A pharmaceutical composition for preventing or treating allergic disease

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of allergic diseases, and specifically to a pharmaceutical composition that exhibits excellent efficacy against allergic diseases by possessing inhibitory activity against MRGPRX2 (Mas-related G-protein coupled receptor member X2). Since the compound of the present invention effectively inhibits MRGPRX2, it can be very usefully employed for the prevention and treatment of allergic diseases such as atopic dermatitis and urticaria.

Description

Technology Field

[0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of allergic diseases, and specifically to a pharmaceutical composition that exhibits excellent efficacy against allergic diseases by having inhibitory activity against MRGPRX2 (Mas-related G-protein coupled receptor member X2). Background Technology

[0003] Most drugs developed to date for the treatment of allergic diseases are symptom-relieving agents that act on the final stage of the allergic mechanism. Due to persistent symptoms, frequent recurrence, and side effects of treatments, allergic diseases remain intractable diseases that have not yet been conquered, and the prevalence of chronic urticaria and atopy continues to increase.

[0004] Therefore, there is a need to develop and discover novel compounds capable of mediating allergic reaction disorders and allergic diseases, including anaphylaxis, chronic pruritus, inflammatory disorders, and pain disorders, as antagonists capable of blocking various pruritic mediators. Prior art literature

[0006] Allergy Asthma Immunol Res. 2021 May;13(3): 498-506Neuron. 2019 Feb 6;101(3):412-420 The problem to be solved

[0007] One object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of allergic diseases, comprising as an active ingredient a compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0008] Another object of the present invention is to provide a method for preventing or treating an allergic disease, comprising the step of administering a compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof to an individual in need thereof.

[0009] Another object of the present invention is to provide the use of the compound of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, or its solvate for the prevention or treatment of allergic diseases.

[0010] Another object of the present invention is to provide the use of the compound of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, or its solvate for the manufacture of a drug for the prevention or treatment of allergic diseases. means of solving the problem

[0012] This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions provided below.

[0014] Compounds of the present invention, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof

[0015] The present invention provides a compound according to any one of the following formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0016] [Chemical Formula 1]

[0017] ;

[0018] [Chemical Formula 2]

[0019] ;

[0020] [Chemical Formula 3]

[0021] ;

[0022] [Chemical Formula 4]

[0023] .

[0024] The compound of chemical formula 1 is named N-(5-(3-fluorobenzyl)thiazole-2-yl)-4,6,7,8-tetrahydro-5H-furo[3,2-c]azepine-5-carboxamide, the compound of chemical formula 2 is named (E)-N-(5-(3-chlorobenzyl)thiazole-2-yl)-3-(furan-2-yl)acrylamide, the compound of chemical formula 3 is named 4-((2-(trifluoromethyl)quinoline-4-yl)amino)cyclohexan-1-ol, and the compound of chemical formula 4 is named 1-isopropyl-6-(5-methylthiophene-2-yl)-N-(3-((2-oxopyrrolidine-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide.

[0025] In the present invention, the term "pharmaceuticalally acceptable" means a compound that is suitable for use in contact with tissues of a subject (e.g., human) and within the scope of sound medical judgment, such that the benefit-risk ratio is reasonable without excessive toxicity, irritation, allergic reaction, or other problems or complications. The pharmaceutically acceptable salts of the present invention may be prepared by conventional methods known to those skilled in the art.

[0026] In the present invention, the compound according to any one of Formulas 1 to 4 may have one or more asymmetric carbon centers, and accordingly may exist as an enantiomer mixture including a racemic mixture, a single enantiomer (optical isomer), a diastereomer mixture, and a single diastereomer. Such isomers can be separated by the prior art, for example, by column chromatography or HPLC. Alternatively, they may be synthesized stereospecifically using optically pure starting materials and / or reagents of a known arrangement.

[0027] In the present invention, "hydrate" is a compound according to any one of the formulas 1 to 4 or a pharmaceutically acceptable salt thereof and water are bonded by non-covalent intermolecular forces, and may contain stoichiometric or non-stoichiometric amounts of water.

