Composition for improving skin tissue abnormalities

Abstract

To provide a composition for ameliorating an abnormality in skin tissue.SOLUTION: The inventors of the present application have found that a compound represented by formula (I) has the effect of ameliorating an abnormality in skin tissue. Accordingly, a composition for ameliorating an abnormality in skin tissue is provided, which contains a compound represented by formula (I) or an ester, oxide, pharmaceutically acceptable salt or solvate thereof.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present disclosure relates to a composition for improving abnormalities of skin tissue.

Background Art

[0002] The skin is an important organ that separates the body from the external environment and maintains the body's homeostasis. The main functions of the skin include retaining the body's moisture, regulating body temperature, protecting the body from external stimuli (such as microorganisms, physical stimuli, ultraviolet rays, etc.), detecting external information such as touch, warmth, and cold, excreting waste products in the body, secreting sebum and sweat, and storing fat under the skin. Thus, the skin plays many roles, and its abnormalities are associated with various diseases.

[0003] For example, itching is a symptom of many skin diseases, and it is known that scratching the skin due to itching can worsen the disease. Skin dryness reduces the skin's barrier function, making it easier for foreign substances such as bacteria and irritants to enter the body. Also, skin dryness causes wrinkles and sagging, which is not preferable from a cosmetic perspective.

[0004] In the prevention and treatment of atopic dermatitis, control of skin dryness and itching is important. Atopic dermatitis is a skin disease in which rashes accompanied by severe itching repeatedly appear. Since skin dryness worsens atopic dermatitis, it is necessary to perform moisturization daily. Also, itching is one of the most painful symptoms for patients with atopic dermatitis, and scratching due to itching damages the skin and worsens atopic dermatitis. Recently, in diseases similar to atopic dermatitis, it has been reported that the expression of kallikrein 7 (KLK7), a type of serine protease, is high in the epidermis, and KLK7 promotes itching through a mechanism independent of inflammation (Non-Patent Document 1).

[0005] Adrenal corticosteroids are used as therapeutic agents for atopic dermatitis. As side effects of topical steroid medications, skin atrophy, telangiectasia, steroid acne, steroid flush, hirsutism, and exacerbation of bacterial, fungal, and viral infections are known. In addition, side effects that occur when steroid medications are taken orally include elevated blood glucose levels, gastric mucosal hypersensitivity, osteoporosis, etc. From such impressions, patients tend not to prefer topical steroid medications. Therefore, there is a need for a therapeutic agent for atopic dermatitis that can replace steroid medications.

[0006] Certain 4-amino-naphthalene-1-sulfonic acid derivatives inhibit the ATPase activity of VCP (valosin-containing protein), which is a major ATPase in cells, and are expected to have therapeutic and / or preventive effects against various diseases (Patent Documents 1 to 8).

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Non-Patent Documents

[0008]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0009] An object of the present disclosure is to provide a new means for improving abnormalities in skin tissue.

Means for Solving the Problems

[0010] In studying the effect of a VCP inhibitor on atopic dermatitis, the present inventors have found that the VCP inhibitor improves abnormalities in skin tissue.

[0011] Therefore, in one aspect, the present disclosure provides a compound of formula (I):

Chemical formula

Advantages of the Invention

[0012] The present disclosure provides a compound for improving abnormalities in skin tissue. The compound can be used for the treatment and / or prevention of skin diseases or for cosmetic purposes.

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Modes for Carrying Out the Invention

[0014] In the present disclosure, when a numerical value is accompanied by the term "about", it is intended to include a range of ±10% of that value. For example, "about 20" shall be taken to include "18 to 22". A numerical range includes all numerical values between and including the two end points. "About" with respect to a range applies to both end points of that range. Thus, for example, "about 20 to 30" shall be taken to include "18 to 33".

[0015] Unless otherwise specifically defined, the terms used in the present disclosure have the meanings generally understood by those skilled in the art in the fields of organic chemistry, medicine, pharmacy, molecular biology, microbiology, etc. Definitions of some of the terms used in the present disclosure are set forth below, but these definitions take precedence over the general understanding in the present disclosure.

[0016] "Alkyl" means a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Alkyl means, for example, straight-chain and branched-chain hydrocarbyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and neopentyl, but is not limited thereto.

[0017] The prefix "substituted" for a group means that one or more hydrogen atoms of the group are substituted by the same or different designated substituents.

[0018] "Alkylene" means a divalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Alkylene groups include branched-chain and straight-chain hydrocarbyl groups.

[0019] "Alkoxy" means a group of -O-alkyl (where alkyl is as defined in the present disclosure). Alkoxy means, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy and n-pentoxy, but is not limited thereto.

