KR101683362B1 - Benzoxazole derivatives for pruritis amelioration - Google Patents

Abstract

TECHNICAL FIELD The present invention relates to novel benzoxazole derivatives having an effect of preventing or treating pruritus in skin diseases, and a method for producing the same. Since the benzoxazole derivative compound of the present invention is excellent in improving the pruritus, it can be effectively used as a preventive, treatment and adjuvant for pruritus, histamine-dependent pruritus and histamine -independent pruritus of various skin diseases including atopic dermatitis.

Description

[0001] The present invention relates to benzoxazole derivatives for pruritis amelioration,

The present invention relates to a novel benzoxazole derivative having an effect of preventing, ameliorating or treating pruritus in skin diseases and a process for producing the same.

Pruritus (itching, pruritus, or itch) is defined as an unpleasant sensation that induces a urge to scratch (Haffenreffer, 1660). Pruritus is a prominent symptom of various skin diseases, and it is a common symptom of various skin diseases such as omphalitis, insect bites, urticaria, eczematous skin diseases (atopic dermatitis, contact dermatitis, paraphatic eczema, neurogenic dermatitis, etc.), psoriasis, dry skin, Pruritus, and the like. In addition, pruritus may occur when hemodialysis is performed in patients with chronic renal failure. In addition, pruritus may also occur in patients with malignant hematologic malignancies such as Huntskin's disease, malignant skin tumors, intestinal parasitosis, hyperthyroidism and hypothyroidism, diabetes and acquired immunodeficiency .

Just as pain relieves the body's excretory reflexes to the noxious stimulus and acts before the defensive period, pruritus also induces scratching reflexes, leading to the penetration of toxic substances or harmful microorganisms into the skin The blocking acts before the defensive period.

However, pruritus does not necessarily have a beneficial role. Pruritus can result in wounds, erythema, skin cracks, ulcers, and urticaria, and it can be rather easy to penetrate pathogens into scars where they are scratched. Or may cause pigmentation or skin wrinkling and thickening, resulting in poor cosmetic results. In particular, in the case of atopic dermatitis, which is a pervasive autoimmune disease in the modern world, pruritus does not act as a beneficial defense mechanism, but rather acts as a chronic stage (immune response based on Th1 cells) (Matsushima et al., 2003). In addition, it has been shown that the effect of the transduction pathway is mediated. Itch-scratch vicious cycle leading to 'pruritus -> scratching reflex -> more severe pruritus'.

Currently, treatments for pruritus include skin-cooling agents, steroids, anesthetics, and antihistamines. Calamine lotions and menthol lotions cool the skin to relieve pruritus, but have only a temporary effect. Steroids exhibit vasoconstriction, anti-proliferative, immunosuppressive and anti-inflammatory effects, which are particularly effective in relieving pruritus in autoimmune diseases such as atopic dermatitis, but are limited in their use due to severe side effects during prolonged use. Phenolic lotions and capsaicin alleviate pruritus by numbing the senses, but their effects are temporary and can cause skin irritation. Antihistamines are mainly used as medicines. In recent years, agents that inhibit only H1 receptors directly involved in pruritus have been developed. However, some antihistamines inhibit H2 receptors and cause side effects such as dry mouth, constipation, blurred vision . In addition, antihistamines are effective in the case of urticaria and allergies, but have been reported to 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 an effect of preventing or treating pruritus and a method for producing the same.

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

[Chemical Formula 1]

In Formula 1,

R ₁ is H, OH, a linear or branched lower alkyl group having ₁ to 3 carbon atoms, NO ₂ , NH ₂ , a lower alkoxy group having 1 to 3 carbon atoms, or a halogen atom,

R ₂ and R ₃ are the same or different from each other and each represents H, OH, a linear or branched C1 to C3 lower alkyl group, NO ₂ , NH ₂ , a C1 to C3 lower alkoxy group, a C1 to C3 halogenated lower alkyl group, A halogen atom, CN, an amino group, a lower dialkylamino group of C1 to C3, SH, a lower alkyl mercapto group of C1 to C3, a halogenated lower alkyl mercapto group of C1 to C3, a lower alkanoyl group of C1 to C3, A hydroxy lower alkyl group, a linear or branched C1 to C3 alkylureido or a linear or branched C1 to C3 dialkylureido. However, N ^2- (4- ethyl-phenyl) benzo [d] oxazole-2,5-diamine ^{[N 2 - (4-ethylphenyl} ) benzo [d] oxazole- 2,5-diamine], and 8-methyl - 2- [N - (4- ethylphenyl) amino-benzoxazole [8-methyl-2- [N - (4-ethylphenyl)] aminobenzoxazole] are 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.

(2)

In Formula 2,

R ₁ is H, OH, a linear or branched lower alkyl group having ₁ to 3 carbon atoms, NO ₂ , NH ₂ , a lower alkoxy group having 1 to 3 carbon atoms, or a halogen atom,

R ₂ and R ₃ are the same or different and each H, OH, C1 ~ C3 lower alkyl group, NO _2, NH _2, C1 ~ C3 lower alkoxy group, C1 ~ C3 halogenated lower alkyl group, a halogen atom, CN of each other, An amino group, a lower dialkylamino group of C1-C3, SH, a linear or branched C1-C3 lower alkyl mercapto group, a C1-C3 halogenated lower alkylmercapto group, a C1-C3 lower alkanoyl group, A straight chain or branched C1 to C3 alkylureido or a straight or branched chain C1 to C3 dialkylureido.

