WO2018003980A1 - Cristaux de sel d'addition acide d'acide aminocarboxylique, et procédé de fabrication de ceux-ci - Google Patents

Cristaux de sel d'addition acide d'acide aminocarboxylique, et procédé de fabrication de ceux-ci Download PDF

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Publication number
WO2018003980A1
WO2018003980A1 PCT/JP2017/024180 JP2017024180W WO2018003980A1 WO 2018003980 A1 WO2018003980 A1 WO 2018003980A1 JP 2017024180 W JP2017024180 W JP 2017024180W WO 2018003980 A1 WO2018003980 A1 WO 2018003980A1
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Prior art keywords
crystal
ray diffraction
powder
peaks
crystals
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PCT/JP2017/024180
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English (en)
Japanese (ja)
Inventor
英治 沼上
正寛 東海林
鈴木　徹也
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第一三共株式会社
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Priority to JP2018525298A priority Critical patent/JPWO2018003980A1/ja
Publication of WO2018003980A1 publication Critical patent/WO2018003980A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/25—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings

Definitions

  • the present invention is a pharmacologically acceptable salt of a bicyclic aminocarboxylic acid derivative, which has activity as an ⁇ 2 ⁇ ligand and has an affinity for the ⁇ 2 ⁇ subunit of a voltage-gated calcium channel.
  • the present invention relates to a pharmacologically acceptable salt crystal and a method for producing the same.
  • ⁇ 2 ⁇ ligands are known as therapeutic agents for neuropathic pain, and examples of such ⁇ 2 ⁇ ligands include gabapentin and pregabalin (Patent Documents 1-4).
  • Applicant has [[1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3.2.0], which is a pharmacologically acceptable salt having activity as an ⁇ 2 ⁇ ligand.
  • Patent Document 5-7 is reported as hept-3-en-6-yl] acetic acid mono (benzenesulfonic acid) salt (salt (I) of the compound shown below) and a production method thereof.
  • a crystal suitable for industrialization is a single crystal with a certain quality with good reproducibility and can be stably supplied as a crystal of the drug substance used in the manufacture of pharmaceuticals. Desirable crystals are desirable. Furthermore, it is desirable that the obtained crystal is excellent in storage stability due to low hygroscopicity and excellent light stability.
  • An object of the present invention is to provide a novel crystal of a salt (I) of a compound and a method for producing the same.
  • the present invention relates to the following.
  • [1] [(1R, 5S, 6S) -6- (Aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl] acetic acid mono (benzenesulfonic acid) salt crystals.
  • [2] The crystal according to [1] (Form I crystal) having peaks at diffraction angles (2 ⁇ (°)) of about 10.9, 17.1, 22.0, 24.0, 27.6, and 33.3 by powder X-ray diffraction.
  • [14] [1] A pharmaceutical composition comprising the crystal according to any one of [13] as an active ingredient. [15] [14] The pharmaceutical composition according to [14], which is a pharmaceutical composition for the treatment of pain. [16] [15] The pharmaceutical composition according to [15], wherein the pain is neuropathic pain and / or pain associated with fibromyalgia. [17] The crystal according to any one of [1]-[13] for the treatment of pain. [18] [1] A method for treating pain, comprising administering an effective amount of the crystal according to any one of [13] to a patient.
  • the powder X-ray diffraction pattern of FormI crystal is shown.
  • the vertical axis represents intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ (°)).
  • a characteristic peak (2 ⁇ (°)), d value ( ⁇ ) and relative intensity (%) of powder X-ray diffraction of Form I crystal are shown.
  • the DTA profile and TG profile of Form I crystal are shown.
  • the vertical axis represents heat ( ⁇ V)
  • the horizontal axis represents temperature (° C.).
  • the vertical axis represents weight change (%)
  • the horizontal axis represents temperature (° C.).
  • the elemental analysis value of FormI crystal is shown.
  • the powder X-ray diffraction pattern of FormII crystal is shown.
  • the vertical axis represents intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ (°)).
  • a characteristic peak (2 ⁇ (°)), d value ( ⁇ ) and relative intensity (%) of powder X-ray diffraction of Form II crystal are shown.
  • the DTA profile and TG profile of Form II crystal are shown.
  • the vertical axis represents heat ( ⁇ V)
  • the horizontal axis represents temperature (° C.).
  • the vertical axis represents weight change (%)
  • the horizontal axis represents temperature (° C.).
  • the elemental analysis value of FormII crystal is shown.
  • the powder X-ray diffraction pattern of FormIII crystal is shown.
  • the vertical axis represents intensity (cps) and the horizontal axis represents diffraction angle (2 ⁇ (°)).
  • a characteristic peak (2 ⁇ (°)), d value ( ⁇ ) and relative intensity (%) of powder X-ray diffraction of Form III crystal are shown.
  • the DTA profile and TG profile of FormIII crystal are shown.
  • the vertical axis represents heat ( ⁇ V)
  • the horizontal axis represents temperature (° C.).
  • the vertical axis represents weight change (%)
  • the horizontal axis represents temperature (° C.).
  • the elemental analysis value of FormIII crystal is shown.
