WO2015115826A1 - Benzoxazole derivative having activity in improving pruritus - Google Patents

Abstract

The present invention relates to a novel benzoxazole derivative having an effect of preventing or treating pruritus in skin disorders, and a method of preparing the same. Due to having excellent activity in improving pruritus, the benzoxazole derivative compound of the present invention may be useful as a prophylactic agent, a therapeutic agent, or a therapeutic adjuvant for pruritus in various skin diseases, including atopic dermatitis, histamine-dependent pruritus, and histamine-independent pruritus.

Description

Benzoxazole derivatives having pruritus improving activity

The present invention relates to a novel benzoxazole derivative having a pruritic prevention, amelioration or therapeutic effect in a skin disease and a method for producing the same.

Pruritus (itch, pruritus, or itch) is defined as an unpleasant sensation that causes the urge to scratch (Haffenreffer, 1660). Pruritus is a prominent symptom of many skin diseases, including scabies, teeth, insect bites, urticaria, eczema skin diseases (atopic dermatitis, contact dermatitis, molecular eczema, neurodermatitis), psoriasis, dry skin, gestational pruritus, senile It may appear in pruritus, etc. Pruritus may also occur when hemodialysis occurs in patients with chronic renal failure, and malignant hematologic malignancies such as Hodgkin's disease, malignant skin tumors, intestinal parasites, hyperthyroidism and hypofunction, diabetes mellitus, and acquired immunodeficiency syndrome may also be present. Can be.

Just as pain acts as a defense mechanism by inducing withdrawal reflexes of the body parts to harmful stimuli, pruritis also induces scratching reflexes to prevent skin penetration of toxic substances or harmful microorganisms. Blocking acts as a defense mechanism.

But pruritus does not necessarily play a beneficial role. Because of pruritus, wounds, erythema, skin cracks, ulcers, hives, etc. may appear, and the pathogen may be easily penetrated into the scratched spots. It can also lead to pigmentation or wrinkles and thickening of the skin, which can lead to cosmetic consequences. Especially in the case of atopic dermatitis, an autoimmune disease prevalent in modern times, pruritus does not act as a beneficial defense mechanism, but rather the chronic stage (Th1 cell-oriented immune response) rather than the early stage of the disease (Th2 cell-oriented immune response). It has been found that it plays a role in migrating to the environment (Matsushima et al., 2003). That is, it causes the Itch-scratch vicious cycle leading to 'pruritus-> scratch-based history-> more severe pruritus'.

Currently, as a therapeutic agent for pruritus, skin-cooling agents, steroids, anesthetics, and antihistamines are used. Calamine or menthol lotions cool the skin and relieve pruritus, but have only a very temporary effect. Steroids have vasoconstrictive, anti-proliferative, immunosuppressive and anti-inflammatory effects, and have immediate effects on relieving pruritus, especially in autoimmune diseases such as atopic dermatitis, but are limited in their long-term use due to severe side effects. Phenol lotion and capsaicin paralyze the sensation and relieve pruritus, but the effect is temporary and can cause skin irritation. Antihistamines are mainly used as drugs to eat. Recently, drugs that inhibit only H1 receptors that are directly involved in pruritus are being developed, but some antihistamines also inhibit H2 receptors, causing side effects such as dry mouth, constipation, and blurred vision. . In addition, antihistamines have been reported to be effective in urticaria and allergies, but do not effectively relieve pruritus in atopic dermatitis (Fujii et al., 2006).

It is an object of the present invention to provide a novel benzoxazole derivative having a pruritic prophylactic or therapeutic effect and a preparation method thereof.

The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[Formula 1]

In Chemical Formula 1,

R ₁ is H, OH, a straight or branched C 1 -C 3 lower alkyl group, NO ₂ , NH ₂ , C ₁ -C 3 lower alkoxy group, or a halogen atom,

R ₂ and R ₃ are the same as or different from each other, and each is H, OH, a straight or branched C 1 to C 3 lower alkyl group, NO ₂ , NH ₂ , C 1 to C 3 lower alkoxy group, C 1 to C 3 halogenated lower alkyl group, Halogen atom, CN, amino group, lower dialkyl amino group of C1-C3, SH, lower alkyl mercapto group of C1-C3, halogenated lower alkyl mercapto group of C1-C3, lower alkanoyl group of C1-C3, C1-C3 Hydroxy lower alkyl group, straight or branched C1-C3 alkyl ureido, or straight or branched C1-C3 dialkyl ureido. Provided that N ^2- (4-ethylphenyl) benzo [ d ] oxazole-2,5-diamine [ N ^2- (4-ethylphenyl) benzo [ d ] oxazole-2,5-diamine], and 8-methyl- 2- [ N- (4-ethylphenyl)] aminobenzoxazole [8-methyl-2- [ N- (4-ethylphenyl)] aminobenzoxazole] is excluded.

The present invention provides a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[Formula 2]

In Chemical Formula 2,

R ₁ is H, OH, a straight or branched C 1 -C 3 lower alkyl group, NO ₂ , NH ₂ , C ₁ -C 3 lower alkoxy group, or a halogen atom,

R ₂ and R ₃ are the same as or different from each other, and each of H, OH, a lower alkyl group of C 1 to C 3, a lower alkoxy group of NO ₂ , NH ₂ , C 1 to C 3, a halogenated lower alkyl group of C 1 to C 3, a halogen atom, CN, Amino group, C1-C3 lower dialkyl amino group, SH, straight or branched C1-C3 lower alkyl mercapto group, C1-C3 halogenated lower alkyl mercapto group, C1-C3 lower alkanoyl group, or C1-C3 Hydroxy lower alkyl group, linear or branched C1 to C3 alkyl ureido or linear or branched C1 to C3 dialkyl ureido.

