Heterocyclic derivative for use in treating atopic dermatitis

Abstract

The present invention relates to heterocyclic derivatives for use in treating atopic dermatitis and, more specifically, to a pharmaceutical composition for preventing or treating atopic dermatitis or pruritus, comprising, as an active ingredient, a compound having a heterocyclic derivative structure, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

Description

[0001]

Description of the invention

Title of the invention

Technical field

Background art

Contents of the invention

Technical problem

Technical Solution

Best Mode for Carrying Out the Invention

[0002] In the above chemical formula I, R1 is -S(=O)(=R a )R b and R a is =O or =NH, and R b is H, C1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylcarbonyl-C 1-6 Alkyl, C 2-7 Alkenyl, amino, or aminoC 1-6 Alkyl, R b At least one H of may be independently substituted with F, Br, Cl or I; R2 and R3 are each independently F, Br, Cl or I. (2) In the above (1), R a is =O, and R b is an unsubstituted C 1-3 It is alkyl. In the present invention, "C m-n " (where m and n are each independently an integer greater than or equal to 1) means the number of carbons, for example, 'C 1-6 'Alkyl' means alkyl having 1 to 6 carbon atoms. In the present invention, unless otherwise stated, "alkyl" means C n H 2n+1 It means a straight-chain or branched saturated hydrocarbon group represented by . Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, neo-pentyl, n-hexyl, etc. In the present invention, unless otherwise stated, "alkenyl" means an unsaturated hydrocarbon group including at least one carbon-carbon double bond in the alkyl. In the present invention, unless otherwise stated, "alkoxy" means, OC n H 2n+1It refers to a monovalent group derived from a straight-chain or branched-chain saturated hydrocarbon moiety represented by. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. (3) In the above (1) or (2), the compound represented by the above chemical formula I may be a compound represented by the following chemical formula II. [Chemical Formula II]

