HK40006594B - Crystals of cyclic amine derivative and pharmaceutical use thereof - Google Patents

Description

Crystallization of cyclic amine derivatives and their medical uses

Technical Field

The present invention relates to the crystallization of cyclic amine derivatives and their medical uses.

Background Art

Pain is the experience of unpleasant sensations and emotions that occur when tissue is damaged or potentially damaged. Pain is primarily categorized by its cause as nociceptive pain, neuropathic pain, or psychopathic pain. Fibromyalgia is also known as an example of pain with an unknown cause.

Neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself. It is pain caused by direct damage or compression of nerve tissue, without the nociceptors receiving noxious stimuli. Neuropathic pain is treated with anticonvulsants, antidepressants, anxiolytics, and antiepileptic drugs such as gabapentin and pregabalin.

Fibromyalgia is a disease characterized by generalized pain as a primary symptom, and neuropsychiatric and autonomic nervous system symptoms as secondary symptoms. Pregabalin, approved in the United States and Japan, and duloxetine and milnacipran, approved in the United States, are the main therapeutic agents used for fibromyalgia. Nonsteroidal anti-inflammatory drugs, opioids, antidepressants, anticonvulsants, and antiepileptics, which are not approved as therapeutic agents for fibromyalgia, are also used. However, it is generally believed that nonsteroidal anti-inflammatory drugs and opioids have low therapeutic effects (Non-Patent Document 1).

In addition, Patent Document 1 discloses that certain substituted piperidines have cardiotonic activity, Patent Document 2 discloses that imidazole derivatives exhibit FXa inhibitory effects, Patent Document 3 suggests that substituted piperidines may be effective for overweight or obesity, and Patent Documents 4 and 5 disclose that imidazole derivatives exhibit analgesic effects.

In addition, medicines need to maintain quality during long-term processes such as circulation and storage, and require that the chemical and physical stability of the compound as the active ingredient is high. Therefore, the active ingredient of the medicine generally adopts a crystallization that can be expected to have a higher stability than an amorphous body. In addition, if crystallization is obtained, the purification effect achieved by recrystallization during manufacture can be expected. Further, from the perspective of maintaining stability, the manufacture of the original medicine, storage, formulation and analysis, it is preferably low hygroscopic.

In order to obtain crystals of compounds that are active ingredients of pharmaceuticals, it is necessary to conduct various studies on the conditions for precipitating crystals from solutions. Generally, a solvent is selected in which the solubility of the compound at room temperature is not too high, and crystallization is performed under conditions in which the compound is dissolved at the highest possible concentration.

Prior art literature

Patent Literature

Patent Document 1: French Patent No. 2567885

Patent Document 2: Japanese Patent Application Laid-Open No. 2006-008664

Patent Document 3: International Publication No. 2003/031432

Patent Document 4: International Publication No. 2013/147160

Patent Document 5: International Publication No. 2015/046403

Non-patent literature

Non-Patent Document 1 Okifuji et al., Pain and Therapy, 2013, Vol. 2, pp. 87-104.

Summary of the Invention

Technical problem to be solved by the invention

However, treatment with conventional neuropathic pain drugs is frequently accompanied by central nervous system side effects such as dizziness, nausea, and vomiting. Therefore, the development of new neuropathic pain drugs is desired to enable long-term administration.

Furthermore, even pregabalin, duloxetine, and milnacipran, which are approved as therapeutic drugs for fibromyalgia, have unsatisfactory clinical therapeutic effects on fibromyalgia and exhibit significant interpatient variability in efficacy. Consequently, there is a strong demand for the development of new fibromyalgia therapeutic drugs with strong pharmacological activity and therapeutic effects across a wide range of patients.

Furthermore, novel therapeutic drugs for neuropathic pain and fibromyalgia that can solve the above-mentioned problems preferably have low hygroscopicity, excellent solubility, and chemical and physical stability, and more preferably crystals that can be expected to have a purification effect during production, considering co-packaging with other drugs.

The substituted piperidines described in Patent Document 1 are suggested to be effective against migraine, and the imidazole derivatives described in Patent Documents 4 and 5 are disclosed to have analgesic effects. However, the present application discloses no disclosure of the compounds themselves, for which analgesic effects are clearly stated, or any suggestion of a correlation between analgesic effects and chemical structures. Regarding the imidazole derivatives described in Patent Document 2 and the substituted piperidines described in Patent Document 3, there is no disclosure or suggestion of the possibility of analgesic effects.

Furthermore, Patent Documents 1 to 5 do not describe the crystallization of the disclosed compounds, nor do they suggest the possibility of obtaining promising crystals as pharmaceuticals.

Therefore, an object of the present invention is to provide crystals of a compound that exhibits analgesic activity against neuropathic pain and/or fibromyalgia, which are useful as pharmaceuticals.

Technical means to solve the problem

The present inventors conducted intensive studies to solve the above problems and, as a result, discovered a compound having a strong analgesic effect on pain, particularly neuropathic pain and/or fibromyalgia, and further discovered a crystal of the compound having low hygroscopicity, excellent solubility, and chemical and physical stability.

That is, the present invention provides a crystal of (S)-1-(4-(dimethylamino)piperidin-1-yl)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)propan-1-one (hereinafter referred to as Compound (I)) represented by the following chemical formula (I) or a pharmacologically acceptable salt thereof.

[Chemistry 1]

The crystal preferably has peaks at diffraction angles 2θ (°) of 15.3, 16.0, 19.0, 21.8, and 23.0 in powder X-ray diffraction, and more preferably has a heat absorption peak at 120-124° C. in simultaneous differential thermal and thermogravimetric analysis.

The crystals are low in hygroscopicity, excellent in solubility, and chemical and physical stability as a pharmaceutical, and have a purification effect during production.

The pharmacologically acceptable salt is preferably an edisylate salt. The crystals of the edisylate salt of Compound (I) preferably have peaks at diffraction angles 2θ (°) of 12.6, 16.0, 17.7, 18.5, and 21.3 in powder X-ray diffraction, and more preferably have a thermal absorption peak at 173-177°C in simultaneous differential thermal and thermogravimetric analysis.