In Formulas 1 and 2 of the present invention, R ₁ , The term “lower alkyl group of C1 ~ C3” used in the definitions of R ₂ and R ₃ means a straight or branched chain alkyl group composed of 1 to 3 carbon atoms, for example, methyl, ethyl, propyl, isopropyl group, etc. have.

In Formulas 1 and 2 of the present invention, R ₁ , The term "lower alkoxy group of C1-C3" as used in the definitions of R ₂ and R ₃ means a straight or branched chain alkoxy group consisting of 1 to 3 carbon atoms, for example methoxy, ethoxy, n-propoxy There is a period.

As used in the definitions of R ₂ and R ₃ in the formulas (1) and (2) of the present invention, “halogen atom” means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

As used in the definitions of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention, the term “C1-C3 halogenated lower alkyl group” refers to a part or all of hydrogen in the above-described lower alkyl group of C1-C3 substituted with the aforementioned halogen atom. Examples thereof include methyl fluoride group, methyl chloride group, ethyl fluoride group, ethyl chloride group and the like.

As used in the definitions of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention, the term “lower dialkyl amino group of C1 to C3” refers to a lower dialkyl amino group derived from the lower alkyl group of C1 to C3 described above. Examples include a dimethylamino group and the like.

As used in the definitions of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention, the term “lower alkyl mercapto group of C1 to C3” means that the lower alkyl group of C1 to C3 is linked to sulfur of the mercapto group instead of hydrogen. Examples thereof include methyl mercapto group and ethyl mercapto group.

As used in the definitions of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention, the term “C1 to C3 halogenated lower alkyl mercapto group” refers to a part or all of hydrogen in the above-mentioned C1 to C3 lower alkyl mercapto group. It means substituted by a halogen atom, and examples thereof include methyl fluoride mercapto group, methyl chloride mercapto group, ethyl fluoride mercapto group, ethyl chloride mercapto group and the like.

The term “lower alkanoyl group of C 1 to C ₃ ” used in the definitions of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention refers to a lower alkyl group having 1 to 3 carbon atoms linked to carbon of a carbonyl group. It means a functional group, for example, formyl, acetyl, propionyl group and the like.

The term "C1-C3 hydroxy lower alkyl group" used in the definitions of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention is connected to the above-described lower alkyl group consisting of 1 to 3 carbon atoms and the carbon atom of the lower alkyl group. It means a functional group consisting of a hydroxy group, and examples thereof include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl group.

As used in the definitions of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention, “C1 to C3 alkyl ureido or C1 to C3 dialkyl ureido” refers to a nitrogen atom of ureido (a radical having the following structure). C1 ~ C3 alkyl is one or two connected. Dimethyl ureido and the like.

In one embodiment of the present invention, in the compound of the present invention (Formula 1 or Formula 2), R ₁ may be a straight or branched C1-C3 lower alkyl group, for example a methyl group, or a halogen atom, for example For example Cl, or NH ₂ . In the compounds of the present invention, R ₂ may be NO ₂ or H, or may be a straight or branched C 1 to C 3 lower alkyl group, for example an ethyl group. In the compounds of the present invention R ₃ may be a C ₁ -C ₃ lower alkoxy group, for example a methoxy group, or a straight or branched C 1 -C 3 alkyl ureido or a straight or branched C 1 -C 3 dialkyl ureido, for example It can be dimethyl ureido, or it can be H.

The compound of the present invention may be a compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[Formula 3]

In the present invention, pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid, sulfuric acid, and the like, Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, Lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, organic acid salts, glycine, arginine, lysine, etc. Although there are amino acid salts prepared as such, the kind of salts used in the present invention is not limited by these salts listed. Such pharmaceutically acceptable salts can be dissolved in conventional methods, for example by dissolving the benzoxazole of the present invention in an aqueous solution in which an excess of the pharmaceutically acceptable acid is dissolved, which can be dissolved in water such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation using miscible organic solvent.

The compound of Formula 1 is 1,1-dimethyl-3- (4-((5-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea (1,1-dimethyl) -3- (4-((5-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea);

1,1-dimethyl-3 (4-((4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea (1,1-dimethyl-3- (4- () (4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea); or

3- (4-((5-chlorobenzo [d] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea (3- (4-((5-chlorobenzo [ d] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[Formula 7]

[Formula 8]

[Formula 9]

The present invention

1) 2-amino-4-methylphenol and 2-methoxy-4-nitrophenyl isothiocyanate are reacted in an organic solvent. 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea (1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4- nitrophenyl) thiourea); And

2) represented by the formula 3, comprising the step of reacting the 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea with potassium peroxide (KO ₂ ) It provides a method for preparing the compound.

The organic solvent may be selected from alcohols such as methanol, ethanol, isopropanol, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, N-methylpyrrolidinone, and the like. no. Of these, methanol is preferred but not limited thereto.

The amount of the organic solvent may be 1 to 20 ml, preferably 8 to 12 ml, but is not limited thereto.

In the preparation method of the present invention, the reaction time may vary depending on the reaction temperature, the reaction solvent and the like, but is preferably about 2 hours to 48 hours, but is not limited thereto.

In the production method of the present invention, it is preferable that the equivalent ratio of 2-amino-4-methylphenol and 2-methoxy-4-nitrophenyl isothiocyanate is 1: 0.9 to 1.5, and 1: 1 is economical of the reagent. Even more preferred but not limited thereto.

