Use of sphingosine-1-phosphate receptor agonist

Abstract

This disclosure relates to the use of compounds of Formula 1 or pharmaceutically acceptable salts thereof for the prevention or treatment of atopic dermatitis: Among them, X, R1, R2, R3, R4, R5 and R6 are the same as those defined in this paper.

Description

Technical Field

[0001] This disclosure relates to the use of compounds of Formula 1 or pharmaceutically acceptable salts thereof for the prevention or treatment of atopic dermatitis: Among them, X, R1, R2, R3, R4, R5 and R6 are the same as those defined in this paper. Prior Technology

[0002] Sphingosine-1-phosphate (S1P) is produced via the intracellular ceramide pathway, in which ceramide is the starting material. Ceramide is produced through two pathways, the first being de novo biosynthesis. Ceramide is also produced by the degradation of sphingomyelin (a cell membrane component) within the cell. The amount of S1P in various tissues is regulated by two biosynthetic sphingosine kinases (SphK) and two biodegradable S1P phosphatases (S1P lyase and lysophospholipid phosphatase). It is known that S1P produced by phosphorylation of sphingosine by sphingosine kinases modulates various cellular responses, such as cell proliferation, cytoskeleton organization and migration, adhesion and tight junction assembly, and body formation. S1P exists in high quantities (100 to 1,000 nM) in plasma bound to plasma proteins, including albumin, but in low quantities in tissues.

[0003] S1P binds to its receptor (G protein-coupled receptor) to exhibit various biological functions. As S1P receptor subtypes, S1P1 through S1P5 have been named endothelial differentiation gene (EDG) receptors 1, 5, 3, 6, and 8, respectively. S1P receptors have been involved in various biological functions, such as leukocyte recirculation, nerve cell proliferation, body shape changes, migration, endothelial function, vasoregulation, and cardiovascular development.

[0004] In recent years, many studies have found that the S1P signaling process via these receptors plays an important role in a series of reactions related to multiple sclerosis, including inflammatory responses and repair processes, and a non-selective S1P1 agonist has actually been approved as a therapeutic agent for multiple sclerosis. The S1P receptors are widely expressed in many cells related to the induction of multiple sclerosis. In particular, the S1P1 receptor plays a major role in the immune system. The S1P1 receptor is mainly expressed on the surface of lymphocytes, such as T cells and B cells, and responds to S1P to participate in the recirculation of lymphocytes. Normally, the concentration of S1P in body fluids is higher than that in lymphoid tissues, and thus lymphocytes leave lymphoid tissues due to the difference in S1P concentration, and after exiting the lymph circulation, they circulate in body fluids. However, if the S1P1 receptor in lymphocytes is downregulated by an S1P1 agonist, lymphocytes will not flow out of lymphoid tissues, resulting in a reduction in the infiltration of autoaggressive lymphocytes that cause inflammation and tissue damage in the central nervous system (CNS). As a result, a therapeutic effect on multiple sclerosis is obtained. Fingolimod, a non-selective S1P1 agonist, has been approved as an oral drug for treating multiple sclerosis. When it binds to and activates the S1P1 receptor, the receptor is counterproductively degraded or internalized from the surface of lymphocytes, thereby exerting a functional S1P1 antagonistic effect.

[0005] Regarding such S1P receptors, International Patent Application No. WO 2014 / 129796 (Publication Date: August 28, 2014) discloses compounds effective as S1P receptor agonists.

[0006] At the same time, atopic dermatitis is a chronic relapsing skin eczema disease. Although the cause has not been clarified yet, it is claimed to be caused by the overreaction of immune-related factors due to the action of external antigens. The drugs used for atopic dermatitis mainly include immunosuppressants, topical steroids, antihistamines, etc. However, the use of these drugs has side effects or limitations in improving atopic dermatitis. Therefore, there is a continuous need for new drugs that can more effectively prevent or treat atopic dermatitis. Summary of the Invention Problems to be Solved by the Invention

[0007] One object of the present disclosure is to provide the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof in preventing or treating atopic dermatitis: Among them, X, R1, R2, R3, R4, R5 and R6 are the same as those defined in this paper. The means to solve the problem

[0008] This disclosure provides a medicament for the prevention or treatment of atopic dermatitis, comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof: in, X is carbon or nitrogen; R1 is hydrogen or alkyl; R2 is hydrogen, alkyl, halogen, CN, CF3, or COCF3; R3 and R4 are each independently hydrogen, alkyl, halogen, haloalkyl, or alkoxyalkyl; R5 is hydrogen, alkyl, or halogen; R6 is ; R7 is hydrogen or alkyl; and m and n are each independently 0, 1, 2 or 3.

[0009] Furthermore, this disclosure provides pharmaceutical compositions for the prevention or treatment of atopic dermatitis, comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0010] Furthermore, this disclosure provides a method for preventing or treating atopic dermatitis, comprising administering to an individual in need a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[0011] Furthermore, this disclosure provides the use of compounds of Formula 1 or pharmaceutically acceptable salts thereof for the prevention or treatment of atopic dermatitis.