The crystals are low in hygroscopicity, excellent in solubility, and chemical and physical stability as a pharmaceutical, and have a purification effect during production.

The present invention also provides a medicament comprising a crystal of Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.

The drug is preferably an analgesic, and more preferably a neuropathic pain therapeutic drug or a fibromyalgia therapeutic drug.

The above-mentioned neuropathic pain therapeutic agent or fibromyalgia therapeutic agent exhibits excellent analgesic effect, particularly therapeutic effect on neuropathic pain or fibromyalgia, has good storage stability, and can be administered orally or parenterally, either directly or by mixing with a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition comprising a crystal of Compound (I) or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.

Furthermore, the present invention provides a crystal of Compound (I) or a pharmacologically acceptable salt thereof for use as a medicament.

The present invention also provides a crystal of Compound (I) or a pharmacologically acceptable salt thereof for use in the treatment of pain, particularly neuropathic pain or fibromyalgia.

Furthermore, the present invention provides use of a crystal of Compound (I) or a pharmacologically acceptable salt thereof for treating pain, particularly neuropathic pain or fibromyalgia.

The present invention also provides use of a crystal of Compound (I) or a pharmacologically acceptable salt thereof in the manufacture of a medicament for treating pain, particularly neuropathic pain or fibromyalgia.

Furthermore, the present invention provides a method for treating pain, particularly neuropathic pain or fibromyalgia, comprising administering a therapeutically effective amount of a crystal of Compound (I) or a pharmacologically acceptable salt thereof to a patient in need of treatment.

Effects of the Invention

The crystals of the present invention exhibit a strong analgesic effect on pain, particularly neuropathic pain and/or fibromyalgia, and have low hygroscopicity, excellent solubility, and chemical and physical stability compared to amorphous forms, making them suitable as active ingredients in pharmaceuticals.

BRIEF DESCRIPTION OF THE DRAWINGS

[ Fig. 1 ] Powder X-ray diffraction pattern of Form A crystal of Compound (I).

[ Fig. 2 ] A differential thermal analysis curve of the A-type crystal of Compound (I) obtained by simultaneous differential thermal analysis and thermogravimetric analysis.

[ Fig. 3 ] Powder X-ray diffraction pattern of type B crystals of edisylate salt of compound (I).

[ Fig. 4 ] A differential thermal analysis curve of the B-type crystal of the edisylate salt of Compound (I) obtained by simultaneous differential thermal analysis and thermogravimetric analysis.

[ Fig. 5 ] A graph showing the effects of Compound (I) on spinal nerve ligation model rats (oral administration).

[ Fig. 6 ] A graph showing the effect of compound (I) on fibromyalgia model rats (oral administration).

DETAILED DESCRIPTION

The crystal of the present invention is characterized in that it is a crystal of Compound (I) or a pharmacologically acceptable salt thereof. Representative crystals of Compound (I) include Form A crystals described in detail below, and representative crystals of salts of Compound (I) include Form B crystals of edisylate.

A crystalline form can be identified by characteristic peaks in a powder X-ray diffraction pattern and/or endothermic peaks in a differential thermal analysis curve (hereinafter referred to as a DTA curve) obtained by simultaneous differential thermal analysis (hereinafter referred to as TG-DTA). It should be noted that powder X-ray diffraction patterns and DTA curves may vary somewhat depending on the measurement conditions. For example, the diffraction angle 2θ in a powder X-ray diffraction pattern generally allows an error of ±0.2°.

As shown in Figure 1, the Form A crystals of Compound (I) are characterized by having peaks at diffraction angles 2θ (°) of 15.3, 16.0, 19.0, 21.8, and 23.0 in powder X-ray diffraction. Furthermore, the Form A crystals of Compound (I) exhibit a DTA curve as shown in Figure 2, which shows an endothermic peak at 122°C, i.e., between 120°C and 124°C.

As shown in Figure 3 , the B-type crystals of the edisylate salt of Compound (I) are characterized by having peaks at diffraction angles 2θ (°) of 12.6, 16.0, 17.7, 18.5, and 21.3 in powder X-ray diffraction. Furthermore, the B-type crystals of the edisylate salt of Compound (I) exhibit a DTA curve as shown in Figure 4 , which has endothermic peaks at 175°C, i.e., at 173-177°C.

Powder X-ray diffraction patterns of the A-form crystals of Compound (I) were obtained by measuring the powder X-ray diffraction pattern using a powder X-ray diffraction apparatus under the following conditions. The measurement sample was prepared by filling a sample plate (material: silicon; depth: 0.2 mm) with the sample and then flattening the sample surface.

Powder X-ray Diffraction Conditions

X-ray source: CuKα rays

*Using bent crystal monochromator (graphite)

Output power: 40kV/50mA

Divergence slit: 1/2°

Divergence longitudinal limiting slit: 5mm

Anti-scatter slit: 1/2°

Receiving slit: 0.15mm

Detector: Scintillation counter

Scanning mode: 2θ/θ scanning, continuous scanning

Measuring range (2θ): 2~40°

Scanning speed (2θ): 2°/min

Counting step (2θ): 0.02°.

Powder X-ray diffraction patterns of the B-form crystals of the edisylate salt of Compound (I) can be obtained using a powder X-ray diffraction apparatus under the following conditions. The measurement sample is prepared by filling a sample plate (material: silicon; depth: 0.2 mm) with the sample and flattening the sample surface.

Powder X-ray Diffraction Conditions

X-ray source: CuKα rays

*Using bent crystal monochromator (graphite)

Output power: 40kV/50mA

Divergence slit: 1/2°

Divergence longitudinal limiting slit: 5mm

Anti-scatter slit: 1/2°

Receiving slit: 0.15mm

Detector: Scintillation counter

Scanning mode: 2θ/θ scanning, continuous scanning

Measuring range (2θ): 2~30°

Scanning speed (2θ): 4°/min

Counting step (2θ): 0.02°.

The endothermic peak refers to the temperature of the peak top shown on the DTA curve. Here, TG-DTA for obtaining the DTA curve can be measured using a TG-DTA apparatus under the following conditions.

TG-DTA Conditions

Heating rate: 5℃/min

Atmosphere: dry nitrogen (flow rate: 100 mL/min)

Sample cell: Aluminum open cell (アルミニウムオープンセル)

Sample size: 1~15mg.