The present invention provides a pharmaceutical composition for the prevention or treatment of pruritus comprising the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

In Chemical Formula 1,

R ₁ is H, OH, a straight or branched C 1 -C 3 lower alkyl group, NO ₂ , NH ₂ , C ₁ -C 3 lower alkoxy group, or a halogen atom,

R ₂ and R ₃ are the same as or different from each other, and each is H, OH, a straight or branched C 1 to C 3 lower alkyl group, NO ₂ , NH ₂ , C 1 to C 3 lower alkoxy group, C 1 to C 3 halogenated lower alkyl group, Halogen atom, CN, amino group, lower dialkyl amino group of C1-C3, SH, lower alkyl mercapto group of C1-C3, halogenated lower alkyl mercapto group of C1-C3, lower alkanoyl group of C1-C3, C1-C3 Or a hydroxy lower alkyl group, or a straight or branched C1-C3 alkyl ureido or a straight or branched C1-C3 dialkyl ureido.

In the composition of the present invention, the compound of Formula 1 may be a compound represented by Formula 2 or a pharmaceutically acceptable salt thereof.

R _1, R ₂ and R ₃ in Formula 2 are the same as in the case of Formula 1, respectively.

The present invention provides a pharmaceutical composition for the prevention or treatment of pruritus comprising the compound represented by the following Chemical Formulas 3 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

The pruritus includes scabies, teeth, insect bites, urticaria, eczema skin diseases (atopic dermatitis, contact dermatitis, molecular eczema, neurodermatitis, etc.), psoriasis, skin dryness, gestational pruritus, senile pruritus, chronic renal failure, Hochkin's disease It may be pruritus resulting from malignant blood tumors, malignant skin tumors, intestinal parasites, hyperthyroidism and hypofunction, dermatitis caused by diabetes, acquired immunodeficiency, and the like. Preferably, the pruritus of the present invention may be related to atopic dermatitis, or may be caused by atopic dermatitis, in which case the pruritus may be chronic. Also preferably the pruritus of the present invention may be histamine dependent pruritus or histamine independent pruritus. The histamine dependent pruritus means pruritus mediated by histamine or histamine, and may be acute. The histamine-independent pruritus means a pruritus that does not mediate histamine, but may be caused by a substance such as chloroquine, for example, but is not limited thereto, and may occur acutely.

The pharmaceutical composition of the present invention may contain one or more known active ingredients having a palliative, prophylactic or therapeutic effect on dermatitis or pruritus.

The pharmaceutical composition of the present invention may include additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusting agents, antioxidants, dissolution aids and the like within the scope of not impairing the effects of the present invention.

The diluent may be sugar, starch, microcrystalline cellulose, lactose (lactose monohydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, or a mixture thereof; Binders are starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose , Hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin, or a mixture thereof.

The disintegrating agent may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.

Lubricants include talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl palmi Tostearate, colloidal silicon dioxide, mixtures thereof, and the like.

pH adjusters include acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid) and precipitated calcium carbonate, ammonia water, meglumine, carbonate Basic agents, such as sodium, magnesium oxide, magnesium carbonate, sodium citrate, and calcium tribasic phosphate, etc. can be used.

Antioxidants may be dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite and the like. In the pre-release compartment of the present invention, the dissolution aid can be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium, poloxamer and the like.

It may also include enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers to make delayed release formulations.

The enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or higher, and for example, hypromellose acetate succinate, hypromellose phthalate (hydrate Hydroxypropylmethyl cellulose phthalate), hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl cellulose and ethyl hydrate Enteric cellulose derivatives such as oxyethyl cellulose phthalate and methyl hydroxyethyl cellulose; Styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylic acid copolymers (e.g., acrylics), butyl acrylate-styrene-acrylic acid copolymers, and methyl acrylate-methacrylic acid-octyl acrylate copolymers. The enteric acrylic acid copolymer; Poly (methacrylate methyl methacrylate) copolymer (e.g. Eudragit L, Eudragit S, Evonik, Germany), poly (methacrylate acrylate) copolymer (e.g. Eudragit L100- Enteric polymethacrylate copolymers such as 55); Vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinylmethyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinylbutyl ether-maleic anhydride copolymer, acrylic Enteric maleic acid copolymers such as ronitrile-methyl methacrylate-maleic anhydride copolymer and butyl styrene-styrene-maleic anhydride copolymer; And enteric polyvinyl derivatives such as polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinylacetacetal phthalate.

The water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug. For example, the water insoluble polymer may be polyvinylacetate (e.g. colicoat SR30D), water insoluble polymethacrylate copolymer [e.g. poly (ethylacrylate-methyl methacrylate) copolymer (e.g. Eudragit NE30D) , Poly (ethylacrylate-methyl methacrylate-trimethylaminoethyl methacrylate) copolymer (e.g., Eudragit RSPO) and the like], ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, Cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate.

The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug. Fatty acids and fatty acid esters such as, for example, glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and threric acid; Fatty acid alcohols such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; Waxes such as carnauba wax, beeswax, and microcrystalline wax; Inorganic materials such as talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and gum.

The hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug. Sugars such as, for example, dextrins, polydextrins, dextrans, pectins and pectin derivatives, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogalactans, starches, hydroxypropylstarches, amylose, and amylopectins ; Cellulose derivatives such as hypromellose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium; Gums such as guar gum, locust bean gum, tragacantha, carrageenan, acacia gum, gum arabic, gellan gum, and xanthan gum; Proteins such as gelatin, casein, and zein; Polyvinyl derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate; Poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g. Eudragit E100, Evonik, Germany), poly (ethyl acrylate-methyl methacrylate- Hydrophilic polymethacrylate copolymers such as triethylaminoethyl- methacrylate chloride) copolymers (eg, Eudragit RL, RS, Evonik, Germany); Polyethylene derivatives such as polyethylene glycol, and polyethylene oxide; Carbomer and the like.

