WO2021153743A1 - Crystals of cyclic amine derivative and pharmaceutical use thereof - Google Patents

Crystals of cyclic amine derivative and pharmaceutical use thereof Download PDF

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Publication number
WO2021153743A1
WO2021153743A1 PCT/JP2021/003275 JP2021003275W WO2021153743A1 WO 2021153743 A1 WO2021153743 A1 WO 2021153743A1 JP 2021003275 W JP2021003275 W JP 2021003275W WO 2021153743 A1 WO2021153743 A1 WO 2021153743A1
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compound
crystals
crystal
solution
type crystal
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PCT/JP2021/003275
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French (fr)
Japanese (ja)
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萌子 久保木
元明 白木
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東レ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to crystals of cyclic amine derivatives and their pharmaceutical uses.
  • Pain is an experience with unpleasant sensations and emotions that occurs when or may cause tissue damage. Pain is mainly classified into nociceptive pain, neuropathic pain or psychogenic pain according to its cause. In addition, fibromyalgia is known as pain of unknown cause.
  • Neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself, and is caused by direct damage or compression of nervous tissue even though nociceptors are not stimulated. It refers to the pain that occurs.
  • an anticonvulsant, an antidepressant, anxiolytic, or an antiepileptic drug such as gabapentin or pregabalin is used.
  • Fibromyalgia is a disease in which systemic pain is the main symptom and neuropsychiatric symptoms and autonomic nervous system symptoms are secondary symptoms.
  • Pregabalin approved in the United States and Japan, duloxetine and milnacipran approved in the United States are mainly used as therapeutic agents for fibromyalgia, and non-approved agents for fibromyalgia are not approved. It has also been used for steroidal anti-inflammatory agents, opioid compounds, antidepressants, anticonvulsants and antiepileptic drugs. However, the therapeutic effects of non-steroidal anti-inflammatory drugs and opioid compounds are generally considered to be low (Non-Patent Document 1).
  • Patent Document 1 discloses that certain substituted piperidins have cardiotonic activity
  • Patent Document 2 discloses that an imidazole derivative exhibits an FXa inhibitory effect
  • Patent Document 3 suggests that the substituted piperidins may have a medicinal effect on overweight or obesity
  • Patent Documents 4 to 6 and Non-Patent Document 2 indicate that the imidazole derivative has an analgesic effect. It is disclosed.
  • the quality of pharmaceutical products needs to be maintained over a long period of time such as distribution and storage, and the compound as an active ingredient is required to have high chemical and physical stability. Therefore, as the active ingredient of a pharmaceutical product, a crystal that can be expected to have higher stability than an amorphous substance is generally adopted. Further, if crystals are obtained, a purification effect due to recrystallization during production can be expected. Further, it is preferable to have low hygroscopicity from the viewpoint of maintaining stability and handling during manufacturing, storage, formulation and analysis of the drug substance. In addition, since a drug needs to be dissolved in the digestive tract in order to exhibit its medicinal effect, it is preferable that the drug has excellent solubility, which is a physical property contrary to stability.
  • neuropathic pain treatments frequently involves central side effects such as dizziness, nausea or vomiting, and new neuropathic pain treatments can be used to enable long-term administration. Development is desired.
  • new therapeutic agents for neuropathic pain and fibromyalgia that can solve the above-mentioned problems have low hygroscopicity, solubility, and chemical and physical in consideration of packaging with other agents. It is considered preferable that the crystal has excellent physical stability.
  • the substituted piperidins described in Patent Document 1 have a description suggesting their effectiveness for migraine, and the imidazole derivative described in Patent Document 5 is disclosed to have an analgesic effect. No disclosure of the compound itself that revealed the analgesic effect or any suggestion of the relationship between the analgesic effect and the chemical structure is made.
  • the imidazole derivative described in Patent Document 2 and the substituted piperidines described in Patent Document 3 have not even been disclosed or suggested to have an analgesic effect.
  • Patent Documents 1 to 3 and Patent Document 5 do not disclose the crystallization of the compound of the present invention and its salt, and do not suggest the possibility of obtaining a promising crystal as a pharmaceutical product.
  • Patent Document 4 and Non-Patent Document 2 disclose that the compound of the present invention has an analgesic effect, but there is no description regarding the formation of crystals.
  • Patent Document 6 it is described that the compound of the present invention is an oily substance, and there is a description suggesting that crystals of a sulfate of the compound of the present invention can be obtained, but it is supported that they are crystals. There is no description of data or description of specifying the crystal form.
  • an object of the present invention is to provide a crystal useful as a pharmaceutical compound having an analgesic effect on neuropathic pain and / or fibromyalgia.
  • the present invention provides crystals of compound (I) or a pharmacologically acceptable salt thereof.
  • the above pharmacologically acceptable salt crystals are preferably B-type crystals (sulfate monohydrate) or C-type crystals (pamoate).
  • the B-type crystal (sulfate monohydrate) is a crystal having peaks at diffraction angles 2 ⁇ (°) 12.3, 17.7, 18.8, 20.5 and 23.1 in powder X-ray diffraction. It is more preferable that the crystal has a heat absorption peak at 153 to 157 ° C. in the simultaneous measurement of differential thermogravimetric analysis.
  • the C-type crystal (pamoate) is a crystal having peaks at diffraction angles 2 ⁇ (°) 9.9, 13.2, 15.2, 19.6 and 22.8 in powder X-ray diffraction. It is preferable that the crystal has a heat absorption peak at 241 to 245 ° C. in the simultaneous measurement of differential thermogravimetric analysis.
  • the B-type crystal (sulfate monohydrate) and the C-type crystal (pamoate) have low hygroscopicity and are excellent in solubility and chemical and physical stability as pharmaceuticals. Highly useful.
  • the A-type crystal is preferably a crystal having peaks at diffraction angles 2 ⁇ (°) 5.9, 16.5, 17.7, 20.8 and 26.7 in powder X-ray diffraction, and has a differential thermal analysis. In the simultaneous measurement of thermogravimetric analysis, it is more preferable that the crystal has an endothermic peak at 53 to 57 ° C.
  • the A-type crystal has excellent solubility, and unlike salt crystals, it does not contain an acid corresponding to a foreign substance with respect to compound (I), so that it is excellent as a drug substance form of a pharmaceutical product.
  • the present invention also provides a medicament containing a crystal of compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the above-mentioned medicine is preferably an analgesic, and more preferably a neuropathic pain therapeutic agent or a fibromyalgia therapeutic agent.
  • neuropathic pain therapeutic agent or fibromyalgia therapeutic agent exerts an excellent analgesic effect, particularly a therapeutic effect on neuropathic pain or fibromyalgia. It has good storage stability and can be administered orally or parenterally as it is or in combination with a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition containing crystals of compound (I) or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides crystals of compound (I) or a pharmacologically acceptable salt thereof for use as a pharmaceutical.
  • the present invention also provides crystals of compound (I) or a pharmacologically acceptable salt thereof for use in the treatment of pain, particularly neuropathic pain or fibromyalgia.
  • the present invention also provides the use of crystals of compound (I) or a pharmacologically acceptable salt thereof for treating pain, particularly neuropathic pain or fibromyalgia.
  • the present invention also provides the use of crystals of compound (I) or a pharmacologically acceptable salt thereof in the manufacture of a medicament for the treatment of pain, particularly neuropathic pain or fibromyalgia.
  • the present invention is also a method for treating pain, particularly neuropathic pain or fibromyalgia, which is pharmacologically acceptable in a therapeutically effective amount of compound (I) or its pharmacologically acceptable to a patient in need of treatment.
  • methods comprising administering salt crystals.
  • the present invention also provides a method for producing crystals of compound (I) or a pharmacologically acceptable salt thereof.
  • the production method includes a step of mechanically stimulating compound (I) of any form. Is preferable.
  • the present production method preferably includes a step of dissolving the compound (I) of an arbitrary form in an arbitrary solvent and adding the A-type crystal of the compound (I) as a seed crystal to the solution.
  • the present production method adds a solvent to the amorphous body of the sulfate of compound (I). It is preferable to include a step of suspending and shaking.
  • the present production method uses an amorphous substance of the pamoate of compound (I) in an alcohol solvent. It is preferable to include a step of adding, dissolving, and shaking.
  • the crystal of the present invention has excellent solubility, low hygroscopicity as compared with an amorphous substance, and excellent chemical and physical stability, so that it can be suitably used as an active ingredient of a pharmaceutical product.
  • the crystals of the present invention can be suitably used as an active ingredient of a neuropathic pain therapeutic agent or a fibromyalgia therapeutic agent.
  • the crystal of the present invention is characterized by being a crystal of compound (I) or a pharmacologically acceptable salt thereof.
  • A-type crystal can be mentioned as a typical crystal of the compound (I)
  • a B-type crystal salt monohydrate
  • C-type crystals pamoate
  • the crystal form is identified by the characteristic peak shown by the powder X-ray diffraction diagram and / or the endothermic peak shown by the differential thermal analysis curve (hereinafter, DTA curve) obtained by the simultaneous measurement of differential thermogravimetric analysis (hereinafter, TG-DTA). can do.
  • the powder X-ray diffraction pattern and the DTA curve may change slightly depending on the measurement conditions. For example, the diffraction angle 2 ⁇ in the powder X-ray diffraction pattern generally allows an error of ⁇ 0.2 °. be.
  • the A-type crystal of compound (I) peaks at diffraction angles 2 ⁇ (°) 5.9, 16.5, 17.7, 20.8 and 26.7 in powder X-ray diffraction. It is characterized by having. Further, the A-type crystal of compound (I) gives the DTA curve shown in FIG. 2 and has an endothermic peak at 55 ° C., that is, 53 to 57 ° C.
  • the B-type crystal (sulfate monohydrate) of compound (I) has a diffraction angle of 2 ⁇ (°) 12.3, 17.7, 18.8, 20 in powder X-ray diffraction. It is characterized by having peaks at .5 and 23.1.
  • the B-type crystal (sulfate monohydrate) of compound (I) gives the DTA curve shown in FIG. 4 and has an endothermic peak at 155 ° C, that is, 153 to 157 ° C.
  • the C-type crystal (pamoate) of compound (I) has a diffraction angle of 2 ⁇ (°) 9.9, 13.2, 15.2, 19.6 and in powder X-ray diffraction. It is characterized by having a peak at 22.8.
  • the C-type crystal (pamoate) of compound (I) gives the DTA curve shown in FIG. 6 and has an endothermic peak at 243 ° C, that is, 241 to 245 ° C.
  • Powder X-ray diffraction measurement of A-type crystal, B-type crystal (sulfate monohydrate) and C-type crystal (pamoate) of compound (I) is performed under the following conditions using a powder X-ray diffractometer. Can be measured.
  • the measurement sample is prepared by filling a sample plate (material: silicon; depth: 0.2 mm) with the sample and flattening the sample surface.
  • the endothermic peak means the temperature of the peak top indicated by the DTA curve.
  • the TG-DTA for obtaining the DTA curve can be measured under the following conditions using the TG-DTA device.
  • the A-type crystal of compound (I) is obtained by purifying the compound (I) of any form with chloroform / methanol by silica gel column chromatography, concentrating it, and then rubbing the wall surface of the flask with a spartel to give a mechanical stimulus. Obtainable. Further, it can be obtained by dissolving the compound (I) of an arbitrary form in an arbitrary solvent, adding the A-type crystal of the compound (I) obtained in advance as a seed crystal, and then allowing it to stand or stir at room temperature. ..
  • Examples of the pharmacologically acceptable salt of the compound (I) include an inorganic acid salt such as a hydrochloride, a sulfate, a nitrate, a hydrobromide or a phosphate, an acetate, a trifluoroacetate, and a lactic acid.
  • an inorganic acid salt such as a hydrochloride, a sulfate, a nitrate, a hydrobromide or a phosphate, an acetate, a trifluoroacetate, and a lactic acid.
  • Organic carboxylates such as salts, silicates, fumarates, mandelates, succinates or pamoates or methanesulfonates, p-toluenesulfonates, camphorsulfonates or ethanedisulfonates.
  • Organic sulfonates such as.
  • Crystals of compound (I) or a salt thereof may be in the form of a hydrate or a solvate.
  • the B-type crystal (sulfate monohydrate) of compound (I) is a solvent, preferably alcohol-based, ether-based, ketone-based, or ester-based, in an amorphous form (10 mg) of sulfate of compound (I).
  • a solvent preferably alcohol-based, ether-based, ketone-based, or ester-based, in an amorphous form (10 mg) of sulfate of compound (I).
  • an aromatic solvent (20 ⁇ L)
  • the C-type crystal (pamoate) of compound (I) is dissolved by adding an alcohol solvent (50 ⁇ L) to an amorphous form (15 mg) of pamoate of compound (I), and shaken at room temperature for 7 days. It can be obtained by doing so.
  • alcohol-based solvent examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol or 3-methyl-1-butanol. Can be mentioned.
  • ether solvent examples include diethyl ether, tetrahydrofuran, t-butyl methyl ether and 1,4-dioxane.
  • ketone solvent examples include acetone, 2-butanone, 4-methyl-2-pentanone and 2-hexanone.
  • ester solvent examples include ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and n-butyl acetate.
  • aromatic solvent examples include benzene, chlorobenzene, toluene, xylene and cumene.
  • the analgesic effect of the crystals of compound (I) or its pharmacologically acceptable salt, particularly the therapeutic effect of neuropathic pain and / or fibromyalgia can be evaluated using an appropriate animal model.
  • Suitable animal models of neuropathic pain include, for example, a mouse or rat spinal nerve ligation model (Kim et al., Pain, 1992, Vol. 50, p. 355-363) or a mouse or rat sciatic nerve partial ligation. Models (Malmberg et al., Pain, 1998, Vol. 76, p. 215-222) can be mentioned.
  • Suitable animal models of fibromyalgia include, for example, mouse or rat fibromyalgia models (Sluca et al., Journal of Pharmacology and Experimental Therapeutics, 2002, Vol. 302, p.1146-1150; Nagakura et al., Pain, 2009, Vol. 146, p.26-33; Sluca et al., Pain, 2009, Vol. 146, p.3-4).
  • Crystals of compound (I) or a pharmacologically acceptable salt thereof have an excellent analgesic effect, particularly a therapeutic effect on neuropathic pain and / or fibromyalgia, and thus should be used as a medicine. It is preferably used as an analgesic, and particularly preferably as a neuropathic pain therapeutic agent and / or a fibromyalgia therapeutic agent.
  • neuropathic pain examples include cancer pain, herpes zoster pain, postherpetic neuralgia, AIDS-related neuralgia, diabetic neuropathy pain or trigeminal neuralgia.
  • fibromyalgia refers to a symptom diagnosed as fibromyalgia by a specialist.
  • the diagnosis of a specialist is generally made with reference to the classification criteria of the American College of Rheumatology.
  • Crystals of compound (I) or its pharmacologically acceptable salt are also useful in the treatment of acute and chronic pain.