Form A crystals of Compound (I) can be obtained by dissolving any form of Compound (I) in ethyl acetate at a concentration of 10 to 400 mg/mL and allowing to stand or stir at room temperature.

Alternatively, the Form A crystals of Compound (I) can be obtained by dissolving any form of Compound (I) in a solvent, preferably an alcohol-based, aromatic-based, ether-based, ketone-based, ester-based, halogen-based or nitrile-based solvent, adding the previously obtained Form A crystals of Compound (I) as seed crystals, and then allowing the mixture to stand or stir at room temperature.

Examples of the alcoholic solvent include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol, and 3-methyl-1-butanol.

Examples of the aromatic solvent include benzene, chlorobenzene, toluene, xylene, and cumene.

Examples of the ether solvent include diethyl ether, tetrahydrofuran, tert-butyl methyl ether, and 1,4-dioxane.

Examples of the ketone solvent include acetone, 2-butanone, 4-methyl-2-pentanone, and 2-hexanone.

Examples of the ester solvent include ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, and n-butyl acetate.

Examples of the halogen-based solvent include chloroform, dichloromethane, and 1,2-dichloroethylene.

Examples of the nitrile solvent include acetonitrile and propionitrile.

Pharmacologically acceptable salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide or phosphate; organic carboxylates such as acetate, trifluoroacetate, lactate, citrate, maleate, benzoate, oxalate, malonate, gluconate, glutarate, malate, tartrate, salicylate, xinafoate, ascorbate, adipate, cinnamate, fumarate, mandelate, succinate or pamoate; and organic sulfonates such as methanesulfonate, p-toluenesulfonate, camphorsulfonate or edisylate.

Form B crystals of the edisylate salt of Compound (I) can be obtained by adding 1,2-ethanedisulfonic acid dihydrate and distilled water to any form of Compound (I), dissolving the mixture, removing the solvent by freeze-drying, and then adding acetone and allowing the mixture to stand or stir at room temperature.

The analgesic effect of the crystals of Compound (I) or a pharmacologically acceptable salt thereof, in particular the therapeutic effect on neuropathic pain and/or fibromyalgia, can be evaluated using appropriate animal models. Suitable animal models for neuropathic pain include, for example, the spinal nerve ligation model in mice or rats (Kim et al., Pain, 1992, Vol. 50, pp. 355-363) or the partial sciatic nerve ligation model in mice or rats (Malmberg et al., Pain, 1998, Vol. 76, pp. 215-222). Suitable animal models for fibromyalgia include, for example, mouse or rat fibromyalgia models (Sluka et al., Journal of Pharmacology and Experimental Therapeutics, 2002, vol. 302, pp. 1146-1150; Nagakura et al., Pain, 2009, vol. 146, pp. 26-33; Sluka et al., Pain, 2009, vol. 146, pp. 3-4).

The crystals of Compound (I) or a pharmacologically acceptable salt thereof have excellent analgesic effects, particularly therapeutic effects on neuropathic pain and/or fibromyalgia, and are therefore useful as pharmaceuticals, preferably as analgesics, and particularly preferably as therapeutic agents for neuropathic pain and/or fibromyalgia.

Examples of the neuropathic pain include cancer pain, herpes zoster pain, postherpetic neuralgia, AIDS-related neuralgia, diabetic neuropathy pain (diabetic neuropathy pain), and trigeminal neuralgia.

The above-mentioned fibromyalgia refers to symptoms diagnosed as fibromyalgia by a specialist. The specialist's diagnosis is usually made based on the classification criteria of the American College of Rheumatology.

Crystals of compound (I) or a pharmacologically acceptable salt thereof are also useful for the treatment of acute and chronic pain. Acute pain is generally short-term and includes, for example, postoperative pain, pain after tooth extraction, or trigeminal neuralgia. Chronic pain is generally defined as pain that lasts for 3 to 6 months and includes both physical and psychological pain, and includes, for example, chronic rheumatoid arthritis, osteoarthritis, or postherpetic neuralgia.

When the crystals of Compound (I) or a pharmacologically acceptable salt thereof are administered to mammals (e.g., mice, rats, hamsters, rabbits, dogs, monkeys, cattle, sheep or humans), they exhibit excellent analgesic effects, particularly therapeutic effects on neuropathic pain and/or fibromyalgia.

When the crystals of Compound (I) or a pharmacologically acceptable salt thereof are used as a drug, the crystals of Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as they are or after being mixed with a pharmaceutically acceptable carrier.

As dosage forms for oral administration of a drug containing a crystal of compound (I) or a pharmacologically acceptable salt thereof as an active ingredient, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions or suspensions can be cited. In addition, as dosage forms for parenteral administration of a drug containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient, for example, injections, infusions, drops, suppositories, coatings (applicators) or patches (attaches) can be cited. Furthermore, it is also effective to combine with an appropriate base (for example, a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid-glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, or a polyglycerol fatty acid ester) to prepare a sustained-release preparation.

The preparation of the above-mentioned dosage form can be carried out according to the known manufacturing method usually adopted in the field of preparation. At this time, as required, it can contain, for example, an excipient, binder, lubricant, disintegrant, sweetener, surfactant, suspending agent or emulsifier usually used in the field of preparation and manufacture.

Tablets can be prepared by containing, for example, excipients, binders, disintegrants, or lubricants, while pills and granules can be prepared by containing, for example, excipients, binders, or disintegrants. Furthermore, powders and capsules can be prepared by containing, for example, excipients, syrups can be prepared by containing, for example, sweeteners, and emulsions or suspensions can be prepared by containing, for example, surfactants, suspending agents, or emulsifiers.

Examples of the excipient include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

Examples of the binder include starch paste, gum arabic solution, gelatin solution, tragacanth gum solution, carboxymethylcellulose solution, sodium alginate solution, and glycerin.

Examples of disintegrants include starch and calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.

Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.

Examples of the surfactant include sodium lauryl sulfate, Tween 80, sorbitan monofatty acid ester, and polyethylene glycol stearate 40.

Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.