In addition, the pharmaceutical composition of the present invention may be formulated by selecting and using a pharmaceutically acceptable additive as various additives selected from colorants and fragrances. Such a formulation method may use, for example, a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, and the like.

In the present invention, the range of the additives is not limited to the use of the above additives, and the above-mentioned additives may be formulated by containing a dose in a normal range by selection.

The pharmaceutical compositions according to the invention can be used in the form of oral formulations, external preparations, suppositories or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, according to conventional methods. have.

The present invention also provides a method of preventing, ameliorating or treating pruritus by administering to a subject in need thereof a therapeutically effective amount of at least one of the compounds of formulas 1 to 9 of the present invention.

The "subject in need" refers to animals, including humans.

The term "administration" means introducing the pharmaceutical composition of the present invention to a subject in need of treatment in any suitable manner, and the route of administration of the pharmaceutical composition of the present invention may be administered through any general route as long as it can reach the target tissue. Can be. Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, endothelial administration, intranasal administration, intrapulmonary administration, rectal administration, intranasal administration, intraperitoneal administration, intradural administration, preferably intraperitoneally It may be administered intravenously, or subcutaneously, but is not limited thereto.

The "therapeutically effective amount" means the amount of the active ingredient or pharmaceutical composition that induces a biological or medical response in an animal or human, as thought by a researcher, veterinarian, doctor or other clinician, which is the disease being treated. Or an amount that induces symptomatic relief of the disorder. It will be apparent to those skilled in the art that the therapeutically effective dosages and frequency of administrations for the active ingredients of the present invention will vary depending on the desired effect.

The present invention provides the use of the compounds of at least one of formulas 1-9 of the present invention in the manufacture of a pharmaceutical formulation for the prevention or treatment of pruritus. Uses of the invention can be used to prepare pharmaceutical formulations for the prevention, amelioration, or treatment of pruritus.

The pharmaceutical composition of the present invention may be administered once or twice a day at regular time intervals.

The pharmaceutical composition of the present invention preferably contains any one of the compounds of Formulas 1 to 9 in an amount of 0.001 to 10% by weight based on the total weight of the composition. However, the content is not limited thereto.

The pharmaceutical composition of the present invention may be administered at 0.1 to 1000 mg / kg / day, which may vary depending on the severity, age, sex, etc. of the patient.

The compound of the present invention is excellent in improving activity of pruritus. Therefore, it can be usefully used as a prophylactic, therapeutic and therapeutic aid for pruritus of various skin diseases including atopic dermatitis. The pruritus to which the present invention can be applied may be a pruritus that occurs chronically in connection with atopic dermatitis, or may be acute pruritus. The pruritus may be histamine dependent or histamine independent pruritus.

1 is a photograph comparing chronic pruritus or atopic dermatitis-induced animal model rats (c and d) and control rats (a and b) used to evaluate the compounds of the present invention.

FIG. 2 is a graph showing the number of scratches per hour (top) and the dermatitis index (bottom) in the animal model rat and the control rat of FIG. 1, respectively.

Figure 3 is a photograph showing the histopathological findings of the skin of the animal model rat and the control rat of FIG.

Figure 4 is a graph showing the findings of the epidermis and mast cells observed in FIG.

FIG. 5 is a graph showing the results of observing the number of times of scraping at 5-minute intervals for 1 hour in the animal model rats when the compounds of Formulas 3 to 5 of the present invention are administered. Vehicle means a control group administered with a solvent.

FIG. 6 is a graph showing one hour accumulation of the result of FIG. 5.

7 is a graph showing the number of scratches accumulated during 1 hour and the number of scratches accumulated during the first 30 minutes and the latter 30 minutes of the 1 hour in the animal model rats when the compounds of Formulas 6 and 7 of the present invention are administered. .

8 is a graph showing the cumulative number of scratches for 30 minutes when acute pruritus was induced by administration of a compound of Formula 3 of the present invention to the normal mouse intraperitoneally, followed by histamine (left side) or chloroquine (right side). .

Examples are provided to help understand the present invention. The following examples are merely provided to more easily understand the present invention, but the contents of the present invention are not limited by the examples.

EXAMPLE

Example 1 Synthesis of Compound of Formula 3

[Formula 3]

Scheme 1

A compound of formula 3 was synthesized according to Scheme 1. The specific process is as follows.

0.812 mmol (1 equivalent) of 2-amino-4-methylphenol was dissolved in 10 ml of methanol. 0.812 mmol (1 equiv) of 2-methoxy-4-nitrophenyl isothiocyanate was added thereto and stirred at room temperature for 24 hours. The methanol was evaporated off under reduced pressure, and the remaining precipitate was filtered under reduced pressure with hexane to give 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea (1- (2-hydroxy). -5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea) was obtained (yield: 92%).

10 ml of acetonitrile was slowly added to 1.5 mmol (5 equivalents) of KO ₂ in an ice bath under nitrogen gas substitution. The 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea is prepared by dissolving in 10 ml of acetonitrile, which is a mixed solution of KO ₂ and acetonitrile. Was added slowly. After reacting for 16 hours at room temperature, the mixture was poured into iced water and diluted. Then extracted with dichloromethane and washed twice with saturated aqueous Nacl solution. After drying using MgSO ₄ , the solvent was removed under reduced pressure to obtain a precipitate. The precipitate was filtered under reduced pressure with a solvent of ethanol: hexane mixed at 1:10 to give N- (2-methoxy-4-nitrophenyl) -5-methylbenzo [ d ] oxazol-2-amine ( N- (2 -methoxy-4-nitrophenyl) -5-methylbenzo [ d ] oxazol-2-amine) was obtained.

