Pharmaceutically acceptable salts of sphingosine-1-phosphate receptor agonists and their crystalline forms

Abstract

The present invention relates to pharma- ceutically acceptable salts of sphingosine-1-phosphate receptor agonists and crystalline forms thereof, more particularly to the potassium salt or methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid of formula (1), and crystalline forms thereof.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutically acceptable salt of a sphingosine-1-phosphate receptor agonist and a crystalline form thereof. More specifically, the present invention relates to a pharmaceutically acceptable salt of a sphingosine-1-phosphate receptor agonist represented by the following formula (1): [ka] The present invention relates to the potassium salt or methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid represented by the formula: and its crystalline form. [Background technology]

[0002] Sphingosine-1-phosphate (S1P) is produced via the intracellular ceramide pathway, starting from ceramide. Ceramide is produced via two pathways: the de novo biosynthetic pathway and the de novo biosynthetic pathway. Ceramide is also produced by the intracellular degradation of sphingomyelin, a cell membrane component. S1P levels in various tissues are regulated by two biosynthetic sphingosine kinases (SphKs) and two biodegradative S1P phosphatases (S1P lyase and lysophospholipid phosphatase). S1P, produced via the phosphorylation of sphingosine by Sphingosine kinases, is known to mediate various cellular responses, including cell proliferation, cytoskeletal organization and migration, adhesion and tight junction assembly, and morphogenesis. S1P is present at high concentrations (100–1000 nM) in plasma bound to plasma proteins, including albumin, and at lower concentrations in tissues.

[0003] S1P binds to G-protein-coupled receptors, called S1P receptors, and exhibits various biological functions. Currently, S1P receptor subtypes, S1P1 to S1P5, are known, and are named endothelial differentiation gene receptors (EDG) 1, 5, 3, 6, and 8, respectively. S1P receptors are known to be involved in various biological functions, such as leukocyte recirculation, neuronal proliferation, morphological changes, migration, endothelial function, blood pressure regulation, and cardiovascular development.

[0004] In recent years, numerous studies have demonstrated that S1P signaling via these receptors plays an important role in a series of reactions associated with multiple sclerosis, including inflammatory and repair responses. Indeed, nonselective S1P1 agonists have been approved as therapeutic agents for multiple sclerosis. S1P1 receptors are widely expressed on many cells involved in the induction of multiple sclerosis. In particular, S1P1 receptors play an important role in the immune system. S1P1 receptors are expressed primarily on the surface of lymphocytes, such as T and B cells, and are involved in lymphocyte recirculation in response to S1P. Under normal conditions, S1P concentrations are higher in body fluids than in lymphoid tissues, and lymphocytes circulate away from lymphoid tissues due to the difference in S1P concentrations after efferent lymph circulation. However, downregulation of lymphocyte S1P1 receptors by S1P1 agonists prevents lymphocyte egress from lymphoid tissues, resulting in reduced infiltration of autoaggressive lymphocytes, which cause inflammation and tissue damage in the central nervous system (CNS). As a result, it has therapeutic potential for multiple sclerosis. The nonselective S1P1 agonist fingolimod has been approved as an oral medication for the treatment of multiple sclerosis. Ironically, upon binding and activating the S1P1 receptor, it acts as a functional S1P1 antagonist, as the receptor is internalized or degraded from the lymphocyte surface.

[0005] Regarding the S1P receptor, Patent Document 1 discloses a compound effective as an S1P receptor agonist. Although the activity of the compound as an S1P receptor agonist is excellent, it is necessary to develop a form that has improved solubility to improve bioavailability and improved pharmaceutical properties such as thermal stability and moisture stability. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO 2014 / 129796 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention relates to a compound represented by the following formula (1) which has pharmaceutical superiority: [ka] The object of the present invention is to provide a pharmaceutically acceptable salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid represented by the formula: [Means for solving the problem]

[0008] To solve the above problems, the present invention provides potassium salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid and its crystalline form.

[0009] The present invention also provides the methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid and a crystalline form thereof.

[0010] The present invention also provides a pharmaceutical composition comprising the potassium salt or methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid, or a crystalline form thereof, as an active ingredient together with a pharmaceutically acceptable carrier.

[0011] The present invention will be described in detail below.

[0012] According to one aspect of the present invention there is provided the potassium salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid.