Examples of the emulsifier include gum arabic, gum tragacanth, gelatin, and Tween 80.

Furthermore, when the drug containing the crystals of Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient is prepared into the above-mentioned dosage form, colorants, preservatives, fragrances, flavoring agents, stabilizers, thickeners, etc. commonly used in the pharmaceutical field may be added.

The dosage of the crystals of Compound (I) or a pharmacologically acceptable salt thereof when administered clinically as a drug is appropriately selected depending on the symptoms, age, body weight, sex, or method of administration. For example, when administered orally to an adult (weighing approximately 60 kg), it is preferably administered in 1 to 3 divided doses in the range of 1 to 1000 mg of the active ingredient. When administered parenterally to an adult (weighing approximately 60 kg), if it is an injection, it is preferably administered by intravenous injection in the range of 0.01 to 100 mg of the active ingredient per 1 kg of body weight.

In order to supplement or enhance the therapeutic or preventive effect, or to reduce the dosage, the crystals of compound (I) or its pharmacologically acceptable salt can be appropriately mixed or used in combination with other drugs. As other drugs in this case, for example, antidepressants such as amitriptyline, milnacipran or duloxetine, antianxiety drugs such as alprazolam, anticonvulsants such as carbamazepine, local anesthetics such as lidocaine, sympathomimetics such as epinephrine, NMDA receptor antagonists such as ketamine, GABA transaminase inhibitors such as sodium valproate, calcium channel blockers such as pregabalin, serotonin receptor antagonists such as risperidone, GABA receptor function promoters such as diazepam, or anti-inflammatory drugs such as diclofenac can be listed.

Example

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Compound (I) and its raw materials and intermediates were synthesized by the methods described in the following Reference Examples. For compounds used in the synthesis of Reference Example compounds for which no synthesis method was described, commercially available compounds were used.

In the following descriptions, the solvent name shown in the NMR data refers to the solvent used in the measurement. 400 MHz NMR spectra were measured using a JNM-AL400 nuclear magnetic resonance instrument (manufactured by JEOL Ltd.). Chemical shifts are expressed in δ (ppm) relative to tetramethylsilane, with signals represented by s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), br (broad), dd (doublet of doublets), dt (double triplet), ddd (triplet of doublets), dq (double quartet), td (triplet of doublets), and tt (triplet of triplets). ESI-MS spectra were measured using an Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology). All solvents were commercially available. Flash column chromatography used a YFLC W-prep2XY (manufactured by Yamazen Co., Ltd.).

(Reference Example 1) Preparation of amorphous compound (I):

To a solution of 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-methyl-1H-imidazol-2-yl)propane-1,3-dione (3.0 g, 10.8 mmol) in isopropanol (90 mL) was added ruthenium(II) chloride (175 mg, 0.263 mmol) under a nitrogen atmosphere. The mixture was stirred at an internal temperature of 80°C for 18 hours. The reaction mixture was concentrated, and 42.8 g of distilled water was transferred to a separatory funnel. After extraction with ethyl acetate, the ethyl acetate layer was extracted with distilled water. All aqueous layers were combined and concentrated. After concentration, ethyl acetate was added, and azeotropic dehydration was performed using an evaporator. The residue was replaced with chloroform, and the concentrate was purified by silica gel column chromatography (NH silica gel, chloroform). The mixture was dried under reduced pressure at 40°C or less for 40 hours to obtain an amorphous form of Compound (I) (2.45 g, 8.7 mmol, 81%). Powder X-ray diffraction analysis confirmed that the compound was amorphous.

High-performance liquid chromatography (HPLC) retention time: 19.0 min, instrument: Prominence HPLC system manufactured by Shimadzu Corporation, detection wavelength: 210 nm, column: Scherzo SS-C18 (inner diameter: 3.0 mm, length: 150 mm, particle size: 3 μm) (intact), column temperature: 40°C, mobile phase A: 10 mmol/L aqueous potassium dihydrogen phosphate solution/acetonitrile = 90/10 (v/v), mobile phase B: 100 mmol/L aqueous potassium dihydrogen phosphate solution/acetonitrile = 50/50 (v/v), mobile phase B composition: 0-5 minutes: 30%, 5-15 minutes: 30→100%, 15-25 minutes: 100%, 25-25.1 minutes: 100→30%, 25.1-30 minutes: 30%, flow rate: 1.0 mL/min, sample injection volume: 10 μL.

(Reference Example 2) Synthesis of 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-methyl-1H-imidazol-2-yl)propane-1,3-dione:

【Chemistry 2】

To a solution of 1-(4-dimethylaminopiperidin-1-yl)ethanone (1.00 g, 5.87 mmol) in tetrahydrofuran (20 mL) was added dropwise a solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 7.05 mL, 14.1 mmol) at -78°C, followed by stirring at the same temperature for 1 hour. A solution of ethyl 1-methyl-1H-imidazole-2-carboxylate (1.09 g, 7.05 mmol) in tetrahydrofuran (9.0 mL) was added to the reaction mixture at the same temperature, followed by stirring for 1 hour and then further stirring at 0°C for 1 hour. Saturated aqueous ammonium chloride and aqueous potassium carbonate were added to the reaction mixture in that order, followed by extraction with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, hexane/ethyl acetate) to obtain 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-methyl-1H-imidazol-2-yl)propane-1,3-dione (0.990 g, 3.56 mmol, 61%) as a colorless oil.

(Reference Example 3) Synthesis of 1-(4-dimethylaminopiperidin-1-yl)ethanone:

【Chemistry 3】

To a solution of 4-dimethylaminopiperidine (1.00 g, 7.79 mmol) in dichloromethane (7.8 mL) at 0°C were added pyridine (0.922 mL, 9.75 mmol) and acetic anhydride (0.946 mL, 11.7 mmol), and the reaction mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform/methanol) to obtain 1-(4-dimethylaminopiperidin-1-yl)ethanone (0.869 g, 6.78 mmol, 87%) as a colorless oil.