[0028] In the present invention, "solvent" is a compound according to any one of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof, and a solvent other than water is bonded by non-covalent intermolecular forces, and may contain the solvent in stoichiometric or non-stoichiometric amounts.

[0029] The compound according to any one of Formulas 1 to 4 of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, or its solvate has MRGPRX2 inhibitory activity and has excellent effects in the prevention and treatment of allergic diseases.

[0031] Pharmaceutical composition comprising the compound of the present invention, a treatment method using the same, and uses thereof

[0032] The present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound according to any one of Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0033] The present invention provides a pharmaceutical composition for the prevention or treatment of allergic diseases comprising, as an active ingredient, a compound according to any one of Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0034] In the present invention, "prevention" means any act of suppressing or delaying the onset of a disease by administering a compound according to any one of Formulas 1 to 4 of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; or a pharmaceutical composition containing the same.

[0035] In the present invention, "treatment" means any act in which the symptoms of an individual suspected of having or suffering from a disease are improved or beneficially altered by the administration of a compound according to any one of Formulas 1 to 4 of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; or a pharmaceutical composition containing the same.

[0036] In the present invention, the term "allergic disease" refers to an allergic reaction, allergic symptoms, or a disease accompanied by any allergen. The expressions "allergic reaction" or "allergic symptoms" as used herein include one or more signs or symptoms among urticaria, angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinusitis, tearing, wheezing, bronchial retardation, reduced peak expiratory flow (PEF), gastrointestinal distress, flushing, swollen lips, swollen tongue, hypotension, anaphylaxis, and tracheal dysfunction / loss of function. Additionally, "allergic reaction" or "allergic symptoms" include, for example, increased IgE production and / or increased production of allergen-specific immunoglobulins. The term "allergen" as used herein includes any substance (compound, particle, protein, or composition, etc.) capable of stimulating an allergic reaction in a susceptible patient. Allergens may be contained in or derived from foods, such as, for example, dairy products (e.g., milk), eggs, celery, sesame seeds, wheat, soybeans, fish, shellfish, carbohydrates (e.g., sugars present in meat such as alpha-galactose), peanuts, other legumes (e.g., beans, peas, soybeans, etc.), and nuts. Additionally, allergens may be contained in or derived from non-foods, such as, for example, dust, pollen, insect venom (e.g., venom of bees, wasps, mosquitoes, fire ants, etc.), mold, animal hair, animal keratin, wool, latex, metals (e.g., nickel), household vacuum cleaners, detergents, drugs, cosmetics (e.g., perfumes, etc.), medicines (e.g., penicillin, sulfonamides, salicylates, etc.), therapeutic monoclonal antibodies (e.g., cetuximab), ragweed, grass, and birch trees.Exemplary pollen allergens include, for example, birch pollen, cedar pollen, oak pollen, alder pollen, hornbeam pollen, horse chestnut pollen, willow pollen, poplar pollen, plane tree pollen, linden pollen, olive pollen, juniper (Ashe juniper) pollen, and tropical Old World tree (Alstonia scholaris) pollen.

[0037] In the present invention, allergic diseases may be, for example, atopic dermatitis, urticaria, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, allergic keratitis, allergic conjunctivitis, hay fever, or anaphylaxis, but are not limited thereto, and all diseases accompanied by clinically manifested allergic symptoms fall within the scope of the present invention. In one embodiment, the allergic disease may be atopic dermatitis or urticaria.

[0038] In the present invention, "atopic dermatitis" refers to an allergic disease characterized by abnormalities in the stratum corneum, which acts as a protective barrier on the outermost layer of the skin, and which worsens in dry climates. The main symptoms include severe itching, dry skin, rashes, oozing, scabs, and scales, which are often accompanied by chronic skin inflammation. The causes of atopic dermatitis have been identified as primarily involving genetic factors and being related to immune responses. Additionally, it is believed to occur as a result of the complex interplay of factors such as dry skin, a tendency to feel skin itching more easily than normal individuals, infections caused by bacteria, viruses, and fungi, as well as emotional and environmental factors.

[0039] In the present invention, "urticaria" refers to a group of diseases characterized by itchy rashes and / or angioedema, and in particular, chronic urticaria defined as urticaria that is present continuously or intermittently may be at issue. In the present invention, urticaria may be, for example, chronic spontaneous urticaria, but is not limited thereto.

