unit dose preparation can be changed or adjusted from 10 ng to 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) depending on the specific application and efficacy of the active component. If necessary, the preparation may also contain other suitable therapeutic agents.

[0092] Preferably, the amount of active ingredient in the unit dose preparation is 10 μg to 10 mg.

[0093] The various dosage forms of the drug of the present invention can be prepared according to conventional production methods in the pharmaceutical field.

[0094] Furthermore, the topical preparation may contain 0.01-99.5% by weight (specifically, 0.01%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.12%, 0.14%, 0.16%, 0.18%, 0.2%, 0.22%, 0.24%, 0.26%, 0.28%, 0.3%, 0.32%, 0.34%, 0.36%, 0.38%, 0.4%, 0.42%, 0.44%, 0.46%, 0.48%, 0.5%, 0.52%, 0.54%, 0.56%, 0.58%, 0.6%, 0.62%, 0.64%, 0.66%, 0.68%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9 %, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%) of the compound of the first aspect and / or the second aspect of the present invention or its pharmaceutically acceptable salt, stereoisomer, isotope derivative, solvate (such as hydrate), prodrug, metal chelate, crystal form or metabolite, preferably 0.02% to 0.5%, more preferably 0.1% to 0.5%.

[0095] Furthermore, the external preparation can be for human or animal use.

[0096] In a specific embodiment of the present invention, the topical preparation comprises: the compound according to the first aspect and / or the second aspect of the present invention or its pharmaceutically acceptable salt, stereoisomer, isotopic derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form or metabolite, an oil phase, an aqueous phase, and an additive;

[0097] The oil phase comprises: paraffin, glyceryl monostearate, white petrolatum and lanolin;

[0098] The aqueous phase comprises: glycerol and water;

[0099] The additives include: emulsifiers and preservatives;

[0100] In a specific embodiment of the present invention, the preservative is ethylparaben.

[0101] In a specific embodiment of the present invention, the emulsifier is triethanolamine.

[0102] The third aspect of the present invention provides a method for preparing the aforementioned external preparation, the method comprising the following steps: (1) mixing an aqueous phase, a preservative, and an emulsifier, heating the mixture, adding an active ingredient, and stirring until dissolved to obtain an aqueous phase mixture, wherein the active ingredient is the compound described in 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, crystal form, or metabolite thereof;

[0103] (2) Mix and heat the components of the oil phase, stir until dissolved, add the aqueous phase mixture obtained in step (1) to the oil phase, and condense into an ointment while stirring.

[0104] Furthermore, the oil phase, water phase, preservative, and emulsifier have the definitions described in the third aspect of the present invention.

[0105] 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.

[0106] In some embodiments of the present invention, in the oil phase, the mass ratio of liquid paraffin, glyceryl monostearate, white petrolatum and lanolin is 2:4:3:2.

[0107] Furthermore, in the aqueous phase, the mass ratio of glycerol to water is 2-4:10-18.

[0108] In some embodiments of the present invention, in the aqueous phase, the mass ratio of glycerol to water is 3:14.11.

[0109] Furthermore, the mass ratio of glycerol, ethylparaben, water, triethanolamine and active ingredient is 2-4: 0.05-0.13: 10-18: 0.1-0.4: 0.01-0.05.

[0110] In some embodiments of the present invention, the mass ratio of glycerol, ethylparaben, water, triethanolamine and active ingredient is 3:0.09:14.11:0.3:0.0285.

[0111] Furthermore, in step (1), the heating temperature is 50-100°C (specifically 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100°C), preferably 70-90°C, and more preferably 75-80°C.

[0112] Furthermore, in step (1), the stirring speed is 200-500 r / min (specifically 200, 250, 300, 350, 400, 450, 500 r / min), preferably 350 r / min.

[0113] Furthermore, the step (1) comprises: mixing the aqueous phase, preservative and emulsifier, heating in a water bath, adding the active ingredient when the temperature reaches 75-80°C, and stirring until dissolved to obtain an aqueous phase mixture.

[0114] Furthermore, in step (2), the heating temperature is 50-100°C (specifically 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100°C), preferably 70-90°C, and more preferably 80°C.

[0115] Furthermore, in step (2), the stirring speed is 200-500 r / min (specifically 200, 250, 300, 350, 400, 450, 500 r / min), preferably 250 r / min.

[0116] Furthermore, the step (2) comprises: mixing the components of the oil phase, heating in a water bath to 80° C., stirring until dissolved, slowly adding the aqueous phase mixture obtained in step (1) to the oil phase, stirring, and then placing at room temperature, while stirring until it condenses into an ointment.

[0117] The fourth aspect of the present invention provides a method for treating and / or preventing psoriasis-like diseases, which comprises administering to an individual the compound of the first aspect of the present invention or its pharmaceutically acceptable salt, stereoisomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystalline form or metabolite, or the topical preparation of the second aspect.

[0118] Furthermore, the administration can be enteral (e.g. oral) or parenteral (e.g. intravenous, intramuscular, subcutaneous, intradermal, intraorgan, intranasal, intraocular, instillation, intracerebral, intrathecal, transdermal, intrarectal, etc.) routes.