(Reference Example 4) Synthesis of ethyl 1-methyl-1H-imidazole-2-carboxylate:

【Chemistry 4】

To a solution of 1-methyl-1H-imidazole (1.00 g, 12.2 mmol) in acetonitrile (4.0 mL) was added triethylamine (3.40 mL, 24.4 mmol) and ethyl chloroformate (2.34 mL, 24.4 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to obtain ethyl 1-methyl-1H-imidazole-2-carboxylate (1.50 g, 9.73 mmol, 80%) as a white solid.

(Example 1) Preparation of Form A Crystal of Compound (I) (Method 1):

The amorphous body (5 mg) of compound (I) was weighed into a borosilicate glass vial, ethyl acetate (28 μL) was added and dissolved (concentration 180 mg/mL). After vibrating and stirring for 6 hours at room temperature and in an airtight state, it was heated at 55 ° C for 10 minutes and then further vibrated and stirred at room temperature for 4 and a half hours. After confirming the precipitate, the solvent was removed and dried under reduced pressure for 30 minutes with a vacuum pump to obtain a white powder. The obtained powder was subjected to powder X-ray diffraction measurement using a powder X-ray diffraction device (Li Gaku Co., Ltd.; 2200/RINT ultima+PC) and TG-DTA using a TG-DTA device (Li Gaku Co., Ltd.; TG8120). The results of these measurements are shown in Figures 1 and 2.

Diffraction angle 2θ: 15.3, 16.0, 19.0, 21.8, 23.0°

Endothermic peak: 122℃.

(Example 2) Preparation of Form A Crystal of Compound (I) (Method 2):

The amorphous body (5 mg) of compound (I) was weighed into a borosilicate glass vial, ethyl acetate (17 μL or 25 μL) was added and dissolved (concentration 300 mg/mL or 200 mg/mL). It was vibrated and stirred for 3 days at room temperature and in an airtight state. Precipitate was confirmed in each system, and therefore, the solvent was removed and dried under reduced pressure for 30 minutes with a vacuum pump to obtain a white powder. The obtained solid was subjected to powder X-ray diffraction under the following conditions, and it was confirmed that the result was consistent with Figure 1.

Powder X-ray Diffraction Conditions

X-ray source: CuKα rays

*Using bent crystal monochromator (graphite)

Output power: 40kV/50mA

Divergence slit: 1/2°

Divergence longitudinal limiting slit: 5mm

Anti-scatter slit: 1/2°

Receiving slit: 0.15mm

Detector: Scintillation counter

Scanning mode: 2θ/θ scanning, continuous scanning

Measuring range (2θ): 2~30°

Scanning speed (2θ): 20°/min

Counting step (2θ): 0.04°.

(Example 3) Preparation of Form A Crystal of Compound (I) (Method 3):

The amorphous body (5 mg) of compound (I) was weighed into a borosilicate glass vial, and each solvent described in Table 1 was added in the amount described in Table 1 and dissolved. After adding type A crystal (0.1 mg) of compound (1) as a seed crystal, the mixture was vibrated and stirred at room temperature for 14 hours. Precipitates were confirmed from each system, and therefore, each solvent was removed and dried under reduced pressure for 30 minutes using a vacuum pump to obtain a white solid. Powder X-ray diffraction was performed on each solid obtained under the following conditions, and it was confirmed that the result was consistent with Figure 1.

[Table 1]

.

Powder X-ray Diffraction Conditions

X-ray source: CuKα rays

*Using bent crystal monochromator (graphite)

Output power: 40kV/50mA

Divergence slit: 1/2°

Divergence longitudinal limiting slit: 5mm

Anti-scatter slit: 1/2°

Receiving slit: 0.15mm

Detector: Scintillation counter

Scanning mode: 2θ/θ scanning, continuous scanning

Measuring range (2θ): 2~30°

Scanning speed (2θ): 20°/min

Counting step (2θ): 0.04°.

(Example 4) Purification Effect of Form A Crystal of Compound (I) by Recrystallization

The A-type crystals (80 mg) of compound (I) were weighed into a borosilicate glass vial, ethyl acetate (0.8 mL) was added, heated to 60 ° C and stirred to dissolve (concentration 100 mg / mL). It was cooled to room temperature and stirred for 3 hours in an airtight state. The precipitate was filtered, washed with ethyl acetate, and then dried under reduced pressure for 1 hour with a vacuum pump to obtain a white powder. The obtained powder was subjected to powder X-ray diffraction measurement using a powder X-ray diffraction device (Ligaku Co., Ltd.; 2200/RINT ultima+PC), and the results were confirmed to be consistent with Figure 1. The chemical purity and optical purity before and after recrystallization were determined by HPLC under the following conditions. The results are shown in Table 2. The 20 mmol/L potassium dihydrogen phosphate and 5 mmol/L sodium octylsulfonate aqueous solution (hereinafter referred to as Solution X) used in the HPLC mobile phase was prepared by weighing potassium dihydrogen phosphate (8.2 g) and sodium 1-octylsulfonate (3.2 g), adding them to distilled water (3 L), and stirring to dissolve them. The sample for HPLC analysis was prepared by dissolving Form A crystals of Compound (I) (1 mg) in 1 mL of methanol.

HPLC conditions for determining chemical purity

Instrument: LC-30AD system manufactured by Shimadzu Corporation

Detection wavelength: 210nm, 300nm

Column: Kinetex 1.7 μm C18 (inner diameter: 2.1 mm, length: 100 mm, particle size: 1.7 μm) (Phenomenex)

Column temperature: 40°C

Mobile phase A: solution X

Mobile phase B: acetonitrile

Composition of mobile phase B: 0-5 minutes: 5→50%, 5-7 minutes: 50%, 7-7.1 minutes: 50→5%, 7.1-10 minutes: 5%

Flow rate: 0.4 mL/min

Sample injection volume: 2.5 μL.

HPLC conditions for optical purity determination

Instrument: LC-20AD system manufactured by Shimadzu Corporation

Detection wavelength: 220nm

Column: CHIRALCEL OZ-3 (inner diameter: 4.6 mm, length: 250 mm, particle size: 3 μm) (Daicel)

Column temperature: 40°C

Mobile phase: methanol/ethylenediamine (100:0.1)

Flow rate: 0.5mL/min

Sample injection volume: 2 μL.