  • Acute pain is usually short-term, but includes, for example, postoperative pain, post-extraction pain or trigeminal neuralgia.
  • Chronic pain is usually defined as pain that lasts for 3 to 6 months and includes somatic and psychogenic pain, including, for example, rheumatoid arthritis, osteoarthritis or postherpetic neuralgia. ..
  • Crystals of compound (I) or a pharmacologically acceptable salt thereof are administered, for example, to mammals (eg, mice, rats, hamsters, rabbits, dogs, monkeys, cows, sheep or humans).
  • mammals eg, mice, rats, hamsters, rabbits, dogs, monkeys, cows, sheep or humans.
  • Excellent analgesic effect especially for neuropathic pain and / or fibromyalgia.
  • the crystal of compound (I) or its pharmacologically acceptable salt is used as a medicine
  • the crystal of compound (I) or its pharmacologically acceptable salt is used as it is or a carrier which is pharmaceutically acceptable is blended. It can be administered orally or parenterally.
  • Dosage forms for oral administration of a drug containing compound (I) or a pharmacologically acceptable salt crystal thereof as an active ingredient include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, and pills. Examples include granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions or suspensions.
  • the dosage form for parenteral administration of a drug containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient includes, for example, injections, infusions, infusions, suppositories, and coatings. Examples include agents or patches.
  • a suitable base eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, mixture of butyric acid polymer and glycolic acid polymer, or polyglycerol fatty acid ester. It is also effective to combine them into a sustained-release preparation.
  • a suitable base eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, mixture of butyric acid polymer and glycolic acid polymer, or polyglycerol fatty acid ester.
  • the preparation of the above-mentioned dosage form can be carried out according to a known production method generally used in the field of preparation. In this case, if necessary, for example, it is produced by containing an excipient, a binder, a lubricant, a disintegrant, a sweetener, a surfactant, a suspending agent or an emulsifier generally used in the pharmaceutical field. can do.
  • the preparation of tablets can be carried out, for example, by incorporating an excipient, a binder, a disintegrant or a lubricant, and the preparation of pills and granules can be carried out, for example, by adding an excipient, a binder or a disintegrant. It can be contained. Also, for the preparation of powders and capsules, for example, excipients, for the preparation of syrups, for example, sweeteners, for the preparation of emulsions and suspensions, for example, surfactants, suspending agents or emulsifiers. Can be contained.
  • excipients examples include lactose, glucose, starch, sucrose, microcrystalline cellulose, citrus powder, mannitol, sodium hydrogen carbonate, calcium phosphate or calcium sulfate.
  • binder examples include starch paste solution, gum arabic solution, gelatin solution, tragant solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.
  • disintegrant examples include starch or calcium carbonate.
  • Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.
  • sweetener examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
  • suspending agent examples include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose or bentonite.
  • emulsifier examples include gum arabic, tragant, gelatin or polysorbate 80.
  • a pharmaceutical containing compound (I) or a pharmacologically acceptable salt crystal thereof is prepared as an active ingredient in the above dosage form
  • a colorant generally used in the pharmaceutical field and storage Agents, fragrances, flavoring agents, stabilizers, thickeners and the like can be added.
  • the dose for clinical administration of the compound (I) or a pharmacologically acceptable salt crystal thereof as a medicine is appropriately selected depending on the symptoms, age, body weight, sex, administration method, etc., but for example.
  • an adult body weight about 60 kg
  • parenterally administer to an adult body weight about 60 kg
  • Crystals of compound (I) or a pharmacologically acceptable salt thereof may be mixed or used in combination with other drugs in an appropriate amount in order to supplement or enhance the therapeutic or preventive effect, or to reduce the dose.
  • Other agents in this case include, for example, antidepressants such as amitriptyline, milnasiplan or duroxetin, anxiolytics such as alprazolam, anticonvulsants such as carbamazepine, local anesthetics such as lidocain, and sympathetic nerves such as adrenaline.
  • An agonist an NMDA receptor antagonist such as ketamine, a GABA transaminase inhibitor such as sodium valproate, a calcium channel blocker such as pregabalin, a serotonin receptor antagonist such as lisperidone, a GABA receptor function promoter such as diazepam, or diclofenac. And other anti-inflammatory agents.
  • the solvent name shown in the NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift was represented by ⁇ (unit: ppm) with reference to tetramethylsilane, and the signals were represented by s (single line), d (double line), and m (multiple line), respectively.
  • the ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technologies). All commercially available solvents were used.
  • YFLC W-prep2XY Yamazen Co., Ltd.
  • As the powder X-ray diffractometer 2200 / RINT ultrama + PC (Rigaku Co., Ltd.) was used.
  • As the TG-DTA apparatus TG8120 (Rigaku Co., Ltd.) was used.
  • Compound (I) was synthesized by the method described in the following reference example. Commercially available compounds were used for the compounds used in the synthesis of the reference example compounds for which the synthesis method was not described.
  • the reaction mixture was stirred at the same temperature for 30 minutes, sodium triacetoxyborohydride (8.1 g, 38.2 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 12 hours.
  • the reaction solution was cooled to 0 ° C.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 1 Production of A-type crystal of compound (I):
  • the amorphous substance (6.98 g) of compound (I) prepared in Reference Example 4 is purified by silica gel column chromatography with chloroform / methanol, concentrated, and then the wall surface of the flask is rubbed with a spartel to apply mechanical stimulation.
  • A-type crystals of compound (I) were obtained as powder.
  • measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT horr + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) was done. The results of these measurements are shown in FIGS. 1 and 2.
  • Example 2 Production of B-type crystal (sulfate monohydrate) of compound (I): 1-Propanol (20 ⁇ L) was added to the amorphous form (10 mg) of the sulfate of compound (I) prepared in Reference Example 1, suspended, and shaken at room temperature for 7 days to obtain the compound (I). B-type crystals (sulfate monohydrate) were prepared. For the obtained crystals, measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT pus + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) was done. The results of these measurements are shown in FIGS. 3 and 4. Diffraction angle 2 ⁇ : 12.3, 17.7, 18.8, 20.5, 23.1 ° Endothermic peak: 155 ° C
  • Example 3 Production of C-type crystal (pamoate) of compound (I): Methanol (50 ⁇ L) was added to an amorphous form (15 mg) of the pamoate of compound (I) prepared in Reference Example 2 to dissolve it, and the mixture was shaken at room temperature for 7 days to obtain C of compound (I). Form crystals (pamoate) were prepared.
  • measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT horr + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) was done. The results of these measurements are shown in FIGS. 5 and 6. Diffraction angle 2 ⁇ : 9.9, 13.2, 15.2, 19.6, 22.8 ° Endothermic peak: 243 ° C
  • Example 4 Hygroscopic evaluation: Fully automatic moisture adsorption measuring device (TA Instruments Co., Ltd .; VTI-SA +) for A-type crystals, B-type crystals (sulfate monohydrate) and C-type crystals (pamoate) of compound (I). ) was used to measure the equilibrium moisture content under the following conditions. The amount of weight increase (moisture absorption) when humidified from 5% to 95% relative humidity was evaluated. At the same time, the change in appearance was confirmed. The results are shown in Table 2.
  • the A-type crystal of compound (I) did not increase in weight due to humidification up to a relative humidity of 20% and did not deliquesce, but deliquescented at a relative humidity of 30% or more.
  • the B-type crystals sulfate monohydrate
  • the crystal form did not change, but deliquescented at a relative humidity of 70%.
  • the C-type crystal did not increase in weight even when humidified to a relative humidity of 95%, did not deliquesce, and did not change in crystal form.
  • the C-type crystal (pamoate) of the compound (I) is excellent in physical stability with respect to humidity, and the A-type crystal and the B-type crystal (sulfate) of the compound (I) are excellent.
  • the monohydrate) can be used as an active ingredient of a pharmaceutical product by controlling the relative humidity to less than 30% and less than 70%, respectively. Since the amorphous forms of the pamoate and the hydrochloride of the compound (I) obtained in Reference Example 2 and Reference Example 3 are deliquescent immediately after preparation, it is not suitable to be used as an active ingredient of a pharmaceutical product. there were.
  • Japanese Pharmacopoeia 16th Revised Disintegration Test 1st Solution / Dissolution Test 1st Solution (pH 1.2) (0.1mL) or Japanese Pharmacopoeia 16th Revised Disintegration Test 2nd Solution (pH 6.8) (0.1mL) ) was added and stirred. As a result of visually checking the inside of the vial after 30 minutes, it was confirmed that all of them were completely dissolved.
  • C-type crystals (pamoate) (10 mg) of this compound (I) were weighed in borosilicate glass vials and placed in a temperature / humidity test tank (Ameflex Co., Ltd .; Norda ⁇ ) adjusted to 37 ° C.
  • Japanese Pharmacopoeia 16th revised disintegration test 1st solution / dissolution test 1st solution (pH 1.2) (2mL) or Japanese Pharmacopoeia 16th revised disintegration test 2nd solution (pH 6.8) (2mL) stirred in suspension. After 2 hours, the suspension was transferred to a glass syringe with a 0.45 ⁇ m filter, the first 0.5 mL filtered was discarded and the remaining suspension was transferred to a borosilicate glass vial.
  • solution X potassium dihydrogen phosphate (2.7 g), 1-octane sulfonic acid.
  • the C-type crystal of compound (I) has a solubility of 2.38 mg / mL or more in the 16th revised disintegration test 1st solution / dissolution test 1st solution (pH 1.2) of the Japanese Pharmacopoeia. It was revealed that it was excellent in solubility.
  • the A-type crystal of compound (I) has a solubility of 300 mg / mL or more in water
  • the B-type crystal (sulfate monohydrate) of compound (I) is the 16th revised disintegration test of the Japanese Pharmacopoeia.
  • Example 6 Storage stability evaluation: The B-type crystals (sulfate monohydrate) and C-type crystals (pamoate) of compound (I) were stored at 60 ° C. in an airtight state for 4 weeks, and were subjected to HPLC under the following conditions to obtain chemical purity before and after storage. Was measured. As a sample for HPLC analysis, B-type crystals (sulfate monohydrate) (2 mg) of compound (I) or C-type crystals (pamoate) (2 mg) of compound (I) were placed in a 10 mL female flask. Each was weighed and prepared with a mixed solution of water / acetonitrile (8 / 2, v / v) to make the total volume 10 mL.
  • the B-type crystal (sulfate monohydrate) of compound (I) does not change in its chemical purity even when stored in an airtight state at 60 ° C. for 4 weeks, and the change in crystal form does not change. I was not able to admit.
  • the C-type crystal (pamoate) of compound (I) was stored at 60 ° C. in an airtight state for 4 weeks for a relative retention time (hereinafter, RRT.
  • RRT is the retention time of the decomposition product of the HPLC chromatogram / HPLC chromatogram). 1.25 decomposition product increased by 0.3%, but the degree of decomposition was small and stable storage was possible under lower temperature conditions. it was thought. From these results, it was clarified that the B-type crystal (sulfate monohydrate) and the C-type crystal (pamoate) of the compound (I) are extremely excellent in chemical and physical stability. ..

Abstract

The present invention addresses the problem of providing crystals of a compound that exhibits an analgesic action against neuropathic pain and/or fibromyalgia, the crystals being useful as a pharmaceutical. The present invention provides crystals of 1-(4-(dimethylamino)piperidin-1-yl)-3-(1-methyl-1H-imidazol-2-yl)propan-1-one or a pharmacologically acceptable salt thereof.

Description

環状アミン誘導体の結晶及びその医薬用途Crystals of cyclic amine derivatives and their pharmaceutical uses
　本発明は、環状アミン誘導体の結晶及びその医薬用途に関する。 The present invention relates to crystals of cyclic amine derivatives and their pharmaceutical uses.
　痛みとは、組織の損傷が引き起こされる時又はその可能性がある時に生じる不快な感覚や不快な情動を伴う体験のことである。痛みは、その原因により、主に、侵害受容性疼痛、神経障害性疼痛又は心因性疼痛に分類される。また、原因不明の痛みとして、線維筋痛症が知られている。 Pain is an experience with unpleasant sensations and emotions that occurs when or may cause tissue damage. Pain is mainly classified into nociceptive pain, neuropathic pain or psychogenic pain according to its cause. In addition, fibromyalgia is known as pain of unknown cause.
　神経障害性疼痛とは、末梢又は中枢神経系そのものの機能異常による病的な痛みであり、侵害受容器が侵害刺激を受けていないにもかかわらず、神経組織の直接的な損傷や圧迫等によって生じる疼痛のことをいう。神経障害性疼痛の治療薬としては、抗痙攣薬、抗うつ薬、抗不安薬又はガバペンチン若しくはプレガバリン等の抗てんかん薬が使用されている。 Neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself, and is caused by direct damage or compression of nervous tissue even though nociceptors are not stimulated. It refers to the pain that occurs. As a therapeutic agent for neuropathic pain, an anticonvulsant, an antidepressant, anxiolytic, or an antiepileptic drug such as gabapentin or pregabalin is used.
　線維筋痛症とは、全身の疼痛を主症状とし、精神神経症状や自律神経系の症状を副症状とする疾患である。線維筋痛症の治療薬としては、米国及び日本で承認されているプレガバリン、米国で承認されているデュロキセチン及びミルナシプランが主に使用され、線維筋痛症の治療薬として承認されていない非ステロイド性抗炎症薬、オピオイド化合物、抗うつ薬、抗痙攣薬及び抗てんかん薬についても使用されている。ただし、非ステロイド性抗炎症薬及びオピオイド化合物の治療効果は、一般的に低いとされている（非特許文献１）。 Fibromyalgia is a disease in which systemic pain is the main symptom and neuropsychiatric symptoms and autonomic nervous system symptoms are secondary symptoms. Pregabalin approved in the United States and Japan, duloxetine and milnacipran approved in the United States are mainly used as therapeutic agents for fibromyalgia, and non-approved agents for fibromyalgia are not approved. It has also been used for steroidal anti-inflammatory agents, opioid compounds, antidepressants, anticonvulsants and antiepileptic drugs. However, the therapeutic effects of non-steroidal anti-inflammatory drugs and opioid compounds are generally considered to be low (Non-Patent Document 1).
　その一方で、特許文献１には、ある種の置換ピペリジン類が強心活性を有していることが開示され、特許文献２には、イミダゾール誘導体がＦＸａ阻害作用を示すことが開示されており、特許文献３には、置換ピペリジン類が超過体重又は肥満に対して薬効を有する可能性が示唆されており、特許文献４～６及び非特許文献２には、イミダゾール誘導体が鎮痛作用を示すことが開示されている。 On the other hand, Patent Document 1 discloses that certain substituted piperidins have cardiotonic activity, and Patent Document 2 discloses that an imidazole derivative exhibits an FXa inhibitory effect. Patent Document 3 suggests that the substituted piperidins may have a medicinal effect on overweight or obesity, and Patent Documents 4 to 6 and Non-Patent Document 2 indicate that the imidazole derivative has an analgesic effect. It is disclosed.