[0020] "Aryl" means a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having one ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). Aryl groups typically include phenyl and naphthyl. "Aryloxy" means a group of -O-aryl (where aryl is as defined in this disclosure), including, for example, phenoxy and naphthoxy.

[0021] "Cyano" means a group of -CN. "Carboxyl" or "carboxy" means -COOH or its salts. "Carboxyester" means a group of -C(O)O-alkyl (where alkyl is as defined in this disclosure). "Halo" means halogen, particularly fluoro, chloro, bromo, and iodo. "Hydroxy" means a group of -OH.

[0022] Unless otherwise specified, the nomenclature of substituents not explicitly defined in this disclosure is carried out by naming the terminal part of the functional group and then naming the adjacent functional group towards the point of attachment. For example, the substituent "arylalkyloxycarbonyl" means (aryl)-(alkyl)-O-C(O)-.

[0023] Depending on the substitution pattern, enantiomers or diastereomers may exist in the compounds of formula (I). The compounds of formula (I) may be racemic or may be separated into stereoisomerically pure components by known methods. Some compounds may exist as tautomers.

[0024] "Ester" means an ester that can be hydrolyzed in vivo, including those that can be easily decomposed in the human body to release the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids (where each alkyl or alkenyl group has, for example, 6 or fewer carbon atoms). Examples of specific esters include formate esters, acetate esters, propionate esters, butyrate esters, acrylate esters and ethyl succinate esters. "Oxide" means a compound in which the nitrogen ring atom of a heteroaryl group is oxidized to form an N-oxide.

[0025] "Pharmaceutically acceptable salts" can be salts of the compounds of formula (I) with inorganic or organic acids. Preferred salts are salts with inorganic acids, for example hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or with organic carboxylic acids or sulfonic acids, for example acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or naphthalenedisulfonic acid.

[0026] Furthermore, pharmaceutically acceptable salts can be salts with conventional bases, for example alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts), or ammonium salts derived from ammonia or organic amines (such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, methylpiperidine, L-arginine, creatine, choline, L-lysine, ethylenediamine, benzathine, ethanolamine, meglumine or tromethamine), especially sodium salts.

[0027] "Solvate" means a compound of formula (I) that forms a complex by coordination with solvent molecules in the solid or liquid state. Preferred solvates are hydrates.

[0028] When referring to "the compound of formula (I)" in the present disclosure, unless inappropriate in the context, it is intended to also include its esters, oxides, pharmaceutically acceptable salts and solvates.

[0029] In certain embodiments, in formula (I), each Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, alkoxy and CHO. In certain embodiments, in formula (I), each Ra is independently selected from the group consisting of halo and alkyl. In certain embodiments, in formula (I), there are two Ra, one is halo and the other is alkyl. In certain embodiments, in formula (I), each Ra is independently selected from the group consisting of alkyl, alkoxy and CHO. In certain embodiments, in formula (I), there are three Ra, one is alkyl, one is alkoxy and one is CHO.

[0030] In certain embodiments, the compound of formula (I) is selected from the compounds in Table 1 below: [Table 1-1]

[0031] [Table 1-2]

[0032] [Table 1-3]

[0033] In certain embodiments, the following formula [Chemical formula] 4-Amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid represented by the formula, or an ester, oxide, pharmaceutically acceptable salt or solvate thereof, preferably the sodium salt, is used.

[0034] In certain embodiments, the following formula

Chemical formula

[0035] The compounds of formula (I), in particular, the properties and synthesis methods of the above compounds are described in detail in WO 2012 / 014994 pamphlet (Patent Document 1).

[0036] As demonstrated by the examples described below, administration of the compounds of formula (I) can improve abnormalities in skin tissue. When used in the present disclosure, abnormalities in skin tissue include symptoms of skin diseases and aesthetically unfavorable conditions, such as erythema, swelling, dryness, and itching. The skin tissue can be at least one of the epidermis, dermis, and subcutaneous tissue. Improvement of abnormalities in skin tissue in the present disclosure means reducing or removing abnormalities in skin tissue, or preventing the occurrence of abnormalities in skin tissue, for medical or non-medical (e.g., cosmetic) purposes. In the present disclosure, medical means the treatment or prevention of diseases carried out under the judgment or instruction of a doctor, and non-medical means the improvement of a living body other than medical treatment. In certain embodiments, improvement of abnormalities in skin tissue is the reduction or removal of abnormalities in skin tissue, preferably the reduction or removal of abnormalities in skin tissue for medical purposes.