[Table 2]

Chemical purity Optical purity Before recrystallization 98.4% 89.1%ee After recrystallization 99.8% 98.4%ee

As shown in Table 2, the chemical purity and optical purity of the Form A crystals of Compound (I) were improved by recrystallization. These results indicate that recrystallization has a purification effect on the crystals of Compound (I).

(Example 5) Preparation of Type B Crystals of Ethylenedisulfonate Salt of Compound (I):

After adding 1,2-ethanedisulfonic acid dihydrate (11 mg) and distilled water (2 mL) to compound (I) (200 mg) and dissolving it, the solution (0.25 mL) was weighed into a borosilicate glass vial and the solvent was removed by freeze drying. Acetone (0.13 mL) was added and stirred at room temperature. After confirming the precipitate, the solvent was removed with a Pasteur pipette and dried under reduced pressure for 3 hours with a vacuum pump to obtain a white solid. The obtained solid was subjected to powder X-ray diffraction measurement using a powder X-ray diffraction device (Ligaku Co., Ltd.; 2200/RINT ultima+PC) and TG-DTA using a TG-DTA device (Ligaku Co., Ltd.; TG8120). The results of these measurements are shown in Figures 3 and 4.

Diffraction angle 2θ: 12.6, 16.0, 17.7, 18.5 and 21.3°

Endothermic peak: 175℃.

(Example 6) Effects in Neuropathic Pain Model Rats:

The analgesic effect of crystals of Compound (I) or a pharmacologically acceptable salt thereof on neuropathic pain was evaluated using the spinal nerve ligation rat model (Kim and Chung, Pain, 1992, Vol. 50, p. 355). Form A crystals of Compound (I) or a pharmacologically acceptable salt thereof were used for the evaluation.

This model rat was prepared as follows. Six- to seven-week-old male SD rats were used, with 5 to 7 rats per group. Under isoflurane inhalation anesthesia, the skin and muscle at the lumbar region were incised to expose the L5 and L6 sciatic nerves. The L5 and L6 spinal nerves were ligated with silk thread, and the wounds were sutured. This served as the nerve ligation group. A group in which the nerves were exposed but not ligated served as the sham surgery group.

The determination of abnormal pain confirmed in the spinal nerve ligation model rat was carried out according to the method described in the known literature (Chaplan et al., J. Neurosci. Methods, 1994, Vol. 53, p. 55), using von Frey filament to obtain the 50% reaction threshold (g). 8 days after the ligation operation, the abnormal pain of the nerve ligation group was measured before oral administration of the A-type crystal of compound (I). Rats with a 50% reaction threshold (average value of the right hind limb and the left hind limb) of 2 g or more and less than 6 g were considered to have abnormal pain, and were equally grouped in a manner that there was no significant difference in the 50% reaction threshold of the neuropathic pain model rats. The abnormal pain was measured 3 hours after oral administration of the A-type crystal of compound (I) to evaluate the analgesic effect. Pregabalin was used as a positive control.

Compound (I) Form A crystals were dissolved in water for injection (distilled water) at concentrations of 5, 10, and 20 mg/mL and orally administered at a volume of 1 mL per kg of body weight. Pregabalin was dissolved in water for injection (distilled water) at a concentration of 10 mg/mL and orally administered at a volume of 1 mL per kg of body weight. Water for injection (distilled water) was orally administered to the sham-operated group. A group in which water for injection (distilled water) was orally administered to rats in the nerve ligation group served as a negative control group.

The results are shown in Figure 5. The horizontal axis represents the amount of each solution administered to each group, i.e., the nerve ligation group or the sham surgery group, and the vertical axis represents the 50% response threshold (g) (mean ± standard error, n = 5-7). The negative control group was used as a control for the efficacy evaluation, and statistical analysis was performed using a t-test (pregabalin-administered group) or a Shirley-Williams test (Form A crystals of Compound (I)) for two unrelated groups. * and # in Figure 5 indicate statistically significant differences compared to the negative control group ("nerve ligation - 0 mg/kg" group in Figure 5) (*: p < 0.05; #: p < 0.025).

Oral administration of 5 mg/kg, 10 mg/kg, and 20 mg/kg of Form A crystals of Compound (I) and oral administration of 10 mg/kg of pregabalin as a positive control significantly improved allodynia observed in neuropathic pain model rats compared to the negative control group. This result indicates that crystals of Compound (I) or a pharmacologically acceptable salt thereof are effective for treating neuropathic pain.

(Example 7) Effects in Fibromyalgia Model Rats:

The analgesic effect of crystals of Compound (I) or a pharmacologically acceptable salt thereof on fibromyalgia was evaluated using fibromyalgia model rats (Sluka et al., Journal of Pharmacology and Experimental Therapeutics, 2002, Vol. 302, pp. 1146-1150; Nagakura et al., Pain, 2009, Vol. 146, pp. 26-33; Sluka et al., Pain, 2009, Vol. 146, pp. 3-4). Form A crystals of Compound (I) or a pharmacologically acceptable salt thereof were used for the evaluation.

The model rats were prepared as follows. 6-7 week old SD male rats were used in the experiment. 5-6 rats were grouped together and, under isoflurane inhalation anesthesia, 100 μL of an acidic saline solution adjusted to pH 4.0 was injected twice into the gastrocnemius muscle of the rat's right hind limb (the acidic saline solution was administered starting day as the first day of the experiment, and was administered once on the first and sixth days of the experiment). This was done as an acidic saline solution group. As a control for the model, a group that was treated similarly with normal saline solution instead of acidic saline solution was used as the normal saline solution group.

The determination of the abnormal pain confirmed in the fibromyalgia model rat was carried out according to the method described in the known literature (Chaplan et al., Journal of Neuroscience Methods, 1994, Vol. 53, p.55-63), using Von Frey filament to obtain 50% reaction threshold (g). The experiment started on the 7th day, and the abnormal pain after 3 hours of oral administration of the A-type crystal of compound (I) was measured to evaluate the analgesic effect. The abnormal pain of the acidic physiological saline group was measured before oral administration of the A-type crystal of compound (I), and the rats whose 50% reaction threshold (the average value of the right hind limb and the left hind limb) before oral administration by intramuscular injection of acidic physiological saline reached 6g or less were considered to be abnormal pain onset. As fibromyalgia model rats, equal groups were grouped so that there was no significant difference in the 50% reaction threshold. The abnormal pain after 3 hours of oral administration of the crystal of compound (I) was measured to evaluate the analgesic effect. Positive control used pregabalin.