[0013] In one embodiment according to the present invention, the potassium salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid may be in crystalline form.

[0014] In one embodiment according to the present invention, the crystalline form of potassium salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid has 3 or more, 5 or more, 7 or more, 9 or more or 10 or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum: 6.14±0.2°, 9.59±0.2°, 10.23±0.2°, 11.25±0.2°, 12.32±0.2°, 12.98±0.2°, 15.39±0.2°, 16.18±0.2°, 18.47±0.2°, 18.89±0.2°, 19.22±0.2°, 20.57±0.2°, 21.14±0.2°, 21.91±0.2°, 22.50±0.2°, 23.34±0.2°, 24.16±0.2°, 24.70±0.2°, 26.12±0.2° and 27.03±0.2°.

[0015] In one embodiment according to the present invention, the crystalline form of potassium salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid has 3 or more, 5 or more, 7 or more, 9 or more, or 10 or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum: 6.14±0.1°, 9.59±0.1°, 10.23±0.1°, 11.25±0.1°, 12.32±0.1°, 12.98±0.1°, 15.39±0.1°, 16.18±0.1°, 18.47±0.1°, 18.89±0.1°, 19.22±0.1°, 20.57±0.1°, 21.14±0.1°, 21.91±0.1°, 22.50±0.1°, 23.34±0.1°, 24.16±0.1°, 24.70±0.1°, 26.12±0.1° and 27.03±0.1°.

[0016] Thermogravimetric analysis (TGA) of the crystalline form of the potassium salt reveals a weight loss of approximately 3.9% between approximately 30 and 100°C. Differential scanning calorimetry (DSC) analysis of the crystalline form of the potassium salt reveals a broad endothermic peak at approximately 45 to 125°C, corresponding to the initial weight loss in TGA, and upon further heating, further endothermic peaks are observed at approximately 173°C, 205°C, and 236°C (onset). Quantitative analysis of the crystalline form of the potassium salt by HPLC (high performance liquid chromatography) reveals a water solubility of 33238.5 μg / mL.

[0017] According to another aspect of the present invention there is provided the methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid.

[0018] In one embodiment according to the present invention, the methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid may be in crystalline form.

[0019] In one embodiment according to the present invention, the crystalline form of methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid has 3 or more, 5 or more, 7 or more, 9 or more, or 10 or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum: 13.16±0.2°, 13.65±0.2°, 14.62±0.2°, 15.71±0.2°, 17.95±0.2°, 18.21±0.2°, 19.73±0.2°, 20.70±0.2°, 22.31±0.2°, 22.49±0.2°, 22.92±0.2°, 24.23±0.2°, 24.95±0.2°, 25.35±0.2°, 29.52±0.2° and 31.78±0.2°.

[0020] In one embodiment according to the present invention, the crystalline form of methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid has 3 or more, 5 or more, 7 or more, 9 or more, or 10 or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum: 13.16±0.1°, 13.65±0.1°, 14.62±0.1°, 15.71±0.1°, 17.95±0.1°, 18.21±0.1°, 19.73±0.1°, 20.70±0.1°, 22.31±0.1°, 22.49±0.1°, 22.92±0.1°, 24.23±0.1°, 24.95±0.1°, 25.35±0.1°, 29.52±0.1° and 31.78±0.1°.

[0021] Thermogravimetric analysis (TGA) of the crystalline form of the methanesulfonate salt reveals a weight loss of about 0.5 vol at temperatures below about 50° C. Differential scanning calorimetry (DSC) of the crystalline form of the methanesulfonate salt reveals an endothermic peak at about 148° C. Quantitative analysis of the crystalline form of the methanesulfonate salt by HPLC reveals a water solubility of 536.8 μg / mL.

[0022] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the potassium salt or methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid together with a pharmaceutically acceptable carrier.

[0023] In the present invention, a "pharmaceutical composition" may contain, in addition to the active compound according to the present invention, other chemical components such as carriers, diluents, excipients, etc. Thus, the pharmaceutical composition may contain a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, as needed. The pharmaceutical composition facilitates administration of the compound into the body. Various methods for administering the compound include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration.

[0024] As used herein, the term "carrier" refers to a compound that facilitates the administration of a compound to cells or tissues. For example, dimethyl sulfoxide (DMSO) is a conventional carrier that facilitates the administration of many organic compounds to cells or tissues of an organism.