[0037] Skin diseases include, for example, allergic dermatitis (e.g., atopic dermatitis, allergic contact dermatitis, urticaria, insect bites or photosensitive dermatitis), contact dermatitis (e.g., irritant contact dermatitis or photocontact dermatitis), pruritus, seborrheic dermatitis, eczema, seborrheic dermatitis, erythema multiforme exudativum and prurigo. In certain embodiments, the skin disease is allergic dermatitis, contact dermatitis, pruritus or seborrheic dermatitis. In certain embodiments, the skin disease is allergic dermatitis or contact dermatitis. In certain embodiments, the skin disease is atopic dermatitis or irritant contact dermatitis. In certain embodiments, the skin disease is allergic dermatitis. In certain embodiments, the skin disease is atopic dermatitis.

[0038] Subjects to which the compound of formula (I) is administered include animals, typically mammals (e.g., humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.), particularly humans.

[0039] The method of administering the compound of formula (I) is not particularly limited and can be through general administration routes such as oral administration, parenteral administration, injection, infusion, etc. Parenteral administration can be systemic administration or local administration, preferably local administration. More specifically, it includes application, spraying or injection to a site with skin abnormalities. Also, for example, intravenous administration, intraarterial administration, intradermal administration, subcutaneous administration, transdermal administration, intramuscular administration, intraperitoneal administration or intranasal administration are included. In certain embodiments, the compound of formula (I) is locally administered by application or spraying.

[0040] The compound of formula (I) can be administered in a composition. The composition can be solid, liquid, or any form in between (e.g., semi-solid), and can take various known pharmaceutical dosage forms depending on the type of skin tissue abnormality, the characteristics of the individual with the abnormality, the method of administration, and the dosage. For example, the composition can be a topical agent such as a spray, lotion, cream, patch, ointment, solution, emulsion, or suspension. Also, dosage forms such as tablets, powders, granules, fine granules, capsules, suppositories, solid injectables that dissolve upon use, liquid injectables, infusions, drip agents, etc. can be mentioned. The composition for cosmetic purposes can be in the form of a topical agent.

[0041] These dosage forms are manufactured by formulating according to conventional methods. Furthermore, depending on pharmaceutical requirements, various pharmaceutical substances that can be used in pharmaceuticals or cosmetics can be incorporated. The pharmaceutical substances can be appropriately selected according to the dosage form of the formulation. Examples include buffering agents, surfactants, stabilizers, preservatives, excipients, diluents, additives, disintegrants, binders, coating agents, lubricants, glidants, flavoring agents, sweetening agents, solubilizing agents, pigments, dyes, fragrances, etc.

[0042] The dosage and frequency of administration of the compound of formula (I) can be appropriately set by those skilled in the art according to the animal species, health status, age, weight, route of administration, dosage form, etc. of the administration subject so that an effective amount of the compound of formula (I) is administered to the subject. The effective amount in a certain situation can be easily determined by routine experiments. For example, the compound of formula (I) can be administered at about 0.001 to about 1000 mg / kg body weight / day, about 0.01 to about 300 mg / kg body weight / day, or about 0.1 to about 100 mg / kg body weight / day. For example, an appropriate amount of a topical agent containing the compound of formula (I) at a concentration of about 0.01 to 10 wt%, about 0.05 to 5 wt%, or about 0.1 to 1 wt% can be applied or sprayed on the abnormal part of the skin.

[0043] The compound of formula (I) may be administered once, multiple times, or continuously. When administered multiple times, for example, it can be administered once to several times a day, for example, at a dosing frequency of once, twice, or three times a day, daily or every few days, for example, every 1 day, 2 days, 3 days, or 7 days. The dosing period is not limited, for example, the administration can be continued until the skin abnormality is improved. A drug withdrawal period may be provided.

[0044] The compound of formula (I) can be used alone or in combination with one or more additional active ingredients, particularly active ingredients that improve skin tissue abnormalities. "Combining" the ingredients means not only the use of a dosage form containing all the ingredients and the use of a combination of dosage forms containing each ingredient separately, but also administering each ingredient simultaneously or delaying the administration of any one of the ingredients as long as they are used for improving skin tissue abnormalities. It is also possible to combine two or more additional active ingredients. For example, in addition to the compound of formula (I), a composition containing one or more additional active ingredients can be used.

[0045] Active ingredients suitable for combination include, for example, non-steroidal anti-inflammatory drugs, steroids, antihistamines, anti-allergy drugs, immunosuppressants, antibiotics / antibacterial drugs, antifungal agents, antiviral agents, anticancer agents, retinoid preparations, sulfur preparations, zinc preparations, antiperspirants, talc, moisturizers (e.g., urea preparations, preparations containing heparin-like substances), moisturizing components (e.g., polyhydric alcohols such as glycerin, dipropylene glycol, 1,3-butylene glycol, ethylene glycol, sugar alcohols such as sorbitol, hyaluronic acid), ultraviolet absorbers (e.g., dimorpholinopyridazinone, octyl paramethoxycinnamate, t-butylmethoxybenzoylmethane), ultraviolet scattering agents (e.g., fine particle titanium oxide, fine particle zinc oxide), vitamins (e.g., L-ascorbic acid), plant extracts, and other cosmetic ingredients.