　また、医薬品は、流通や保管等の長期過程に渡って品質が保持される必要があり、有効成分となる化合物には、化学的及び物理学的に高い安定性が要求されている。このため、医薬品の有効成分は、非晶質体に比べて高い安定性が期待できる結晶が採用されることが一般的である。また、結晶が得られれば、製造時の再結晶による精製効果が期待できる。さらに、安定性の維持や原薬の製造、貯蔵、製剤化及び分析時の取り扱いの観点から低吸湿性であることが好ましい。また、医薬品が薬効を示すためには、消化管内で溶解する必要があるため、安定性とは相反する物性である、溶解性においても優れていることが好ましい。 In addition, the quality of pharmaceutical products needs to be maintained over a long period of time such as distribution and storage, and the compound as an active ingredient is required to have high chemical and physical stability. Therefore, as the active ingredient of a pharmaceutical product, a crystal that can be expected to have higher stability than an amorphous substance is generally adopted. Further, if crystals are obtained, a purification effect due to recrystallization during production can be expected. Further, it is preferable to have low hygroscopicity from the viewpoint of maintaining stability and handling during manufacturing, storage, formulation and analysis of the drug substance. In addition, since a drug needs to be dissolved in the digestive tract in order to exhibit its medicinal effect, it is preferable that the drug has excellent solubility, which is a physical property contrary to stability.
　医薬品の有効成分となる化合物の結晶を取得するためには、溶液から結晶を析出させる条件を種々検討する必要があるが、室温における化合物の溶解度があまり大きくない溶媒を選択し、できる限り高濃度に溶解させた条件下で結晶化を行うことが一般的である。 In order to obtain crystals of a compound that is an active ingredient of a pharmaceutical product, it is necessary to study various conditions for precipitating crystals from the solution. It is common to carry out crystallization under the condition of being dissolved in.
仏国特許発明第２５６７８８５号明細書French Patent Invention No. 2567885 特開２００６－００８６６４号公報Japanese Unexamined Patent Publication No. 2006-0008664 国際公開第２００３／０３１４３２号International Publication No. 2003/031432 国際公開第２０１３／１４７１６０号International Publication No. 2013/147160 国際公開第２０１５／０４６４０３号International Publication No. 2015/046403 国際公開第２０１６／１３６９４４号International Publication No. 2016/136944
　しかしながら、従来の神経障害性疼痛の治療薬による治療では、めまい、悪心又は嘔吐等の中枢性の副作用が高い頻度で伴い、長期投与を可能にするには、新たな神経障害性疼痛治療薬の開発が望まれている。 However, treatment with conventional neuropathic pain treatments frequently involves central side effects such as dizziness, nausea or vomiting, and new neuropathic pain treatments can be used to enable long-term administration. Development is desired.
　また、線維筋痛症の治療薬として承認されているプレガバリン、デュロキセチン及びミルナシプランであっても、線維筋痛症に対する治療効果は臨床的に満足のいくものではなく、患者間における薬効差も大きいため、薬理活性が強く、広範囲の患者に対して治療効果を発揮する新たな線維筋痛症治療薬の開発が切望されている。 In addition, even with pregavalin, duloxetine, and milnacipran, which are approved as therapeutic agents for fibromyalgia, the therapeutic effect on fibromyalgia is not clinically satisfactory, and there are differences in drug efficacy among patients. Due to its large size, the development of a new therapeutic agent for fibromyalgia, which has strong pharmacological activity and exerts a therapeutic effect on a wide range of patients, is eagerly desired.
　さらに、上記の課題を解決し得る新たな神経障害性疼痛治療薬や線維筋痛症治療薬は、他剤との一包化を考慮して、吸湿性が低く、溶解性並びに化学的及び物理学的安定性に優れた結晶であることが好ましいと考えられる。 Furthermore, new therapeutic agents for neuropathic pain and fibromyalgia that can solve the above-mentioned problems have low hygroscopicity, solubility, and chemical and physical in consideration of packaging with other agents. It is considered preferable that the crystal has excellent physical stability.
　特許文献１に記載の置換ピペリジン類については、偏頭痛への有効性を示唆する記載があり、特許文献５に記載のイミダゾール誘導体については、鎮痛作用を有することが開示されているが、本願で鎮痛作用を明らかにした化合物自体の開示や鎮痛作用と化学構造との関連性についての示唆は一切されていない。特許文献２に記載のイミダゾール誘導体及び特許文献３に記載の置換ピペリジン類については、鎮痛作用を有する可能性すら開示も示唆もされていない。 The substituted piperidins described in Patent Document 1 have a description suggesting their effectiveness for migraine, and the imidazole derivative described in Patent Document 5 is disclosed to have an analgesic effect. No disclosure of the compound itself that revealed the analgesic effect or any suggestion of the relationship between the analgesic effect and the chemical structure is made. The imidazole derivative described in Patent Document 2 and the substituted piperidines described in Patent Document 3 have not even been disclosed or suggested to have an analgesic effect.
　さらに、特許文献１～３及び特許文献５には、本発明の化合物及びその塩の結晶化についての開示は一切なく、医薬品として有望な結晶が取得できる可能性についての示唆もされていない。特許文献４及び非特許文献２では、本発明の化合物が鎮痛作用を有することを開示しているが、結晶の形成に関する記載は一切ない。特許文献６においては、本発明の化合物は油状物であると記載されており、また、本発明の化合物の硫酸塩の結晶が取得できることを示唆する記載があるが、結晶であることを支持するデータの記載も、結晶形を特定する記載も一切ない。 Furthermore, Patent Documents 1 to 3 and Patent Document 5 do not disclose the crystallization of the compound of the present invention and its salt, and do not suggest the possibility of obtaining a promising crystal as a pharmaceutical product. Patent Document 4 and Non-Patent Document 2 disclose that the compound of the present invention has an analgesic effect, but there is no description regarding the formation of crystals. In Patent Document 6, it is described that the compound of the present invention is an oily substance, and there is a description suggesting that crystals of a sulfate of the compound of the present invention can be obtained, but it is supported that they are crystals. There is no description of data or description of specifying the crystal form.
　そこで本発明は、神経障害性疼痛及び／又は線維筋痛症に対して鎮痛作用を示す化合物の医薬品として有用な結晶を提供することを目的とする。 Therefore, an object of the present invention is to provide a crystal useful as a pharmaceutical compound having an analgesic effect on neuropathic pain and / or fibromyalgia.
　本発明者らは上記課題を解決するために鋭意研究を重ねた結果、痛み、特に神経障害性疼痛及び／又は線維筋痛症に対して強い鎮痛作用を示し、さらに、溶解性に優れ、吸湿性並びに化学的及び物理学的安定性に優れた化合物の結晶を見出すに至った。具体的には、下記の化学式（Ｉ）で示される１－（４－（ジメチルアミノ）ピペリジン－１－イル）－３－（１－メチル－１Ｈ－イミダゾール－２－イル）プロパン－１－オン（以下、化合物（Ｉ））の結晶として、Ａ形結晶を見出し、さらに、化合物（Ｉ）の薬理学的に許容される塩の結晶として、Ｂ形結晶（硫酸塩一水和物）、Ｃ形結晶（パモ酸塩）、塩酸塩結晶、メタンスルホン酸塩結晶、マレイン酸塩結晶及びフマル酸塩結晶が存在することを見出した。 As a result of intensive studies to solve the above problems, the present inventors have shown a strong analgesic effect on pain, particularly neuropathic pain and / or fibromyalgia, and also have excellent solubility and moisture absorption. We have found crystals of compounds with excellent properties and chemical and physical stability. Specifically, 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one represented by the following chemical formula (I) (Hereinafter, A-type crystals are found as crystals of compound (I)), and B-type crystals (sulfate monohydrate) and C are further used as pharmaceutically acceptable salt crystals of compound (I). It has been found that form crystals (pamoate), hydrochloride crystals, methanesulfonate crystals, maleate crystals and fumarate crystals are present.
　すなわち、本発明は、化合物（Ｉ）又はその薬理学的に許容される塩の結晶を提供する。
Figure JPOXMLDOC01-appb-C000001
 That is, the present invention provides crystals of compound (I) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000001
　上記の薬理学的に許容される塩の結晶は、Ｂ形結晶（硫酸塩一水和物）又はＣ形結晶（パモ酸塩）であることが好ましい。上記Ｂ形結晶（硫酸塩一水和物）は、粉末Ｘ線回折において、回折角２θ（°）１２．３、１７．７、１８．８、２０．５及び２３．１にピークを有する結晶であることが好ましく、示差熱熱重量同時測定において、１５３～１５７℃に熱吸収ピークを有する結晶であることがより好ましい。また、上記Ｃ形結晶（パモ酸塩）は、粉末Ｘ線回折において、回折角２θ（°）９．９、１３．２、１５．２、１９．６及び２２．８にピークを有する結晶であることが好ましく、示差熱熱重量同時測定において、２４１～２４５℃に熱吸収ピークを有する結晶であることがより好ましい。 The above pharmacologically acceptable salt crystals are preferably B-type crystals (sulfate monohydrate) or C-type crystals (pamoate). The B-type crystal (sulfate monohydrate) is a crystal having peaks at diffraction angles 2θ (°) 12.3, 17.7, 18.8, 20.5 and 23.1 in powder X-ray diffraction. It is more preferable that the crystal has a heat absorption peak at 153 to 157 ° C. in the simultaneous measurement of differential thermogravimetric analysis. The C-type crystal (pamoate) is a crystal having peaks at diffraction angles 2θ (°) 9.9, 13.2, 15.2, 19.6 and 22.8 in powder X-ray diffraction. It is preferable that the crystal has a heat absorption peak at 241 to 245 ° C. in the simultaneous measurement of differential thermogravimetric analysis.
　上記Ｂ形結晶（硫酸塩一水和物）及び上記Ｃ形結晶（パモ酸塩）は、吸湿性が低く、溶解性並びに化学的及び物理学的安定性に優れた結晶である点で医薬品として有用性が高い。 The B-type crystal (sulfate monohydrate) and the C-type crystal (pamoate) have low hygroscopicity and are excellent in solubility and chemical and physical stability as pharmaceuticals. Highly useful.
　上記Ａ形結晶は、粉末Ｘ線回折において、回折角２θ（°）５．９、１６．５、１７．７、２０．８及び２６．７にピークを有する結晶であることが好ましく、示差熱熱重量同時測定において、５３～５７℃に熱吸収ピークを有する結晶であることがより好ましい。 The A-type crystal is preferably a crystal having peaks at diffraction angles 2θ (°) 5.9, 16.5, 17.7, 20.8 and 26.7 in powder X-ray diffraction, and has a differential thermal analysis. In the simultaneous measurement of thermogravimetric analysis, it is more preferable that the crystal has an endothermic peak at 53 to 57 ° C.
　上記Ａ形結晶は、溶解性に優れ、さらに、塩の結晶とは異なり、化合物（Ｉ）に対して異物に相当する酸を含有しないため、医薬品の原薬形態としては優れている。 The A-type crystal has excellent solubility, and unlike salt crystals, it does not contain an acid corresponding to a foreign substance with respect to compound (I), so that it is excellent as a drug substance form of a pharmaceutical product.
　また本発明は、化合物（Ｉ）又はその薬理学的に許容される塩の結晶を有効成分として含有する医薬を提供する。 The present invention also provides a medicament containing a crystal of compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.
　上記医薬は、鎮痛薬であることが好ましく、神経障害性疼痛治療薬又は線維筋痛症治療薬であることがより好ましい。 The above-mentioned medicine is preferably an analgesic, and more preferably a neuropathic pain therapeutic agent or a fibromyalgia therapeutic agent.
　上記の神経障害性疼痛治療薬又は線維筋痛症治療薬は、優れた鎮痛作用、特に神経障害性疼痛又は線維筋痛症に対し治療効果を発揮する。良好な保存安定性を有し、そのまま又は医薬として許容される担体を配合して、経口的又は非経口的に投与することができる。 The above-mentioned neuropathic pain therapeutic agent or fibromyalgia therapeutic agent exerts an excellent analgesic effect, particularly a therapeutic effect on neuropathic pain or fibromyalgia. It has good storage stability and can be administered orally or parenterally as it is or in combination with a pharmaceutically acceptable carrier.
　また本発明は、化合物（Ｉ）又はその薬理学的に許容される塩の結晶及び医薬として許容される担体を含む医薬組成物を提供する。 The present invention also provides a pharmaceutical composition containing crystals of compound (I) or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.
　また本発明は、医薬として使用するための、化合物（Ｉ）又はその薬理学的に許容される塩の結晶を提供する。 The present invention also provides crystals of compound (I) or a pharmacologically acceptable salt thereof for use as a pharmaceutical.
　また本発明は、痛み、特に神経障害性疼痛又は線維筋痛症の治療に使用するための、化合物（Ｉ）又はその薬理学的に許容される塩の結晶を提供する。 The present invention also provides crystals of compound (I) or a pharmacologically acceptable salt thereof for use in the treatment of pain, particularly neuropathic pain or fibromyalgia.
　また本発明は、痛み、特に神経障害性疼痛又は線維筋痛症を治療するための、化合物（Ｉ）又はその薬理学的に許容される塩の結晶の使用を提供する。 The present invention also provides the use of crystals of compound (I) or a pharmacologically acceptable salt thereof for treating pain, particularly neuropathic pain or fibromyalgia.
　また本発明は、痛み、特に神経障害性疼痛又は線維筋痛症の治療用医薬の製造における、化合物（Ｉ）又はその薬理学的に許容される塩の結晶の使用を提供する。 The present invention also provides the use of crystals of compound (I) or a pharmacologically acceptable salt thereof in the manufacture of a medicament for the treatment of pain, particularly neuropathic pain or fibromyalgia.
　また本発明は、痛み、特に神経障害性疼痛又は線維筋痛症を治療する方法であって、治療の必要のある患者に、治療有効量の化合物（Ｉ）又はその薬理学的に許容される塩の結晶を投与することを含む方法を提供する。 The present invention is also a method for treating pain, particularly neuropathic pain or fibromyalgia, which is pharmacologically acceptable in a therapeutically effective amount of compound (I) or its pharmacologically acceptable to a patient in need of treatment. Provided are methods comprising administering salt crystals.