In the formulas (1) and (2) of the present invention, R ₁ , The term "C1 to C3 lower alkyl group" as used in the definition of R ₂ and R ₃ means a straight or branched chain alkyl group composed of 1 to 3 carbon atoms, examples of which include methyl, ethyl, propyl, have.

In the formulas (1) and (2) of the present invention, R ₁ , The term "C1-C3 lower alkoxy group" as used in the definition of R ₂ and R ₃ means a straight or branched alkoxy group consisting of one to three carbon atoms and examples thereof include methoxy, ethoxy, n-propoxy Time.

"Halogen atom" used in the definition of R ₂ and R ₃ in formulas (1) and (2) of the present invention means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

"A halogenated lower alkyl group of C1 ~ C3" terms used in the definition of R ₂ and R ₃ in the formulas (1) and (2) of the present invention, the one, some or all of the hydrogen from the lower alkyl group for the aforementioned C1 ~ C3 above-described halogen atoms , And examples thereof include a fluorinated methyl group, a methyl chloride group, an ethyl fluoride group, and an ethyl chloride group.

The term "lower dialkylamino group of C1 ~ C3" terms used in the definition of R ₂ and R ₃ in Formula 1 and 2 of the present invention refers to a lower dialkylamino group derived from the lower alkyl group for the aforementioned C1 ~ C3, and its Examples include a dimethylamino group and the like.

The term "C1-C3 lower alkyl mercapto group" as used in the definition of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention means that the lower alkyl group of the above-mentioned C1-C3 is connected to the sulfur of the mercapto group instead of hydrogen , Examples thereof include a methyl mercapto group and an ethyl mercapto group.

"A halogenated lower alkyl mercapto group, a C1 ~ C3" terms used in the definition of R ₂ and R ₃ in the formulas (1) and (2) of the present invention, one, some or all of the hydrogen from the lower alkyl mercapto group of the aforementioned C1 ~ C3 above Means a fluoromethyl mercaptan group, a methyl mercaptan group, an ethyl mercaptan group, an ethyl mercaptan group, and the like.

The term "C1-C3 lower alkanoyl group " as used in the definition of R ₂ and R ₃ in formulas (1) and (2) of the present invention means a lower alkanoyl group having 1 to 3 carbon atoms, Functional group, and examples thereof include formyl, acetyl, propionyl and the like.

"A hydroxy lower alkyl group of C1 ~ C3" terms used in the definition of R ₂ and R ₃ in Formula 1 and 2 of the present invention is attached to a carbon atom of the above-mentioned lower alkyl group and the lower alkyl group composed of 1 to 3 carbon atoms Means a functional group composed of a hydroxy group, and examples thereof include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl groups.

The "C1 to C3 alkylureido or C1 to C3 dialkylureido" used in the definitions of R ₂ and R ₃ in the general formulas (1) and (2) of the present invention refers to a nitrogen atom of a ureido C1 to C3 alkyl refers to one or two linked. For example, dimethyl ureido, and the like.

In one embodiment of the present invention, R ₁ in the compound of the present invention (Chemical Formula 1 or Chemical Formula 2) may be a linear or branched lower alkyl group of C1-C3, for example, a methyl group or a halogen atom, this example may be Cl, or may be NH _2. In the compounds of the present invention, R ₂ may be NO ₂ or H, or may be a straight or branched chain C1 to C3 lower alkyl group, for example, an ethyl group. In the compounds of the present invention R ₃ can be a C1 to C3 lower alkoxy group, for example a methoxy group, or a straight or branched C1 to C3 alkylureido or straight or branched C1 to C3 dialkylureido, for example Lt; / RTI > may be < RTI ID = 0.0 > dimethylureido, < / RTI >

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

(3)

In the present invention, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, and includes, for example, an inorganic acid salt prepared by hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid, Citric acid, maleic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, tartaric acid, Organic acid salts such as lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillyric acid and hydroiodic acid, glycine, arginine and lysine And the like. However, the kind of salt as referred to in the present invention is not limited by these listed salts. Such pharmaceutically acceptable salts may be prepared by conventional methods, for example by dissolving the benzoxazole of the present invention in an excess of the above pharmaceutically acceptable acid in an aqueous solution and dissolving it in a solvent such as methanol, ethanol, acetone or acetonitrile And precipitating with a miscible organic solvent.

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

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

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

(7)

[Chemical Formula 8]

[Chemical Formula 9]

The present invention

1) Reaction of 2-amino-4-methylphenol with 2-methoxy-4-nitrophenyl isothiocyanate in an organic solvent 2- (2-methoxy-4-nitrophenyl) thiourea (1- (2-hydroxy-5-methylphenyl) -3- nitrophenyl) thiourea; And

2) reacting the 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea with potassium peroxide (KO ₂ ) ≪ / RTI >

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

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

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

In the production process of the present invention, the equivalent ratio of 2-amino-4-methylphenol to 2-methoxy-4-nitrophenylisothiocyanate is preferably 1: 0.9 to 1.5, But is not limited thereto.