[0012] This disclosure is described in detail below.

[0013] According to one aspect of this disclosure, a medicament for the prevention or treatment of atopic dermatitis is provided, comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[0014] According to another aspect of this disclosure, a pharmaceutical composition for the prevention or treatment of atopic dermatitis is provided, comprising a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0015] The method for preparing the compound of Formula 1 is described in detail in International Patent No. WO 2014 / 129796A1, which is incorporated herein by reference.

[0016] In one embodiment according to the present disclosure, in Formula 1 X is either C or N; R1 is hydrogen or a C1-C5 alkyl group; R2 is hydrogen, C1-C5 alkyl, halogen, CN, CF3, or COCF3; R3 and R4 are each independently hydrogen, C1-C5 alkyl, halogen, halo-C1-C5 alkyl, or C1-C5 alkoxy-C1-C5 alkyl; R5 is hydrogen, C1-C5 alkyl, or halogen; R6 is ; R7 is hydrogen or a C1-C5 alkyl group; and m and n are each independently 0, 1, 2 or 3.

[0017] In another embodiment according to this disclosure, the compound of Formula 1 is 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylic acid of Formula 2:

[0018] In another embodiment according to this disclosure, pharmaceutically acceptable salts include, for example, acid addition salts formed from non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid; organic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid; or sulfonic acids like methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, but are not limited thereto.

[0019] In another embodiment according to this disclosure, the "therapeutic effective amount" for an individual refers to an amount sufficient to achieve the aforementioned pharmacological effect—that is, the therapeutic effect as described above. The amount of compound may vary depending on the individual's condition and severity, the route of administration, and the age of the individual being treated, but may be determined by a person skilled in the art based on their knowledge.

[0020] In another embodiment according to this disclosure, the therapeutically effective amount of the compound of formula 1 is typically in the range of, for example, about 0.1 to 500 mg per day, depending on the frequency and intensity of administration. The usual daily dose for adults, administered intramuscularly or intravenously, is in the range of about 0.1 to 300 mg per day, which may be administered in separate unit doses. Some patients require higher daily doses.

[0021] In this disclosure, "pharmaceutical composition" may include other components besides the active ingredient disclosed herein, such as carriers, diluents, excipients, etc. Therefore, if necessary, pharmaceutical composition may include pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof. This pharmaceutical composition facilitates the delivery of the compound into the body. Various methods of compound delivery include, but are not limited to, oral, injection, inhalation, parenteral, and topical administration.

[0022] In this article, "carrier" refers to a compound that facilitates the addition of a compound to cells or tissues. For example, dimethyl monoxide (DMSO) is a common carrier that helps deliver many organic compounds to living cells or tissues.

[0023] In this paper, "diluent" refers to a compound that not only stabilizes the biologically active form but also dissolves the compound in a solvent. The dissolving salt in a buffer solution is used as a diluent in this field. Commonly used buffer solutions are phosphate-buffered saline solutions that mimic the salt form found in bodily fluids. Because buffer solutions can adjust the pH of the solution at low concentrations, buffer diluents are unlikely to alter the biological activity of the compound.

[0024] In this article, "pharmaceutically acceptable" means a property that does not impair the biological activity and physical properties of a compound.

[0025] The compounds disclosed herein can be formulated into various drug delivery formulations. In the preparation of the pharmaceutical compositions disclosed herein, the active ingredient—specifically, the compound of Formula 1 or a pharmaceutically acceptable salt thereof—is mixed with a selected pharmaceutically acceptable carrier, taking into account the desired dosage form. For example, the pharmaceutical compositions disclosed herein can be formulated into injections, oral formulations, etc., as needed.

[0026] The compounds of the present disclosure can be formulated by conventional methods using known pharmaceutical carriers and excipients and inserted into single or multiple unit containers. The formulations can be solutions, suspensions or emulsions in oily or aqueous solvents and include conventional dispersing, suspending or stabilizing agents. Additionally, the compounds can be in the form of dry powder that is dissolved in sterile pyrogen-free water before use. The compounds of the present disclosure can be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric-coated. The solid forms are prepared by mixing the compounds of the present disclosure with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrants, binders, etc. Additionally, it can be formulated into a transdermal dosage form - for example, as a lotion, ointment, gel, cream, patch or spray.

[0027] As used herein, the term "prevention" refers to reducing or eliminating the likelihood of contracting a disease.

[0028] As used herein, the term "treatment" is used to mean arresting, delaying or improving the progression of a disease in an individual showing symptoms of the disease. Advantages of the Invention

[0029] The drugs or pharmaceutical compositions of the present disclosure can effectively prevent or treat atopic dermatitis. Brief Description of the Drawings

[0030] FIG. 1 is a schematic diagram of the induction process of an atopic dermatitis animal model.