  • the salt (I) of the compound is [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3.2.0] hept-3-en-6-yl] acetic acid mono (benzenesulfonic acid) It is a salt and is described in Patent Documents 5-7 and the like, and is expected to be used as a therapeutic agent for neuropathic pain.
  • the “Form I crystal”, “Form II crystal” and “Form III crystal” of the salt (I) of the compound of the present invention are reproducible as a single crystal having a certain quality under specific controllable conditions. Well obtained. Further, these crystals can be supplied stably and are suitable for industrialization of the salt (I) of the compound.
  • the crystal shows an endothermic peak due to crystal conversion to Form II at around 140 ° C., and an endothermic peak due to decomposition following melting and melting at around 185 ° C. It is a crystal that does not show a decrease in mass by the melting temperature or is only about 1%.
  • the equivalent amount of benzenesulfonic acid added is [(1R, 5S, 6S) -6- (aminomethyl) -3-ethylbicyclo [3,2,0] hept-3-en-6-yl] acetic acid, 1.00-1.1 is preferable, and 1.02-1.06 is more preferable.
  • the precipitated crystals are separated by filtration, washed with a solvent, and dried under reduced pressure to obtain crystals.
  • thermogravimetry In thermogravimetry / differential thermal analysis, it is a crystal that shows an endothermic peak due to melting and subsequent decomposition following melting at around 180 ° C. The mass loss up to the melting temperature was about 0.3%, supporting that the Form II crystals were solvated.
  • Form II crystal manufacturing method The Form I crystal obtained in Example 1 is heated to about 140 to 185 ° C. to obtain Form II crystal. Preferably, the temperature is gradually raised from room temperature and heated from about 160 ° C. to 185 ° C. More preferably, it is heated to about 180 ° C. at 10 ° C./min. Thereafter, the Form II crystal is obtained by returning to room temperature.
  • the heating method is not particularly limited, but the heating operation is preferably performed using a differential scanning calorimeter (DSC).
  • Form III crystal It is a crystal having peaks at about 10.7, 21.5, 23.3, 27.0, 32.5, 33.8 and 38.2 as the diffraction angle (2 ⁇ (°)) of powder X-ray diffraction obtained using Cu-K ⁇ rays, , About 4.84, 5.34, 5.62, 5.90, 10.70, 21.52, 23.32, 27.00, 28.48, 32.54, 33.80 and 38.16.
  • thermogravimetry In thermogravimetry / differential thermal analysis, it is a crystal that shows an endothermic peak due to melting and subsequent decomposition following melting at about 180 ° C. The mass loss up to the melting temperature was about 0.4%, and it was supported that Form III was a solvate-free product.
  • Form III crystal manufacturing method The Form I crystals obtained in Example 1 are freeze-dried as an aqueous solution.
  • concentration of the aqueous solution is not particularly limited, but is preferably about 10 mg / mL.
  • the freeze-drying conditions are below the melting temperature and after the preliminary drying, it is sufficiently dried around room temperature. Desirably, it is dried at a low temperature, and then dried while raising the temperature stepwise, and finally dried sufficiently above room temperature. For example, by gradually raising the temperature at -40 ° C for 600 minutes, -20 ° C for 1200 minutes, and -5 ° C for 1200 minutes, and finally leaving at 25 ° C to -30 ° C for about 1440 minutes or more. Get Form III crystals.
  • the value of the powder X-ray diffraction analysis is a value obtained using Cu-K ⁇ rays.
  • these are merely representations of the crystal of the present invention by other substantially equivalent expression methods, and are included in the scope of the present invention, which can be easily understood by those skilled in the crystal field.
  • the relative intensity of the peaks shown by these charts can vary depending on, for example, the degree of crystallization of the sample or the preparation method.
  • the value of the powder X-ray diffraction analysis is important in determining the identity of the crystal because of the nature of the data.
  • the crystal lattice spacing and the overall pattern are important.
  • the relative strength depends on the crystal growth direction, particle size, and measurement conditions. Is a variable and should not be interpreted strictly.
  • the endothermic peak in thermogravimetry / differential thermal analysis “near” means ⁇ 5 ° C., and in another embodiment, ⁇ 2 ° C.
  • the endothermic peak of Form III crystals means around 180 ° C., that is, 175-185 ° C.
  • the present invention relates to “Form I crystal”, “Form II crystal” and “Form III crystal” of the salt (I) of the pure compound, but “Form I crystal” and “Form II crystal” of the salt (I) of the compound. And mixtures of “Form III crystals” are also encompassed by the present invention.
  • Form I crystals (4.39 mg), mannitol (83.51 mg), carmellose calcium (10 mg), magnesium stearate (10.7 mg), coating agent (appropriate amount) are prepared according to well-known methods to produce coated tablets.
  • Form II crystals (4.39 mg), mannitol (83.51 mg), carmellose calcium (10 mg), magnesium stearate (10.7 mg), coating agent (appropriate amount) are prepared according to well-known methods to produce coated tablets.
  • Form III crystals (4.39 mg), mannitol (83.51 mg), carmellose calcium (10 mg), magnesium stearate (10.7 mg), coating agent (appropriate amount) are prepared according to well-known methods to produce coated tablets.