　また本発明は、化合物（Ｉ）又はその薬理学的に許容される塩の結晶の製造方法を提供する。例えば、化合物（Ｉ）又はその薬理学的に許容される塩の結晶が上記Ａ形結晶である場合、本製造方法は、任意の形態の化合物（Ｉ）に機械的な刺激を与える工程を含むことが好ましい。或いは、本製造方法は、任意の形態の化合物（Ｉ）を任意の溶媒に溶解し、該溶液に化合物（Ｉ）のＡ形結晶を種晶として添加する工程を含むことが好ましい。例えば、化合物（Ｉ）又はその薬理学的に許容される塩の結晶が上記Ｂ形結晶である場合、本製造方法は、化合物（Ｉ）の硫酸塩の非晶質体に、溶媒を加えて懸濁し、振とうする工程を含むことが好ましい。例えば、化合物（Ｉ）又はその薬理学的に許容される塩の結晶が上記Ｃ形結晶である場合、本製造方法は、化合物（Ｉ）のパモ酸塩の非晶質体に、アルコール系溶媒を加えて溶解し、振とうする工程を含むことが好ましい。 The present invention also provides a method for producing crystals of compound (I) or a pharmacologically acceptable salt thereof. For example, when the crystal of compound (I) or a pharmacologically acceptable salt thereof is the A-type crystal, the production method includes a step of mechanically stimulating compound (I) of any form. Is preferable. Alternatively, the present production method preferably includes a step of dissolving the compound (I) of an arbitrary form in an arbitrary solvent and adding the A-type crystal of the compound (I) as a seed crystal to the solution. For example, when the crystal of compound (I) or a pharmacologically acceptable salt thereof is the B-type crystal, the present production method adds a solvent to the amorphous body of the sulfate of compound (I). It is preferable to include a step of suspending and shaking. For example, when the crystal of compound (I) or a pharmacologically acceptable salt thereof is the above-mentioned C-type crystal, the present production method uses an amorphous substance of the pamoate of compound (I) in an alcohol solvent. It is preferable to include a step of adding, dissolving, and shaking.
　本発明の結晶は、溶解性に優れ、非晶質体に比べて、吸湿性が低く、化学的及び物理学的安定性に優れるため、医薬品の有効成分として好適に使用できる。また、本発明の結晶は、神経障害性疼痛治療薬又は線維筋痛症治療薬の有効成分として好適に使用できる。 The crystal of the present invention has excellent solubility, low hygroscopicity as compared with an amorphous substance, and excellent chemical and physical stability, so that it can be suitably used as an active ingredient of a pharmaceutical product. In addition, the crystals of the present invention can be suitably used as an active ingredient of a neuropathic pain therapeutic agent or a fibromyalgia therapeutic agent.
　本明細書は、本願の優先権の基礎である日本国特許出願第２０２０－０１４３８４号の明細書及び／又は図面に記載される内容を包含する。 This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2020-014384, which is the basis of the priority of the present application.
化合物（Ｉ）のＡ形結晶の粉末Ｘ線回折図である。It is a powder X-ray diffraction pattern of the A type crystal of compound (I). 化合物（Ｉ）のＡ形結晶の示差熱熱重量同時測定により得られた示差熱分析曲線を示す図である。It is a figure which shows the differential thermal analysis curve obtained by the differential thermogravimetric analysis simultaneous measurement of the A type crystal of compound (I). 化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）の粉末Ｘ線回折図である。It is a powder X-ray diffraction pattern of the B-type crystal (sulfate monohydrate) of compound (I). 化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）の示差熱熱重量同時測定により得られた示差熱分析曲線を示す図である。It is a figure which shows the differential thermal analysis curve obtained by the differential thermogravimetric analysis simultaneous measurement of the B-type crystal (sulfate monohydrate) of compound (I). 化合物（Ｉ）のＣ形結晶（パモ酸塩）の粉末Ｘ線回折図である。It is a powder X-ray diffraction pattern of the C-type crystal (pamoate) of compound (I). 化合物（Ｉ）のＣ形結晶（パモ酸塩）の示差熱熱重量同時測定により得られた示差熱分析曲線を示す図である。It is a figure which shows the differential thermal analysis curve obtained by the differential thermogravimetric analysis simultaneous measurement of the C-type crystal (pamoate) of compound (I).
　本発明の結晶は、化合物（Ｉ）又はその薬理学的に許容される塩の結晶であることを特徴としている。化合物（Ｉ）の結晶の代表的なものとしては、Ａ形結晶を挙げることができ、化合物（Ｉ）の塩の結晶の代表的なものとしては、Ｂ形結晶（硫酸塩一水和物）及びＣ形結晶（パモ酸塩）を挙げることができる。 The crystal of the present invention is characterized by being a crystal of compound (I) or a pharmacologically acceptable salt thereof. A-type crystal can be mentioned as a typical crystal of the compound (I), and a B-type crystal (salt monohydrate) is a typical example of the salt crystal of the compound (I). And C-type crystals (pamoate) can be mentioned.
　結晶形は、粉末Ｘ線回折図が示す特徴的なピーク及び／又は示差熱熱重量同時測定（以下、ＴＧ－ＤＴＡ）により得られる示差熱分析曲線（以下、ＤＴＡ曲線）が示す吸熱ピークによって識別することができる。なお、粉末Ｘ線回折図及びＤＴＡ曲線は測定条件によって多少変わり得るものであり、例えば、粉末Ｘ線回折図における回折角２θは、一般的に±０．２°の誤差は許容されるものである。 The crystal form is identified by the characteristic peak shown by the powder X-ray diffraction diagram and / or the endothermic peak shown by the differential thermal analysis curve (hereinafter, DTA curve) obtained by the simultaneous measurement of differential thermogravimetric analysis (hereinafter, TG-DTA). can do. The powder X-ray diffraction pattern and the DTA curve may change slightly depending on the measurement conditions. For example, the diffraction angle 2θ in the powder X-ray diffraction pattern generally allows an error of ± 0.2 °. be.
　化合物（Ｉ）のＡ形結晶は、図１に示すように、粉末Ｘ線回折において、回折角２θ（°）５．９、１６．５、１７．７、２０．８及び２６．７にピークを有することを特徴とする。また、化合物（Ｉ）のＡ形結晶は、図２に示すＤＴＡ曲線を与え、５５℃、すなわち５３～５７℃に吸熱ピークを有する。 As shown in FIG. 1, the A-type crystal of compound (I) peaks at diffraction angles 2θ (°) 5.9, 16.5, 17.7, 20.8 and 26.7 in powder X-ray diffraction. It is characterized by having. Further, the A-type crystal of compound (I) gives the DTA curve shown in FIG. 2 and has an endothermic peak at 55 ° C., that is, 53 to 57 ° C.
　化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）は、図３に示すように、粉末Ｘ線回折において、回折角２θ（°）１２．３、１７．７、１８．８、２０．５及び２３．１にピークを有することを特徴とする。また、化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）は、図４に示すＤＴＡ曲線を与え、１５５℃、すなわち１５３～１５７℃に吸熱ピークを有する。 As shown in FIG. 3, the B-type crystal (sulfate monohydrate) of compound (I) has a diffraction angle of 2θ (°) 12.3, 17.7, 18.8, 20 in powder X-ray diffraction. It is characterized by having peaks at .5 and 23.1. The B-type crystal (sulfate monohydrate) of compound (I) gives the DTA curve shown in FIG. 4 and has an endothermic peak at 155 ° C, that is, 153 to 157 ° C.
　化合物（Ｉ）のＣ形結晶（パモ酸塩）は、図５に示すように、粉末Ｘ線回折において、回折角２θ（°）９．９、１３．２、１５．２、１９．６及び２２．８にピークを有することを特徴とする。また、化合物（Ｉ）のＣ形結晶（パモ酸塩）は、図６に示すＤＴＡ曲線を与え、２４３℃、すなわち２４１～２４５℃に吸熱ピークを有する。 As shown in FIG. 5, the C-type crystal (pamoate) of compound (I) has a diffraction angle of 2θ (°) 9.9, 13.2, 15.2, 19.6 and in powder X-ray diffraction. It is characterized by having a peak at 22.8. The C-type crystal (pamoate) of compound (I) gives the DTA curve shown in FIG. 6 and has an endothermic peak at 243 ° C, that is, 241 to 245 ° C.
　化合物（Ｉ）のＡ形結晶、Ｂ形結晶（硫酸塩一水和物）及びＣ形結晶（パモ酸塩）の粉末Ｘ線回折測定は、粉末Ｘ線回折装置を用いて、以下の条件で測定することができる。なお、測定試料は、試料板（材質：ケイ素；深さ：０．２ｍｍ）に試料を充填し、試料表面を平らにならして作製される。 Powder X-ray diffraction measurement of A-type crystal, B-type crystal (sulfate monohydrate) and C-type crystal (pamoate) of compound (I) is performed under the following conditions using a powder X-ray diffractometer. Can be measured. The measurement sample is prepared by filling a sample plate (material: silicon; depth: 0.2 mm) with the sample and flattening the sample surface.
≪粉末Ｘ線回折条件≫
　　Ｘ線源　　　　　　　　：　ＣｕＫα線
　　＊湾曲結晶モノクロメータ（グラファイト）を使用
　　出力　　　　　　　　　：　４０ｋＶ／５０ｍＡ
　　発散スリット　　　　　：　１／２°
　　発散縦制限スリット　　：　５ｍｍ
　　散乱スリット　　　　　：　１／２°
　　受光スリット　　　　　：　０．１５ｍｍ
　　検出器　　　　　　　　：　シンチレーションカウンタ
　　スキャン方式　　　　　：　２θ／θスキャン、連続スキャン
　　測定範囲（２θ）　　　：　２～４０°（Ａ形結晶、Ｂ形結晶（硫酸塩一水和物））、２～３０°（Ｃ形結晶（パモ酸塩））
　　スキャン速度（２θ）　：　２°／ｍｉｎ（Ａ形結晶、Ｂ形結晶（硫酸塩一水和物））、４°／ｍｉｎ（Ｃ形結晶（パモ酸塩））
　　計数ステップ（２θ）　：　０．０２° ≪Powder X-ray diffraction conditions≫
X-ray source: CuKα ray * Curved crystal monochromator (graphite) is used Output: 40kV / 50mA
Divergence slit: 1/2 °
Divergence vertical restriction slit: 5 mm
Scattering slit: 1/2 °
Light receiving slit: 0.15 mm
Detector: Scintillation counter Scan method: 2θ / θ scan, continuous scan Measurement range (2θ): 2 to 40 ° (A type crystal, B type crystal (sulfate monohydrate)), 2 to 30 ° (C type) Crystal (pamoate))
Scan rate (2θ): 2 ° / min (A-type crystal, B-type crystal (sulfate monohydrate)), 4 ° / min (C-type crystal (pamoate))
Counting step (2θ): 0.02 °
　吸熱ピークとは、ＤＴＡ曲線が示すピークトップの温度をいう。ここでＤＴＡ曲線を得るためのＴＧ－ＤＴＡは、ＴＧ－ＤＴＡ装置を用いて、以下の条件で測定することができる。 The endothermic peak means the temperature of the peak top indicated by the DTA curve. Here, the TG-DTA for obtaining the DTA curve can be measured under the following conditions using the TG-DTA device.
≪ＴＧ－ＤＴＡ条件≫
　　昇温速度　：　５℃／ｍｉｎ（Ｂ形結晶（硫酸塩一水和物））、１０℃／ｍｉｎ（Ａ形結晶、Ｃ形結晶（パモ酸塩））
　　雰囲気　　：　乾燥窒素（流量：１００ｍＬ／ｍｉｎ）
　　試料セル　：　アルミニウムオープンセル
　　試料量　　：　５～６ｍｇ（Ａ形結晶、Ｃ形結晶（パモ酸塩））
１０ｍｇ（Ｂ形結晶（硫酸塩一水和物）） ≪TG-DTA conditions≫
Temperature rise rate: 5 ° C / min (B-type crystal (sulfate monohydrate)), 10 ° C / min (A-type crystal, C-type crystal (pamoate))
Atmosphere: Dry nitrogen (flow rate: 100 mL / min)
Sample cell: Aluminum open cell Sample amount: 5 to 6 mg (A-type crystal, C-type crystal (pamoate))
10 mg (B-type crystal (sulfate monohydrate))
　化合物（Ｉ）のＡ形結晶は、任意の形態の化合物（Ｉ）をシリカゲルカラムクロマトグラフィーにてクロロホルム/メタノールで精製、濃縮後、スパーテルでフラスコの壁面を擦り、機械的な刺激を与えることにより得ることができる。また、任意の形態の化合物（Ｉ）を任意の溶媒に溶解し、予め得ておいた化合物（Ｉ）のＡ形結晶を種晶として添加後、室温で静置又は撹拌して得ることができる。 The A-type crystal of compound (I) is obtained by purifying the compound (I) of any form with chloroform / methanol by silica gel column chromatography, concentrating it, and then rubbing the wall surface of the flask with a spartel to give a mechanical stimulus. Obtainable. Further, it can be obtained by dissolving the compound (I) of an arbitrary form in an arbitrary solvent, adding the A-type crystal of the compound (I) obtained in advance as a seed crystal, and then allowing it to stand or stir at room temperature. ..
　化合物（Ｉ）の薬理学的に許容される塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩若しくはリン酸塩等の無機酸塩、酢酸塩、トリフルオロ酢酸塩、乳酸塩、クエン酸塩、マレイン酸塩、安息香酸塩、シュウ酸塩、マロン酸塩、グルコン酸塩、グルタル酸塩、リンゴ酸塩、酒石酸塩、サリチル酸塩、キシナホ酸塩、アスコルビン酸塩、アジピン酸塩、ケイ皮酸塩、フマル酸塩、マンデル酸塩、コハク酸塩若しくはパモ酸塩等の有機カルボン酸塩又はメタンスルホン酸塩、ｐ－トルエンスルホン酸塩、カンファースルホン酸塩若しくはエタンジスルホン酸塩等の有機スルホン酸塩が挙げられる。 Examples of the pharmacologically acceptable salt of the compound (I) include an inorganic acid salt such as a hydrochloride, a sulfate, a nitrate, a hydrobromide or a phosphate, an acetate, a trifluoroacetate, and a lactic acid. Salt, citrate, maleate, benzoate, oxalate, malonate, gluconate, glutarate, malate, tartrate, salicylate, xinafoate, ascorbate, adipic acid Organic carboxylates such as salts, silicates, fumarates, mandelates, succinates or pamoates or methanesulfonates, p-toluenesulfonates, camphorsulfonates or ethanedisulfonates. Organic sulfonates such as.
　化合物（Ｉ）又はその塩の結晶は、水和物又は溶媒和物の形態であってもよい。 Crystals of compound (I) or a salt thereof may be in the form of a hydrate or a solvate.
　化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）は、化合物（Ｉ）の硫酸塩の非晶質体（１０ｍｇ）に、溶媒、好ましくはアルコール系、エーテル系、ケトン系、エステル系又は芳香族系の溶媒（２０μＬ）を加えて懸濁し、室温で７日間振とうすることで得ることができる。 The B-type crystal (sulfate monohydrate) of compound (I) is a solvent, preferably alcohol-based, ether-based, ketone-based, or ester-based, in an amorphous form (10 mg) of sulfate of compound (I). Alternatively, it can be obtained by adding an aromatic solvent (20 μL), suspending the mixture, and shaking at room temperature for 7 days.