[0046] In addition to the administration of the compound of formula (I), medical or non-medical acts other than drug therapy, such as laser treatment, skin grafting, regenerative medicine, surgical therapy, phototherapy, radiation therapy, cryotherapy, thermotherapy, local immunotherapy, iontophoresis, chemical peeling, and gene therapy, can also be carried out.

[0047] The compound of formula (I) or a composition containing the same may be used for the treatment and / or prevention of skin diseases. As used in the present disclosure, "treating" or "treatment" means reducing or eliminating the cause of a disease, delaying or stopping its progression, and / or reducing or eliminating its symptoms in a subject suffering from the disease.

[0048] As used in the present disclosure, "preventing" or "prevention" means preventing the onset of a disease or reducing the likelihood of contracting a disease in a subject, particularly in a subject who is at high risk of contracting the disease but has not yet contracted it. For example, subjects who may develop atopic dermatitis but have not yet developed it include subjects having risk factors for atopic dermatitis. Examples of risk factors for atopic dermatitis include genetic predisposition, exposure to allergens, stress, age, chemical irritation, and physical irritation.

[0049] In the examples described below, it was shown that the compound of formula (I) has a moisturizing effect on abnormal skin and healthy skin. Therefore, the compound of formula (I) can be used for moisturizing for medical purposes or non-medical purposes (e.g., cosmetic purposes). For example, a composition containing the compound of formula (I) can be used as a medical or cosmetic moisturizing composition.

[0050] In one aspect, a composition for improving skin tissue abnormalities containing the compound of formula (I) is provided. In one aspect, a method for improving skin tissue abnormalities is provided, which includes administering an effective amount of the compound of formula (I) to a subject in need of improving skin tissue abnormalities. In one aspect, a compound of formula (I) is provided for improving abnormalities of skin tissue. In one aspect, the use of a compound of formula (I) for improving abnormalities of skin tissue is provided. In one aspect, the use of a compound of formula (I) in the manufacture of a composition for improving abnormalities of skin tissue is provided.

[0051] In one aspect, a pharmaceutical composition for treating and / or preventing skin diseases comprising a compound of formula (I) is provided. In one aspect, a method for treating and / or preventing skin diseases is provided, which comprises administering to a subject in need of treatment and / or prevention of skin diseases an effective amount of a compound of formula (I). In one aspect, a compound of formula (I) for treating and / or preventing skin diseases is provided. In one aspect, the use of a compound of formula (I) for treating and / or preventing skin diseases is provided. In one aspect, the use of a compound of formula (I) in the manufacture of a pharmaceutical composition for treating and / or preventing skin diseases is provided.

[0052] In one aspect, a moisturizing composition comprising a compound of formula (I) is provided. In one aspect, a method for moisturizing the skin is provided, which comprises administering to a subject in need of skin moisturization an effective amount of a compound of formula (I). In one aspect, a compound of formula (I) for moisturizing is provided. In one aspect, the use of a compound of formula (I) for moisturizing is provided. In one aspect, the use of a compound of formula (I) in the manufacture of a moisturizing composition is provided.

[0053] For example, the following embodiments are provided. [1] Formula (I):

Chemical formula

[0054] [6] The composition according to any one of items 1 to 5, which is a pharmaceutical composition. [7] The composition according to any one of items 1 to 6, wherein the abnormal skin tissue is a symptom of a skin disease. [8] The composition according to item 7, wherein the skin disease is allergic dermatitis, contact dermatitis, pruritus, seborrheic dermatitis, eczema, seborrheic dermatitis, erythema multiforme exudativum or prurigo. [9] The composition according to item 7 or 8, wherein the skin disease is allergic dermatitis, contact dermatitis, pruritus or seborrheic dermatitis.

[10] The composition according to any one of items 7 to 9, wherein the skin disease is allergic dermatitis or contact dermatitis.

[11] The composition according to any one of items 7 to 10, wherein the skin disease is atopic dermatitis or irritant contact dermatitis.

[12] The composition according to any one of items 7 to 10, wherein the skin disease is allergic dermatitis.

[13] The composition according to any one of items 7 to 12, wherein the skin disease is atopic dermatitis.

[14] The composition according to any one of items 1 to 13, wherein the abnormality of the skin tissue is swelling, dryness or itching in atopic dermatitis.