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

[Chemical Formula 1]

In Formula 1,

R ₁ is H, OH, a linear or branched lower alkyl group having ₁ to 3 carbon atoms, NO ₂ , NH ₂ , a lower alkoxy group having 1 to 3 carbon atoms, or a halogen atom,

R ₂ and R ₃ are the same or different from each other and each represents H, OH, a linear or branched C1 to C3 lower alkyl group, NO ₂ , NH ₂ , a C1 to C3 lower alkoxy group, a C1 to C3 halogenated lower alkyl group, A halogen atom, CN, an amino group, a lower dialkylamino group of C1 to C3, SH, a lower alkyl mercapto group of C1 to C3, a halogenated lower alkyl mercapto group of C1 to C3, a lower alkanoyl group of C1 to C3, A hydroxy lower alkyl group, or a linear or branched C1 to C3 alkylureido or a straight or branched chain C1 to C3 dialkylureido.

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.

In the formula (2), R _1, R ₂ and R ₃ are the same as those in the above formula (1).

The present invention provides a pharmaceutical composition for preventing or treating pruritis comprising, as an active ingredient, a compound represented by the following general formulas (3) to (7) or a pharmaceutically acceptable salt thereof.

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

The pruritus may be at least one selected from the group consisting of atopic dermatitis, insect bites, urticaria, eczematous skin diseases (atopic dermatitis, contact dermatitis, paraoxidative eczema, neurogenic dermatitis, etc.), psoriasis, dry skin, pregnancy pruritus, geriatric pruritus, Malignant skin tumors, intestinal parasitism, hyperthyroidism and hypothyroidism, diabetes mellitus, dermatitis caused by acquired immunodeficiency syndrome, etc., and the like. Preferably, the pruritus of the present invention may be associated with atopic dermatitis or caused by atopic dermatitis, wherein the pruritus may be chronic. Also preferably, the pruritus of the present invention may be histamine-dependent pruritus or histamine-non-dependent pruritus. The histamine-dependent pruritus refers to pruritus mediated by histamine or by histamine, which may be acute. The histamine non-dependent pruritus refers to pruritus not mediated by histamine, for example, it may be caused by a substance such as chloroquine, but it is not limited to this and may occur acutely.

The pharmaceutical composition of the present invention may contain at least one known active ingredient having mitigating, preventing or treating effects on dermatitis or pruritus.

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

The diluent may be sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, or a mixture thereof; The binder may be selected from the group consisting of starch, microcrystalline cellulose, highly disperse silica, mannitol, di-mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer , Hydroxypropylcellulose, natural gum, synthetic gum, copovidone, gelatin, or a mixture thereof.

The disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clays such as bentonite, montmorillonite, or veegum; Cellulose such as microcrystalline cellulose, hydroxypropylcellulose or carboxymethylcellulose; Alginates such as sodium alginate and alginic acid; Crosslinked celluloses such as croscarmellose sodium; Guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Sodium bicarbonate, citric acid and the like, or a mixture thereof.

The lubricant may be selected from the group consisting of talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monolate, glyceryl monostearate, Stearate, colloidal silicon dioxide, or a mixture thereof may be used.

The pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ethoxide, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid) and precipitated calcium carbonate, ammonia water, meglumine, Basic agents such as sodium, magnesium oxide, magnesium carbonate, sodium citrate, and tribasic calcium phosphate can be used.

As the antioxidant, dibutylhydroxytoluene, butylated hydroxyanisole, tocopheryl acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyroa sulfate and the like can be used. In the prior-release compartment of the present invention, the dissolution aid may be a polyoxyethylene sorbitan fatty acid ester such as sodium lauryl sulfate or polysorbate, docusate sodium, poloxamer, or the like.

In addition, an enteric polymer, a water-insoluble polymer, a hydrophobic compound, and a hydrophilic polymer may be included to form a delayed-release preparation.

The enteric polymer is a polymer that is insoluble or stable under acidic conditions of less than pH 5 and dissolves or degrades under specific pH conditions of pH 5 or higher. Examples of the enteric polymer include hydroperoxides such as hypromellose acetate succinate, Hydroxyethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose and ethylhydroxyethylcellulose phthalate), hydroxypropylmethylcellulose phthalate An enteric cellulose derivative such as hydroxyethylcellulose phthalate, methylhydroxyethylcellulose; Styrene-acrylic acid copolymers such as styrene-acrylic acid copolymers, acrylic acid methyl-acrylic acid copolymers, acrylic acid methyl methacrylic acid copolymers (e.g., acrylic acid), butyl acrylate-styrene-acrylic acid copolymers, and methyl methacrylate- Said enteric acrylic acid-based copolymer; Poly (methacrylic acid methyl acrylate) copolymers (e.g., Eudragit L100-E), poly (methacrylic acid methyl methacrylate) copolymers such as Eudragit L, Eudragit S, An enteric polymethacrylate copolymer such as < RTI ID = 0.0 > Maleic anhydride copolymers, styrene-maleic anhydride copolymers, styrene-maleic anhydride copolymers, styrene-maleic anhydride copolymers, vinyl styrene-maleic anhydride copolymers, styrene-maleic anhydride copolymers, styrene-maleic anhydride copolymers, Maleic anhydride copolymers such as styrene-maleic anhydride copolymer, maleic anhydride copolymer, maleic anhydride copolymer, maleic anhydride copolymer, maleic anhydride copolymer, maleic anhydride copolymer, 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 does not dissolve in a pharmaceutically acceptable water to control the release of the drug. For example, the water-insoluble polymer can be selected from the group consisting of polyvinyl acetate (e.g., Colicot SR30D), water insoluble polymethacrylate copolymer (e.g., poly (ethyl acrylate-methyl methacrylate) , Poly (ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate) copolymer (such as Eudragit RSPO), ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose diacylate, Cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate.