[0119] In some embodiments of the present invention, the administration can be injection administration or transdermal administration (such as application administration or microneedle administration).

[0120] Furthermore, the pharmaceutical or topical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a capsule, tablet, or any other dosage form; in addition, the unit dosage form can also be a packaged preparation, such as tablets, capsules, and powders packaged in vials or ampoules.

[0121] Furthermore, the medicine or external preparation can be used alone or in combination with other types of active ingredients.

[0122] Furthermore, the amount of the active ingredient in the unit dose preparation can be changed or adjusted from 10 ng to 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) depending on the specific application and efficacy of the active component. If necessary, the medicine or topical preparation may also contain other suitable therapeutic agents.

[0123] Preferably, the amount of active ingredient in the unit dose preparation is 10 μg to 10 mg.

[0124] The present invention has the following beneficial effects:

[0125] (1) The present invention discovered that compounds 1, 2, and 5 can be used to treat psoriasis-related diseases, especially compound 1.

[0126] (2) The present invention found that under the same dosage, topical administration is more effective than injection in treating psoriasis-like diseases.

[0127] (3) Compound 1 is a conventional antiarrhythmic drug. The present invention has discovered that not all compounds with antiarrhythmic properties are effective in treating psoriasis-related diseases. Compared with flecainide ointment, which has similar antiarrhythmic properties, the present invention's compound has no effect on treating psoriasis, but the present invention's compound 1 (i.e., propafenone) ointment has a particularly outstanding therapeutic effect.

[0128] (4) The present invention has 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, because Compound 1 contains Compound 2 (i.e., S-propafenone), the relative concentration of Compound 3 in Compound 1 is lower than that of the group with Compound 3 alone. This may be the main reason why the therapeutic effect of Compound 1 is slightly lower than that of Compound 3.

[0129] The terms “include” or “comprising” described in the present invention are open-ended descriptions, which include the specified components or steps described and other specified components or steps that will not be substantially affected.

[0130] As used herein, "treating" means slowing, interrupting, preventing, controlling, stopping, alleviating, or reversing the progression or severity of a sign, symptom, disorder, condition, or disease after the disease has begun to develop, but does not necessarily involve the complete elimination of all disease-associated signs, symptoms, conditions, or disorders.

[0131] The term "prevention" used in the present invention refers to a method implemented to prevent or delay the occurrence of a disease, disorder or symptom in the body.

[0132] The "product" described in the present invention may be a drug, a device, a kit, etc.

[0133] The term "pharmaceutically acceptable" as used herein means that the substance neither significantly stimulates the organism nor inhibits the biological activity and properties of the active substance of the administered product.

[0134] The "pharmaceutically acceptable salt" described in the present invention refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base, wherein the acid or base includes an inorganic acid or base or an organic acid or base. 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.

[0135] The "stereoisomers" described in the present invention include enantiomers, diastereomers and geometric isomers.

[0136] As used herein, a "hydrate" refers to a compound containing water, wherein the water 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 resulting crystals are considered a hydrate.

[0137] The "prodrug" mentioned in the present invention refers to a compound that is obtained by chemically modifying the drug structure and has no or low activity in vitro or at non-specific target sites, and releases active drugs (such as the compounds of the present invention) through enzymatic or non-enzymatic conversion in vivo to exert its pharmacological effect.

[0138] As used herein, a "solvate" represents a physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0139] The "metabolites" of the present invention refer to products obtained by chemical degradation of the compounds of the present invention under physiological conditions in vivo.

[0140] The "derivative" mentioned in the present invention refers to a product formed by replacing an atom or an atomic group in a compound molecule with another atom or an atomic group, or a product formed by hydrolysis of the compound.

[0141] The "individual" described in the present invention can be a human or a non-human mammal, and the non-human mammal can be a wild animal, a zoo animal, a commercial animal, a pet, an experimental animal, etc. Preferably, the non-human mammal includes but is not limited to pigs, cattle, sheep, horses, donkeys, foxes, raccoon dogs, minks, camels, dogs, cats, rabbits, mice (e.g., rats, mice, guinea pigs, hamsters, gerbils, chinchillas, squirrels), monkeys, etc.

[0142] The "intradermal injection" mentioned in the present invention means injecting the drug below the epidermis of the skin, generally above the dermis but not into the subcutaneous tissue.

[0143] The "alkyl" of the present invention represents a straight or branched hydrocarbon chain radical that does not contain an unsaturated bond, and the hydrocarbon chain radical is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 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, C0 alkyl refers to H, i.e., C 0-10 Alkyl (or C0-C 10 Alkyl) includes H and C 1-10 Alkyl (or C1-C 10 alkyl).

[0144] The "alkylene" mentioned in the present invention refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule. It can be a straight chain or a branched chain and is connected to the rest of the molecule by a single bond. Typical alkylene groups 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) includes single bonds and C 1-10 Alkylene (or C1-C 10 alkylene).

[0145] The "alkoxy" group described in the present invention is composed of an alkyl group and an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, 2-ethylbutoxy, n-pentoxy, isopentoxy, 1-methylpentoxy, 1,3-dimethylbutoxy, n-hexyloxy, 1-methylhexyloxy, n-heptyloxy, isoheptyloxy, 1,1,3,3-tetramethylbutoxy, 1-methylheptyloxy, 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.