[15] The composition according to any one of items 1 to 5, which is a cosmetic composition.

[0055]

[16] Formula (I): [Chemical formula] [In the formula, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo- or alkyl-substituted aryl, alkoxy, hydroxy- or carboxy-substituted alkoxy, aryloxy, halo- or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxylate and cyano, m is an integer selected from 0 to 4] A pharmaceutical composition for treating and / or preventing skin diseases, comprising a compound of formula (I) or its ester, oxide, pharmaceutically acceptable salt or solvate.

[17] The composition according to item 16, wherein the skin disease is allergic dermatitis, contact dermatitis, pruritus cutis, seborrheic dermatitis, eczema, seborrheic dermatitis, erythema multiforme exudativum or prurigo.

[18] The composition according to item 16 or 17, wherein the skin disease is allergic dermatitis, contact dermatitis, pruritus cutis or seborrheic dermatitis.

[19] The composition according to any one of items 16 to 18, wherein the skin disease is allergic dermatitis or contact dermatitis.

[20] The composition according to any one of items 16 to 19, wherein the skin disease is atopic dermatitis or irritant contact dermatitis.

[21] The composition according to any one of items 16 to 19, wherein the skin disease is allergic dermatitis.

[22] The composition according to any one of items 16 to 21, wherein the skin disease is atopic dermatitis.

[0056]

[23] Formula (I): [Chemical formula] [wherein, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo- or alkyl-substituted aryl, alkoxy, hydroxy- or carboxy-substituted alkoxy, aryloxy, halo- or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxylate and cyano, m is an integer selected from 0 to 4] A moisturizing composition comprising a compound of or an ester, oxide, pharmaceutically acceptable salt or solvate thereof.

[24] The composition according to item 23, which is a pharmaceutical composition.

[25] The composition according to item 23, which is a cosmetic composition.

[0057]

[26] The composition according to any one of items 1 to 25, wherein Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, alkoxy and CHO.

[27] The composition according to any one of items 1 to 26, wherein Ra is independently selected from the group consisting of halo and alkyl.

[28] The composition according to any one of items 1 to 27, wherein two Ra are present, one is halo and the other is alkyl.

[29] The composition according to any one of items 1 to 26, wherein Ra is independently selected from the group consisting of alkyl, alkoxy and CHO.

[30] The composition according to any one of items 1 to 26, wherein three Ra are present, one is alkyl, one is alkoxy and one is CHO.

[31] The composition according to any one of items 1 to 25, wherein the compound of formula (I) is selected from the compounds described in Table 1.

[32] The composition according to any one of claims 1 to 26, wherein the compound of formula (I) is 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid or 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid.

[33] The composition according to any one of claims 1 to 26, wherein the compound of formula (I) is 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid.

[34] The composition according to any one of claims 1 to 26, comprising the sodium salt of 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid.

[35] The composition according to any one of claims 1 to 26, wherein the compound of formula (I) is 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid.

[36] The composition according to any one of claims 1 to 26, comprising the sodium salt of 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid.

[37] The composition according to any one of claims 1 to 36, which is an external preparation.

[38] The composition according to any one of claims 1 to 37, which is a spray, lotion, cream, patch, ointment, liquid, emulsion or suspension.

[0058] All documents cited in this specification are incorporated herein by reference as part of this specification. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. Also, the above descriptions are all non-limiting, and the present invention is defined in the appended claims, and various modifications are possible without departing from the technical idea thereof.

Examples

[0059] In the examples, the following compounds were used. KUS121: Sodium 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonate KUS187: Sodium 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonate KUS121 and KUS187 were produced by the method described in International Publication No. 2012 / 014994.

[0060] Example 1 The effect of KUS121 application on atopic dermatitis was evaluated. As an atopic dermatitis model, an atopic-like dermatitis mouse model induced by repeated application of MC903, an active vitamin D3 derivative, was used. The mice used were 8-week-old female C57BL / 6N mice (purchased from Shimizu Laboratory Supplies). Under isoflurane anesthesia, the following reagent applications were performed for a total of 10 days. After applying 10 μL of 5 mM KUS121 (solvent: 90% EtOH) or 90% EtOH to both sides of the left earpinna, 10 μL of 100 μM MC903 (solvent: 100% EtOH) was applied to both sides. From the first application of the reagent, KUS121 or 90% EtOH was applied daily, and MC903 was applied every other day. The earpinna thickness was measured using a constant-pressure thickness gauge (Tec-lock), and measurements were taken every other day starting immediately before the first application during the entire 10-day application period, with the measurement taken immediately before the application of the reagent. Furthermore, the following reagent application was used to evaluate the effect of applying KUS121 alone. 10 μL of 5 mM KUS121 was applied to both sides of the left earpinna and 10 μL of 90% EtOH was applied to both sides of the right earpinna daily, and the earpinna thickness was measured every other day for 10 days starting immediately before the first application. Also, blood was collected from the cheek vein of the mice on the 11th day after the start of the application (14 hours after the drug treatment on the 10th day). Serum was separated from the blood that had been allowed to stand at room temperature for 30 minutes or more by centrifugation (1500 x g, for 10 minutes), and the amounts of immunoglobulins (IgE, IgG1) contained in the serum were measured using an Elisa kit (Bethyl Laboratories).