The hydrophobic compound refers to a pharmaceutically acceptable water-insoluble substance that controls the release of the drug. For example, fatty acid and fatty acid esters such as glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate, and stearic acid; Fatty acid alcohols such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; Waxes such as carnauba wax, beeswax, and microcrystalline wax; Talc, precipitated calcium carbonate, calcium monohydrogenphosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and insoluble materials.

The hydrophilic polymer refers to a polymeric substance that dissolves in a pharmaceutically acceptable water to control the release of a drug. For example, there may be mentioned sugars such as dextrin, polydextrin, dextran, pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinozaylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin ; Cellulose derivatives such as hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose and carboxymethylcellulose sodium; Gums such as guar gum, locust bean gum, tragacanth, 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 diethylaminoacetate; Poly (ethyl acrylate-methyl methacrylate-methyl methacrylate) copolymer (e.g., Eudragit E100, Ebonic, Germany), poly (butyl methacrylate- (2-dimethylaminoethyl) Hydrophilic polymethacrylate copolymers such as triethylaminoethyl-methacrylate chloride) copolymer (e.g., Eudragit RL, RS, Evonik, Germany); Polyethylene derivatives such as polyethylene glycol, and polyethylene oxide; And carbomers.

In addition, a pharmaceutical composition of the present invention can be formulated by selectively using pharmaceutically acceptable additives as various additives selected from coloring agents and perfumes. For example, Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA) can be used for such a formulation.

The range of the additive in the present invention is not limited to the use of the additive, and the additive may be formulated to contain the usual range of capacity by selection.

The pharmaceutical composition according to the present invention may be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup and aerosol, oral formulation, external preparation, suppository or sterilized injection solution according to a conventional method 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 one or more of the compounds of Formulas 1 to 9 of the present invention.

The above-mentioned "subject requiring treatment" means an animal including a human being.

The "administration" means introducing the pharmaceutical composition of the present invention to a subject in need of treatment by any appropriate method, and the administration route of the pharmaceutical composition of the present invention is administered through any general route as long as it can reach the target tissue . Intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intraperitoneal, intrathecal, rectal, , Intravenously, or subcutaneously.

Said "therapeutically effective amount" refers to the amount of active ingredient or pharmaceutical composition that elicits a biological or medical response in an animal or human considered by a researcher, veterinarian, physician or other clinician, Or an amount that induces symptomatic relief of the disorder. It will be apparent to those skilled in the art that the therapeutically effective dose and the number of administrations of the active ingredient of the present invention will vary depending on the desired effect.

The present invention provides a use of at least one compound of the formulas (1) to (9) of the present invention for the preparation of a pharmaceutical preparation for preventing or treating pruritus. The use of the present invention can be used to prepare pharmaceutical preparations for the prevention, amelioration, or treatment of pruritus.

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

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

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

The compounds of the present invention are excellent in the activity of improving pruritus. Therefore, it can be effectively used as a prophylactic, therapeutic, and therapeutic adjuvant for pruritus of various skin diseases including atopic dermatitis. Pruritus to which the present invention may be applied may be chronic pruritus associated with atopic dermatitis or acute pruritus. The pruritus may be histamine-dependent or histamine-independent pruritus.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a photograph showing comparison of rat models (c and d) and control rats (a and b) induced with chronic pruritus or atopic dermatitis used in the evaluation of the compounds of the present invention.
FIG. 2 is a graph showing the number of scratches per hour (top) and dermatitis index (bottom) in the animal model rats and the control rats of FIG. 1, respectively.
FIG. 3 is a photograph showing the histopathological findings of the skin of the animal model rats and the control rats of FIG. 1. FIG.
FIG. 4 is a graph showing the findings of the epidermis and mast cells in FIG. 3. FIG.
FIG. 5 is a graph showing the results of observing the number of scratches at 5 minute intervals for 1 hour in an animal model rat when the compounds of formulas (3) to (5) of the present invention were administered. Vehicle refers to the control group to which the solvent is administered.
6 is a graph showing cumulative 1-hour accumulation of the result of FIG.
7 is a graph showing the number of scratches accumulated in an animal model rat for 1 hour and the number of scratches cumulatively accumulated in the first 30 minutes and the second 30 minutes in the case of administration of the compounds of Formulas 6 and 7 of the present invention .
8 is a graph showing the number of scratches accumulated for 30 minutes when acute pruritus was induced by administration of histamine (left figure) or chloroquine (right figure) after intraperitoneal administration of the compound of formula 3 of the present invention to a normal mouse .

Embodiments are provided to facilitate understanding of the present invention. The following examples are provided to further understand the present invention, but the present invention is not limited by the examples.

[Example]

Example 1. Synthesis of Compound (3)

(3)

[Reaction Scheme 1]

The compound of Chemical Formula 3 was synthesized according to Reaction Scheme 1 above. The concrete procedure is as follows.

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

In an ice bath under nitrogen gas substitution, 10 ml of acetonitrile was slowly added to 1.5 mmol (5 eq.) Of KO _{2 with} stirring. The above 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea was dissolved in 10 ml of acetonitrile and the mixture was treated with a mixture of KO ₂ and acetonitrile Lt; / RTI > After reacting at room temperature for 16 hours, it was poured into ice water and diluted. It was then extracted with dichloromethane and washed twice with saturated aqueous NaCl solution. After drying with MgSO ₄ , the solvent was removed under reduced pressure to obtain a precipitate. The precipitates ethanol as a solvent a mixture of hexane and vacuum filtered to 1:10 N - (2- methoxy-4-nitro-phenyl) -5-methyl-benzo [d] oxazol-2-amine (N - (2 -methoxy-4-nitrophenyl) -5-methylbenzo [ d ] oxazol-2-amine.