[0025] As used herein, the term "diluent" refers to a compound diluted in a solvent that dissolves the compound as well as stabilizes the biologically active form. In this field, salts dissolved in buffer solutions are used as diluents. A conventionally used buffer solution is phosphate buffered saline, which mimics the salt forms present in body fluids. Buffer diluents do not alter the biological activity of the compound because buffer solutions can control the pH of the solution at low concentrations.

[0026] As used herein, the term "pharmaceutically acceptable" refers to a property that does not impair the biological activity and physical properties of a compound.

[0027] In the present invention, the potassium salt or methanesulfonate salt of the compound of formula (1) can be formulated into various pharmaceutical dosage forms. In preparing the pharmaceutical composition of the present invention, the active ingredient, specifically the potassium salt or methanesulfonate salt of the compound of formula (1), is mixed with a pharmaceutically acceptable carrier selected taking into consideration the administration form. For example, the pharmaceutical composition according to the present invention can be formulated as an injection, oral agent, etc. as needed.

[0028] The potassium salt or methanesulfonate salt of the compound of formula (1) of the present invention can be formulated using known pharmaceutical carriers and excipients in a known manner and inserted into unit-dose or multi-dose containers. The formulation may be a solution, suspension, or emulsion in an oily or aqueous solvent, containing conventional dispersing, suspending, or stabilizing agents. Furthermore, the compound may be in the form of a dry powder, for example, to be dissolved in sterile, pyrogen-free water before use. The potassium salt or methanesulfonate salt of the compound of formula (1) of the present invention 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 particularly preferred. Tablets and pills are preferably enteric-coated. The solid form is prepared by mixing the crystalline form of the compound of formula (1) of the present invention with at least one carrier selected from an inert diluent such as sucrose, lactose, or starch, a lubricant such as magnesium stearate, a disintegrant, a binder, and the like. They can also be formulated as transdermal dosage forms such as lotions, ointments, gels, creams, patches or sprays.

[0029] The pharmaceutical composition according to the present invention is suitable for the prevention or treatment of diseases associated with sphingosine-1-phosphate receptors. In one embodiment of the present invention, the pharmaceutical composition can be used for the treatment of autoimmune diseases, including multiple sclerosis. In one embodiment of the present invention, the pharmaceutical composition can be used for the prevention or treatment of diseases caused by unwanted lymphocyte infiltration associated with sphingosine-1-phosphate. In one embodiment of the present invention, the pharmaceutical composition can be used for the prevention or treatment of immune dysregulation. In one embodiment of the present invention, the immune dysregulation may be, for example, an autoimmune or chronic inflammatory disease selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), arteriosclerosis, atherosclerosis, scleroderma, and autoimmune hepatitis, but is not limited thereto.

[0030] As used herein, the term "prevention" refers to reducing or eliminating the chance of contracting a disease.

[0031] As used herein, the term "treating" means preventing, slowing, or alleviating the progression of a disease in a subject who exhibits symptoms of the disease. [Effects of the Invention]

[0032] The potassium salt or methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid of the present invention and its crystalline form have pharmacological activity as sphingosine-1-phosphate receptor agonists, and at the same time, they have excellent pharmaceutical properties such as excellent bioavailability due to high solubility, as well as stability, for example, thermal stability and storage stability. [Brief explanation of the drawings]

[0033] [Figure 1] 1 is an X-ray powder diffraction (XRPD) spectrum of the crystalline form of the potassium salt. [Figure 2] 1 shows the results of thermogravimetric analysis (TGA) / differential scanning calorimetry (DSC) analysis of the crystalline form of the potassium salt. [Figure 3] 1 is an X-ray powder diffraction (XRPD) spectrum of the crystalline form of the methanesulfonate salt. [Figure 4] 1 shows the results of thermogravimetric analysis (TGA) / differential scanning calorimetry (DSC) analysis of the crystalline form of the methanesulfonate salt. [Example]

[0034] The present invention will be described in more detail below with reference to examples, but it should be understood that the scope of protection of the present invention is not limited to these examples.

[0035] Preparation Example: Synthesis of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid (hereinafter referred to as "Compound 1") was prepared in accordance with the method described in Example 153 of WO2014 / 129796 A1.