[0061] The appearance of the left auricle on the 11th day from the start of application is shown in Fig. 1. The experimental schedule and the measurement results of auricle thickness are shown in Fig. 2. In the MC903 application group treated with EtOH, skin erythema, desquamation, and crust formation were observed, and the auricle thickness increased. In contrast, in the MC903 application group treated with KUS121, the above skin disorders and the increase in auricle thickness were suppressed. Next, the blood concentrations of IgE and IgG1, which are immunoglobulins characteristic of Th2-type allergic reactions including atopic dermatitis, are shown in Fig. 3. In the MC903 application group treated with KUS121, a decrease in the blood concentrations of IgE and IgG1 was observed compared with the MC903 application group treated with EtOH. These results suggest that KUS121 can suppress atopic dermatitis.

[0062] Example 2 The mice in Example 1 were sacrificed by cervical dislocation after blood sampling, and auricle sections were collected. Some of the auricle sections were paraffin-embedded, and some were used as RNA extraction samples. The paraffin-embedded sections were observed by hematoxylin-eosin (HE) staining. In addition, after RNA extraction from the auricle sections, cDNA was synthesized. Using each cDNA as a template, the expression levels of various genes were analyzed by real-time PCR using SYBR Green. Gapdh was used as an internal standard.

[0063] Typical HE staining images are shown in Fig. 4. In the MC903 application group treated with EtOH, epidermal hyperplasia and infiltration of inflammatory cells such as eosinophils into the dermis were observed compared with the EtOH-alone application group or the KUS121-alone application group. In the MC903 application group treated with KUS121, these abnormalities were suppressed compared with the MC903 application group treated with EtOH.

[0064] The expression levels of each gene are shown in Fig. 5. Keratin 6a (Krt6a) is a characteristic keratin that is upregulated in skin injury, wound repair, and the initiation of the immune system. Krt6a expression was increased in the MC903 application group treated with EtOH compared to the EtOH alone application group, but the induction of Krt6a expression was attenuated in the MC903 application group treated with KUS121. This result suggests that KUS121 can suppress skin injury associated with dermatitis. Filaggrin (Flg) is a natural moisturizing factor present in the upper layer of the epidermis and is known as an important protein for skin barrier function. Interestingly, Flg expression did not change in the MC903 application group treated with EtOH compared to the EtOH alone application group, but it increased in the MC903 application group treated with KUS121. This result suggests that KUS121 has a skin moisturizing effect by maintaining the skin barrier function through the induction of filaggrin expression.

[0065] Example 3 The effect of KUS121 application on skin barrier function was evaluated by the trans-epidermal water loss. Six- to eight-week-old C57BL6 / N female mice (purchased from Oriental Bioservices) were used. A mixture of three anesthetics (1 mg / mL medetomidine hydrochloride, 5 mg / mL midazolam, 5 mg / mL butorphanol tartrate, solvent: sterilized distilled water) was subcutaneously injected at 150 μL, and under anesthesia, the following reagent applications were performed for a total of 12 days. 5 mM KUS121 was applied to the left ear pinna of the same individual, and 90% EtOH was applied to the right ear pinna, 10 μL on both sides daily. Furthermore, in some individuals, 100 μM MC903 was applied to both sides of both ear pinnae, 10 μL every other day. When applying both reagents, MC903 was applied after applying KUS121 or 90% EtOH. The trans-epidermal water loss was measured using APO SCAN AS-VT100 (Asahi Technolo Lab). The ear pinna thickness was measured daily from immediately before the first application during the entire 12-day application period, and the trans-epidermal water loss was measured on days 0, 2, 4, 6, 8, 10, 11, and 12. The measurement was taken immediately before applying the reagent.

[0066] The results are shown in Fig. 6. In the MC903-applied group treated with EtOH, the transepidermal water loss and ear thickness of the auricular skin increased compared with the group treated with EtOH alone. In the MC903-applied group treated with KUS121, these increases were suppressed. This result suggests that KUS121 is effective in maintaining the skin barrier function.