[0003] The compound represented by chemical formula II corresponds to compound 1 of the present invention, and is also named N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-4-(methylsulfonyl)-3,4-dihydro-2H-thieno[3,2-g]chromene-7-carboxamide. The term "pharmaceutically acceptable" as used herein means a compound that is suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic reaction or other problems or complications and has a reasonable benefit / risk ratio, and is within the scope of sound medical judgment. The pharmaceutically acceptable salt of the present invention can be prepared by conventional methods known to those skilled in the art. In the present invention, the compound according to any one of (1) to (3) above may have one or more asymmetric carbon centers, and thus may exist as an enantiomer mixture including a racemic mixture, a single enantiomer (optical isomer), a diastereomeric mixture, and a single diastereoisomer. Such isomers can be separated by resolution using conventional techniques, for example, column chromatography or HPLC. Alternatively, they can be stereospecifically synthesized using optically pure starting materials and / or reagents of known arrangements. In the present invention, a "hydrate" is a compound according to any one of (1) to (3) above, or a pharmaceutically acceptable salt thereof, and water are non-covalently bound by intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of water. In the present invention, a “solvate” is a compound according to any one of (1) to (3) above or a pharmaceutically acceptable salt thereof, and a solvent other than water are bound by non-covalent intermolecular forces, and may contain the solvent in a stoichiometric or non-stoichiometric amount.The compound according to any one of (1) to (3) of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof reduces the expression of inflammation-related cytokine genes, thereby reducing the epidermal thickness in inflamed tissues and having excellent anti-pruritic efficacy, and therefore can be usefully used as a composition for preventing and treating atopic dermatitis and pruritus. Composition comprising heterocyclic derivative compound, treatment method using same and use thereof The present invention provides a pharmaceutical composition comprising a compound according to any one of (1) to (3) above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof as an active ingredient. The present invention provides a pharmaceutical composition for preventing or treating atopic dermatitis or pruritus, comprising a compound according to any one of (1) to (3) above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof as an active ingredient. In the present invention, "prevention" means any act of inhibiting or delaying the onset of a disease by administering a compound according to any one of (1) to (3) of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; or a pharmaceutical composition comprising the same. In the present invention, "treatment" means any act of improving or beneficially changing the symptoms of a subject suspected of having or developing a disease by administering a compound according to any one of (1) to (3) of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; or a pharmaceutical composition comprising the same. In the present invention, "atopic dermatitis" is one of the allergic diseases that is worse in dry climates due to an abnormality in the stratum corneum, which acts as a protective barrier on the outermost part of the skin.The main symptoms are severe itching, dry skin, rash, oozing, crusting, and scales, and are mainly accompanied by chronic skin inflammation. The cause of atopic dermatitis is mainly genetic and has been found to be related to the immune response. In addition, it is thought to be caused by a complex interaction of dry skin, a tendency to itch more easily than normal people, infection by bacteria, viruses, and fungi, emotional factors, and environmental factors. In the present invention, "pruritus (itching)" is the most major symptom in skin diseases, and it is a symptom that appears to protect the skin from harmful or irritating external substances as a physiological self-protection function. Itching is caused by various causes, and it causes secondary skin lesions such as wounds and rashes. Scratching due to itching causes the release of inflammatory factors along with the itching-inducing substances, creating a vicious cycle in which the itching becomes more painful and worsens. In a specific embodiment of the present invention, the antipruritic activity and the preventive and therapeutic activity for atopic dermatitis of a compound according to any one of (1) to (3) of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof were confirmed. The pharmaceutical composition of the present invention is characterized by reducing the expression of one or more cytokines selected from the group consisting of IL-4, IL-5, IFN-γ, H4R, IL-17, and IL-31. Thus, the pharmaceutical composition of the present invention suppresses the expression of inflammatory cytokines, reduces the thickness of the skin epidermis induced by atopic dermatitis, and reduces itching, and thus can be usefully used for the prevention or treatment of atopic dermatitis and itching. The pharmaceutical composition of the present invention can be manufactured in the form of a unit dose by formulating it using a pharmaceutically acceptable carrier and excipient, or can be manufactured by inserting it into a multi-dose container.The formulations are prepared by conventional methods used in the art or by methods described in Remington's Pharmaceutical Science (19. thed., 1995) and can be formulated into various formulations depending on each disease or component. The pharmaceutical composition of the present invention can be administered orally or parenterally depending on the intended method. The pharmaceutically effective amount and effective dosage of the pharmaceutical composition of the present invention can vary depending on the method of formulating the pharmaceutical composition, the method of administration, the time of administration, and / or the route of administration, and also can vary depending on various factors including the type and degree of the response to be achieved by administration of the pharmaceutical composition, the type, age, weight, general health condition, symptoms or degree of the disease, sex, diet, excretion, drugs used simultaneously or simultaneously in the subject, other components of the composition, and similar factors well known in the medical field. A person having ordinary skill in the art can easily determine and prescribe an effective dosage for the desired treatment. That is, a person skilled in the art can take all of the above factors into consideration and administer the pharmaceutical composition of the present invention in an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art to which the present invention pertains. The pharmaceutical composition of the present invention can exhibit excellent effects even when used alone, but can be additionally used in combination with various methods such as hormone therapy and drug therapy to increase therapeutic efficiency. The present invention provides a method for preventing or treating atopic dermatitis or pruritus, comprising a step of administering to a subject in need thereof a compound according to any one of (1) to (3), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition comprising the same. In the present invention, "administration" means introducing a predetermined substance into a subject by an appropriate method.In the present invention, "subject" means all animals, such as rats, mice, livestock, etc., including humans, that have developed or may develop atopic dermatitis or pruritus, and may specifically be mammals including humans, but is not limited thereto. The method for preventing or treating atopic dermatitis or pruritus of the present invention may be a method for administering a therapeutically effective amount of a compound according to any one of (1) to (3), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. The "therapeutically effective amount" in the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects, and this can be determined by those skilled in the art based on factors including the patient's sex, age, weight, health condition, type of disease, severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route, excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field. It is preferable that the specific therapeutically effective amount for a specific patient be applied differently depending on various factors including the type and degree of response to be achieved, the specific composition including whether other agents are used in some cases, the patient's age, body weight, general health, sex and diet, the time of administration, the route of administration and the secretion rate of the composition, the treatment period, drugs used together or simultaneously with the specific composition, and similar factors well known in the medical field. The method for preventing or treating atopic dermatitis or pruritus of the present invention includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms thereof by administering a compound according to any one of the above (1) to (3), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or a pharmaceutical composition comprising the same.In the management of a disease, the prophylactic or therapeutic dosage of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. The dosage and frequency of administration will vary depending on the age, weight, and response of the individual patient. Appropriate dosage regimens can be readily selected by those skilled in the art, taking these factors into account. In addition, the method for preventing or treating atopic dermatitis or pruritus of the present invention may further comprise administering a therapeutically effective amount of an additional active agent helpful in the prevention or treatment of the disease, together with the compound according to any one of (1) to (3), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. The additional active agent may exhibit a synergistic or additive effect with the compound according to any one of (1) to (3), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. The present invention provides a use of a compound according to any one of (1) to (3) above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition comprising the same, for the prevention or treatment of atopic dermatitis or pruritus. The present invention provides a use of a compound according to any one of (1) to (3) above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention or treatment of atopic dermatitis or pruritus. For the manufacture of a medicament, a compound according to any one of (1) to (3) above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof of the present invention may be mixed with a pharmaceutically acceptable adjuvant, diluent, carrier, etc., and may be manufactured into a composite formulation with other active agents to have a synergistic effect.