Yellow powder (78%),

^{1 H NMR (Acetone-D6,} 400MHz), δ 9.306 (s, 1H), 8.816 (d, J = 9.2Hz, 1H), 8.043 (d, J = 6.4Hz, 1H) 7.874 (d, J = 2.4Hz , 1H), 7.342 (t, J = 9.0Hz, 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 (4)

[Chemical Formula 4]

According to the method described in Korean Patent Laid-Open Publication No. 10-2011-0137868, the N ^2- (4-ethylphenyl) benzo [ d ] oxazole-2,5-diamine [ N ² - (4-ethylphenyl) benzo [ d ] oxazole-2,5-diamine].

Example 3. Synthesis of Compound (5)

[Chemical Formula 5]

According to the production process described in Korean Patent Laid-Open No. 10-2008-0027191, the 8-methyl-2- [ N - (4-ethylphenyl)] aminobenzoxazole [ 8-methyl-2- [ N - (4-ethylphenyl)] aminobenzoxazole].

Example 4. Confirmatory effect of compounds of formulas 3 to 5 on pruritus improvement

4-1. Statistical analysis

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

4-2. Animal model preparation

(1) Production of animal models

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

Capsaicin (50 mg / kg) was dissolved in physiological saline (0.9% saline) containing 10% Tween 80 and 10% ethanol in the dorsal side of white rat pups within 48 hours after birth. 10 < / RTI > Capsaicin can cause apnea, which is overcome by pushing the chest several times until spontaneous respiration resumes. After that, the offspring were returned to the mother rats and kept in the same weed until they were able to distinguish between male and female at 3 weeks of age.

(2) Evaluation of pruritus in animal models

The pruritus was evaluated weekly in the animal model rats prepared in the above (1) by the following method.

Control and animal models Rats were placed in a transparent plastic container with a mirror and allowed to adapt to the environment for about 30 minutes and then recorded for 1 hour each week with a digital video camera (DCR-SR300, Sony, Japan). We recorded the number of scratches while playing the recorded video file at double speed on the computer. We observed that the rats were scratching the continuous action of scratching the skin until it was removed from the floor and put down on the floor again. The number of scratches observed for 1 hour was used as a measure of the degree of pruritus.

The behavior of the rats was photographed in a space free of human interference, and the analysis was carried out by a blind test by an experimenter who did not know the animal information.

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

As a result, sporadic scratching was observed in the control group, but the number of scraping was less than 10 times per hour. On the other hand, the animal model to which capsaicin was administered started to scratch the face, ear and back skin very seriously from the third week after birth, and this phenomenon lasted for up to 10 weeks.

From the above results, it can be seen that the animal model which is administered subcutaneously with a large amount of capsaicin immediately after birth in rats causes serious chronic pruritus with early latency period.

(3) Evaluation of dermatitis in animal models

Each week, the skin condition of the animal was examined just before the photograph for the evaluation of pruritus, and the degree of the dermatitis was quantified and analyzed. Scores were assigned to all wound areas according to the skin condition on the face, ears and back as described 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). That is, the higher the score, the greater the severity of dermatitis.

[Table 1]

The results of the dermatitis index evaluation are shown in the lower graph of FIG. As a result of the experiment, it was found that the dermatitis index rapidly increased from the third week in the animal model rats.

At 3 weeks and 6 weeks after birth, biopsy was performed to obtain skin tissue and hematoxylin and eosin (H & E) or toluidine blue (TB) staining was performed for histological examination. Respectively. Lesional tissue was selected at 6 weeks while non-lesional tissue was taken at 3 weeks after capsaicin administration because no gross skin lesions were observed. After the toluidine blue staining, the number of mast cells observed in a 400-fold microscope (BX51, Olympus, Japan) field of view was measured.

The experimental results are shown in FIG. 3 and FIG. In rats with anemia, hyperkeratosis and hyperplasia (epidermal hypertrophy) were observed, and the thickness of the epidermis increased and the number of mast cells increased. The mean diameter of mast cells and the number of degranulated mast cells increased, indicating that mast cells were activated. These histopathological findings are very similar to those observed in patients with atopic dermatitis.

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

4-3. Administration of compound

The compounds of formulas (3) to (5) were prepared by dissolving 30 mg each of 2 ml of methyl pyrrolidone: Tween 80: saline in a volume ratio of 1: 1: 8 by volume. When rats were induced to develop chronic pruritus and atopic dermatitis as prepared in 4-2, the mice were divided into 4 groups and injected with 2 ml / kg of each of the solvents dissolved in each of the 3 groups. One group was used as a control group and the solvent was injected into the abdominal cavity at 2 ml / kg.

4-4. Assessment of pruritus

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

The rats in each group were placed in a transparent plastic container with a mirror and placed in a plastic bottle for 30 minutes. After being injected into the environment for 30 minutes, a digital video camera (DCR-SR300, Sony, Japan) was used from 30 minutes to 1 hour 30 minutes after injection The activity was recorded one hour per week. We recorded the number of scratches while playing the recorded video file at double speed on the computer. We observed that the rats were scratching the continuous action of scratching the skin until it was removed from the floor and put down on the floor again. The number of scratches observed for 1 hour was used as a measure of the degree of pruritus. In the case of a statistically significant decrease in scratching behavior compared to the control group, it was judged to be effective in improving pruritus.