[0146] As used herein, "alkenyl" refers to a straight or branched hydrocarbon radical having at least two carbon atoms, at least one unsaturated bond, and attached to the rest of the molecule by a single bond. Typical alkenyl groups contain 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as vinyl, 1-methylvinyl, 1-propenyl, 2-propenyl, or butenyl.

[0147] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms, at least one carbon-carbon triple bond, and attached to the rest of the molecule by a single bond. Typical alkynyl groups contain 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), and the like.

[0148] The "halogen atom" mentioned in the present invention includes fluorine, chlorine, bromine and iodine.

[0149] The "cycloalkyl" mentioned in the present invention refers to an alicyclic hydrocarbon, such as a group containing 1 to 4 single rings and / or condensed rings, 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.

[0150] The "haloalkyl" mentioned in the present invention refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (such as fluorine, chlorine, bromine or iodine), such as -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2CH2-CF3, and -CH2CH2CH2-CF3.

[0151] The "aryl" in the present invention refers to a monocyclic or polycyclic free radical, including a polycyclic free radical containing a monocyclic aromatic group and / or a condensed aromatic group, such as a free radical containing 1-3 monocyclic or condensed rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. 12 The aryl group refers to an aryl group containing 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0152] The term "heterocyclyl" as used herein refers to a 3- to 18-membered non-aromatic ring group containing 2- to 17 carbon atoms and 1- to 10 heteroatoms. A heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spirocyclic, or bridged ring systems. A heterocyclyl group may be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups 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, furazolyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heterocycloalkyl groups 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, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, Heptyl, triazepine, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolizinyl. In the present invention, for the optionally substituted heterocyclic group, the substituted position can be any suitable carbon atom or heteroatom, for example, for The substitution position of R can be any suitable carbon atom or nitrogen atom, which can be, for example

[0153] In the present invention, "D" refers to deuterium; "substituted by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0154] It will be appreciated that, depending on the source of the chemical materials used in the synthesis, some variation in natural isotopic abundance will exist in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentrations of these naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E. et al., Seikagaku, 1994, 66:15; Gannes, L.Z. et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0155] In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Similarly, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium at an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0156] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0157] In other embodiments, the 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).

[0158] The "isotopologue" of the present invention refers to a substance in which the chemical structure differs from the specific compound of the present invention only in its isotopic composition.

[0159] The "psoriasis-like diseases" described in the present invention include diseases such as psoriasis (such as psoriasis vulgaris, pustular psoriasis (such as generalized pustular psoriasis (Zumbusch), localized pustular psoriasis (Barber type, also known as palmoplantar pustular psoriasis)), arthritic psoriasis, erythrodermic psoriasis), parapsoriasis (such as guttate parapsoriasis, plaque parapsoriasis, lichenoid parapsoriasis, and acne-like parapsoriasis), pityriasis rubra pilaris, pityriasis rosea, lichen planus, lichen sclerosus, lichen pilaris, chronic eczema, psoriasis-like diseases (such as guttate parapsoriasis, plaque parapsoriasis, lichenoid psoriasis, and acne-like psoriasis), or seborrheic dermatitis. In particular, the psoriasis-like diseases described in the present invention are preferably psoriasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0160] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, in which:

[0161] Figure 1: HPLC profile before separation.

[0162] Figure 2: HPLC profile of compound 2 standard.

[0163] Figure 3: HPLC profile of compound 3 standard.

[0164] Figure 4: Psoriasis scoring results of different administration methods of compound 1 in the treatment of psoriasis.

[0165] Figure 5: Comparative study on the efficacy of compound 1 and flecainide in the treatment of psoriasis.

[0166] Figure 6: Dose-effect experiment of compound 1 in treating psoriasis.

[0167] Figure 7: PASI score evaluation of the efficacy of compounds 2 and 3 in treating psoriasis.

[0168] Figure 8: PASI score evaluation of the efficacy of compounds 4 and 5 in treating psoriasis. DETAILED DESCRIPTION

[0169] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0170] Sources of animals and reagents used in the examples:

[0171] The mice used were purchased from Vital River, female, weighing 18–20 g;

[0172] Recombinant IL-23 was purchased from Novoprotein, catalog number CS31;

[0173] Flecainide, purchased from MedChem Express, product number HY-17429;

[0174] 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:

[0175] Compound 1 injection was purchased from Shanghai Xinyi, catalog number: 0114006.

[0176] Compound 1 powdered API was purchased from Henan Qixin, catalog number: H22091.

[0177] Compounds 4-1, 4-2, 4-4, 5-4, and n-propylamine were purchased from Shanghai Bid Pharmaceutical Co., Ltd., with the following numbers: Compound 4-1: BD20230110, Compound 4-2: BD20221219, Compound 4-4: BD20221118, Compound 5-4: BD20230511, and n-propylamine: BD20231015.