[0067] Example 4 The effect of KUS121 application on itching was evaluated. An atopic dermatitis mouse model induced by repeated application of MC903 was used as an itching model. Eight-week-old female C57BL / 6N mice (purchased from Shimizu Laboratory Supplies) were used. Under isoflurane anesthesia, the following reagent applications were performed for a total of 15 days. 10 μL of 100 μM MC903 was applied to both sides of both auricles of the mice every 3 days. Furthermore, 10 μL of 5 mM KUS121 was applied to the left auricle and 10 μL of 90% EtOH was applied to the right auricle of the same individual to both sides every day. Note that KUS121 or 90% EtOH was administered after the 6th day from the start of reagent application. Also, when applying both reagents, MC903 was applied after applying KUS121 or 90% EtOH. On the 12th day after the start of treatment, 1-2 hours after reagent application, mice (n = 5) that had awakened from anesthesia were placed in a photographing box (manufactured by Shinanomfg Co., Ltd., W25xD25xH30 cm), and the behavior of the mice was photographed using a video camera (Victor) from above. As scratching behavior, the total number of ear contacts by the forepaw and the total scratching behavior time by the hind paw within 1 hour from the start of photographing were measured by video analysis. The combined value of 5 mice was adopted as the measured value.

[0068] The experimental schedule and the measurement results of auricle thickness are shown in Fig. 7. The measurement results of scratching behavior are shown in Fig. 8. In the auricles coated with MC903 and KUS121, and in the MC903-coated group treated with KUS121, the scratching behavior was less than that in the MC903-coated group treated with EtOH. Also, even when the KUS121 treatment was started from the 6th day after the start of MC903 coating, the increase in auricle thickness due to MC903 coating was suppressed. These results suggest that KUS121 suppresses itching. Also, it suggests that a therapeutic effect can be obtained by using KUS121 after the onset of atopic dermatitis.

[0069] Example 5 The expression level of the KLK7 gene in the mice treated in the same manner as in Example 1 was analyzed by the same method as in Example 2. The results are shown in Fig. 9. KLK7 is a serine protease that has been reported to promote itching by a mechanism independent of inflammation (Non-Patent Document 1). In the MC903-coated group treated with EtOH, the expression of KLK7 increased, but in the MC903-coated group treated with KUS121, the increase was suppressed. This result suggests that KUS121 suppresses the expression of KLK7 and thereby suppresses itching.

[0070] Example 6 The effect of KUS121 application on psoriasis was evaluated. As a psoriasis model, a psoriasis mouse model was used by repeatedly applying 5% imiquimod cream. The mice used were 6- to 8-week-old C57BL6 / N female mice (purchased from Oriental Bioservices). 150 μL of a three-kind mixed anesthesia was subcutaneously injected, and under anesthesia, the following reagent applications were performed for a total of 6 or 18 days. After applying 10 μL of 5 mM KUS121 or 90% EtOH to both sides of the left auricle, 5 mg of 5% imiquimod cream (manufactured by Mochida Pharmaceutical Co., Ltd.) was applied to both sides. KUS121 or 90% EtOH was applied daily, and imiquimod cream was applied on days 0, 2, 4, 7, 9, 11, 14, and 16. The auricle thickness was measured immediately before the reagent application.

[0071] The results are shown in Fig. 10. There was no difference in auricle thickness between the group treated with 5% imiquimod cream with EtOH treatment and the group treated with 5% imiquimod cream with KUS121 treatment. These results suggest that KUS121 is not effective for psoriasis.

[0072] Example 7 The effect of KUS121 application on irritant contact dermatitis was evaluated. A mouse model of sodium dodecyl sulfate (SDS)-induced contact dermatitis was used as an irritant contact dermatitis model. Ten-week-old male C57BL6 / J mice (purchased from Oriental Bioservices) were used. 150 μL of a mixture of three anesthetics was subcutaneously injected, and under anesthesia, the following reagent applications were performed for a total of 4 days. After applying 10 μL of 5 mM KUS121 or 90% EtOH to both sides of the left auricle, 10 μL of 4% SDS was applied to both sides. Each reagent was applied daily, and the auricle thickness was measured immediately before reagent application.

[0073] The results are shown in Fig. 11. In the SDS application group treated with EtOH, the auricle thickness increased over time, but in the SDS application group treated with KUS121, the increase was suppressed. These results suggest that KUS121 is effective for irritant contact dermatitis.

[0074] Example 8 Similar to Example 1, except that KUS187 was used instead of KUS121, the appearance of the auricle was observed and the auricle thickness was measured. The results are shown in Fig. 12. In the MC903 application group treated with EtOH, skin erythema, scaling, and crust formation were observed, and the auricle thickness increased. In contrast, in the MC903 application group treated with KUS187, the above skin disorders and the increase in auricle thickness were suppressed. These results suggest that KUS187 can suppress atopic dermatitis.