The behavior of the rats was photographed in a space free of human interference, and the analysis was carried out by a blind test by an experimenter who did not know the animal information.

The results are shown in Fig. 5 and Fig. FIG. 5 is a graph showing the number of scratches at intervals of 5 minutes (the number on the horizontal axis indicates elapsed time from the start of shooting), and FIG. 6 shows the result of FIG.

The number of scratches in the control group was 123.67 ± 38.50 cycles. On the other hand, the scratching frequency of the compound (3) was 25.43 ± 6.80 times, the compound (4) was 77.83 ± 25.40 times, and the compound (5) was 19.67 ± 8.00 times. From these, it can be seen that the compounds of the formulas (3) to (5) have an excellent pruritus improvement effect.

Example 5. Synthesis of Compound of Chemical Formula 6

[Chemical Formula 6]

Bioorg. Med. Chem. 16 (2008) 5405 -5412 (p. 5407, see Formula 3a).

Example 6. Synthesis of Compound (7)

(7)

[Reaction Scheme 2]

The compound of formula (7) was synthesized according to Reaction Scheme 2 above. The concrete procedure is as follows.

0.812 mmol (1 equivalent) of 2-amino-4-methylphenol was dissolved in 10 ml of methanol. 0.812 mmol (1 eq.) Of 4-nitrophenol-thiocyanate was added thereto, and the mixture was stirred at room temperature for 24 hours. Methanol was evaporated under reduced pressure and the remaining precipitate was filtered under reduced pressure with hexane to obtain 1- (2-hydroxy-5-methylphenyl) -3- (4-nitrophenyl) thiourea 3- (4-nitrophenyl) thiourea.

In an ice bath under nitrogen gas substitution, 10 ml of acetonitrile was slowly added to 1.5 mmol (5 eq.) Of KO _{2 with} stirring. The 1- (2-hydroxy-5-methylphenyl) -3- (4-nitrophenyl) thiourea was dissolved in 10 ml of acetonitrile and slowly added to the mixture of KO ₂ and acetonitrile. The mixture was allowed to react at room temperature for 16 hours and then poured into ice water to dilute it to obtain N - (4-nitrophenyl) -5-methylbenzo [ d ] oxazole-2-amine. Which was then reacted for 5 hours at room temperature under H ₂ and Pd / c catalyst N - (5- methyl-benzo [d] oxazol-2-yl) benzene-1,4-diamine (N - (5-methylbenzo [ d] oxazol-2-yl) benzene-1,4-diamine. 1.045 mmol (equivalent) of the above N- (5-methylbenzo [d] oxazol-2-yl) benzene-1,4-diamine was dissolved in 5 ml of a dimethylformamide solution, to which dimethyl carbamyl chloride ) 0.418 mmol (1 eq.) Was added and stirred at 100 < 0 > C for 24 hours. After cooling to room temperature, the mixture was extracted three times with 20 ml of ethanol. 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 Dried, filtered, concentrated under reduced pressure, and then purified by column chromatography using a 1: 3 mixture of ethanol and hexane to obtain 1,1-dimethyl-3- (4 - ((5-methylbenzo [ 2-yl) amino) phenyl) urea (formula (7)) was obtained.

Ivory solid (19.4%),

^{mp 228-230 ℃, 1 H NMR (} DMSO-D 6, 400MHz) δ 10.342 (s, 1H), 8.210 (s, 1H), 7.572 (dd, J = 2.4Hz, J = 6.8Hz, 2H), 7.421 (dd, J = 2.0Hz, J = 6.8Hz, 2H), 7.313 (d, J = 8.4Hz, 1H), 7.219 (s, 1H), 6.897 (dd, J = 1.2Hz, J = 8.4Hz, 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 (8)

[Chemical Formula 8]

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

Ivory solid (14.9%),

^{mp 219-220 ℃, 1 H NMR (} DMSO-D6, 400MHz), δ 10.337 (s, 1H), 8.211 (s, 1H), 7.598 (dd, J = 2.4Hz, J = 6.8Hz, 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), < RTI ID =

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

Example 7. Synthesis of Compound (9)

[Chemical Formula 9]

According to Reaction Scheme 2, 3- (4 - ((5-chlorobenzo [d] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea ] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea (Formula 9). The compound of Formula 9 was prepared in the same manner as in Example 5 except that the same amount of 2-amino-4-chlorophenol was used instead of 2-amino-4-methylphenol in Formula 7.

Ivory solid (20.2%),

^{mp 214-216 ℃, 1 H NMR (} DMSO-D 6, 400MHz) 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. Confirmatory effect of compounds of formulas 6 and 7 on pruritus improvement

8-1. Administration of compounds of formulas 6 and 7

The compound of Formula 6 and the compound of Formula 7 were prepared by dissolving 30 mg each in 2 ml of a mixed solvent of methylpyrrolidone: Tween 80: saline in a volume ratio of 1: 1: 8. When rats with chronic pruritus and atopic dermatitis prepared at 4-2 were in the 4th week, the mice were divided into 3 groups and each group was injected with 2 ml / kg of each solvent dissolved in the peritoneal cavity. One group was used as a control group and the solvent was injected into the abdominal cavity at 2 ml / kg.