[0178] Example 1 Preparation of Compound 2 and Compound 3

[0179] Get 150 milligrams of free alkali of compound 1 (R / S-propafenone), be dissolved in 2 milliliters of ethanol, as sample solution.Adopt high performance liquid chromatography method to separate compound 1, result as shown in Figure 1, chromatogram shows the separation degree height between two peaks.Respectively with retention time be 3.1min (peak 1) and 5.8min (peak 2) obtained solution concentrating under reduced pressure, obtain white powder 50mg (peak 1) and 60mg (peak 2).Use HPLC to characterize the compound corresponding to peak 1 and peak 2, and contrast with the HPLC figure (as shown in Figure 2 and Figure 3) of compound 2 standard substance and compound 3 standard substance, result shows, peak 1 is S-propafenone (i.e. compound 2), and peak 2 is R-propafenone (i.e. compound 3).

[0180] The HPLC conditions were as follows:

[0181] Liquid chromatography instrument: 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.

[0182] Example 2 Synthesis of Compound 4

[0183] (1) Synthesis of compound 4-3

[0184] Compound 4-1 (876 mg, 8.26 mmol) was dissolved in EtOH (80 mL), and compound 4-2 (2.00 g, 8.26 mmol) was added. Subsequently, sodium hydroxide (1.32 g, 33.02 mmol) dissolved in water (13.2 mL) was added dropwise. After the addition was complete, the reaction was stirred at 25°C for 16 h. LCMS monitoring indicated the presence of the desired product. The reaction solution was poured into ice water, and 1 M hydrochloric acid solution was slowly added to pH 4-5. The product was extracted with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, compressed onto silica gel, and purified by flash column chromatography (eluent: ethyl acetate: petroleum ether = 0-30%) to obtain compound 4-3 (1.8 g, yield: 46.2%, purity: 70%). The structure of the compound was confirmed by LCMS.

[0185] LCMS: MS=331.1[M+H] + .

[0186] (2) Synthesis of Compound 4-5

[0187] Compound 4-3 (940 mg, 2.85 mmol) and compound 4-4 (1.32 g, 14.23 mmol) were dissolved in a sealed flask containing acetonitrile (20 mL). Potassium carbonate (786.5 mg, 5.69 mmol) was added. After the addition was complete, the reaction was stirred at 100°C for 12 h. LCMS detected the presence of product. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, compressed and mixed with silica gel, and purified by Flash column chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain compound 4-5 (330 mg, yield: 30%), the structure of which was confirmed by LCMS.

[0188] LCMS: MS=387.1[M+H] + .

[0189] (3) Synthesis of Compounds 4-6

[0190] Compound 4-5 (330 mg, 0.854 mmol) and n-propylamine (101 mg, 1.71 mmol) were added to a sterile flask containing acetonitrile (6 mL) and stirred at 60°C for 2 h. LCMS detected the presence of product, and the reaction solution was directly passed through a Flash reverse-phase column to obtain compound 4-6 (160 mg, 42% yield), the structure of which was confirmed by LCMS.

[0191] LCMS: MS=446.3[M+H] + .

[0192] (4) Synthesis of Compound 4

[0193] 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 addition, the mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere for 1 h. LCMS monitored the reaction completion, and the mixture was filtered through a filter head. The filtrate was collected, mixed with silica gel, and purified by Flash column chromatography (methanol:dichloromethane = 0-50%, 1% ammonia water) to obtain compound 4 (39 mg, yield: 30%). Its structure was confirmed by LCMS and HNMR.

[0194] LCMS: M=358.2[M+H] + .

[0195] 1 H NMR (400MHz, DMSO) δ7.29–7.20(m,4H),7.17(d,J=6.8Hz,1H),6.96(dd,J=15.8,5.9Hz,2H),6.90(dd,J=8.8,3.1Hz,1H),4.08–3.84(m,3H) ,2.89(t,J=7.5Hz,2H),2.68(dt,J=12.2,6.7Hz,2H),2.50–2.38(m,4H),1.42(dd,J=14.6,7.3Hz,2H),1.23(s,2H),0.84(t,J=7.4Hz,3H).

[0196] Example 3 Synthesis of Compound 5

[0197] (1) Synthesis of compound 5-3

[0198] 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. A sodium hydroxide solution (1.32 g, 33.02 mmol) dissolved in water (13.2 mL) was then added dropwise. The reaction was stirred at 25°C for 16 h. LCMS monitoring confirmed the presence of the desired product. The reaction solution was poured into ice water, and 1 M hydrochloric acid solution was slowly added to a pH of 4-5. The product was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, compressed onto silica gel, and purified by automated column chromatography (eluent: ethyl acetate:petroleum ether = 0-30%) to afford compound 5-1 (750 mg, yield: 27.5%). The structure of the product was confirmed by LCMS.

[0199] LCMS: MS=331.1[M+H] + .

[0200] (2) Synthesis of compound 5-5

[0201] Compound 5-3 (400 mg, 1.21 mmol) and compound 5-4 (118 mg, 4.84 mmol) were dissolved in a reaction flask containing acetonitrile (10 mL). Potassium carbonate (335 mg, 2.42 mmol) was added. After the addition, the reaction was stirred at 100°C for 12 h. LCMS detected the presence of product. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, compressed and mixed with silica gel, and purified by Flash column chromatography (eluent: ethyl acetate: petroleum ether = 0-50%) to obtain compound 5-5 (330 mg, yield: 70%). Its structure was confirmed by LCMS.

