WO2021153743A1 - Cristaux de dérivé d'amine cyclique, et application pharmaceutique de ceux-ci - Google Patents

Cristaux de dérivé d'amine cyclique, et application pharmaceutique de ceux-ci Download PDF

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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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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. ..

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Abstract

L'invention a pour objet de fournir des cristaux d'un composé présentant un effet analgésique sur la douleur neuropathique et/ou la fibromyalgie, utiles en tant que médicament. Plus précisément, l'invention fournit des cristaux d'un １－（４－（diméthylamino）pipéridine－１－yle）－３－（１－méthyle－１Ｈ－imidazole－２－yle）propane－１－one, ou d'un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2021/003275 2020-01-31 2021-01-29 Cristaux de dérivé d'amine cyclique, et application pharmaceutique de ceux-ci WO2021153743A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013147160A1 (fr) * 2012-03-29 2013-10-03 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
WO2019189781A1 (fr) * 2018-03-30 2019-10-03 東レ株式会社 Agent permettant d'inhiber une augmentation de la concentration intraneuronale en calcium

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013147160A1 (fr) * 2012-03-29 2013-10-03 東レ株式会社 Dérivé d'amine cyclique et son utilisation à des fins médicales
WO2019189781A1 (fr) * 2018-03-30 2019-10-03 東レ株式会社 Agent permettant d'inhiber une augmentation de la concentration intraneuronale en calcium

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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