Yellow powder (78%),

¹ H NMR (Acetone-D6, 400 MHz), δ 9.306 (s, 1H), 8.816 (d, J = 9.2 Hz, 1H), 8.043 (d, J = 6.4 Hz, 1H) 7.874 (d, J = 2.4 Hz , 1H), 7.342 (t, J = 9.0 Hz, 2H), 7.044 (m, 1H), 4.117 (s, 3H), 2.427 (s, 3H),

HR-FABMS Calcd for C ₁₅ H ₁₄ N ₃ O ₄ (M ++ H): 300.0906, Found: 300.0984

Example 2. Synthesis of Compound of Formula 4

[Formula 4]

N ^2- (4-ethylphenyl) benzo [ d ] oxazole-2,5-diamine [according to the method described in paragraphs [0080] to [0080] of Korean Patent Publication No. 10-2011-0137868 [ N ^2- (4-ethylphenyl) benzo [ d ] oxazole-2,5-diamine] was synthesized.

Example 3. Synthesis of Compound of Formula 5

[Formula 5]

According to the production method described in paragraphs [0041] to [0046] of Korean Patent Publication No. 10-2008-0027191, the above 8-methyl-2- [ N- (4-ethylphenyl)] aminobenzoxazole [ 8-methyl-2- [ N- (4-ethylphenyl)] aminobenzoxazole] was synthesized.

Example 4. Confirmation of the effect of improving the pruritus of the compound of Formulas 3 to 5

4-1. Statistical analysis

All data are expressed as mean ± SEM. Statistical significance was analyzed by Student's t-test or the Mann-Whitney Rank Sum Test through a normal distribution test. When the P value obtained from the analysis result was less than 0.05, it was judged to have statistical significance. All statistical analyzes were conducted using the Sigma Stat (ver. 3.5, Systat Software Inc., IL, USA) program.

4-2. Animal model preparation

(1) animal model making

Korean Patent No. 10-1338521 and J. Dermat. Sci. 67, 111-119 The chronic pruritus or atopic dermatitis induced rats disclosed in 2012 were prepared as follows.

Within 48 hours of birth, purified capsaicin (50 mg / kg) was dissolved in physiological saline (0.9% saline) containing 10 % Tween 80 and 10% ethanol in the dorsal subcutaneous white rat pups per 1 g of body weight. 10 μl injection. Capsaicin can cause apnea, which is overcome by compressing the chest several times until spontaneous breathing resumes. The rats were then returned to the mother rats and raised in the same cage until they were 3 weeks old and were able to identify the sexes.

(2) Pruritus evaluation of animal models

Pruritus was evaluated weekly in the animal model rat produced in the above (1).

Control and animal model rats were placed in a transparent plastic pail with a mirror and allowed to acclimate to the environment for about 30 minutes, and then the behavior was recorded for 1 hour each week using a digital video camera (DCR-SR300, Sony, Japan). The number of scratches was recorded while playing back the recorded video file at twice the speed of the computer. The rats were seen to scratch one continuous action of scratching the skin until the hind foot was removed from the floor and put back on the floor. The number of scratches observed during 1 hour was used as a measure of pruritus degree.

Rat behavior was photographed in a room free of human intervention, and analysis was conducted by blind test by an experimenter who did not know the information of the animal.

The top graphs of FIGS. 1 and 2 are the results for the time course of pruritus in the animal model. 1 a and b are control rats, not animal models, c and d are photographs of the animal model rats. 2 shows the time course of the number of scratches observed in the animal model rats.

As a result, sporadic scratches were also observed in the control group, but the frequency was less than 10 times per hour. In contrast, animal models in which capsaicin was administered began to scratch the skin of the face, ears and back more severely than 3 weeks after birth, and this phenomenon persisted for up to 10 weeks.

From the above results, it was found that the animal model in which a large amount of capsaicin was administered subcutaneously immediately after birth developed severe chronic pruritus with an initial incubation period.

(3) Evaluation of dermatitis in animal models

Each week, the skin condition of the animals was examined immediately before the photographing for pruritus evaluation and the degree of dermatitis was quantified and analyzed. All wounds were scored according to the condition of the skin in the face, ears and back as shown below, and the sum of the scores was used as a measure of the degree of dermatitis (Mihara et al, Br J). Dermatol 15: 335-345, 2004). In other words, the higher the score, the more severe the dermatitis.

TABLE 1

Dermatitis index evaluation results are shown in the bottom graph of FIG. As a result, it was found that the dermatitis index increased sharply from 3 weeks in the animal model rats.

For histological examination, skin tissues were obtained by biopsy at 3 and 6 weeks after birth and stained with hematoxylin and eosin (H & E) or toluidine blue (TB). It was. At 3 weeks after capsaicin administration, non-lesional tissues were taken because no gross skin damage was observed, whereas at 6 weeks the lesions were selected. After toluidine blue staining, the number of mast cells observed in a 400-fold microscope (BX51, Olympus, Japan) field of view was measured.

Experimental results are shown in FIGS. 3 and 4. In animal model rats, hyperkeratosis and hyperplasia (epidermal thickening) were observed and epidermal thickness was increased compared to the control group, and the number of mast cells was increased. The average diameter of the mast cells and the number of degranulated mast cells increased, indicating that the mast cells were activated. These histopathological findings are very similar to those observed in patients with atopic dermatitis.

Through the evaluation of pruritus and dermatitis, it was confirmed that the animal model rat was very suitable as an animal model for pruritus and atopic dermatitis. Hereinafter, the effect of the compound of the present invention on pruritus was evaluated using this animal model rat.