[0031] FIG. 2 shows the measurement results of the reduction in ear thickness after administration of a test substance in an atopic dermatitis animal model.

[0032] FIG. 3 shows the measurement results of the reduction in ear weight after administration of a test substance in an atopic dermatitis animal model.

[0033] FIG. 4 shows the measurement results of the reduction in the blood level of IgE after administration of a test substance in an atopic dermatitis animal model.

[0034] FIG. 5 shows the measurement results of the reduction in epidermal thickness after administration of a test substance in an atopic dermatitis animal model.

[0035] FIG. 6 shows the measurement results of the reduction in mast cell accumulation after administration of a test substance in an atopic dermatitis animal model.

[0036] Figure 7 shows the results of the comparison with etrasimod, a comparative compound, in an animal model of atopic dermatitis. Implementation

[0037] The following examples will explain this disclosure in more detail. However, it must be understood that the scope of protection of this disclosure is not limited to these examples. [Preparation Example: Synthesis of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylic acid]

[0038] 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylic acid (hereinafter referred to as "test compound") was prepared according to the method disclosed in Example 153 of International Patent No. WO2014 / 129796A1. [Example 1: Induction of an animal model of atopic dermatitis]

[0039] By using A mouse (Balb / c) animal model of atopic dermatitis was induced by oxazolone. The first sensitization day of zozolinone is designated as day 0, and administration begins once daily, either orally or transdermally, starting on day 7. When the administration date of zozoline overlaps with the administration date of the drug, during administration... The drug is administered approximately 6 hours after the administration of zolinone.

[0040] For all mice, at the first administration The day before, azolinone was used to remove abdominal hair. Then, a 1% or 0.2% solution was prepared using a 4:1 ratio of acetone and corn oil. Zoltrinone was used to sensitize and induce the scraped abdomen and ears of mice at the same doses and schedules as shown in Table 1 and Figure 1.

[0041] [Table 1] [Example 2: Preparation of substances for oral administration]

[0042] As shown in Table 2 below, test substances (test compounds and dexamethasone as positive control) were prepared for different dosages using 0.5% methylcellulose. The test compounds were prepared in HCl salt form. The test substances were dissolved in 0.5% methylcellulose and then subjected to ultrasonic treatment. If not completely dissolved, they were administered as suspensions. [Example 3: Preparation of substances for transdermal (topical) drug delivery]

[0043] The test substance was prepared by dissolving PEG400 in a solution (PEG400:100% ethanol = 1:1) at a concentration of 0.1% (w / v). 5 mL of PEG400 was added to 10 mg of the test substance and ultrasonically treated. When the substance was partially dissolved, 5 mL of 100% ethanol was added and ultrasonically treated to ensure complete dissolution. Fresh media and test substance were prepared and used daily.

[0044] [Table 2] [Example 4: Measurement Results]

[0045] The reduction in ear thickness was measured on days 14 and 21 after administration of the test substance, and the results are shown in Table 3 and Figure 2. On day 21 after administration of the test substance, the reduction in ear weight was measured after autopsy, and the results are shown in Table 3 and Figure 3. On day 21 after administration of the test substance, the decrease in IgE blood levels was measured, and the results are shown in Table 3 and Figure 4. Furthermore, on day 21 after administration of the test substance, the reduction in ear tissue epidermal thickness and mast cell accumulation was measured, and the results are shown in Table 3, Figure 5, and Figure 6.

[0046] [Table 3]

[0047] As can be seen from Table 3 and Figures 2 to 6, in In an animal model of atopic dermatitis induced by azolinone, the tested compound showed superior efficacy in a dose-dependent manner compared to dexamethasone (positive control group). These results confirm that the disclosed compound can be used as a drug for the prevention or treatment of atopic dermatitis. [Example 5: Comparative Experiment]

[0048] To compare with another S1P receptor agonist, ezetimibe (2-[(3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopentane[b]indol-3-yl]acetic acid) was used in the same manner as in Example 4 to measure the reduction in ear thickness, the reduction in ear weight, the blood level of IgE, epithelial thickness, and mast cell accumulation, and the results are shown in Table 4 and Figure 7.

[0049] [Table 4]

[0050] As shown in Table 4 and Figure 7, the test compound exhibited the same or better efficacy than the comparative compound ezetimibe, even at lower doses. These results suggest that systemic exposure-related side effects can be minimized by administering the same dose to achieve better efficacy or by administering a lower dose to achieve a specific therapeutic level. Furthermore, the low affinity for GIRKs (G protein-coupled inward rectifying potassium channels) is expected to offer advantages in terms of side effects, as GIRKs can induce brachycardia via S1P receptor agonists.

Claims

1. The use of a compound of formula 2, 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphth-2-ylmethyl]-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of atopic dermatitis:

2. The use as described in claim 1, wherein, The pharmaceutically acceptable salts are selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid.

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