　化合物（Ｉ）のＣ形結晶（パモ酸塩）は、化合物（Ｉ）のパモ酸塩の非晶質体（１５ｍｇ）に、アルコール系溶媒（５０μＬ）を加えて溶解し、室温で７日間振とうすることで得ることができる。 The C-type crystal (pamoate) of compound (I) is dissolved by adding an alcohol solvent (50 μL) to an amorphous form (15 mg) of pamoate of compound (I), and shaken at room temperature for 7 days. It can be obtained by doing so.
　上記のアルコール系溶媒としては、例えば、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、２－メチル－１－プロパノール、１－ペンタノール又は３－メチル－１－ブタノールが挙げられる。 Examples of the alcohol-based solvent include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 1-pentanol or 3-methyl-1-butanol. Can be mentioned.
　上記のエーテル系溶媒としては、例えば、ジエチルエーテル、テトラヒドロフラン、ｔ－ブチルメチルエーテル又は１，４－ジオキサンが挙げられる。 Examples of the above-mentioned ether solvent include diethyl ether, tetrahydrofuran, t-butyl methyl ether and 1,4-dioxane.
　上記のケトン系溶媒としては、例えば、アセトン、２－ブタノン、４－メチル－２－ペンタノン又は２－ヘキサノンが挙げられる。 Examples of the above-mentioned ketone solvent include acetone, 2-butanone, 4-methyl-2-pentanone and 2-hexanone.
　上記のエステル系溶媒としては、例えば、ギ酸エチル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸イソブチル又は酢酸ｎ－ブチルが挙げられる。 Examples of the above ester solvent include ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and n-butyl acetate.
　上記の芳香族系溶媒としては、例えば、ベンゼン、クロロベンゼン、トルエン、キシレン又はクメンが挙げられる。 Examples of the above aromatic solvent include benzene, chlorobenzene, toluene, xylene and cumene.
　化合物（Ｉ）又はその薬理学的に許容される塩の結晶の鎮痛作用、特に神経障害性疼痛及び／又は線維筋痛症の治療効果は、適切な動物モデルを用いて評価することができる。神経障害性疼痛の適切な動物モデルとしては、例えば、マウス若しくはラットの脊髄神経結紮モデル（Ｋｉｍら、Ｐａｉｎ、１９９２年、第５０巻、ｐ．３５５－３６３）又はマウス若しくはラットの坐骨神経部分結紮モデル（Ｍａｌｍｂｅｒｇら、Ｐａｉｎ、１９９８年、第７６巻、ｐ．２１５－２２２）が挙げられる。線維筋痛症の適切な動物モデルとしては、例えば、マウス又はラットの線維筋痛症モデル（Ｓｌｕｋａら、Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ　ａｎｄ　Ｅｘｐｅｒｉｍｅｎｔａｌ　Ｔｈｅｒａｐｅｕｔｉｃｓ、２００２年、第３０２巻、ｐ．１１４６－１１５０；　Ｎａｇａｋｕｒａら、Ｐａｉｎ、２００９年、第１４６巻、ｐ．２６－３３；　Ｓｌｕｋａら、Ｐａｉｎ、２００９年、第１４６巻、ｐ．３－４）が挙げられる。 The analgesic effect of the crystals of compound (I) or its pharmacologically acceptable salt, particularly the therapeutic effect of neuropathic pain and / or fibromyalgia, can be evaluated using an appropriate animal model. Suitable animal models of neuropathic pain include, for example, a mouse or rat spinal nerve ligation model (Kim et al., Pain, 1992, Vol. 50, p. 355-363) or a mouse or rat sciatic nerve partial ligation. Models (Malmberg et al., Pain, 1998, Vol. 76, p. 215-222) can be mentioned. Suitable animal models of fibromyalgia include, for example, mouse or rat fibromyalgia models (Sluca et al., Journal of Pharmacology and Experimental Therapeutics, 2002, Vol. 302, p.1146-1150; Nagakura et al., Pain, 2009, Vol. 146, p.26-33; Sluca et al., Pain, 2009, Vol. 146, p.3-4).
　化合物（Ｉ）又はその薬理学的に許容される塩の結晶は、優れた鎮痛作用、特に神経障害性疼痛及び／又は線維筋痛症の治療効果を有していることから、医薬として用いることができ、鎮痛薬として好ましく用いられ、特に神経障害性疼痛治療薬及び／又は線維筋痛症治療薬として好ましく用いられる。 Crystals of compound (I) or a pharmacologically acceptable salt thereof have an excellent analgesic effect, particularly a therapeutic effect on neuropathic pain and / or fibromyalgia, and thus should be used as a medicine. It is preferably used as an analgesic, and particularly preferably as a neuropathic pain therapeutic agent and / or a fibromyalgia therapeutic agent.
　上記の神経障害性疼痛としては、例えば、癌性疼痛、帯状疱疹痛、帯状疱疹後神経痛、エイズ関連神経痛、糖尿病性神経障害痛又は三叉神経痛が挙げられる。 Examples of the above-mentioned neuropathic pain include cancer pain, herpes zoster pain, postherpetic neuralgia, AIDS-related neuralgia, diabetic neuropathy pain or trigeminal neuralgia.
　上記の線維筋痛症とは、専門医により線維筋痛症であると診断された症状をいう。専門医の診断は、一般には、米国リウマチ学会の分類基準を参考に行われる。 The above-mentioned fibromyalgia refers to a symptom diagnosed as fibromyalgia by a specialist. The diagnosis of a specialist is generally made with reference to the classification criteria of the American College of Rheumatology.
　化合物（Ｉ）又はその薬理学的に許容される塩の結晶は、急性及び慢性疼痛の治療にも有用である。急性疼痛は、通常短期間であるが、例えば、術後疼痛、抜歯後疼痛又は三叉神経痛が挙げられる。慢性疼痛は、通常３～６ヶ月間持続する疼痛と定義され、かつ、体因性疼痛及び心因性疼痛を含むが、例えば、慢性関節リウマチ、変形性関節症又は帯状疱疹後神経痛が挙げられる。 Crystals of compound (I) or its pharmacologically acceptable salt are also useful in the treatment of acute and chronic pain. Acute pain is usually short-term, but includes, for example, postoperative pain, post-extraction pain or trigeminal neuralgia. Chronic pain is usually defined as pain that lasts for 3 to 6 months and includes somatic and psychogenic pain, including, for example, rheumatoid arthritis, osteoarthritis or postherpetic neuralgia. ..
　化合物（Ｉ）又はその薬理学的に許容される塩の結晶は、例えば、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、イヌ、サル、ウシ、ヒツジ又はヒト）に対して投与した場合に、優れた鎮痛作用、特に神経障害性疼痛及び／又は線維筋痛症に対し治療効果を発揮する。 Crystals of compound (I) or a pharmacologically acceptable salt thereof are administered, for example, to mammals (eg, mice, rats, hamsters, rabbits, dogs, monkeys, cows, sheep or humans). , Excellent analgesic effect, especially for neuropathic pain and / or fibromyalgia.
　化合物（Ｉ）又はその薬理学的に許容される塩の結晶を医薬として用いる場合、化合物（Ｉ）又はその薬理学的に許容される塩の結晶を、そのまま又は医薬として許容される担体を配合して、経口的又は非経口的に投与することができる。 When the crystal of compound (I) or its pharmacologically acceptable salt is used as a medicine, the crystal of compound (I) or its pharmacologically acceptable salt is used as it is or a carrier which is pharmaceutically acceptable is blended. It can be administered orally or parenterally.
　化合物（Ｉ）又はその薬理学的に許容される塩の結晶を有効成分として含有する医薬を経口投与する場合の剤形としては、例えば、錠剤（糖衣錠及びフィルムコーティング錠を含む）、丸剤、顆粒剤、散剤、カプセル剤（ソフトカプセル剤及びマイクロカプセル剤を含む）、シロップ剤、乳剤又は懸濁剤が挙げられる。また、化合物（Ｉ）又はその薬理学的に許容される塩を有効成分として含有する医薬を非経口投与する場合の剤形としては、例えば、注射剤、注入剤、点滴剤、坐剤、塗布剤又は貼付剤が挙げられる。さらには、適当な基剤（例えば、酪酸の重合体、グリコール酸の重合体、酪酸－グリコール酸の共重合体、酪酸の重合体とグリコール酸の重合体との混合物又はポリグリセロール脂肪酸エステル）と組み合わせて、徐放性製剤とすることも有効である。 Dosage forms for oral administration of a drug containing compound (I) or a pharmacologically acceptable salt crystal thereof as an active ingredient include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, and pills. Examples include granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions or suspensions. The dosage form for parenteral administration of a drug containing compound (I) or a pharmacologically acceptable salt thereof as an active ingredient includes, for example, injections, infusions, infusions, suppositories, and coatings. Examples include agents or patches. In addition, with a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, mixture of butyric acid polymer and glycolic acid polymer, or polyglycerol fatty acid ester). It is also effective to combine them into a sustained-release preparation.
　上記の剤形の製剤の調製は、製剤分野において一般的に用いられる公知の製造方法に従って行うことができる。この場合、必要に応じて、例えば、製剤分野において一般的に用いられる賦形剤、結合剤、滑沢剤、崩壊剤、甘味剤、界面活性剤、懸濁化剤又は乳化剤を含有させて製造することができる。 The preparation of the above-mentioned dosage form can be carried out according to a known production method generally used in the field of preparation. In this case, if necessary, for example, it is produced by containing an excipient, a binder, a lubricant, a disintegrant, a sweetener, a surfactant, a suspending agent or an emulsifier generally used in the pharmaceutical field. can do.
　錠剤の調製は、例えば、賦形剤、結合剤、崩壊剤又は滑沢剤を含有させて行うことができ、丸剤及び顆粒剤の調製は、例えば、賦形剤、結合剤又は崩壊剤を含有させて行うことができる。また、散剤及びカプセル剤の調製は、例えば、賦形剤を、シロップ剤の調製は、例えば、甘味剤を、乳剤及び懸濁剤の調製は、例えば、界面活性剤、懸濁化剤又は乳化剤を含有させて行うことができる。 The preparation of tablets can be carried out, for example, by incorporating an excipient, a binder, a disintegrant or a lubricant, and the preparation of pills and granules can be carried out, for example, by adding an excipient, a binder or a disintegrant. It can be contained. Also, for the preparation of powders and capsules, for example, excipients, for the preparation of syrups, for example, sweeteners, for the preparation of emulsions and suspensions, for example, surfactants, suspending agents or emulsifiers. Can be contained.
　賦形剤としては、例えば、乳糖、ブドウ糖、デンプン、ショ糖、微結晶セルロース、カンゾウ末、マンニトール、炭酸水素ナトリウム、リン酸カルシウム又は硫酸カルシウムが挙げられる。 Examples of excipients include lactose, glucose, starch, sucrose, microcrystalline cellulose, citrus powder, mannitol, sodium hydrogen carbonate, calcium phosphate or calcium sulfate.
　結合剤としては、例えば、デンプンのり液、アラビアゴム液、ゼラチン液、トラガント液、カルボキシメチルセルロース液、アルギン酸ナトリウム液又はグリセリンが挙げられる。 Examples of the binder include starch paste solution, gum arabic solution, gelatin solution, tragant solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.
　崩壊剤としては、例えば、デンプン又は炭酸カルシウムが挙げられる。 Examples of the disintegrant include starch or calcium carbonate.
　滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム又は精製タルクが挙げられる。 Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.
　甘味剤としては、例えば、ブドウ糖、果糖、転化糖、ソルビトール、キシリトール、グリセリン又は単シロップが挙げられる。 Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.
　界面活性剤としては、例えば、ラウリル硫酸ナトリウム、ポリソルベート８０、ソルビタンモノ脂肪酸エステル又はステアリン酸ポリオキシル４０が挙げられる。 Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
　懸濁化剤としては、例えば、アラビアゴム、アルギン酸ナトリウム、カルボキシメチルセルロースナトリウム、メチルセルロース又はベントナイトが挙げられる。 Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose or bentonite.
　乳化剤としては、例えば、アラビアゴム、トラガント、ゼラチン又はポリソルベート８０が挙げられる。 Examples of the emulsifier include gum arabic, tragant, gelatin or polysorbate 80.
　さらに、化合物（Ｉ）又はその薬理学的に許容される塩の結晶を有効成分として含有する医薬を、上記の剤形に調製する場合には、製剤分野において一般的に用いられる着色剤、保存剤、芳香剤、矯味剤、安定剤又は粘稠剤等を添加することができる。 Furthermore, when a pharmaceutical containing compound (I) or a pharmacologically acceptable salt crystal thereof is prepared as an active ingredient in the above dosage form, a colorant generally used in the pharmaceutical field and storage Agents, fragrances, flavoring agents, stabilizers, thickeners and the like can be added.
　化合物（Ｉ）又はその薬理学的に許容される塩の結晶を医薬として、臨床で投与する場合の用量は、症状、年齢、体重、性別又は投与方法等に応じて適宜選択されるが、例えば、成人（体重約６０ｋｇ）に経口投与する場合には、有効成分量として１～１０００ｍｇの範囲で、１～３回に分けて投与することが好ましく、成人（体重約６０ｋｇ）に非経口投与する場合には、注射剤であれば、有効成分量として体重１ｋｇあたり０．０１～１００ｍｇの範囲で静脈注射により投与することが好ましい。 The dose for clinical administration of the compound (I) or a pharmacologically acceptable salt crystal thereof as a medicine is appropriately selected depending on the symptoms, age, body weight, sex, administration method, etc., but for example. When orally administered to an adult (body weight about 60 kg), it is preferable to administer the active ingredient in 1 to 3 divided doses in the range of 1 to 1000 mg, and parenterally administer to an adult (body weight about 60 kg). In some cases, if it is an injection, it is preferable to administer it by intravenous injection in the range of 0.01 to 100 mg per 1 kg of body weight as the amount of the active ingredient.
　化合物（Ｉ）又はその薬理学的に許容される塩の結晶は、治療若しくは予防効果の補完又は増強、あるいは投与量の低減のために、他の薬剤と適量配合又は併用しても構わない。この場合の他の薬剤としては、例えば、アミトリプチリン、ミルナシプラン若しくはデュロキセチン等の抗うつ薬、アルプラゾラム等の抗不安薬、カルバマゼピン等の抗痙攣薬、リドカイン等の局所麻酔薬、アドレナリン等の交感神経作動薬、ケタミン等のＮＭＤＡ受容体拮抗薬、バルプロ酸ナトリウム等のＧＡＢＡトランスアミナーゼ阻害薬、プレガバリン等のカルシウムチャネル遮断薬、リスペリドン等のセロトニン受容体拮抗薬、ジアゼパム等のＧＡＢＡ受容体機能促進薬又はジクロフェナク等の抗炎症薬が挙げられる。 Crystals of compound (I) or a pharmacologically acceptable salt thereof may be mixed or used in combination with other drugs in an appropriate amount in order to supplement or enhance the therapeutic or preventive effect, or to reduce the dose. Other agents in this case include, for example, antidepressants such as amitriptyline, milnasiplan or duroxetin, anxiolytics such as alprazolam, anticonvulsants such as carbamazepine, local anesthetics such as lidocain, and sympathetic nerves such as adrenaline. An agonist, an NMDA receptor antagonist such as ketamine, a GABA transaminase inhibitor such as sodium valproate, a calcium channel blocker such as pregabalin, a serotonin receptor antagonist such as lisperidone, a GABA receptor function promoter such as diazepam, or diclofenac. And other anti-inflammatory agents.