4-3. Administration of the Compound

The compounds of Chemical Formulas 3 to 5 were prepared by dissolving 30 mg of each of 2 ml in a solvent in which methylpyrrolidone: twin 80: saline was mixed at a volume ratio of 1: 1: 8. When chronic pruritus and atopic dermatitis-induced rats prepared in 4-2 became the 4th week, divided into four groups, three groups were injected intraperitoneally with 2 ml / kg of a solvent in which each compound was dissolved. One group was used as a control and the solvent was injected intraperitoneally at 2 ml / kg.

4-4. Evaluation of Pruritus

Pruritus was evaluated by the following method in the control group prepared in 4-3 and rats to which each compound was administered.

Rats in each group were placed in a transparent plastic container with a mirror after injection, and adapted to the environment for about 30 minutes, and then with a digital video camera (DCR-SR300, Sony, Japan) from 30 minutes after injection to 1 hour and 30 minutes. Actions were recorded for 1 hour each week. The number of scratches was recorded while playing back the recorded video file at twice the speed of the computer. The rats were seen to scratch one continuous action of scratching the skin until the hind foot was removed from the floor and put back on the floor. The number of scratches observed during 1 hour was used as a measure of pruritus degree. Compared with the control group, it was determined that there was an improvement in pruritus when the scratching behavior was statistically significantly reduced.

Rat behavior was photographed in a room free of human intervention, and analysis was conducted by blind test by an experimenter who did not know the information of the animal.

The results are shown in FIGS. 5 and 6. FIG. 5 is a graph recording the number of scratches at 5-minute intervals (the number of horizontal axes means the time elapsed from the start of photographing), and FIG. 6 shows the results of FIG. 5 in one hour accumulation.

The number of scratches in the control group was 123.67 ± 38.50. On the other hand, the number of scratches of the compound of the compound of Formula 3 was 25.43 ± 6.80 times, 77.83 ± 25.40 of the compound of the compound of Formula 4, and 19.67 ± 8.00 of the group of the compound of Compound 5 showed significantly better scratch reduction than the control group. From this it can be seen that the compound of Formula 3 to 5 has an excellent pruritus improving effect.

Example 5 Synthesis of Compound of Formula 6

[Formula 6]

Bioorg. Med. Chem. The compound of formula 6 was synthesized according to the method described in 16 (2008) 5405-5412 (see p. 5407, formula 3a).

Example 6 Synthesis of Compound of Formula 7

[Formula 7]

Scheme 2

A compound of formula 7 was synthesized according to Scheme 2. The specific process is as follows.

0.812 mmol (1 equivalent) of 2-amino-4-methylphenol was dissolved in 10 ml of methanol. To this was added 0.812 mmol (1 equiv) of 4-nitrophenol-thiocyanate and stirred at room temperature for 24 hours. The methanol was evaporated off under reduced pressure, and the remaining precipitate was filtered under reduced pressure with hexane to give 1- (2-hydroxy-5-methylphenyl) -3- (4-nitrophenyl) thiourea (1- (2-hydroxy-5-methylphenyl) -3- (4-nitrophenyl) thiourea) was obtained.

10 ml of acetonitrile were slowly added to 1.5 mmol (5 equivalents) of KO ₂ in an ice bath under nitrogen gas substitution. The 1- (2-hydroxy-5-methylphenyl) -3- (4-nitrophenyl) thiourea was prepared by dissolving in 10 ml of acetonitrile, which was slowly added to the mixed solution of KO ₂ and acetonitrile. After reacting for 16 hours at room temperature, the mixture was poured into iced water and diluted to obtain N- (4-nitrophenyl) -5-methylbenzo [ d ] oxazol-2-amine. This was reacted with H ₂ at Pd / c catalyst for 5 hours at room temperature to give N- (5-methylbenzo [d] oxazol-2-yl) benzene-1,4-diamine ( N- (5-methylbenzo [d] oxazol-2-yl) benzene-1,4-diamine). 1.045 mmol (equivalent) of N- (5-methylbenzo [d] oxazol-2-yl) benzene-1,4-diamine was dissolved in 5 ml of a dimethylformamide solution, and dimethyl carbamyl chloride was added thereto. 0.418 mmol (1 equiv) was added and stirred at 100 ° C for 24 h. After cooling to room temperature, the mixture was extracted three times with 20 ml of ethanol, and the organic layer was extracted twice with 1 N HCl aqueous solution, twice with NaHCO ₃ aqueous solution and twice with NaCl aqueous solution. Then with Na ₂ SO ₄ After drying, filtration and concentration under reduced pressure, the mixture was purified by column chromatography using a solution of ethanol: hexane mixed at 1: 3, and then purified by 1,1-dimethyl-3- (4-((5-methylbenzo [d] oxa). Zol-2-yl) amino) phenyl) urea (1,1-dimethyl-3- (4-((5-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea) (Formula 7) was obtained.

Ivory solid (19.4%),

mp 228-230 ° C., ¹ H NMR (DMSO-D ₆ , 400 MHz) δ 10.342 (s, 1H), 8.210 (s, 1H), 7.572 (dd, J = 2.4Hz, J = 6.8Hz, 2H), 7.421 (dd, J = 2.0 Hz, J = 6.8 Hz, 2H), 7.313 (d, J = 8.4 Hz, 1H), 7.219 (s, 1H), 6.897 (dd, J = 1.2 Hz, J = 8.4 Hz, 1H ), 2.918 (s, 6H), 2.362 (s, 3H),

HR-FABMS Calcd for C ₁₇ H ₁₉ N ₄ O ₂ (M ⁺ + H): 311.1503, Found: 311.1506

Example 6 Synthesis of Compound of Formula 8

[Formula 8]

According to Scheme 2, 1,1-dimethyl-3 (4-((4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea (1,1-dimethyl-3- (4-(( 4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea) (Formula 8) was synthesized. A compound of Formula 8 was prepared in the same manner as in Example 5, except for using the same amount of 2-amino-3-methylphenol instead of 2-amino-4-methylphenol in Scheme 2.