[0040] In relation to this, in a specific embodiment of the present invention, the preventive and therapeutic activities for allergic diseases of a compound according to any one of Formulas 1 to 4 of the present invention, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, or its solvate were confirmed.

[0041] The pharmaceutical composition of the present invention is characterized by inhibiting MRGPRX2. In the present invention, "inhibiting MRGPRX2" includes all of the following: inhibiting the activity of the protein, inhibiting gene and / or protein expression, etc. Therefore, although not limited thereto, in the present invention, allergic diseases may be, in particular, cases in which MRGPRX2 is activated or expressed, i.e., MRGPRX2 positive.

[0042] MRGPRX2 (Mas-related G-protein coupled receptor member X2) is a mast cell receptor that undergoes degranulation independently of immunoglobulin E (Ig E), is functionally expressed in the skin, and is known to exhibit activity against multiple agents, including various endogenous peptides, allergens, infectious agents, toxins, and FDA-approved drugs, including receptors on basophils and eosinophils.

[0043] Indications for MRGPRX2 include neuroinflammatory, painful, itchy, and pruritic skin diseases, including chronic spontaneous urticaria and atopic dermatitis.

[0044] According to Allergy Asthma Immunol Res. 2021 May;13(3): 498-506 regarding molecular mechanisms and pathophysiological roles, the number of MRGPRX2-positive cells increased in the skin of patients with chronic spontaneous urticaria, and further studies confirmed that patients developed a wheal reaction upon intradermal application of the protein's agonist. Additionally, according to Neuron. 2019 Feb 6;101(3):412-420, knocking out the murine homolog of MRGPRX2 reduced house dust mite-induced allergic reactions and lowered immune cell recruitment and inflammation-induced hypersensitivity in a mouse model of postoperative inflammatory pain.

[0045] The compounds of Formulas 1 to 4 of the present invention have excellent inhibitory activity against MRGPRX2, so they can be very usefully used as compositions for the prevention and treatment of allergic diseases.

[0046] The pharmaceutical composition of the present invention may be prepared in a unit dose form or contained in a multi-dose container by formulation using pharmaceutically acceptable carriers and excipients. The formulation may be prepared by conventional methods used in the art for formulation or by methods disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and may be formulated into various formulations depending on each disease or component.

[0047] The pharmaceutical composition of the present invention may be administered orally or parenterally depending on the intended method.

[0048] The pharmaceutical effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time and / or administration route, etc., and may also vary depending on various factors and similar factors well known in the pharmaceutical field, including the type and degree of response to be achieved by administering the pharmaceutical composition, the type of individual to be administered, age, body weight, general health condition, symptoms or severity of disease, gender, diet, excretion, and components of other compositions used simultaneously or at different times with the individual. A person skilled in the art can easily determine and prescribe a dosage effective for the intended treatment.

[0049] That is, a person skilled in the art can administer the pharmaceutical composition of the present invention in an amount that obtains maximum effect with a minimum amount without side effects, taking into account all of the above factors, and this can be easily determined by a person skilled in the art to which the present invention belongs.

[0050] The pharmaceutical composition of the present invention can exhibit excellent effects even when used alone, but it may be used in combination with various methods such as hormone therapy and drug therapy to increase therapeutic efficiency.

[0052] The present invention provides a method for preventing or treating an allergic disease, comprising the step of administering to an individual in need a compound according to any one of Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or a pharmaceutical composition containing the same.

[0053] In the present invention, "administration" means introducing a specific substance to an individual by an appropriate method.

[0054] In the present invention, "individual" refers to all animals, including humans, rats, mice, and livestock, that have developed or may develop an allergic disease; specifically, it may be mammals, including humans, but is not limited thereto.