　以下、実施例及び参考例を用いて本発明を詳細に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.
　以下の記載において、ＮＭＲデータ中に示される溶媒名は、測定に使用した溶媒を示している。また、４００　ＭＨｚ　ＮＭＲスペクトルは、ＪＮＭ－ＡＬ４００型核磁気共鳴装置（日本電子社）を用いて測定した。ケミカルシフトは、テトラメチルシランを基準として、δ（単位：ｐｐｍ）で表し、シグナルはそれぞれｓ（一重線）、ｄ（二重線）、ｍ（多重線）で表した。ＥＳＩ－ＭＳスペクトルは、Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ　１２００　Ｓｅｒｉｅｓ、Ｇ６１３０Ａ（ＡｇｉｌｅｎｔＴｅｃｈｎｏｌｏｇｙ製）を用いて測定した。溶媒は全て市販のものを用いた。フラッシュクロマトグラフィーはＹＦＬＣ　Ｗ－ｐｒｅｐ２ＸＹ（山善社）を用いた。粉末Ｘ線回折装置は、２２００／ＲＩＮＴ　ｕｌｔｉｍａ＋ＰＣ（リガク社）を用いた。ＴＧ－ＤＴＡ装置は、ＴＧ８１２０（リガク社）を用いた。 In the following description, the solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift was represented by δ (unit: ppm) with reference to tetramethylsilane, and the signals were represented by s (single line), d (double line), and m (multiple line), respectively. The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technologies). All commercially available solvents were used. For flash chromatography, YFLC W-prep2XY (Yamazen Co., Ltd.) was used. As the powder X-ray diffractometer, 2200 / RINT ultrama + PC (Rigaku Co., Ltd.) was used. As the TG-DTA apparatus, TG8120 (Rigaku Co., Ltd.) was used.
（参考例１）　化合物（Ｉ）の硫酸塩の非晶質体の調製：
　化合物（Ｉ）と、化合物（Ｉ）に対して１当量の硫酸を、ジメチルスルホキシド／１，４－ジオキサン（１／１，ｖ／ｖ）に溶解し、塩の５０ｍｇ／ｍＬジメチルスルホキシド／１，４－ジオキサン（１／１，ｖ／ｖ）溶液を調製した。当該溶液２００μＬを硼硅酸ガラス製バイアル瓶に量り取り、凍結乾燥により溶媒を除去することで、化合物（Ｉ）の硫酸塩の非晶質体を調製した。 (Reference Example 1) Preparation of Amorphous Sulfate of Compound (I):
Compound (I) and 1 equivalent of sulfuric acid relative to compound (I) are dissolved in dimethyl sulfoxide / 1,4-dioxane (1/1, v / v) and the salt is 50 mg / mL dimethyl sulfoxide / 1, A 4-dioxane (1/1, v / v) solution was prepared. 200 μL of the solution was weighed in a glass vial made of borosilicate, and the solvent was removed by freeze-drying to prepare an amorphous form of the sulfate of compound (I).
（参考例２）　化合物（Ｉ）のパモ酸塩の非晶質体の調製：
　化合物（Ｉ）と、化合物（Ｉ）に対して０．５当量のパモ酸を、ジメチルスルホキシド／１，４－ジオキサン（１／１，ｖ／ｖ）に溶解し、塩の５０ｍｇ／ｍＬジメチルスルホキシド／１，４－ジオキサン（１／１，ｖ／ｖ）溶液を調製した。当該溶液３００μＬを硼硅酸ガラス製バイアル瓶に量り取り、凍結乾燥により溶媒を除去することで、化合物（Ｉ）のパモ酸塩の非晶質体を調製した。 (Reference Example 2) Preparation of Amorphous Pamoate of Compound (I):
Compound (I) and 0.5 equivalents of pamoic acid relative to compound (I) were dissolved in dimethyl sulfoxide / 1,4-dioxane (1/1, v / v) and 50 mg / mL dimethyl sulfoxide in salt. A / 1,4-dioxane (1/1, v / v) solution was prepared. 300 μL of the solution was weighed in a borosilicate glass vial, and the solvent was removed by freeze-drying to prepare an amorphous form of the pamoate of compound (I).
（参考例３）　化合物（Ｉ）の塩酸塩の非晶質体の調製：
　化合物（Ｉ）と、化合物（Ｉ）に対して２当量の濃塩酸を、ジメチルスルホキシド／１，４－ジオキサン（１／１，ｖ／ｖ）に溶解し、塩の５０ｍｇ／ｍＬジメチルスルホキシド／１，４－ジオキサン（１／１，ｖ／ｖ）溶液を調製した。当該溶液２００μＬを硼硅酸ガラス製バイアル瓶に量り取り、凍結乾燥により溶媒を除去することで、化合物（Ｉ）の塩酸塩の非晶質体を調製した。 (Reference Example 3) Preparation of Amorphous Hydrochloride of Compound (I):
Compound (I) and 2 equivalents of concentrated hydrochloric acid with respect to compound (I) were dissolved in dimethyl sulfoxide / 1,4-dioxane (1/1, v / v), and 50 mg / mL dimethyl sulfoxide / 1 of the salt was dissolved. , 4-Dioxane (1/1, v / v) solution was prepared. 200 μL of the solution was weighed in a glass vial made of borosilicate, and the solvent was removed by freeze-drying to prepare an amorphous compound (I) hydrochloride.
　化合物（Ｉ）は、以下の参考例に記載する方法で合成した。なお、参考例化合物の合成に使用される化合物で合成法の記載のないものについては、市販の化合物を使用した。 Compound (I) was synthesized by the method described in the following reference example. Commercially available compounds were used for the compounds used in the synthesis of the reference example compounds for which the synthesis method was not described.
（参考例４）　化合物（Ｉ）の非晶質体の合成：
Figure JPOXMLDOC01-appb-C000002
 　粗エチル　３－（１－メチル－１Ｈ－イミダゾール－２－イル）プロパノエート（５．００ｇ、２７．４ｍｍｏｌ）の２－プロパノール（５５ｍＬ）溶液に、水酸化ナトリウム水溶液（１．０Ｎ、３０．２ｍＬ、３０．２ｍｍｏｌ）を０℃で加え、室温で１２時間撹拌した。反応液に２－プロパノール（２２０ｍＬ）を室温で加え、粗４－（ジメチルアミノ）ピペリジン（３．１７ｇ、２４．７ｍｍｏｌ）及びＤＭＴ－ＭＭ（８．３５ｇ、３０．２ｍｍｏｌ）を室温で加え、反応液を同じ温度で３時間撹拌した。反応液に１０％塩化ナトリウム水溶液、１．０Ｎ水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮し、化合物（Ｉ）（６．９８ｇ）を非晶質体として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 (5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J=1.2 Hz), 6.91 (1H, d, J=1.2 Hz).
ESI-MS: m/z= 265 (M+H)+. (Reference Example 4) Synthesis of amorphous compound (I):
Figure JPOXMLDOC01-appb-C000002
 Aqueous solution of sodium hydroxide (1.0N, 30.2 mL) in a solution of crude ethyl 3- (1-methyl-1H-imidazol-2-yl) propanol (5.00 g, 27.4 mmol) in 2-propanol (55 mL). 30.2 mmol) was added at 0 ° C. and the mixture was stirred at room temperature for 12 hours. 2-Propanol (220 mL) was added to the reaction solution at room temperature, and crude 4- (dimethylamino) piperidine (3.17 g, 24.7 mmol) and DMT-MM (8.35 g, 30.2 mmol) were added at room temperature to react. The solution was stirred at the same temperature for 3 hours. A 10% aqueous sodium chloride solution and a 1.0N aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound (I) (6.98 g) as an amorphous substance.
1 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 (5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz) ), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) + .
（参考例５）　粗４－（ジメチルアミノ）ピペリジンの合成：
Figure JPOXMLDOC01-appb-C000003
 　１－ベンジルオキシカルボニル－４－（ジメチルアミノ）ピペリジン（２０．１ｇ、７７．０ｍｍｏｌ）のメタノール（１５４．０ｍＬ）溶液に、パラジウム－炭素（１０％ｗｅｔ、２．０１ｇ）を加え、水素雰囲気下、室温で１９時間撹拌した。反応液をセライト濾過後、濾液を減圧濃縮し、４－（ジメチルアミノ）ピペリジンの粗生成物（９．８６ｇ）を得た。 (Reference Example 5) Synthesis of crude 4- (dimethylamino) piperidine:
Figure JPOXMLDOC01-appb-C000003
 Palladium-carbon (10% wet, 2.01 g) was added to a solution of 1-benzyloxycarbonyl-4- (dimethylamino) piperidine (20.1 g, 77.0 mmol) in methanol (154.0 mL) under a hydrogen atmosphere. , Stirred at room temperature for 19 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a crude product of 4- (dimethylamino) piperidine (9.86 g).
（参考例６）　粗エチル　３－（１－メチル－１Ｈ－イミダゾール－２－イル）プロパノエートの合成：
Figure JPOXMLDOC01-appb-C000004
 　水素化ナトリウム（５５％、４．３６ｇ、１００ｍｍｏｌ）水溶液とテトラヒドロフラン（１５０ｍＬ）の混合液に、トリエチルホスホノアセタート（１９．１ｍＬ、９５．０ｍｍｏｌ）を０℃で加えた。反応液を２０分間撹拌した後に、１－メチル－１Ｈ－イミダゾール－２－カルバルデヒド（１０．０ｇ、９１．０ｍｍｏｌ）のテトラヒドロフラン（１５０ｍＬ）溶液を０℃で加えた後、エタノール（３０ｍＬ）を同じ温度で加え、室温にて２時間撹拌した。反応液に１０％塩化ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。残渣をフラッシュクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製した。残渣にメタノール（３１０ｍＬ）を加えた後、パラジウム－炭素（１０％ｗｅｔ、１．４０ｇ）を加え、水素雰囲気下、室温で３時間撹拌した。反応液をセライト濾過後、濾液を減圧濃縮し、エチル　３－（１－メチル－１Ｈ－イミダゾール－２－イル）プロパノエートの粗生成物（１４．２ｇ）を得た。 (Reference Example 6) Synthesis of crude ethyl 3- (1-methyl-1H-imidazol-2-yl) propanoate:
Figure JPOXMLDOC01-appb-C000004
 Triethylphosphonoacetate (19.1 mL, 95.0 mmol) was added to a mixture of an aqueous solution of sodium hydride (55%, 4.36 g, 100 mmol) and tetrahydrofuran (150 mL) at 0 ° C. After stirring the reaction solution for 20 minutes, a solution of 1-methyl-1H-imidazol-2-carbaldehyde (10.0 g, 91.0 mmol) in tetrahydrofuran (150 mL) was added at 0 ° C., and then ethanol (30 mL) was added in the same manner. The mixture was added at temperature and stirred at room temperature for 2 hours. A 10% aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform / methanol). After adding methanol (310 mL) to the residue, palladium-carbon (10% wet, 1.40 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (14.2 g) of ethyl 3- (1-methyl-1H-imidazol-2-yl) propanoate.
（参考例７）　１－ベンジルオキシカルボニル－４－（ジメチルアミノ）ピペリジンの合成：
Figure JPOXMLDOC01-appb-C000005
 　１－ベンジルオキシカルボニル－４－オキソピペリジン（１３．０ｇ、５５．７ｍｍｏｌ）のジクロロメタン（５５．７ｍＬ）溶液に、ジメチルアミンのテトラヒドロフラン溶液（２．０Ｍ、３４．８ｍＬ、６９．７ｍｍｏｌ）、酢酸（０．３２ｍＬ、５．６ｍｍｏｌ）及びナトリウムトリアセトキシボロヒドリド（４．８ｇ、２２．６ｍｍｏｌ）を０℃で加えた。反応液を同じ温度で３０分撹拌した後、ナトリウムトリアセトキシボロヒドリド（４．８ｇ、２２．６ｍｍｏｌ）を０℃で加えた。反応液を同じ温度で３０分撹拌した後、ナトリウムトリアセトキシボロヒドリド（８．１ｇ、３８．２ｍｍｏｌ）を０℃で加え、室温にて１２時間撹拌を行った。反応液を０℃まで冷却した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。残渣をフラッシュクロマトグラフィー（シリカゲル、ｎ－ヘキサン／酢酸エチル）で精製した後、再度、フラッシュクロマトグラフィー（シリカゲル、クロロホルム／メタノール）で精製し、１－ベンジルオキシカルボニル－４－（ジメチルアミノ）ピペリジン（１３．６ｇ、５１．８ｍｍｏｌ、９３％）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 1.34-1.46 (2H, m), 1.78-1.86 (2H, m), 2.28 (6H, s), 2.29-2.34 (1H, m), 2.75-2.85 (2H, m), 4.14-4.28 (2H, m),5.12 (2H, s), 7.29-7.36 (5H, m).
ESI-MS: m/z= 263 (M+H)+. (Reference Example 7) Synthesis of 1-benzyloxycarbonyl-4- (dimethylamino) piperidine:
Figure JPOXMLDOC01-appb-C000005
 1-benzyloxycarbonyl-4-oxopiperidine (13.0 g, 55.7 mmol) in dichloromethane (55.7 mL), dimethylamine in tetrahydrofuran (2.0 M, 34.8 mL, 69.7 mmol), acetic acid ( 0.32 mL (5.6 mmol) and sodium triacetoxyborohydride (4.8 g, 22.6 mmol) were added at 0 ° C. After stirring the reaction solution at the same temperature for 30 minutes, sodium triacetoxyborohydride (4.8 g, 22.6 mmol) was added at 0 ° C. The reaction mixture was stirred at the same temperature for 30 minutes, sodium triacetoxyborohydride (8.1 g, 38.2 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 12 hours. The reaction solution was cooled to 0 ° C. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane / ethyl acetate) and then again by flash chromatography (silica gel, chloroform / methanol) to obtain 1-benzyloxycarbonyl-4- (dimethylamino) piperidine (dimethylamino) piperidine (silica gel, chloroform / methanol). 13.6 g, 51.8 mmol, 93%) was obtained as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.34-1.46 (2H, m), 1.78-1.86 (2H, m), 2.28 (6H, s), 2.29-2.34 (1H, m), 2.75-2.85 (2H, m), 4.14-4.28 (2H, m), 5.12 (2H, s), 7.29-7.36 (5H, m).
ESI-MS: m / z = 263 (M + H) + .