Industrial Applicability

[0075] The present disclosure provides a method for improving skin abnormalities and can be used in the medical or cosmetic fields. For example, it is expected to be used for the treatment and / or prevention of skin diseases or for cosmetic purposes.

Claims

1. Formula (I): 【Chemical 1】 〔Wherein, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo- or alkyl-substituted aryl, alkoxy, hydroxy- or carboxy-substituted alkoxy, aryloxy, halo- or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxylate and cyano, m is an integer selected from 0 to 4〕 A composition for improving the symptoms of atopic dermatitis or irritant contact dermatitis, comprising a compound of formula (I) or its oxide, pharmaceutically acceptable salt or solvate.

2. The composition according to claim 1, wherein Ra is independently selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl and alkoxy.

3. The compound of formula (I) is 4-amino-3-(6-phenylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-p-tolylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-m-tolylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-o-tolylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-amino-3-(6-biphenyl-2-ylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 3-[6-(2-acetylphenyl)pyridin-3-ylazo]-4-aminonaphthalene-1-sulfonic acid; 3-[6-(3-acetylphenyl)pyridin-3-ylazo]-4-aminonaphthalene-1-sulfonic acid; 3-[6-(4-acetylphenyl)pyridin-3-ylazo]-4-aminonaphthalenesulfonic acid; 4-amino-3-[6-(2,4-dichlorophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-trifluoromethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(4-trifluoromethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(2-chlorophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-amino-3-[6-(3-chlorophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-chlorophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-methoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-methoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-isopropoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-isopropoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-phenoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-methoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2,3-dimethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2,5-dimethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3,5-dimethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-trifluoromethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-{4-[5-(1-Amino-4-sulfonaphthalen-2-ylazo)pyridin-2-yl]phenyl}-4-oxobutyric acid; 4-Amino-3-(6-biphenyl-3-ylpyridin-3-ylazo)naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-cyanophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-cyanophenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3,5-bistrifluoromethylphenyl)pyridin-3-ylazo]naphthalenesulfonic acid; 4-Amino-3-[6-(4-benzoylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-propoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(5-fluoro-2-propoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-fluoro-6-propoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-fluoro-2-propoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(5-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-fluoro-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-butoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-hexyloxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-butylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-hydroxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-{6-[2-(6-hydroxyhexyloxy)phenyl]pyridin-3-ylazo}naphthalene-1-sulfonic acid; 4-{2-[5-(1-amino-4-sulfonaphthalen-2-ylazo)pyridin-2-yl]phenoxy}butyric acid; 4-Amino-3-{6-[2-(3-hydroxypropoxy)phenyl]pyridin-3-ylazo}naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2-isobutoxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(5-chloro-2-hydroxyphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4-methylbiphenyl-2-yl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4'-chloro-4-methylbiphenyl-2-yl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(4,3',5'-trimethylbiphenyl-2-yl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3'-chloro-4-methylbiphenyl-2-yl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(2,6-dimethylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; 4-Amino-3-[6-(3-formyl-2-isopropoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; and, 4-Amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid; The composition according to claim 1, selected from the group consisting of.

4. The composition according to any one of claims 1 to 3, wherein the compound of formula (I) is 4-amino-3-[6-(4-fluoro-2-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid or 4-amino-3-[6-(3-formyl-2-butoxy-5-methylphenyl)pyridin-3-ylazo]naphthalene-1-sulfonic acid.

5. The composition according to any one of claims 1 to 4, wherein the symptoms of atopic dermatitis or irritant contact dermatitis are swelling, dryness or itching.

6. The composition according to any one of claims 1 to 5, which is a pharmaceutical composition.

7. The composition according to any one of claims 1 to 6, which is a topical preparation.

8. The composition according to any one of claims 1 to 7, which is in the form of a spray, lotion, cream, patch, ointment, liquid, emulsion or suspension.

9. Formula (I): 【Chemical 2】 [Wherein, Ra is selected from the group consisting of halo, hydroxy, alkyl, halo-substituted alkyl, aryl, halo or alkyl-substituted aryl, alkoxy, hydroxy or carboxy-substituted alkoxy, aryloxy, halo or alkyl-substituted aryloxy, CHO, C(O)-alkyl, C(O)-aryl, C(O)-alkyl-carboxyl, C(O)-alkylene-carboxylate and cyano, m is an integer selected from 0 to 4]] A pharmaceutical composition for the treatment of atopic dermatitis or irritant contact dermatitis, comprising a compound of formula (I) or an oxide, pharmaceutically acceptable salt or solvate thereof.

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