[0036] Example 1: Preparation of potassium salts and crystalline forms 3 g of compound 1 (free form), 30 mL of methanol, 1 equivalent of potassium hydroxide, and 1 mL of water were added to a reactor and stirred. The solution was heated (60 °C), but remained in a suspension state, so it was cooled (room temperature) and the solvent was removed by distillation under reduced pressure. The solid was dissolved in 6 mL of dichloromethane, and then crystallized using 30 mL of methyl tert-butyl ether as a poor solvent.

[0037] Example 2: Analysis of the crystalline form of the potassium salt (1) XRPD (X-ray powder diffraction) XRPD analysis was performed using a PANalytical X'pert Pro MPD diffractometer with an incident beam of Cu radiation. Approximately 20–30 mg of sample was compressed flat on a glass sample holder, and measurements were performed in reflection mode (non-spin) with the instrument generator set to 45 kV (accelerating voltage) and 40 mA (filament emission). Bragg angles (2θ) ranging from 4 to 40° were measured with a step size of 0.026° and a time per step of 51 seconds. XRPD patterns were classified and processed using HighScore Plus 2.2c software; the results are shown in Figure 1 and Table 2.

[0038] (2) DSC (differential scanning calorimetry) DSC was performed using a Mettler-Toledo DSC1 system. Approximately 2–5 mg of sample was weighed and placed in a 40 μL aluminum crucible (a flat-bottom aluminum pan with a pinhole lid). A pinhole was drilled through the crucible. The sample was then heated from 25°C to 350°C at a rate of 10°C / min, and the DSC was measured. During the measurement, nitrogen gas was supplied to the instrument at a rate of 70 mL / min to prevent the inflow of oxygen and other gases. Data collection and evaluation were performed using the software STARe (Figure 2).

[0039] (3)TGA (thermogravimetric analysis) TGA was performed using a Mettler-Toledo TGA / DSC1 module. Approximately 4–8 mg of sample was weighed and placed in a 100 μL Al crucible (flat-bottomed aluminum crucible). The sample was then heated from 30 to 350 °C at a rate of 10 °C / min, and TGA measurements were performed. Nitrogen gas was supplied to the instrument at a rate of 80 mL / min during the measurements to prevent the inflow of oxygen and other gases. Data collection and evaluation were performed using the software STARe (Figure 2).

[0040] (4) Quantitative analysis (HPLC) Approximately 26.7 mg of sample was accurately weighed and placed in a 500 mL flask. 450 mL of diluent (methanol:purified water ≒ 1:1) was added and completely dissolved, after which the flask was filled with diluent up to the marked line. The HPLC equipment and analytical method are shown in Table 1 below. [Table 1]

[0041] (5) Results XRPD analysis confirmed that the compound was in crystalline form. [Table 2]

[0042] As a result of TGA measurement, a weight loss of about 3.9% was observed between about 30 and 100°C.

[0043] DSC measurements revealed a broad endothermic peak at approximately 45–125°C, corresponding to the initial weight loss observed in TGA. Upon further heating, endothermic peaks were observed at approximately 173°C, 205°C, and 236°C (onset), which were predicted to be endothermic peaks due to the melting of the solid.

[0044] Quantitative analysis by HPLC revealed that the aqueous solubility of the crystalline potassium salt was 33238.5 μg / mL.

[0045] Example 3: Preparation of methanesulfonate salt and crystalline forms The methanesulfonate salt and its crystalline form were prepared by the following two methods. (1) A solution was prepared by mixing 3 g of Compound 1 (free form), 30 mL of water, and methanesulfonic acid. After cooling the solution on ice, 45 mL of methyl tert-butyl ether was added, followed by washing with 9 mL of water.

[0046] (2) A solution was prepared by mixing 5 g of Compound 1 (free form), 25 mL of water, and methanesulfonic acid. After cooling the solution on ice, 45 mL of methyl tert-butyl ether was added. The solution was then washed with 15 mL of a water / methyl tert-butyl ether mixture.

[0047] Example 4: Analysis of crystalline forms of the methanesulfonate salt (1) XRPD (X-ray powder diffraction) XRPD analysis was carried out in the same manner as in Example 2 (FIG. 3). [Table 3]

[0048] (2) DSC (differential scanning calorimetry) and TGA (thermogravimetric analysis) DSC and TGA were measured in the same manner as in Example 2 (FIG. 4).