[0202] LCMS: M=387.2[M+H] + .

[0203] (3) Synthesis of Compound 5-6

[0204] Compound 5-5 (330 mg, 0.854 mmol) and n-propylamine (101 mg, 1.71 mmol) were added to a reaction flask containing acetonitrile (6 mL) and stirred at 60°C for 2 h. LCMS detected the presence of product, and the reaction solution was directly purified by reverse-phase column (filled with C18) to obtain compound 5-6 (160 mg, yield: 42%), the structure of which was confirmed by LCMS.

[0205] LCMS: M=446.3[M+H] + .

[0206] (4) Synthesis of Compound 5

[0207] 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 addition, the mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere for 1 h. LCMS monitored the reaction completion, and the mixture was filtered through a filter cartridge. The filtrate was collected, mixed with silica gel, and purified by Flash column chromatography (eluent: MeOH:DCM = 0-50%, 1% aqueous ammonia) to obtain compound 5 (27.24 mg, yield: 21%). Its structure was confirmed by LCMS and HNMR.

[0208] LCMS: M=358.2[M+H] + .

[0209] 1 H NMR (400MHz, CDCl3) δ7.19(t,J=6.5Hz,4H),7.12(d,J=7.4Hz,1H),6.98(s,1H),6.71(d,J=8.5Hz,1H),6.62(d,J=8.7Hz,1H),3.90(t,J =24.6Hz,3H),3.19(s,2H),2.94(t,J=7.2Hz,2H),2.80–2.16(m,4H),1.47(dd,J=14.3,6.9Hz,2H),1.19(s,2H),0.85(t,J=7.3Hz,3H).

[0210] Example 4 Preparation of Compound 1 Ointment

[0211] The formula of the ointment dosage form of Compound 1 is as follows:

[0212] Oil phase: liquid paraffin 2g, glyceryl monostearate 4g, white petrolatum 3g, lanolin 2g;

[0213] Aqueous phase: 3 g glycerol, 14.11 g ultrapure water;

[0214] Main drug: Compound 1 0.0285 g (drug loading: 0.1%);

[0215] Emulsifier: triethanolamine 0.3g;

[0216] Preservative: ethylparaben 0.09g;

[0217] Preparation method: Weigh the water phase, preservative and emulsifier according to the formula into a 100mL beaker, place it in a 500mL beaker with a magnetic stirrer, heat it in a water bath, add compound 1 powder when the temperature reaches 75°C, and stir until dissolved (80°C, 350r / min). Weigh the oil phase according to the formula into another 100mL beaker, heat it in a water bath, and stir until dissolved (80°C, 250r / min). Slowly add the water phase to the oil phase and stir for 10min (80°C, 300r / min). Then take it out and place it at room temperature. Continue stirring in the same direction until it condenses into an ointment. The prepared ointment is placed in a 50mL centrifuge tube and sealed with sealing film.

[0218] The mass concentration of compound 1 in the ointment is 0.1%.

[0219] Example 5: Treatment of Psoriasis with the Compound of Formula I

[0220] 1. Establishment of a mouse psoriasis model

[0221] The mouse psoriasis model was established by intradermal injection of recombinant IL-23 (1 ng / 20 μL PBS per mouse per day for 4 consecutive days) into the back of depilated mice.

[0222] 2. Test steps

[0223] On the second day after modeling, psoriasis model mice were randomly divided into three groups, with an equal number of mice in each group: a model group and a treatment group (the treatment group included a subcutaneous treatment group and an intradermal treatment group). The model group served as a control. Starting on the second day, compound 1 was injected subcutaneously into the backs of mice in the subcutaneous treatment group at a rate of 0.7 mg per mouse per day to simulate the effects of injection on psoriasis in mice. Compound 1 was injected intradermally into the backs of mice in the intradermal treatment group at a rate of 0.07 mg per mouse per day to simulate the therapeutic effects of topical administration on psoriasis in mice. The model group was intradermally injected with 20 μL of normal saline. All three groups were injected continuously for four days. On the sixth day, the symptoms of mice in the model and treatment groups were scored.

[0224] The rule for calculating the number of days is: start counting the days from the completion of model building, the day when model building is completed is recorded as day 0, followed by day 1, day 2... and so on.

[0225] The concentration of compound 1 in the injection solution of the subcutaneous treatment group and the intradermal treatment group was 35 mg / 10 mL.

[0226] Scoring criteria: 0 points, no symptoms; 1 point, skin rash; 2 points, scattered dandruff; 3 points, diffuse dandruff; 4 points, skin sclerosis; 5 points, erythroderma or death.

[0227] 3. Test results

[0228] The results are shown in Figure 4. The scores of the model group and the subcutaneous treatment group were close to 3 points, while the score of the intradermal treatment group was around 2 points. This indicates that the intradermal treatment group had a significant therapeutic effect when injected with Compound 1 compared to the model group and the subcutaneous treatment group. This demonstrates that topical administration of Compound 1 is more effective than injection in treating psoriasis.