Ivory solid (14.9%),

mp 219-220 ° C., ¹ H NMR (DMSO-D6, 400 MHz), δ 10.337 (s, 1H), 8.211 (s, 1H), 7.598 (dd, J = 2.4 Hz, J = 6.8 Hz, 1H), 7.425 (dd, J = 2.0Hz, J = 6.8Hz, 2H), 7.263 (dd, J = 0.8Hz, J = 6.8Hz, 1H), 6.969-7.036 (m, 2H), 5.755 (s, 1H), 2.923 (s, 6H), 2.454 (s, 3H),

HR-FABMS Calcd for C ₁₇ H ₁₉ N ₄ O ₂ (M ++ H): 311.1503, Found: 311.1505

Example 7 Synthesis of Compound of Formula 9

[Formula 9]

3- (4-((5-chlorobenzo [d] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea (3- (4-((5-chlorobenzo [d) according to Scheme 2 above. ] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea) (Formula 9) was synthesized. A compound of Chemical Formula 9 was prepared in the same manner as in Example 5 except for using the same amount of 2-amino-4-chlorophenol in Chemical Formula 7 instead of 2-amino-4-methylphenol.

Ivory solid (20.2%),

mp 214-216 ° C., ¹ H NMR (DMSO-D ₆ , 400 MHz) δ 10.582 (s, 1H), 8.237 (s, 1H), 7.544-7.575 (m, 2H), 7.426-7.489 (m, 3H), 7.123 (dd, J = 2.4 Hz, J = 4.8 Hz, 1H), 2.920 (s, 6H),

HR-FABMS Calcd for C ₁₆ H ₁₆ ClN ₄ O ₂ (M ⁺ + H): 331.0956, Found: 331.0956

Example 8. Confirmation of the effect of improving pruritus of the compounds of formulas (6) and (7)

8-1. Administration of Compounds of Formulas 6 and 7

Compounds of formula 6 and compound 7 were prepared by dissolving 30 mg of methylpyrrolidone: Tween80: saline in a solvent in a volume ratio of 1: 1: 8, respectively, per 2 ml. When chronic pruritus and atopic dermatitis-induced rats prepared in 4-2 became the 4th week, divided into three groups, two groups were injected intraperitoneally with 2 ml / kg of a solvent in which each compound was dissolved. One group was used as a control and the solvent was injected intraperitoneally at 2 ml / kg.

8-2. Evaluation of Pruritus

Pruritus was evaluated in the same manner as in Example 4-4. The number of scratches observed during 1 hour was used as a measure of pruritus degree. Compared with the control group, it was determined that there was an improvement in pruritus when the scratching behavior was statistically significantly reduced.

The results are shown graphically in FIG. In Figure 7, ** P <0.01, * P <0.05 vs. Vehicle (methylpyrrolidone: Tween80: salt mixed in a volume ratio of 1: 1: 8) ( t -test).

The leftmost bars in Figure 7 represent the cumulative number of scratches for 1 hour between 30 minutes and 1 hour and 30 minutes after injection in each group. The total number of scratches in 1 hour of the control group was 132.80 ± 8.79. On the other hand, the number of scratches of the compound-treated group of Formula 6 was 87.00 ± 8.30 times (P = 0.005), and the number of scratches of the compound-treated group of Formula 7 was 66.80 ± 12.22 (P = 0.002), which significantly reduced the number of scratches compared to the control group. It became. This means that the compound of formula 6 and compound of formula 7 have an improvement effect on chronic pruritus associated with atopic dermatitis.

The bars in the center of FIG. 7 represent the number of scratches accumulated between 30 minutes and 1 hour after injection in each group, and the rightmost bars represent the number of scratches accumulated between 1 hour and 1 hour and 30 minutes after injection in each group. will be. '~ 30 minutes' and '30 minutes to 1 hour' on the horizontal axis of the graph in FIG. 7 mean elapsed time after photographing start.

The number of scratches in the control, Formula 6, and Formula 7 groups was 61.20 ± 10.71, 75.60 ± 8.33, and 42.40 ± 7.93, respectively, for 30 minutes between 30 minutes and 1 hour after injection of each compound, with significant differences between the groups. There was no. However, the number of scratches between 1 hour and 1 hour 30 minutes after injection of the compound was 71.60 ± 13.97 times in the control group, 11.40 ± 6.38 times in the Formula 6 administration group (P = 0.004) and 24.40 ± 6.27 times in the Formula 7 administration group ( P = 0.015), the number of scratches was significantly reduced in both the formula (6) administration group and the formula (7) administration group. The results indicate that the pruritic improvement effect of the compound of Formula 6 and compound of Formula 7 appears in earnest from 1 hour after administration.

Example 9 Amelioration of Acute Pruritus of the Compound of Formula 3

9-1. Induction of Acute Pruritus and Administration of Compound of Formula 3 in Normal Mice

Normal mice (non-pruritic mice) were prepared.

Histamine, a type of endogenous amine, is a pruritogen that causes pruritus. In addition, chloroquine, a malaria treatment, is known to cause histamine-independent non-histaminergic pruritus. Therefore, the following experiment was conducted to confirm the effect of the compound of Formula 3 on acutely induced histamine-dependent and histamine-independent pruritus.

The normal mice were divided into two groups, and the compound of Formula 3 was dissolved in a solvent in which methylpyrrolidone: twin 80: saline was mixed at a volume ratio of 1: 1: 8, and administered intraperitoneally at 30 mg / kg. . The other group was used as a control and 10 μl / g of the solvent was administered.