Compound (I) Form A crystals were dissolved in water for injection (distilled water) at concentrations of 0.1, 1, and 10 mg/mL and orally administered at a volume of 1 mL per kg of body weight. Pregabalin was dissolved in water for injection (distilled water) at a concentration of 10 mg/mL and orally administered at a volume of 1 mL per kg of body weight. A group in which rats in the acidic saline group were administered water for injection (distilled water) served as a negative control group.

The results are shown in Figure 6. The horizontal axis represents the amount of each solution administered to each group, i.e., the acidic saline solution group or the saline solution group, while the vertical axis represents the 50% response threshold (g) (average of the right and left hindlimbs) (mean ± standard error, n = 5-6). The negative control group was used as a control for the efficacy evaluation, and statistical analysis was performed using a t-test (pregabalin-administered group) or a William's test (compound (I) crystal-administered group) for two unrelated groups. The ‡ or $ in Figure 6 indicate a statistically significant difference compared to the negative control group (the "acidic saline solution - 0 mg/kg" group in Figure 6) (‡: p < 0.05; $: p < 0.025).

Oral administration of 1 mg/kg and 10 mg/kg of Form A crystals of Compound (I) and oral administration of 10 mg/kg of pregabalin as a positive control significantly improved allodynia observed in fibromyalgia model rats compared to the negative control group. This result indicates that crystals of Compound (I) or a pharmacologically acceptable salt thereof are effective for treating fibromyalgia.

(Comparative Example 1) Study on the acquisition of crystals of Compound (I) (Selection of crystallization solvent: Initial crystallization study using various solvents):

The amorphous body of compound (I) (10 mg) was weighed into a borosilicate glass vial, and the solvents described in Table 3 were added in the amounts of each solvent described in Table 3 to confirm whether it was dissolved. As a result, it was completely dissolved in any solvent at 500 mg/mL or more. Then, it was stirred and vibrated for 7 days at room temperature in an airtight state, but no solid was precipitated. Cyclohexane and heptane were not completely dissolved at low concentrations (3 mg/mL) and were therefore judged to be unsuitable as crystallization solvents.

[Table 3]

.

These results indicate that even at high solute concentrations of 500 mg/mL or higher, crystals of Compound (I) could not be obtained. Furthermore, these solvents have very high solubility at room temperature and are therefore unsuitable as crystallization solvents.

(Example 8) Hygroscopicity evaluation:

The equilibrium moisture content of the A-type crystal and amorphous form of Compound (I) was measured using a fully automatic moisture adsorption analyzer (VTI-SA+, TI Instruments, Inc.) under the following conditions. The weight gain (moisture absorption) was evaluated when the relative humidity was increased from 5% to 70%. Changes in appearance were also confirmed. The results are shown in Table 4.

Equilibrium Moisture Content Measurement Conditions

Sample size: 5~15mg

Measurement temperature: 30°C

Balance setting weight/time: 0.01wt%/5 minutes

Maximum balancing time: 180 minutes

Measuring range: relative humidity 5%~relative humidity 70%~relative humidity 5%

Measuring interval: relative humidity 5%.

In order to also evaluate whether the crystal form has changed, the A-type crystals after the hygroscopicity evaluation test were subjected to powder X-ray diffraction measurement.

The weight of Form A crystals of Compound (I) did not increase with humidification to a relative humidity of 65%, nor did they deliquesce or change their crystalline form. On the other hand, the amorphous form deliquesced into an oily substance at a relative humidity of less than 5%. These results demonstrate that the crystals of Compound (I) or a pharmacologically acceptable salt thereof have excellent physical stability.

[Table 4]

Weight gain† Appearance changes A-type crystals 0.1% Maintain white powder (no deliquesce)

†Indicates the weight increase when humidifying from 5% relative humidity to 65% relative humidity.

(Example 9) Solubility evaluation:

Compound (I) Form A crystals (100 mg) were weighed into a borosilicate glass vial and added with 1 mL of the Japanese Pharmacopoeia No. 16 Revised Disintegration Test Solution 1/Dissolution Test Solution 1 (pH 1.2) or 1 mL of the Japanese Pharmacopoeia No. 16 Revised Disintegration Test Solution 2 (pH 6.8) in a temperature and humidity test chamber (Ameflex Corporation; NO DOORα) adjusted to 37°C, followed by stirring. Compound (I) Form B crystals (10 mg) of the edisylate salt were weighed into a borosilicate glass vial and added with 0.1 mL of the Japanese Pharmacopoeia No. 16 Revised Disintegration Test Solution 2 (pH 6.8) in a temperature and humidity test chamber (Ameflex Corporation; NO DOORα) adjusted to 37°C, followed by stirring. After 30 minutes, the contents of the vial were visually inspected to confirm complete dissolution.

[Table 5]

.

As shown in Table 5, the solubility of the Form A crystal of Compound (I) and the Form B crystal of the edisylate salt of Compound (I) was 100 mg/mL or more. This result indicates that the crystals of Compound (I) or a pharmacologically acceptable salt thereof have very excellent solubility.

(Example 10) Storage stability evaluation:

The chemical purity and optical purity of the Form A crystals and amorphous form of Compound (I) were measured by HPLC before and after storage at 40°C in an airtight state for 8 weeks or at 60°C in an airtight state for 4 weeks under the following conditions. The results are shown in Table 6. The sample for HPLC analysis was prepared by dissolving the Form A crystals (1 mg) of Compound (I) or the amorphous form (1 mg) of Compound (I) in 1 mL of methanol.

HPLC conditions for determining chemical purity

Instrument: LC-30AD system manufactured by Shimadzu Corporation

Detection wavelength: 210nm, 300nm

Column: Kinetex C18 (inner diameter: 2.1 mm, length: 100 mm, particle size: 1.7 μm) (Phenomenex)

Column temperature: 40°C

Mobile phase A: solution X

Mobile phase B: acetonitrile

Composition of mobile phase B: 0-5 minutes: 5→50%, 5-7 minutes: 50%, 7-7.1 minutes: 50→5%, 7.1-10 minutes: 5%

Flow rate: 0.4 mL/min

Sample injection volume: 2.5 μL.