[0049] (3) Quantitative analysis method (HPLC) Quantitative analysis was carried out in the same manner as in Example 2.

[0050] (4) Results XRPD analysis confirmed that it was in crystalline form.

[0051] TGA measurements showed that a weight loss of about 0.5% was observed at an initial temperature below about 50°C.

[0052] As a result of DSC measurement, an endothermic peak was observed at about 148°C, which was expected to be an endothermic peak due to the melting of a solid.

[0053] Quantitative analysis by HPLC revealed that the aqueous solubility of the crystalline form of the methanesulfonate salt was 536.8 μg / mL.

[0054] Example 5: Comparison of properties with other salts Various salts were prepared and characterized in the same manner as above, and a comparison with the potassium salt and methanesulfonate (mesylate) salt is shown in Table 4 below. [Table 4]

Claims

1. A crystal of potassium salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid, characterized in that it has 10 or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum: 6.14±0.2°, 9.59±0.2°, 10.23±0.2°, 11.25±0.2°, 12.32±0.2°, 12.98±0.2°, 15.39±0.2°, 16.18±0.2°, 18.47±0.2°, 18.89±0.2°, 19.22±0.2°, 20.57±0.2°, 21.14±0.2°, 21.91±0.2°, 22.50±0.2°, 23.34±0.2°, 24.16±0.2°, 24.70±0.2°, 26.12±0.2° and 27.03±0.2°.

2. The crystal of potassium salt according to claim 1, characterized in that it has three or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum: 6.14±0.1°, 9.59±0.1°, 10.23±0.1°, 11.25±0.1°, 12.32±0.1°, 12.98±0.1°, 15.39±0.1°, 16.18±0.1°, 18.47±0.1°, 18.89±0.1°, 19.22±0.1°, 20.57±0.1°, 21.14±0.1°, 21.91±0.1°, 22.50±0.1°, 23.34±0.1°, 24.16±0.1°, 24.70±0.1°, 26.12±0.1° and 27.03±0.1°.

3. A crystalline methanesulfonate salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid, characterized in that it has 10 or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum: 13.16±0.2°, 13.65±0.2°, 14.62±0.2°, 15.71±0.2°, 17.95±0.2°, 18.21±0.2°, 19.73±0.2°, 20.70±0.2°, 22.31±0.2°, 22.49±0.2°, 22.92±0.2°, 24.23±0.2°, 24.95±0.2°, 25.35±0.2°, 29.52±0.2° and 31.78±0.2°.

4. The crystalline methanesulfonate salt according to claim 3, characterized in that it has three or more characteristic peaks (2θ) selected from the following X-ray diffraction pattern spectrum: 13.16±0.1°, 13.65±0.1°, 14.62±0.1°, 15.71±0.1°, 17.95±0.1°, 18.21±0.1°, 19.73±0.1°, 20.70±0.1°, 22.31±0.1°, 22.49±0.1°, 22.92±0.1°, 24.23±0.1°, 24.95±0.1°, 25.35±0.1°, 29.52±0.1° and 31.78±0.1°.

5. A pharmaceutical composition for treating an autoimmune disease, comprising a crystal of the potassium salt or a crystal of the methanesulfonate (mesylate) salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid according to claim 1 or 3, together with a pharmaceutically acceptable carrier.

6. A pharmaceutical composition for the prevention or treatment of a disease caused by undesired lymphocyte infiltration associated with sphingosine-1-phosphate, comprising a crystal of the potassium salt or a crystal of the methanesulfonate (mesylate) salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid according to claim 1 or 3, together with a pharmaceutically acceptable carrier.

7. A pharmaceutical composition for preventing or treating an immune dysregulation disorder, comprising a crystal of the potassium salt or a crystal of the methanesulfonate (mesylate) salt of 1-[1-chloro-6-(3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy)-3,4-dihydro-naphthalen-2-ylmethyl]-piperidine-4-carboxylic acid according to claim 1 or 3, together with a pharmaceutically acceptable carrier.

8. 8. The pharmaceutical composition of claim 7, wherein the immunoregulatory disorder is an autoimmune or chronic inflammatory disease selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), arteriosclerosis, atherosclerosis, scleroderma, and autoimmune hepatitis.