[0055] The method for preventing or treating allergic diseases according to the present invention may involve administering a therapeutically effective amount of a compound according to any one of Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0056] In the present invention, "therapeutically effective amount" refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects. This amount may be determined by a person skilled in the art based on factors including the patient's gender, age, weight, health status, type and severity of the disease, drug activity, sensitivity to the drug, method of administration, time of administration, route of administration, release rate, duration of treatment, drugs used in combination or simultaneously, and other factors well known in the medical field. It is preferable to apply a specific therapeutically effective amount for a specific patient differently depending on various factors and similar factors well known in the medical field, including the specific composition, such as the type and degree of response to be achieved and whether other preparations are used in some cases, the patient's age, weight, general health status, gender and diet, time of administration, route of administration and release rate of the composition, duration of treatment, and drugs used with or simultaneously with the specific composition.

[0057] The method for the prevention or treatment of allergic diseases according to the present invention comprises administering a compound according to any one of Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition containing such a compound, thereby not only treating the disease itself before the onset of symptoms but also inhibiting or avoiding the symptoms thereof. In the management of the disease, the prophylactic or therapeutic dose of a specific active ingredient will vary depending on the characteristics and severity of the disease or condition and the route of administration of the active ingredient. The dose and frequency of administration will vary depending on the age, weight, and response of the individual patient. A suitable dosage regimen can be readily selected by a person of ordinary skill in the art who naturally takes these factors into account. Furthermore, the method for the prevention or treatment of allergic diseases according to the present invention may further include the administration of a therapeutically effective amount of an additional active agent that aids in the prevention or treatment of the disease, together with a compound according to any one of Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof. Additional active agents may exhibit synergistic or additive effects with a compound according to any one of Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

[0059] The present invention provides the use of a compound according to any one of Formulas 1 to 4, 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 allergic diseases.

[0060] The present invention provides the use of a compound according to any one of Formulas 1 to 4, 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 drug for the prevention or treatment of allergic diseases.

[0061] For the manufacture of a pharmaceutical product, a compound according to any one of Formulas 1 to 4 of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof may be mixed with a pharmaceutically acceptable adjuvant, diluent, carrier, etc., and may be manufactured as a complex formulation together with other active agents to have a synergistic effect.

[0063] Embodiments of the present invention may be modified in various different forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Moreover, throughout the specification, the term "comprising" any component means that, unless specifically stated otherwise, it does not exclude other components but may include additional components. Effects of the invention

[0065] Since the compound of the present invention effectively inhibits MRGPRX2, it can be very useful for the prevention and treatment of allergic diseases such as atopic dermatitis and urticaria. Specific details for implementing the invention

[0067] The structure and effects of the present invention will be explained in more detail below through examples. These examples are solely for the purpose of illustrating the present invention, and the scope of the present invention is not limited by these examples.

[0069] Experimental Example 1. IP-one assay for confirming MrgprX2 activity

[0070] The efficacy of the compounds in Table 1 below was evaluated using the HEK293 stable cell line expressing human MrgprX2 (hereinafter, MrgprX2-HEK293). All compounds were purchased from the Korea Chemical Bank.

[0072] No structure Name / Identification Number 1 N-(5-(3-fluorobenzyl)thiazole-2-yl)-4,6,7,8-tetrahydro-5H-puro[3,2-c]azepine-5-carboxamide, K-289(0042-23-912261) 2 (E)-N-(5-(3-chlorobenzyl)thiazole-2-yl)-3-(furan-2-yl)acrylamide, K-328(0042-23-373297) 3 4-((2-(trifluoromethyl)quinoline-4-yl)amino)cyclohexane-1-ol, K-339(0042-23-7702) 4 1-Isopropyl-6-(5-methylthiophene-2-yl)-N-(3-((2-oxopyrrolidine-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide, K-356(0042-23-789606)

[0074] The cells were cultured in a cell culture incubator at 37°C and 5% CO2 conditions using a culture medium containing 10% FBS (Corning; 35-015-CV) and 1 μg / mL puromycin (Gibco; A1113802) in high-glucose DMEM (Gibco; 10564029) containing GlutaMAX.