After injection, the mouse was placed in a transparent plastic container with a mirror and acclimated to the experimental environment for about 30 minutes. Histamine 27 mM or chloroquine 27 mM was dissolved in 25 μl of physiological saline solution (0.9% NaCl solution). Acute pruritus was induced by injection into the back skin using an insulin syringe (31G).

9-2. Evaluation of Acute Pruritus

The effect of the compound of formula 3 on acute pruritus was evaluated. The behavior of the mouse was recorded using a digital video camera, and the number of times the histamine or chloroquine was injected was scratched for 30 minutes immediately after administration of histamine or chloroquine. As in Example 4-4, a continuous action of scratching the skin until the hind foot was removed from the floor and put back on the floor was considered as a scratch bout.

The results are shown in FIG. In Figure 8 ** P <0.001, ** P = 0.002 vs. Vehicle (methylpyrrolidone: Tween80: salt mixed in a volume ratio of 1: 1: 8) ( t -test).

(1) Confirmation of effects on histamine-induced pruritus

The total number of scratches accumulated in the control group for 30 minutes was 117.67 ± 9.31, and the number of scratches in the compound-treated group of Formula 3 was 44.00 ± 12.87. From the above results, it can be seen that the compound of Formula 3 has an effect of reducing histamine-dependent pruritus.

(2) Confirmation of effects on chloroquine-induced pruritus

The total number of scratches accumulated in the control group for 30 minutes was 305.25 ± 39.54, and the number of scratches in the compound-treated group of Formula 3 was 128.86 ± 23.23. From the above results, it can be seen that the compound of Formula 3 has a significant improvement effect on histamine-independent non-histaminergic pruritus.

Claims (7)

1. A compound represented by formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

   [Formula 1]

   

   In Chemical Formula 1,

   R ₁ is H, OH, a straight or branched C 1 -C 3 lower alkyl group, NO ₂ , NH ₂ , C ₁ -C 3 lower alkoxy group, or a halogen atom,

   R ₂ and R ₃ are the same as or different from each other, and each is H, OH, a straight or branched C 1 to C 3 lower alkyl group, NO ₂ , NH ₂ , C 1 to C 3 lower alkoxy group, C 1 to C 3 halogenated lower alkyl group, Halogen atom, CN, amino group, lower dialkyl amino group of C1-C3, SH, lower alkyl mercapto group of C1-C3, halogenated lower alkyl mercapto group of C1-C3, lower alkanoyl group of C1-C3, of C1-C3 Hydroxy lower alkyl group, straight or branched C1-C3 alkyl ureido, or straight or branched C1-C3 dialkyl ureido.

   Provided that N ^2- (4-ethylphenyl) benzo [ d ] oxazole-2,5-diamine [ N ^2- (4-ethylphenyl) benzo [ d ] oxazole-2,5-diamine], and 8-methyl- 2- [ N- (4-ethylphenyl)] aminobenzoxazole [8-methyl-2- [ N- (4-ethylphenyl)] aminobenzoxazole] is excluded.
2. To N of the formula (3) - (2-methoxy-4-nitro-phenyl) -5-methyl-benzo [d] oxazol-2-amine (N - (2-methoxy- 4-nitrophenyl) -5-methylbenzo [ d ] oxazol-2-amine) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

   [Formula 3]

   
3. The compound of claim 1 wherein

   1,1-dimethyl-3- (4-((5-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea (1,1-dimethyl-3- (4-) ((5-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea);

   1,1-dimethyl-3 (4-((4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea (1,1-dimethyl-3- (4- () (4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea); or

   3- (4-((5-chlorobenzo [d] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea (3- (4-((5-chlorobenzo [ d] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

   [Formula 7]

   

   [Formula 8]

   

   [Formula 9]

   
4. 1) 2-amino-4-methylphenol and 2-methoxy-4-nitrophenyl isothiocyanate are reacted in an organic solvent. 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea (1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4- nitrophenyl) thiourea); And

   2) reacting 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea with potassium peroxide (KO ₂ ), Method for preparing the compound to be displayed.

   [Formula 3]

   
5. A pharmaceutical composition for pruritus prevention or treatment comprising the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

   [Formula 1]

   

   In Chemical Formula 1,

   R ₁ is H, OH, a straight or branched C 1 -C 3 lower alkyl group, NO ₂ , NH ₂ , C ₁ -C 3 lower alkoxy group, or a halogen atom,

   R ₂ and R ₃ are the same as or different from each other, and each is H, OH, a straight or branched C 1 to C 3 lower alkyl group, NO ₂ , NH ₂ , C 1 to C 3 lower alkoxy group, C 1 to C 3 halogenated lower alkyl group, Halogen atom, CN, amino group, lower dialkyl amino group of C1-C3, SH, lower alkyl mercapto group of C1-C3, halogenated lower alkyl mercapto group of C1-C3, lower alkanoyl group of C1-C3, C1-C3 Hydroxy lower alkyl group, straight or branched C1-C3 alkyl ureido, or straight or branched C1-C3 dialkyl ureido.
6. A pharmaceutical composition for the prevention or treatment of pruritus comprising at least one selected from a compound represented by the following Chemical Formulas 3 to 7, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

   [Formula 3]

   

   [Formula 4]

   

   [Formula 5]

   

   [Formula 6]

   [Formula 7]

   
7. The pharmaceutical composition for preventing or treating pruritus according to claim 5 or 6, wherein the pruritus is any one of pruritus, histamine-dependent pruritus, or histamine-independent pruritus associated with atopic dermatitis.

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