[0229] Dose exploration showed that compound 1 had therapeutic effects at intradermal injection doses of 10μg, 20μg, 50μg, 100μg, 200μg, 500μg, 1mg, 2mg, 5mg and 10mg.

[0230] Comparative efficacy study of Example 6 and flecainide

[0231] 1. Establishment of a mouse psoriasis model

[0232] Same as Example 5.

[0233] 2. Test steps

[0234] Compound 1 and flecainide are similar conventional antiarrhythmic drugs, but their target sites and modes of action are different. To explore whether both antiarrhythmic drugs have the effect of treating psoriasis, this experiment compared the effects of compound 1 and flecainide in a mouse disease model.

[0235] On the second day after modeling, the psoriasis model mice were divided into four groups: model group, ointment group, compound 1 ointment group, and flecainide ointment group. Different substances (as shown in Table 1) were applied to the backs of mice in each group for four consecutive days. Starting from the first day, the symptoms of the model mice and the treatment group mice were scored.

[0236] Table 1 Substances and dosages applied to the backs of mice in each group

[0237] The rule for calculating the number of days is: start counting the days from the completion of model building, the day when model building is completed is recorded as day 0, followed by day 1, day 2... and so on.

[0238] The formula and preparation method of the ointment group refer to Example 4, the only difference from Example 4 is that the main drug is not added;

[0239] The formula and preparation method of the Compound 1 ointment group refer to Example 4 (wherein the mass concentration of Compound 1 in the Compound 1 ointment is 0.1%);

[0240] The formula 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 (wherein the mass concentration of flecainide in flecainide ointment is 0.1%).

[0241] Scoring criteria: 0 points, no symptoms; 1 point, skin rash; 2 points, scattered dandruff; 3 points, diffuse dandruff; 4 points, skin sclerosis; 5 points, erythroderma or death.

[0242] 3. Test results

[0243] The results are shown in Figure 5. During the period from day 1 to day 5, the score of the flecainide ointment group reached 3 points on day 2, and then remained at 3 points from day 2 to day 7. The score of the compound 1 ointment group reached 2 points on day 2, 3 points on days 3 to 4, and dropped to 2 points or below from day 5, and dropped to 1 point on days 7 and 8. The above data indicate that under the same dosage, the therapeutic effect of compound 1 is significantly stronger than that of flecainide.

[0244] Overall, compared with the model group, applying compound 1 ointment had a significant therapeutic effect, while flecainide ointment and single ointment had no therapeutic effect, indicating that compound 1 had a significant effect in treating psoriasis compared with flecainide.

[0245] Example 7 Dose-effect relationship of compound 1

[0246] 1. Establishment of a mouse psoriasis model

[0247] Same as Example 5.

[0248] 2. Test steps

[0249] On the second day after modeling, psoriasis model mice were divided into seven groups: a model group, a group receiving the ointment alone, and five treatment groups receiving different doses. The model group served as a control. Different substances (as shown in Table 2) were applied to the backs of mice in each group for four consecutive days. On the sixth day, symptoms of the model mice and the treatment groups were scored.

[0250] Table 2 Substances and dosages applied to the backs of mice in each group

[0251] The rule for calculating the number of days is: start counting the days from the completion of model building, the day when model building is completed is recorded as day 0, followed by day 1, day 2... and so on.

[0252] The formula and preparation method of the ointment group alone refer to Example 4, the only difference from Example 4 is that the main drug is not added;

[0253] The formula and preparation method of the ointment of 0.01%, 0.1%, 0.2%, 0.5% and 1% of Compound 1 were prepared by referring to Example 4, adjusting the mass of the main drug in the formula of Example 4 to prepare ointments with mass fractions of 0.01%, 0.1%, 0.2%, 0.5% and 1% of Compound 1, respectively.

[0254] Scoring criteria: 0 points, no symptoms; 1 point, skin rash; 2 points, scattered dandruff; 3 points, diffuse dandruff; 4 points, skin sclerosis; 5 points, erythroderma or death.

[0255] 3. Test results

[0256] The results are shown in Figure 6. Compared with the model group, the effective window dose of Compound 1 ointment is 0.1% to 0.5%. In a more detailed dose exploration, it was found 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 significant therapeutic effect when the mass concentration of Compound 1 in the ointment is 0.02% to 0.5%.

[0257] Example 8 Evaluation of the efficacy of Compound 2 and Compound 3

[0258] 1. Preparation of Compound 2 and 3 Ointments

[0259] Same as Example 4.

[0260] 2. Construction of a mouse psoriasis model

[0261] Same as Example 5.

[0262] 3. Test steps

[0263] On the second day after modeling, the psoriasis model mice were randomly divided into an ointment group, a compound 1 ointment treatment group, a compound 2 ointment treatment group, and a compound 3 ointment treatment group. Different substances (as shown in Table 3) were applied to the backs of the mice in each group for 6 consecutive days. Starting from the first day, the symptoms of the back skin of the model mice and the treatment group mice were scored every day.

[0264] Table 3 Substances and dosages applied to the backs of mice in each group

[0265] The rule for calculating the number of days is: start counting the days from the completion of model building, the day when model building is completed is recorded as day 0, followed by day 1, day 2... and so on.