[0075] On the day before the experiment, MrgprX2-HEK293 cells were placed in 96-well assay plates at 100 μL of cell culture medium per well, containing 1.0 x 10 4The cells were dispensed individually and cultured in a cell culture incubator (n = 3). On the day of the experiment, the cell culture medium was carefully removed, and 100 μL of DPBS (Gibco; 14190-144) was dispensed into each well and removed to perform washing. Subsequently, the 10 mM compound dissolved in DMSO was serially diluted at a 1:3 ratio and then diluted in the assay buffer included in the IP-one Gq kit (Cisbio; 62IPAPEB) to prepare a total of 10 dilutions with concentrations ranging from 1 nM to 30 μM. The final DMSO concentration of each dilution was 0.3%, and an equal amount of DMSO was added to the control group. 100 μL of the prepared compound dilutions was dispensed into washed MrgprX2-HEK293 cells and treated in a 37 ℃, 5% CO2 cell culture incubator for 1 hour. Subsequently, to stimulate MrgprX2, 200 nM Cortistatin-14 (hereinafter Cort14) (MedchemExpress; HYP1932A) was prepared in assay buffer and dispensed into each well at a volume of 100 μL (final concentration 100 nM). For the action of Cort14, MrgprX2-HEK293 cells were incubated for 1 hour in a 37°C, 5% CO2 incubator. Afterward, all assay buffer was removed from each well, and 30 μL of the lysis buffer included in the IP-one Gq kit was dispensed to lyse the cell membranes. After removing 15 μL of the lysate, 6 μL of the detection buffer included in the IP-one Gq kit was dispensed into the remaining half of the lysate, and the reaction was allowed to proceed at room temperature for 1 hour in the dark. HTRF measurements were performed on the plates using a Tecan Spark 10m instrument. The measured HTRF ratio was graphed and IC using GraphPad Prism 10 50 The value was calculated.

[0076] The results are listed in Table 2 below, where A, B, and C each represent the following.

[0077] A: IC 50<20 μM, B: 20 ​​μM IC 50 < 100 μM, C: 100 μM IC 50 < 300 μM

[0079] Compound number Activity (Experimental Example 1) 1 A 2 B 3 A 4 A

[0081] Through Experimental Example 1 above, it was confirmed that the compounds of the present invention exhibit excellent MRGPRX2 inhibitory activity. In addition, it was confirmed that the compounds of the present invention have excellent physical properties and low toxicity in ADMET (metabolic stability, PK, CYP, hERG), etc. Therefore, the compounds of the present invention can be very usefully employed as compositions for the prevention and treatment of allergic diseases such as atopic dermatitis and urticaria.

[0083] From the foregoing description, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as including all modifications or variations derived from the meaning and scope of the claims set forth below and their equivalents, rather than from the detailed description above.

Claims

Claim 1 A pharmaceutical composition for the prevention or treatment of allergic diseases, comprising as an active ingredient a compound according to any one of the following Chemical Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof: [Chemical Formula 1] ;[Chemical Formula 2] ;[Chemical Formula 3] ;[Chemical Formula 4] . Claim 2 A pharmaceutical composition for the prevention or treatment of allergic diseases according to claim 1, wherein the allergic disease is selected from the group consisting of atopic dermatitis, urticaria, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, allergic keratitis, allergic conjunctivitis, hay fever, and anaphylaxis. Claim 3 A pharmaceutical composition for the prevention or treatment of an allergic disease, wherein, in claim 1 or 2, the allergic disease is MRGPRX2 positive. Claim 4 In any one of claims 1 to 3, the pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of allergic diseases that inhibits MRGPRX2. Claim 5 In any one of claims 1 to 4, the pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of allergic diseases, administered orally. Claim 6 A method for the prevention or treatment of an allergic disease, comprising the step of administering to an individual in need a compound according to any one of the following Formulas 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof: [Formula 1] ;[Chemical Formula 2] ;[Chemical Formula 3] ;[Chemical Formula 4] . Claim 7 Use of a compound according to any one of the following Formulas 1 to 4, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, or its solvate for the prevention or treatment of allergic diseases: [Formula 1] ;[Chemical Formula 2] ;[Chemical Formula 3] ;[Chemical Formula 4] . Claim 8 Use of a compound according to any one of the following Formulas 1 to 4, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, or its solvate for the manufacture of a drug for the prevention or treatment of allergic diseases: [Formula 1] ;[Chemical Formula 2] ;[Chemical Formula 3] ;[Chemical Formula 4] .

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