Form for carrying out the invention

Claims

【Scope of Claims】

1. A pharmaceutical composition for preventing or treating atopic dermatitis or itching, comprising a compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient: [Chemical formula I] In the above chemical formula I, R1 is -S(=O)(=R a )R b and R a is =O or =NH, and R b is H, C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylcarbonyl-C 1-6 Alkyl, C 2-7 Alkenyl, amino, or aminoC 1-6 It is alkyl, R b At least one H of may be independently substituted with F, Br, Cl or I; R2 and R3 are each independently F, Br, Cl or I.

2. In claim 1, R a is =O, and R b is an unsubstituted C 1-3 A pharmaceutical composition for the prevention or treatment of alkyl dermatitis, atopic dermatitis or pruritus.

3. In claim 1, the compound represented by the chemical formula I is represented by the following chemical formula II, a pharmaceutical composition for preventing or treating atopic dermatitis or itching: [Chemical formula II] . 【

4. A pharmaceutical composition for preventing or treating atopic dermatitis or pruritus, according to claim 1, wherein the pharmaceutical composition reduces the expression of one or more cytokines selected from the group consisting of IL-4, IL-5, IFN-γ, H4R, IL-17, and IL-31.

5. A pharmaceutical composition for preventing or treating atopic dermatitis or itching, according to claim 1, wherein the pharmaceutical composition is administered orally. Claim 6】 A compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, for use in a subject in need thereof. Method for preventing or treating atopic dermatitis or pruritus, comprising the step of administering: [Chemical Formula I] In the above chemical formula I, R1 is -S(=O)(=R a )R b and R a is =O or =NH, and R b is H, C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylcarbonyl-C 1-6 Alkyl, C 2-7 Alkenyl, amino, or aminoC 1-6 Alkyl, R b At least one H of may be independently substituted with F, Br, Cl or I; R2 and R3 are each independently F, Br, Cl or I.

7. Use of a compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof for the prevention or treatment of atopic dermatitis or pruritus: [Chemical formula I] In the above chemical formula I, R1 is -S(=O)(=R a )R b and R a is =O or =NH, and R b is H, C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylcarbonyl-C 1-6 Alkyl, C 2-7 Alkenyl, amino, or aminoC 1-6 Alkyl, R b At least one H of which may be independently substituted with F, Br, Cl or I; R2 and R3 are each independently F, Br, Cl or I.

8. Use of a compound represented by the following chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof for the manufacture of a drug for preventing or treating atopic dermatitis or pruritus: [Chemical formula I] In the above chemical formula I, R1 is -S(=O)(=R a )R b and R a is =O or =NH, and R b is H, C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 1-6 Alkylcarbonyl-C 1-6 Alkyl, C 2-7 alkenyl, Amino, or amino C 1-6 Alkyl, R b At least one H of may be independently substituted with F, Br, Cl or I; R2 and R3 are each independently F, Br, Cl or I.

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