8-2. Assessment of pruritus

Pruritus was evaluated in the same manner as in Example 4-4. The number of scratches observed for 1 hour was used as a measure of the degree of pruritus. In the case of a statistically significant decrease in scratching behavior compared to the control group, it was judged to be effective in improving pruritus.

The results are shown graphically in FIG. ** P < 0.01, * P < ( T- test) in which the vehicle (methyl pyrrolidone: Tween 80: a solvent in which a saline solution is mixed at a volume ratio of 1: 1: 8).

The leftmost bars in Fig. 7 show the number of scratches accumulated in each group for 1 hour between 30 minutes and 1 hour 30 minutes after injection. The total number of scratches in the control group was 132.80 ± 8.79. On the other hand, the scratching frequency of the compound of the formula (6) was 87.00 ± 8.30 (P = 0.005), and the scratching frequency of the compound of the formula (7) was 66.80 ± 12.22 (P = 0.002) . This means that the compound of Formula 6 and the compound of Formula 7 have an improving effect on chronic pruritus associated with atopic dermatitis and the like.

7 shows the number of scratches accumulated between 30 minutes and 1 hour after injection in each group and the number of scratches accumulated in each group from 1 hour to 1 hour 30 minutes after injection in the right side bars will be. In FIG. 7, '~ 30 minutes' and '30 minutes ~ 1 hour' on the horizontal axis represent elapsed time after the start of shooting, respectively.

The number of scratching times was 61.20 ± 10.71 times, 75.60 ± 8.33 times, and 42.40 ± 7.93 times, respectively, in the control group, the treatment group of the compound of formula 6, and the treatment group of the compound of the formula 7 for 30 minutes from 30 minutes to 1 hour after each injection, . However, the number of scratches was 71.60 ± 13.97 times in the control group, 11.40 ± 6.38 times (P = 0.004) in the compound of the formula 6, 24.40 ± 6.27 times in the compound of the formula 7 (30 minutes) P = 0.015), indicating that the number of scratches was significantly reduced in both the treatment group of the formula (6) and the treatment group of the formula (7). The above results indicate that the compound of formula (VI) and the compound of formula (VII) show full improvement after 1 hour of administration.

Example 9. Identification of improving effect of the compound of formula 3 on acute pruritus

9-1. Induction of acute pruritus in normal mice and administration of the compound of formula (III)

Normal mice (non-pruritic mice) were prepared.

Histamine, a kind of endogenous amine, is a pruritogen. In addition, chloroquine, a malaria treatment, is known to cause histamine-non-histaminergic pruritus as a side effect. Therefore, the following experiment was conducted to confirm the effect of administration of the compound of formula (3) on acute-induced histamine-dependent and histamine-independent pruritus.

The above normal mice were divided into two groups and the compound of formula (3) was dissolved in a solvent mixture of methylpyrrolidone: Tween 80: saline at a ratio of 1: 1: 8 by volume, and the mixture was intraperitoneally administered at 30 mg / kg . One other group was used as a control group and 10 μl / g of the solvent was administered.

After the injection, the mice were placed in a transparent plastic bottle with a mirror and the mice were placed in a laboratory environment for 30 minutes. Histamine 27 mM or chloroquine 27 mM was dissolved in 25 μl of physiological saline (0.9% NaCl solution) back skin) using an insulin syringe (31G) to induce acute pruritus.

9-2. Assessment of acute pruritus

The effect of the compound of formula (3) on acute pruritus was evaluated. The behavior of the mice was recorded using a digital video camera and the number of scratched areas immediately after the administration of histamine or chloroquine for 30 minutes or 30 minutes for histamine or chloroquine injection was recorded. As in Examples 4-4, the continuous action of scratching the skin until it was removed from the floor and put down on the floor was considered a scratch bout.

The results are shown in Fig. ** P < 0.001, ** P = 0.002 vs. &lt; ( T- test) in which the vehicle (methyl pyrrolidone: Tween 80: a solvent in which a saline solution is mixed at a volume ratio of 1: 1: 8).

(1) The effect of histamine-induced pruritus 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 scratching was 44.00 ± 12.87 in the compound 3 group. From the above results, it can be seen that the compound of Chemical Formula 3 has an effect of reducing histaminergic 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 group of the compound of Formula 3 was 128.86 ± 23.23 times. From the above results, it can be seen that the compound of Chemical Formula 3 also has a significant improvement effect on histamine-non-dependent pruritus.

Claims (7)

Claims 1. A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:
[Chemical Formula 1]