（参考例８）　１－ベンジルオキシカルボニル－４－オキソピペリジンの合成：
Figure JPOXMLDOC01-appb-C000006
 　４－ピペリジノン塩酸塩一水和物（１０．０ｇ、６５．１ｍｍｏｌ）のテトラヒドロフラン（１３０ｍＬ）と水（１３０ｍＬ）との混合溶液に、炭酸ナトリウム（１３．８ｇ、１３０．２ｍｍｏｌ）及びクロロギ酸ベンジル（８．７９ｍＬ、６１．８ｍｍｏｌ）を０℃で加え、室温にて３時間撹拌を行った。反応液を酢酸エチルで抽出した。有機層を１０％塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。残渣をフラッシュクロマトグラフィー（シリカゲル、ｎ－ヘキサン／酢酸エチル）で精製し、１－ベンジルオキシカルボニル－４－オキソピペリジン（１３．１ｇ、５６．２ｍｍｏｌ、８６％）を無色油状物として得た。
1H-NMR (400 MHz, CDCl3) δ: 2.42-2.50 (4H, m), 3.78-3.82 (4H, m), 5.18 (2H, s), 7.32-7.38 (5H, m). (Reference Example 8) Synthesis of 1-benzyloxycarbonyl-4-oxopiperidine:
Figure JPOXMLDOC01-appb-C000006
 Sodium carbonate (13.8 g, 130.2 mmol) and benzyl chloroformate (13.8 g, 130.2 mmol) in a mixed solution of 4-piperidinone hydrochloride monohydrate (10.0 g, 65.1 mmol) in tetrahydrofuran (130 mL) and water (130 mL). 8.79 mL (61.8 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with 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 chromatography (silica gel, n-hexane / ethyl acetate) to give 1-benzyloxycarbonyl-4-oxopiperidine (13.1 g, 56.2 mmol, 86%) as a colorless oil.
1 1 H-NMR (400 MHz, CDCl 3 ) δ: 2.42-2.50 (4H, m), 3.78-3.82 (4H, m), 5.18 (2H, s), 7.32-7.38 (5H, m).
（実施例１）　化合物（Ｉ）のＡ形結晶の製造：
　参考例４で調製した化合物（Ｉ）の非晶質体（６．９８ｇ）をシリカゲルカラムクロマトグラフィーにてクロロホルム/メタノールで精製、濃縮後、スパーテルでフラスコの壁面を擦り、機械的な刺激を加えることで、化合物（Ｉ）のＡ形結晶を粉末として得た。得られた結晶について、粉末Ｘ線回折装置（株式会社リガク社；２２００／ＲＩＮＴ　ｕｌｔｉｍａ＋ＰＣ）を用いた粉末Ｘ線回折の測定及びＴＧ－ＤＴＡ装置（株式会社リガク社；ＴＧ８１２０）を用いたＴＧ－ＤＴＡを行った。これら測定の結果を、図１及び図２に示す。
　　回折角２θ　：　５．９、１６．５、１７．７、２０．８、２６．７°
　　吸熱ピーク　：　５５℃ (Example 1) Production of A-type crystal of compound (I):
The amorphous substance (6.98 g) of compound (I) prepared in Reference Example 4 is purified by silica gel column chromatography with chloroform / methanol, concentrated, and then the wall surface of the flask is rubbed with a spartel to apply mechanical stimulation. As a result, A-type crystals of compound (I) were obtained as powder. For the obtained crystals, measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT ultima + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) Was done. The results of these measurements are shown in FIGS. 1 and 2.
Diffraction angle 2θ: 5.9, 16.5, 17.7, 20.8, 26.7 °
Endothermic peak: 55 ° C
（実施例２）　化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）の製造：
　　参考例１で調製した化合物（Ｉ）の硫酸塩の非晶質体（１０ｍｇ）に、１－プロパノール（２０μＬ）を加えて懸濁し、室温で７日間振とうすることで、化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）を調製した。得られた結晶について、粉末Ｘ線回折装置（株式会社リガク社；２２００／ＲＩＮＴ　ｕｌｔｉｍａ＋ＰＣ）を用いた粉末Ｘ線回折の測定及びＴＧ－ＤＴＡ装置（株式会社リガク社；ＴＧ８１２０）を用いたＴＧ－ＤＴＡを行った。これら測定の結果を、図３及び図４に示す。
　　回折角２θ　：　１２．３、１７．７、１８．８、２０．５、２３．１°
　　吸熱ピーク　：　１５５℃ (Example 2) Production of B-type crystal (sulfate monohydrate) of compound (I):
1-Propanol (20 μL) was added to the amorphous form (10 mg) of the sulfate of compound (I) prepared in Reference Example 1, suspended, and shaken at room temperature for 7 days to obtain the compound (I). B-type crystals (sulfate monohydrate) were prepared. For the obtained crystals, measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT ultima + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) Was done. The results of these measurements are shown in FIGS. 3 and 4.
Diffraction angle 2θ: 12.3, 17.7, 18.8, 20.5, 23.1 °
Endothermic peak: 155 ° C
（実施例３）　化合物（Ｉ）のＣ形結晶（パモ酸塩）の製造：
　　参考例２で調製した化合物（Ｉ）のパモ酸塩の非晶質体（１５ｍｇ）に、メタノール（５０μＬ）を加えて溶解し、室温で７日間振とうすることで、化合物（Ｉ）のＣ形結晶（パモ酸塩）を調製した。得られた結晶について、粉末Ｘ線回折装置（株式会社リガク社；２２００／ＲＩＮＴ　ｕｌｔｉｍａ＋ＰＣ）を用いた粉末Ｘ線回折の測定及びＴＧ－ＤＴＡ装置（株式会社リガク社；ＴＧ８１２０）を用いたＴＧ－ＤＴＡを行った。これら測定の結果を、図５及び図６に示す。
　　回折角２θ　：　９．９、１３．２、１５．２、１９．６、２２．８°
　　吸熱ピーク　：　２４３℃ (Example 3) Production of C-type crystal (pamoate) of compound (I):
Methanol (50 μL) was added to an amorphous form (15 mg) of the pamoate of compound (I) prepared in Reference Example 2 to dissolve it, and the mixture was shaken at room temperature for 7 days to obtain C of compound (I). Form crystals (pamoate) were prepared. For the obtained crystals, measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT ultima + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) Was done. The results of these measurements are shown in FIGS. 5 and 6.
Diffraction angle 2θ: 9.9, 13.2, 15.2, 19.6, 22.8 °
Endothermic peak: 243 ° C
（比較例１）　化合物（Ｉ）の結晶の取得の検討（種々の溶媒を用いた最初の結晶化検討）：
　化合物（Ｉ）（１５ｍｇ）を硼硅酸ガラス製バイアル瓶に量り取り、各々、室温で、できる限り少量の表１記載の溶媒で溶解し、表１記載の高濃度溶液を調製した。引き続き、室温、気密状態で７日間静置したが、いずれの系においても、化合物（Ｉ）の析出物は認められなかった。 (Comparative Example 1) Examination of acquisition of crystals of compound (I) (examination of initial crystallization using various solvents):
Compound (I) (15 mg) was weighed in a glass vial made of borosilicate glass and dissolved in as little solvent as possible in Table 1 at room temperature to prepare a high-concentration solution shown in Table 1. Subsequently, the mixture was allowed to stand at room temperature and in an airtight state for 7 days, but no precipitate of compound (I) was observed in any of the systems.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
　これらの結果から、高い溶質濃度条件においても、化合物（Ｉ）の結晶は得られないことが明らかとなった。また、表１記載の全ての溶媒について、６０℃でできる限り高濃度の化合物（Ｉ）の溶液を調製し室温で静置する方法、及び、化合物（Ｉ）の希釈溶液を調製し溶媒を自然蒸発させる方法についても実施したが、何れの系からも化合物（Ｉ）の析出物は認められなかった。 From these results, it was clarified that crystals of compound (I) could not be obtained even under high solute concentration conditions. Further, for all the solvents shown in Table 1, a method of preparing a solution of the compound (I) having a concentration as high as possible at 60 ° C. and allowing it to stand at room temperature, and a method of preparing a diluted solution of the compound (I) and using the solvent naturally. The method of evaporation was also carried out, but no precipitate of compound (I) was observed from any of the systems.
（実施例４）　吸湿性評価：
　化合物（Ｉ）のＡ形結晶、Ｂ形結晶（硫酸塩一水和物）及びＣ形結晶（パモ酸塩）について、全自動水分吸着測定装置（ティー・エイ・インスツルメント社；ＶＴＩ－ＳＡ＋）を用いて、以下の条件で平衡水分率測定を行った。相対湿度５％から９５％に加湿したときの重量増加量（吸湿量）を評価した。併せて外観の変化も確認した。結果を表２に示す。 (Example 4) Hygroscopic evaluation:
Fully automatic moisture adsorption measuring device (TA Instruments Co., Ltd .; VTI-SA +) for A-type crystals, B-type crystals (sulfate monohydrate) and C-type crystals (pamoate) of compound (I). ) Was used to measure the equilibrium moisture content under the following conditions. The amount of weight increase (moisture absorption) when humidified from 5% to 95% relative humidity was evaluated. At the same time, the change in appearance was confirmed. The results are shown in Table 2.
≪平衡水分率測定条件≫
　　試料量　　　　　　　：　５～１５ｍｇ
　　測定温度　　　　　　：　３０℃（Ａ形結晶）、２５℃（Ｂ形結晶（硫酸塩一水和物）、Ｃ形結晶（パモ酸塩））
　　平衡設定重量／時間　：　０．０１ｗｔ％／５分間
　　最大平衡時間　　　　：　１８０分間
　　測定範囲　　　　　　：　相対湿度５％～相対湿度９５％
　　測定間隔　　　　　　：　相対湿度５％ ≪Equilibrium moisture content measurement conditions≫
Sample amount: 5 to 15 mg
Measurement temperature: 30 ° C (A-type crystal), 25 ° C (B-type crystal (sulfate monohydrate), C-type crystal (pamoate))
Equilibrium set weight / time: 0.01 wt% / 5 minutes Maximum equilibrium time: 180 minutes Measurement range: Relative humidity 5% to 95% relative humidity
Measurement interval: Relative humidity 5%
　化合物（Ｉ）のＡ形結晶は相対湿度２０％までの加湿に伴う重量増加はなく、潮解しないが、相対湿度３０％以上では潮解した。また、Ｂ形結晶（硫酸塩一水和物）は相対湿度５５％までの加湿に伴う重量増加はなく、潮解せず、結晶形にも変化はないが、相対湿度７０％では潮解した。一方、Ｃ形結晶（パモ酸塩）は相対湿度９５％までの加湿においても重量増加はなく、潮解せず、結晶形にも変化はなかった。これらの結果から、化合物（Ｉ）のＣ形結晶（パモ酸塩）は、湿度に対して物理学的安定性に優れること、並びに、化合物（Ｉ）のＡ形結晶及びＢ形結晶（硫酸塩一水和物）は、相対湿度を、それぞれ、３０％未満及び７０％未満に管理することで、医薬品の有効成分として使用できることが明らかとなった。なお、参考例２及び参考例３で得られた化合物（Ｉ）のパモ酸塩及び塩酸塩の非晶質体は調製後すぐに潮解するため、医薬品の有効成分として使用することは不適当であった。 The A-type crystal of compound (I) did not increase in weight due to humidification up to a relative humidity of 20% and did not deliquesce, but deliquescented at a relative humidity of 30% or more. In addition, the B-type crystals (sulfate monohydrate) did not increase in weight with humidification up to a relative humidity of 55% and did not deliquesce, and the crystal form did not change, but deliquescented at a relative humidity of 70%. On the other hand, the C-type crystal (pamoate) did not increase in weight even when humidified to a relative humidity of 95%, did not deliquesce, and did not change in crystal form. From these results, the C-type crystal (pamoate) of the compound (I) is excellent in physical stability with respect to humidity, and the A-type crystal and the B-type crystal (sulfate) of the compound (I) are excellent. It has been clarified that the monohydrate) can be used as an active ingredient of a pharmaceutical product by controlling the relative humidity to less than 30% and less than 70%, respectively. Since the amorphous forms of the pamoate and the hydrochloride of the compound (I) obtained in Reference Example 2 and Reference Example 3 are deliquescent immediately after preparation, it is not suitable to be used as an active ingredient of a pharmaceutical product. there were.
Figure JPOXMLDOC01-appb-T000008
 　１）相対湿度５％から相対湿度２０％に加湿したときの重量増加量を意味する。
　２）相対湿度５％から相対湿度５５％に加湿したときの重量増加量を意味する。
　３）相対湿度５％から相対湿度９５％に加湿したときの重量増加量を意味する。
Figure JPOXMLDOC01-appb-T000008
 1) It means the amount of weight increase when humidified from a relative humidity of 5% to a relative humidity of 20%.
2) It means the amount of weight increase when humidified from a relative humidity of 5% to a relative humidity of 55%.
3) It means the amount of weight increase when humidified from a relative humidity of 5% to a relative humidity of 95%.