HPLC conditions for optical purity determination

Instrument: LC-20AD system manufactured by Shimadzu Corporation

Detection wavelength: 220nm

Column: CHIRALCEL OZ-3 (inner diameter: 4.6 mm, length: 250 mm, particle size: 3 μm) (Daicel)

Column temperature: 40°C

Mobile phase: methanol/ethylenediamine (100:0.1)

Flow rate: 0.5mL/min

Sample injection volume: 2 μL

[Table 6]

1) Regarding the increase in the amount of each decomposition product, the relative retention time (hereinafter referred to as RRT. RRT is calculated by dividing the retention time of the decomposition product by the HPLC chromatogram by the retention time of the original compound by the HPLC chromatogram) of 0.8 was 0.40%, the decomposition product with RRT0.8 was 0.60%, the decomposition product with RRT0.9 was 1.47%, and the decomposition product with RRT1.1 was 0.21%.

2) Regarding the increase in the amount of each decomposition product, the decomposition product of RRT0.7 is 0.16%, the decomposition product of RRT0.8 is 0.63%, the decomposition product of RRT0.8 is 2.22%, the decomposition product of RRT0.9 is 3.71%, the decomposition product of RRT1.1 is 0.17%, the decomposition product of RRT1.1 is 0.59%, and the decomposition product of RRT1.2 is 0.45%.

Table 6 shows that the purity of the crystals of Compound (I) or its pharmacologically acceptable salt after storage in an airtight state under accelerated conditions does not change from the initial value, and the chemical stability is much better than that of the amorphous form.

(Example 11) Evaluation of storage stability of A-type crystals:

Form A crystals of Compound (I) were stored under three different storage conditions (Storage Test 1: 25°C, 60% relative humidity, open for 6 months; Storage Test 2: 40°C, 75% relative humidity, airtight for 6 months; Storage Test 3: 60°C, airtight for 6 months). The chemical and optical purities before and after storage were measured by HPLC. The HPLC conditions are as follows. The 5 mmol/L potassium dihydrogen phosphate aqueous solution (hereinafter referred to as Solution Y) used in the HPLC mobile phase was prepared by weighing potassium dihydrogen phosphate (1.4 g), adding distilled water (2.1 L), and stirring to dissolve. Separately, the 200 mmol/L potassium dihydrogen phosphate aqueous solution (hereinafter referred to as Solution Z) was prepared by weighing potassium dihydrogen phosphate (40.8 g), adding distilled water (1.5 L), and stirring to dissolve. In addition, samples for HPLC analysis were prepared by weighing crystals of Compound (I) (10 mg) into 10 mL volumetric flasks and adjusting the total volume to 10 mL with a mixture of Solution Y/acetonitrile = 70:30 (v/v).

HPLC conditions for determining chemical purity

Instrument: LC-10ADvp system manufactured by Shimadzu Corporation

Detection wavelength: 210nm

Column: Scherzo SS-C18 (inner diameter: 4.6 mm, length: 150 mm, particle size: 3 μm) (intact)

Column temperature: 30°C

Mobile phase A: solution Y/acetonitrile = 70:30 (v/v)

Mobile phase B: solution Z/acetonitrile = 50:50 (v/v)

Composition of mobile phase B: 0-5 minutes: 0%, 5-50 minutes: 0→35%, 50-60 minutes: 35→100%, 60-83 minutes: 100%, 83-83.1 minutes: 100→0%, 83.1-95 minutes: 0%

Flow rate: 1.0 mL/min

Sample injection volume: 10 μL.

HPLC conditions for optical purity determination

Instrument: LC-10ADvp system manufactured by Shimadzu Corporation

Detection wavelength: 220nm

Column: CHIRALCEL OZ-3 (inner diameter: 4.6 mm, length: 250 mm, particle size: 3 μm) (Daicel)

Column temperature: 30°C

Mobile phase: methanol/1-propanol/ethylenediamine (60:40:0.1)

Flow rate: 0.3mL/min

Sample injection volume: 20 μL.

In addition, powder X-ray diffraction and TG-DTA were performed to evaluate whether the crystal form changed during storage. The results are shown in Table 7.

[Table 7]

.

As shown in Table 7, the purity and crystalline form of Compound (I) Form A crystals remained unchanged during storage tests 1 to 3. These results indicate that the crystals of Compound (I) or a pharmacologically acceptable salt thereof have excellent chemical and physical stability.

Claims (10)

1. Crystals of (S)-1-(4-(dimethylamino)piperidin-1-yl)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)propane-1-one, which exhibit peaks in powder X-ray diffraction at diffraction angles 2θ (°) of 15.3±0.2, 16.0±0.2, 19.0±0.2, 21.8±0.2 and 23.0±0.2. 2. The crystal according to claim 1, which has a thermal absorption peak at 120~124℃ in differential thermal-thermogravimetric analysis. 3. Crystals of (S)-1-(4-(dimethylamino)piperidin-1-yl)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)propane-1-one ethanedisulfonate, which exhibit peaks in powder X-ray diffraction at diffraction angles of 2θ (°) 12.6±0.2, 16.0±0.2, 17.7±0.2, 18.5±0.2 and 21.3±0.2. 4. The crystallization according to claim 3, wherein it has a thermal absorption peak at 173~177℃ in simultaneous differential thermal and thermogravimetric analysis. 5. A medicine comprising the crystal as an active ingredient as described in any one of claims 1 to 4. 6. An analgesic, comprising the crystal as any one of claims 1 to 4 as an active ingredient. 7. A treatment for neuropathic pain or fibromyalgia, comprising the crystals as any one of claims 1 to 4 as an active ingredient. 8. A pharmaceutical composition comprising crystals as described in any one of claims 1 to 4 and a support permitted as a pharmaceutical. 9. Use of the crystal according to any one of claims 1 to 4 in the manufacture of analgesics. 10. Use of the crystal according to any one of claims 1 to 4 in the manufacture of a medicament for treating neuropathic pain or fibromyalgia.