[0266] The formula and preparation method of the ointment group refer to Example 4, the only difference from Example 4 is that the main drug is not added;

[0267] The formula and preparation method of the ointment group of compound 1, compound 2, and compound 3 were referred to Example 4 (mass concentration of each was 0.025%). Scoring criteria: 0, no symptoms; 1, skin rash; 2, scattered dandruff; 3, diffuse dandruff; 4, skin sclerosis; 5, erythroderma or death.

[0268] 4. Test results

[0269] The PASI score results are shown in Figure 7. Over time, the skin scores of mice in each group showed a typical trend of psoriasis, first increasing and then decreasing. At the end of the experiment, compared with the ointment group, the skin scores of compound 1 and compound 3 ointments were significantly reduced after treatment, and the symptoms were effectively relieved. The score of compound 3 was even lower, proving that the therapeutic effect was more obvious, while the compound 2 ointment did not show a therapeutic effect. Since compound 3 and compound 2 were both isolated from compound 1, judging from the treatment results, compound 2 had no therapeutic effect, while compound 3 had a therapeutic effect, which proved that compound 3 was the active ingredient of compound 1. At the same mass concentration, because compound 1 contains compound 2, the relative concentration of compound 3 in compound 1 is lower than that of the compound 3 group alone. This may be the main reason why the therapeutic effect of compound 1 is slightly lower than that of the compound 3 ointment group.

[0270] Example 9 Evaluation of the efficacy of compound 4 and compound 5

[0271] 1. Establishment of a mouse psoriasis model

[0272] Same as Example 5.

[0273] 2. Test steps

[0274] Due to the poor transdermal effect of compounds 4 and 5, we turned to microneedle administration (MN) to verify their therapeutic efficacy. On the second day after modeling, psoriasis model mice were randomly divided into a model group, a compound 4 microneedle treatment group, and a compound 5 microneedle treatment group. After the mouse skin was broken with a microneedle, 100 μL of compound 4 / 5 was dropped on the back of the mouse with a pipette and gently spread evenly (as shown in Table 3). The treatment was continued for 8 consecutive days. Starting from the first day, the symptoms of the back skin of the model mice and the treatment group mice were scored daily.

[0275] Table 4 Types and dosages of drug administration to the back of mice in each group

[0276] The rule for calculating the number of days is: start counting the days from the completion of model building, the day when model building is completed is recorded as day 0, followed by day 1, day 2... and so on.

[0277] Scoring criteria: 0 points, no symptoms; 1 point, skin rash; 2 points, scattered dandruff; 3 points, diffuse dandruff; 4 points, skin sclerosis; 5 points, erythroderma or death.

[0278] 3. Test results

[0279] PASI scores are shown in Figure 8. Over time, the skin scores in all groups of mice showed a typical psoriasis trend of initially increasing and then decreasing, but the scores varied between groups. Compared to the microneedle-only model group, compound 5 treatment showed a rapid decrease in skin scores starting on day 5, indicating effective symptom relief.

[0280] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0281] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form or metabolite thereof in the preparation of a product for treating and / or preventing psoriasis-related diseases, wherein the compound has the following structure: in, X is selected from: 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 Alkynylidene; R0 is selected from: H, -CO(C 1-10 Alkyl), -CO(C 6-10 Aryl); R1, R1' are independently selected from: H, C1-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 heterocyclic group), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -O(C 0-10 or, R1 and R1' together with the nitrogen atom to which they are attached form a heterocyclic ring, wherein the H on the heterocyclic ring is optionally substituted by one or more groups selected from the following: 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(C 0-10 alkyl); R2, R3, R4, R5, R6, R7, R8, R9, R 10 are independently selected from: H, halogen, cyano, nitro, azido, 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 heterocyclic group), -N(C 0-10 Alkyl)(C 0-10 Alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl); Preferably, X is selected from: C1-C6 alkylene, C2-C6 alkenylene, more preferably -CH2CH2- or -CH=CH-; Preferably, R0 is selected from: H, -CO(C 1-6 alkyl); Preferably, R1 and R1' are independently selected from: H, C1-C6 alkyl, -(C0-C6 alkylene)-(C6-C 10 or, R1 and R1' together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein the H on the 4-6 membered nitrogen-containing heterocyclic ring is optionally substituted by one or more groups selected from the following: C1-C6 alkyl; Preferably, R2, R3, R4, R5, R6, R7, R8, R9, R 10 are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O(C 0-6 alkyl).

2. The use according to claim 1, characterized in that: The compound has the following structure: Preferably, the compound has the following structure: More preferably, R4 is H, F, Cl, Br, I or -CF3; More preferably, R7 and R9 are H or -OH.

3. The use according to claim 1, characterized in that: The compound has the following structure: wherein X is selected from a single bond, -O-, -S- or an alkylene group; R1 is selected from H, alkyl, alkoxy, alkenyl or alkynyl; R2, R3, R4, R5, and R6 are independently selected from H, an alkyl group or a halogen atom.

4. The use according to claim 3, characterized in that: The X is selected from a single bond or a C1-C 10 of alkylene.

5. The use according to claim 3 or 4, characterized in that: The R1 is selected from C1-C 10 of alkyl.

6. The use according to any one of claims 3 to 5, characterized in that: The R2, R3, R4, R5 and R6 are independently selected from H, F, Cl, Br, I, methyl or ethyl.