（実施例５）　溶解性評価：
　化合物（Ｉ）のＡ形結晶（１５ｍｇ）を硼硅酸ガラス製バイアル瓶に量り取り、室温で、蒸留水（０．０５ｍＬ）を加え、振とうした。３０分後にバイアル瓶内を目視確認した結果、完全に溶解したことを確認した。化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）（１０ｍｇ）を硼硅酸ガラス製バイアル瓶に量り取り、３７℃に調整した温湿度試験槽（アメフレック社；ノードアα）内で、日本薬局方第１６改正崩壊試験第１液／溶出試験第１液（ｐＨ１．２）（０．１ｍＬ）、又は、日本薬局方第１６改正崩壊試験第２液（ｐＨ６．８）（０．１ｍＬ）を加えて、撹拌した。３０分後にバイアル瓶内を目視確認した結果、いずれも完全に溶解したことを確認した。本化合物（Ｉ）のＣ形結晶（パモ酸塩）（１０ｍｇ）をそれぞれ硼硅酸ガラス製バイアル瓶に量り取り、３７℃に調整した温湿度試験槽（アメフレックス社；ノードアα）内にて、日本薬局方第１６改正崩壊試験第１液／溶出試験第１液（ｐＨ１．２）（２ｍＬ）、又は、日本薬局方第１６改正崩壊試験第２液（ｐＨ６．８）（２ｍＬ）を加え、懸濁状態で撹拌した。２時間後に０．４５μｍのフィルターを付けたガラスシリンジに懸濁液を移し、フィルターを通した最初の０．５ｍＬを廃棄し、残りの懸濁液を硼硅酸ガラス製バイアル瓶に移した。移した溶液から１ｍＬをホールピペットで取り、１００ｍＬメスフラスコに移して、日本薬局方第１６改正崩壊試験第１液／溶出試験第１液（ｐＨ１．２）、又は、日本薬局方第１６改正崩壊試験第２液（ｐＨ６．８）で定容し、高速液体クロマトグラフィー（以下、「ＨＰＬＣ」）の分析用試料溶液とした。以下の条件でＨＰＬＣにより分析用試料溶液の濃度を絶対検量線法により定量することで、３７℃における日本薬局方第１６改正崩壊試験第１液／溶出試験第１液（ｐＨ１．２）、又は、日本薬局方第１６改正崩壊試験第２液（ｐＨ６．８）に対する溶解度を評価した。なお、ＨＰＬＣの移動相調製に用いる２０ｍｍｏｌ／Ｌリン酸二水素カリウム・５ｍｍｏｌ／Ｌオクタンスルホン酸ナトリウム水溶液（以下、溶液Ｘ）は、リン酸二水素カリウム（２．７ｇ）、１－オクタンスルホン酸ナトリウム（１．１ｇ）を量り取り、蒸留水（１Ｌ）に加え、撹拌溶解し調製した。 (Example 5) Solubility evaluation:
A-type crystals (15 mg) of compound (I) were weighed in a borosilicate glass vial, distilled water (0.05 mL) was added at room temperature, and the mixture was shaken. As a result of visually checking the inside of the vial after 30 minutes, it was confirmed that the vial was completely dissolved. B-type crystals (sulfate monohydrate) (10 mg) of compound (I) were weighed in a borosilicate glass vial and placed in a temperature / humidity test tank (Ameflec; Norda α) adjusted to 37 ° C. Japanese Pharmacopoeia 16th Revised Disintegration Test 1st Solution / Dissolution Test 1st Solution (pH 1.2) (0.1mL) or Japanese Pharmacopoeia 16th Revised Disintegration Test 2nd Solution (pH 6.8) (0.1mL) ) Was added and stirred. As a result of visually checking the inside of the vial after 30 minutes, it was confirmed that all of them were completely dissolved. C-type crystals (pamoate) (10 mg) of this compound (I) were weighed in borosilicate glass vials and placed in a temperature / humidity test tank (Ameflex Co., Ltd .; Norda α) adjusted to 37 ° C. , Japanese Pharmacopoeia 16th revised disintegration test 1st solution / dissolution test 1st solution (pH 1.2) (2mL) or Japanese Pharmacopoeia 16th revised disintegration test 2nd solution (pH 6.8) (2mL) , Stirred in suspension. After 2 hours, the suspension was transferred to a glass syringe with a 0.45 μm filter, the first 0.5 mL filtered was discarded and the remaining suspension was transferred to a borosilicate glass vial. Take 1 mL from the transferred solution with a whole pipette, transfer to a 100 mL volumetric flask, and transfer to the Japanese Pharmacopoeia 16th revised disintegration test 1st solution / dissolution test 1st solution (pH 1.2) or the Japanese Pharmacopoeia 16th revised disintegration. The volume was adjusted with the second test solution (pH 6.8) to prepare a sample solution for analysis by high performance liquid chromatography (hereinafter, “HPLC”). By quantifying the concentration of the sample solution for analysis by HPLC under the following conditions by the absolute calibration curve method, the Japanese Pharmacopoeia 16th revised disintegration test 1st solution / dissolution test 1st solution (pH 1.2) or , The solubility in the second solution (pH 6.8) of the 16th revised disintegration test of the Japanese Pharmacopoeia was evaluated. The 20 mmol / L potassium dihydrogen phosphate / 5 mmol / L sodium octane sulfonate aqueous solution (hereinafter, solution X) used for the mobile phase preparation of HPLC is potassium dihydrogen phosphate (2.7 g), 1-octane sulfonic acid. Sodium (1.1 g) was weighed, added to distilled water (1 L), and dissolved by stirring to prepare.
≪ＨＰＬＣ条件≫
　　機器　　　　　　：　株式会社島津製作所製ＬＣ－１０ＡＤｖｐシステム
　　検出波長　　　　：　２１０ｎｍ
　　カラム　　　　　：　クロモリス　パフォーマンスＲＰ－１８ｅ（メルク）
内径３ｍｍ、長さ１０ｃｍ
　　カラム温度　　　：　４０℃
　　移動相Ａ　　　　：　溶液Ｘ
　　移動相Ｂ　　　　：　アセトニトリル
　　移動相Ｂの組成　：　０～４分：５→７０％、４～６分：７０％、６～６．１
　　　　　　　　　　　　分：７０→５％、６．１～８分：５％
　　流量　　　　　　：　２．０ｍＬ／ｍｉｎ
　　試料注入量　　　：　２５μＬ << HPLC conditions >>
Equipment: LC-10ADvp system manufactured by Shimadzu Corporation Detection wavelength: 210 nm
Column: Chromoris Performance RP-18e (Merck)
Inner diameter 3 mm, length 10 cm
Column temperature: 40 ° C
Mobile phase A: Solution X
Mobile phase B: Acetonitrile Mobile phase B composition: 0-4 minutes: 5 → 70%, 4-6 minutes: 70%, 6-6.1
Minutes: 70 → 5%, 6.1-8 minutes: 5%
Flow rate: 2.0 mL / min
Sample injection volume: 25 μL
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　表３に示すように、化合物（Ｉ）のＣ形結晶は日本薬局方第１６改正崩壊試験第１液／溶出試験第１液（ｐＨ１．２）に対して２．３８ｍｇ／ｍＬ以上の溶解度であり、溶解性において優れていることが明らかとなった。また、化合物（Ｉ）のＡ形結晶は水に対して３００ｍｇ／ｍＬ以上の溶解度であり、化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）は日本薬局方第１６改正崩壊試験第１液／溶出試験第１液（ｐＨ１．２）、及び、日本薬局方第１６改正崩壊試験第２液（ｐＨ６．８）に対して１００ｍｇ／ｍＬ以上の溶解度であったことから、化合物（Ｉ）のＡ形結晶及びＢ形結晶（硫酸塩一水和物）は、溶解性において極めて優れていることが明らかとなった。 As shown in Table 3, the C-type crystal of compound (I) has a solubility of 2.38 mg / mL or more in the 16th revised disintegration test 1st solution / dissolution test 1st solution (pH 1.2) of the Japanese Pharmacopoeia. It was revealed that it was excellent in solubility. In addition, the A-type crystal of compound (I) has a solubility of 300 mg / mL or more in water, and the B-type crystal (sulfate monohydrate) of compound (I) is the 16th revised disintegration test of the Japanese Pharmacopoeia. Since the solubility was 100 mg / mL or more in the 1st solution / dissolution test 1st solution (pH 1.2) and the 16th revised disintegration test 2nd solution (pH 6.8) of the Japanese Pharmacopoeia, the compound (I) ) A-type crystal and B-type crystal (sulfate monohydrate) were found to be extremely excellent in solubility.
（実施例６）　保存安定性評価：
　化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）及びＣ形結晶（パモ酸塩）について、６０℃、気密状態で４週間保存し、以下の条件でＨＰＬＣにより、保存前後の化学純度を測定した。なお、ＨＰＬＣの分析用試料は、化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）（２ｍｇ）又は化合物（Ｉ）のＣ形結晶（パモ酸塩）（２ｍｇ）を１０ｍＬメスフラスコにそれぞれ量り取り、水／アセトニトリル（８／２，ｖ／ｖ）の混液で全量を１０ｍＬにして調製した。 (Example 6) Storage stability evaluation:
The B-type crystals (sulfate monohydrate) and C-type crystals (pamoate) of compound (I) were stored at 60 ° C. in an airtight state for 4 weeks, and were subjected to HPLC under the following conditions to obtain chemical purity before and after storage. Was measured. As a sample for HPLC analysis, B-type crystals (sulfate monohydrate) (2 mg) of compound (I) or C-type crystals (pamoate) (2 mg) of compound (I) were placed in a 10 mL female flask. Each was weighed and prepared with a mixed solution of water / acetonitrile (8 / 2, v / v) to make the total volume 10 mL.
≪ＨＰＬＣ条件≫
　　機器　　　　　　：　株式会社島津製作所製ＬＣ－３０ＡＤシステム
　　検出波長　　　　：　２１０ｎｍ
　　カラム　　　　　：　Ｋｉｎｅｔｅｘ　Ｃ１８（フェノメネックス）
　　カラム温度　　　：　４０℃
　　移動相Ａ　　　　：　溶液Ｘ
　　移動相Ｂ　　　　：　アセトニトリル
　　移動相Ｂの組成　：　０～１分：５％、１～５分：５→７０％、５～７分：
　　　　　　　　　　　　７０％、７～７．１分：７０→５％、７．１～１０分：
　　　　　　　　　　　　５％
　　流量　　　　　　：　０．４ｍＬ／ｍｉｎ
　　試料注入量　　　：　５μＬ << HPLC conditions >>
Equipment: LC-30AD system manufactured by Shimadzu Corporation Detection wavelength: 210 nm
Column: Kinex C18 (Phenomenex)
Column temperature: 40 ° C
Mobile phase A: Solution X
Mobile phase B: Acetonitrile Mobile phase B composition: 0 to 1 minute: 5%, 1 to 5 minutes: 5 to 70%, 5 to 7 minutes:
70%, 7 to 7.1 minutes: 70 → 5%, 7.1 to 10 minutes:
5%
Flow rate: 0.4 mL / min
Sample injection volume: 5 μL
　また、粉末Ｘ線回折の測定及びＴＧ－ＤＴＡを行い、保存による結晶形の変化の有無を評価した。結果を表４に示す。 In addition, powder X-ray diffraction was measured and TG-DTA was performed to evaluate the presence or absence of a change in crystal shape due to storage. The results are shown in Table 4.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
　表４に示すように、化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）は、６０℃、気密状態で４週間保存してもその化学純度に変化はなく、結晶形の変化は認められなかった。また、化合物（Ｉ）のＣ形結晶（パモ酸塩）は、６０℃、気密状態、４週間保存で相対保持時間（以下、ＲＲＴ。ＲＲＴは、ＨＰＬＣクロマトグラムの分解物の保持時間／ＨＰＬＣクロマトグラムの化合物（Ｉ）の保持時間により算出される。）が１．２５の分解物が０．３％増加したが、分解の程度は小さく、より低温な条件にて安定に保管可能であると考えられた。これらの結果から、化合物（Ｉ）のＢ形結晶（硫酸塩一水和物）及びＣ形結晶（パモ酸塩）は、化学的及び物理的安定性において極めて優れていることが明らかとなった。 As shown in Table 4, the B-type crystal (sulfate monohydrate) of compound (I) does not change in its chemical purity even when stored in an airtight state at 60 ° C. for 4 weeks, and the change in crystal form does not change. I was not able to admit. The C-type crystal (pamoate) of compound (I) was stored at 60 ° C. in an airtight state for 4 weeks for a relative retention time (hereinafter, RRT. RRT is the retention time of the decomposition product of the HPLC chromatogram / HPLC chromatogram). 1.25 decomposition product increased by 0.3%, but the degree of decomposition was small and stable storage was possible under lower temperature conditions. it was thought. From these results, it was clarified that the B-type crystal (sulfate monohydrate) and the C-type crystal (pamoate) of the compound (I) are extremely excellent in chemical and physical stability. ..
　本明細書で引用した全ての刊行物、特許及び特許出願をそのまま参考として本明細書にとり入れるものとする。 All publications, patents and patent applications cited in this specification shall be incorporated herein by reference as is.

Claims (12)

  1. 　１－（４－（ジメチルアミノ）ピペリジン－１－イル）－３－（１－メチル－１Ｈ－イミダゾール－２－イル）プロパン－１－オン又はその薬理学的に許容される塩の結晶。 Crystals of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one or a pharmacologically acceptable salt thereof.
  2. 　粉末Ｘ線回折において、回折角２θ（°）５．９、１６．５、１７．７、２０．８及び２６．７にピークを有する、請求項１記載の結晶。 The crystal according to claim 1, which has peaks at diffraction angles 2θ (°) 5.9, 16.5, 17.7, 20.8 and 26.7 in powder X-ray diffraction.
  3. 　示差熱熱重量同時測定において、５３～５７℃に熱吸収ピークを有する、請求項２記載の結晶。 The crystal according to claim 2, which has an endothermic peak at 53 to 57 ° C. in the simultaneous measurement of differential thermogravimetric analysis.
  4. 　前記薬理学的に許容される塩は、硫酸塩である、請求項１記載の結晶。 The crystal according to claim 1, wherein the pharmacologically acceptable salt is a sulfate.
  5. 　粉末Ｘ線回折において、回折角２θ（°）１２．３、１７．７、１８．８、２０．５及び２３．１にピークを有する、請求項４記載の結晶。 The crystal according to claim 4, which has peaks at diffraction angles 2θ (°) 12.3, 17.7, 18.8, 20.5 and 23.1 in powder X-ray diffraction.
  6. 　示差熱熱重量同時測定において、１５３～１５７℃に熱吸収ピークを有する、請求項５記載の結晶。 The crystal according to claim 5, which has an endothermic peak at 153 to 157 ° C. in the simultaneous measurement of differential thermogravimetric analysis.
  7. 　前記薬理学的に許容される塩は、パモ酸塩である、請求項１記載の結晶。 The crystal according to claim 1, wherein the pharmacologically acceptable salt is pamoate.
  8. 　粉末Ｘ線回折において、回折角２θ（°）９．９、１３．２、１５．２、１９．６及び２２．８にピークを有する、請求項７記載の結晶。 The crystal according to claim 7, which has peaks at diffraction angles 2θ (°) 9.9, 13.2, 15.2, 19.6 and 22.8 in powder X-ray diffraction.
  9. 　示差熱熱重量同時測定において、２４１～２４５℃に熱吸収ピークを有する、請求項８記載の結晶。 The crystal according to claim 8, which has an endothermic peak at 241 to 245 ° C. in the simultaneous measurement of differential thermogravimetric analysis.
  10. 　請求項１～９のいずれか一項記載の結晶を有効成分として含有する、医薬。 A pharmaceutical agent containing the crystal according to any one of claims 1 to 9 as an active ingredient.
  11. 　請求項１～９のいずれか一項記載の結晶を有効成分として含有する、鎮痛薬。 An analgesic containing the crystal according to any one of claims 1 to 9 as an active ingredient.
  12. 　請求項１～９のいずれか一項記載の結晶を有効成分として含有する、神経障害性疼痛治療薬又は線維筋痛症治療薬。 A neuropathic pain therapeutic agent or a fibromyalgia therapeutic agent containing the crystal according to any one of claims 1 to 9 as an active ingredient.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013147160A1 (en) * 2012-03-29 2013-10-03 東レ株式会社 Cyclic amine derivative and use thereof for medical purposes
WO2019189781A1 (en) * 2018-03-30 2019-10-03 東レ株式会社 Agent for inhibiting rise in intraneuronal calcium concentration

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013147160A1 (en) * 2012-03-29 2013-10-03 東レ株式会社 Cyclic amine derivative and use thereof for medical purposes
WO2019189781A1 (en) * 2018-03-30 2019-10-03 東レ株式会社 Agent for inhibiting rise in intraneuronal calcium concentration

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PANDEY, B. ET AL.: "Importance of Polymorphs and Salts in the Pharmaceutical Industry", DRUG DISCOVERY AND DEVELOPMENT, vol. 2, no. chapter 24, 2007, pages 201 - 217, XP055845131 *

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