In Formula 1,
R ₁ is H, OH, a linear or branched alkyl group having ₁ to 3 carbon atoms, NO ₂ , NH ₂ , an alkoxy group having 1 to 3 carbon atoms, or a halogen atom,
When R ₁ is H, R ₂ and R ₃ are different from each other and are selected from the group consisting of H, OH, NH ₂ , an alkoxy group of C 1 to C 3, a halogenated alkyl group of C 1 to C 3, a halogen atom, CN, An amino group, SH, an alkyl mercapto group of C1 to C3, a halogenated alkyl mercapto group of C1 to C3, an alkanoyl group of C1 to C3, a hydroxyalkyl group of C1 to C3, a linear or branched C1 to C3 alkylureido, Or branched C1 to C3 dialkyl ureido;
When R ₁ is OH, R ₂ and R ₃ are different and are H, OH, a linear or branched alkyl group having 1 to 3 carbon atoms, NO ₂ , NH ₂ , CN, an amino group, , A C1 to C3 alkylmercapto group, a C1 to C3 halogenated alkylmercapto group, a C1 to C3 alkanoyl group, a C1 to C3 hydroxyalkyl group, a straight-chain or branched C1 to C3 alkylureido group or a linear or branched C1-C3 dialkyl ureido;
When R ₁ is an alkyl group of C1 ~ C3 straight or branched chain, R ₂ and R ₃ are different from each other, H, OH, NH _2, a C1 ~ C3 halogenated alkyl group, a halogen atom, CN, amino, C1 ~ C3 of A halogenated alkyl mercapto group of C1 to C3, an alkanoyl group of C1 to C3, a hydroxyalkyl group of C1 to C3, a C1 to C3 alkylureido of straight or branched chain, or a C1 to C3 straight- C3 dialkyl ureido;
When R ₁ is NO ₂ , R ₂ and R ₃ are different from each other and are selected from the group consisting of H, OH, NO ₂ , NH ₂ , a halogenated alkyl group of C 1 to C 3, a halogen atom, CN, an amino group, , A C1 to C3 alkylmercapto group, a C1 to C3 halogenated alkylmercapto group, a C1 to C3 alkanoyl group, a C1 to C3 hydroxyalkyl group, a straight-chain or branched C1 to C3 alkylureido group or a linear or branched C1-C3 dialkyl ureido;
When R ₁ is NH ₂ , R ₂ and R ₃ are different and are H, OH, a linear or branched alkyl group having ₁ to 3 carbon atoms, NO ₂ , NH ₂ , a halogenated alkyl group having 1 to 3 carbon atoms, An amino group, a dialkylamino group of C1 to C3, an alkyl mercapto group of C1 to C3, a halogenated alkyl mercapto group of C1 to C3, an alkanoyl group of C1 to C3, a hydroxyalkyl group of C1 to C3, a linear or branched A C1 to C3 alkylureido or a straight or branched C1 to C3 dialkylureido;
When R ₁ is an alkoxy group having ₁ to 3 carbon atoms, R ₂ and R ₃ are different from each other and are selected from the group consisting of H, OH, NO ₂ , NH ₂ , an alkoxy group of C 1 to C 3, a halogenated alkyl group of C 1 to C 3, A halogenated alkyl mercapto group of C1 to C3, an alkanoyl group of C1 to C3, a hydroxyalkyl group of C1 to C3, a C1 to C3 alkyl ureido group of straight or branched chain or a linear or branched C1-C3 dialkyl ureido; or
When R ₁ is a halogen atom, R ₂ and R ₃ are different from each other and are selected from the group consisting of H, OH, NH ₂ , an alkoxy group of C 1 to C 3, a halogenated alkyl group of C 1 to C 3, a halogen atom, CN, An alkylamino group, SH, an alkyl mercapto group of C1-C3, a halogenated alkyl mercapto group of C1-C3, an alkanoyl group of C1-C3, a hydroxyalkyl group of C1-C3, a linear or branched C1- Linear or branched C1 to C3 dialkyl ureido.
However, N ^2- (4- ethyl-phenyl) benzo [d] oxazole-2,5-diamine ^{[N 2 - (4-ethylphenyl} ) benzo [d] oxazole- 2,5-diamine], and 8-methyl - 2- [N - (4- ethylphenyl) amino-benzoxazole [8-methyl-2- [N - (4-ethylphenyl)] aminobenzoxazole] are excluded. 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.
(3)

The compound of claim 1, wherein the compound of formula (1)
(4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea (1,1-dimethyl- ((5-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea;
(4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea (1,1-dimethyl- (4-methylbenzo [d] oxazol-2-yl) amino) phenyl) urea; or
(3- (4 - ((5-chlorobenzo [d] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea d] oxazol-2-yl) amino) phenyl) -1,1-dimethylurea) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
(7)

[Chemical Formula 8]

[Chemical Formula 9]

1) Reaction of 2-amino-4-methylphenol with 2-methoxy-4-nitrophenyl isothiocyanate in an organic solvent 2- (2-methoxy-4-nitrophenyl) thiourea (1- (2-hydroxy-5-methylphenyl) -3- nitrophenyl) thiourea; And
2) reacting the 1- (2-hydroxy-5-methylphenyl) -3- (2-methoxy-4-nitrophenyl) thiourea with potassium peroxide (KO ₂ ) Lt; / RTI &gt;
(3)

A pharmaceutical composition for preventing or treating pruritus comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]

In Formula 1,
R ₁ is H, OH, a linear or branched alkyl group having ₁ to 3 carbon atoms, NO ₂ , NH ₂ , an alkoxy group having 1 to 3 carbon atoms, or a halogen atom,
R ₂ and R ₃ are the same or different from each other and each represents H, OH, a linear or branched alkyl group having ₁ to 3 carbon atoms, NO ₂ , NH ₂ , a C 1 to C 3 alkoxy group, a C 1 to C 3 halogenated alkyl group, CN, an amino group, a dialkylamino group of C1 to C3, SH, an alkyl mercapto group of C1 to C3, a halogenated alkylmercapto group of C1 to C3, an alkanoyl group of C1 to C3, a hydroxyalkyl group of C1 to C3, Chain C1-C3 alkylureido or a straight or branched C1-C3 dialkylureido. A pharmaceutical composition for preventing or treating pruritus comprising at least one compound selected from the compounds represented by the following formulas (3) to (7), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.
(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

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

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