7. The use according to any one of claims 3 to 6, characterized in that: X is selected from C1-C4 alkylene; R1 is selected from C1-C4 alkyl; R2, R3, R4, R5, R6 are 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:

9. The use according to claim 8, characterized in that: The stereoisomers of the compound have the following structures: Preferably 10. The use according to claim 1, characterized in that: The compound has the following structure: Preferably, the stereoisomer has the following structure: More preferably, the stereoisomer has the following structure: Preferably, the isotope derivative has the following structure:

11. The use according to any one of claims 1 to 10, characterized in that: The product described is a drug; The medicine is an external preparation, an injection or an oral preparation; The topical preparation is selected from the group consisting of: aqueous solution, tincture, spirit, paste, oil, ointment, cream, ointment, cream, gel, film coating, coating, liniment, lotion, spray, suspension, solution, emulsion, microemulsion, suspension, plaster, gel, patch, powder spray, suppository, eye drops or nasal drops; The injection is selected from: aqueous solution, solution, suspension, emulsion or powder injection; The oral preparation is selected from the group consisting of tablets, pills, pellets, powders, granules, capsules, lozenges, syrups, suspensions, emulsions, microemulsions, powder sprays, pastes, sublingual tablets or suppositories; Preferably, the dosage form of the drug is an external preparation, especially an ointment.

12. An external preparation for treating and / or preventing psoriasis-related diseases, characterized in that: The topical preparation comprises a compound as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form or metabolite thereof; The external preparation further comprises pharmaceutically acceptable excipients.

13. The external preparation according to claim 12, characterized in that The topical preparation is selected from: aqueous solutions, tinctures, spirits, pastes, oils, ointments, creams, ointments, creams, gels, coatings, spreads, liniments, lotions, sprays, suspensions, solutions, emulsions, microemulsions, suspensions, plasters, gels, patches, powder sprays, suppositories, eye drops or nasal drops.

14. The external preparation according to claim 13, characterized in that The auxiliary materials include one or more of the following: solubilizer, oil phase, water phase, additive; Preferably, the solubilizer includes: one or more of fatty alcohol polyoxyethylene ether, fatty acid polyoxyethylene ester, castor oil polyoxyethylene ether, alkylphenol polyoxyethylene ether, fatty amine polyoxyethylene ether, polyoxyethylene polyoxypropylene copolymer, polyethylene glycol, polyethylene glycol stearate, sorbitan ester polyoxyethylene ether, and dehydrated sorbitan fat; Preferably, the oil phase comprises: one or more of liquid paraffin, solid paraffin, stearic acid, white vaseline, cetyl alcohol, stearyl alcohol, glyceryl monostearate, isopropyl myristate, dimethicone, silicone, beeswax, lanolin, spermaceti, caprylic acid triglyceride, isooctyl palmitate, isopropyl palmitate, PEG-100 stearate, vegetable oil, and animal oil; Preferably, the aqueous phase comprises: one or more of water, ethanol, glycerol, hexadecanol, stearyl alcohol, hexylene glycol, propylene glycol, glycerol, dipropylene glycol, butylene glycol, and pentylene glycol; Preferably, the additives include: one or more of an emulsifier, a transdermal penetration enhancer, a pH regulator, and a preservative; More preferably, the transdermal penetration enhancer includes: one or more of azone, dimethyl sulfoxide, decyl methyl sulfoxide, menthol, borneol, clove oil, ethanol, laurel oil, urea, capsaicin, oleic acid, and urea; More preferably, the pH adjuster includes: one or more of citric acid, salicylic acid, boric acid, fatty acid, sodium hydroxide, potassium hydroxide; More preferably, the emulsifier is selected from: one or more of triethanolamine, fatty acid soap, sodium lauryl sulfate, polyoxyethylene ether, polyoxypropylene ether, ethylene oxide, lecithin, and gum arabic; More preferably, the preservative includes: one or more of imidazolidinyl urea, diazolidinyl urea, DMDMH, quaternary ammonium salt-15, benzoic acid and its derivative preservatives, phenoxyethanol, benzyl alcohol, polyol preservatives, chlorphenesin, bromopol, kaison, benzalkonium bromide, benzalkonium chloride, ethylparaben, methylparaben, isopropyl alcohol, salicylic acid, and sorbic acid; And / or, the additive further includes: one or more of vitamin E, dextran, betaine, butylated hydroxyanisole, ascorbic acid, dipropionic acid, ethanol, benzalkonium bromide, and hydroxyphenylpropionamide benzoic acid.

15. The external preparation according to claim 13, characterized in that When the external preparation is a gel, the auxiliary materials further include: one or more of gelatin, carbomer, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, glycerol, propylene glycol, dipropylene glycol, and water.

16. The external preparation according to claim 13, characterized in that The topical preparation contains 0.01-99.5% by weight of a compound as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, isotope derivative, solvate (e.g., hydrate), prodrug, metal chelate, crystal form or metabolite thereof, preferably 0.02-0.5%, more preferably 0.1%-0.5%.

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