  • the present invention also relates to a pharmaceutical composition comprising the crystal of the present invention.
  • the pharmaceutical composition of the present invention contains at least part of Form I crystal, Form II crystal or Form III crystal.
  • FormI crystals when FormI crystals are contained in the pharmaceutical composition, crystal forms other than FormI crystals (for example, FormII crystals and / or FormIII) may exist.
  • the proportion of Form I crystals contained in the pharmaceutical composition is in the range of 0.01% -99.9% by weight, for example, 0.01% by weight or more, 0.1% by weight or more, based on the total active ingredients contained in the pharmaceutical composition. 1% or more, 10% or more, 50% or more, 90% or more, 95% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, It may be contained at 99.8% by weight or more or 99.9% by weight or more. Whether or not Form I crystals are contained in the pharmaceutical composition can be confirmed by an instrumental analysis method described in the present specification (for example, powder X-ray diffraction, thermal analysis, etc.).
  • the medicament containing the crystal of the present invention as an active ingredient is preferably provided in the form of a pharmaceutical composition comprising the crystal of the present invention and one or more pharmaceutically acceptable carriers.
  • the dosage form of the medicament of the present invention is not particularly limited and can be administered orally or parenterally, but is preferably administered orally.
  • Examples of the pharmaceutically acceptable carrier used in the production of the above pharmaceutical composition include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, Examples thereof include, but are not limited to, a solubilizer or a solubilizer, an isotonic agent, a pH adjuster, a stabilizer, a propellant, or an adhesive.
  • preparations suitable for oral administration include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like.
  • preparations suitable for parenteral administration include injections, drops, suppositories, inhalants, and patches.
  • the dose of the crystal of the present invention is not particularly limited, and can be appropriately selected according to various conditions such as the age, weight, and symptoms of the patient.
  • the following administration methods are conceivable.
  • the active ingredient (as a free form) is usually divided into 1-50 mg daily as an initial dose for adults divided into twice a day. Orally, then gradually increase to a daily dose of about 5-50 mg over 1 week. The dose may be adjusted according to age and symptoms, but the maximum daily dose should not exceed a certain level.
  • X-ray diffraction measurement (XRD, X-ray diffraction) Equipment used for measurement: RINT TTR-III manufactured by Rigaku Corporation X-ray source: CuK ⁇ Method: Reflection method Tube voltage: 50 kV Tube current: 300 mA Scanning range: 2 ° -40 ° Scanning speed: 2 ° / min Sampling width: 0.02 ° Rotation speed: 120 rpm Sample amount: about 10 mg
  • Example 1 Production of Form I Crystals [(1R, 5S, 6S) -6- (Aminomethyl) -3-ethylbicyclo [3,2,0] hept-3-en-6-yl] acetic acid (8.0 g 38.2 mmol) was suspended in anisole (156 mL), and benzenesulfonic acid (6.29 g, 39.78 mmol) dissolved in anisole (20 mL) was added dropwise over 2 hours.
  • Example 2 Production of Form II crystal Form I crystal (694.345 mg) obtained in Example 1 was divided into multiple times (20-30 mg each) and the following was performed using a differential scanning calorimeter (DSC). The mixture was heated to room temperature after being heated with the following temperature program. The obtained Form II crystals were collectively sieved using No. 100 sieve (671.74 mg, yield: 96.7%).
  • Example 3 Production of Form III crystal To Form I crystal (800.13 mg) obtained in Example 1, about 80 mL of water was added and dissolved. This solution was poured into 16 glass bottles. After preliminary freezing, it was freeze-dried according to the following temperature program to obtain Form III crystals (744.81 mg, yield: 93.1%). 1) -40 °C: 600 minutes 2) -20 °C: 1200 minutes 3) -5 °C: 1200 minutes 4) Final temperature (25 °C -30 °C) More than 1440 minutes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention a pour objet de fournir des cristaux d'un sel pharmacologiquement acceptable d'un dérivé d'acide aminocarboxylique bicyclique. Plus précisément, l'invention concerne des cristaux d'un sel d'acide [(1R,5S,6S)-6-(aminométhyl)-3-éthylbicylco[3.2.0] hept-3-én-6-yl] acétique一(acide benzène sulfonique).
PCT/JP2017/024180 2016-07-01 2017-06-30 Cristaux de sel d'addition acide d'acide aminocarboxylique, et procédé de fabrication de ceux-ci WO2018003980A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2018525298A JPWO2018003980A1 (ja) 2016-07-01 2017-06-30 アミノカルボン酸の酸付加塩の結晶とその製造方法

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JP2016131325 2016-07-01
JP2016-131325 2016-07-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3831373A4 (fr) * 2018-07-30 2022-06-01 Daiichi Sankyo Company, Limited Formulation de médicament solide contenant un stabilisant

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009041453A1 (fr) * 2007-09-28 2009-04-02 Daiichi Sankyo Company, Limited Dérivé d'acide aminé γ bicyclique
WO2010079668A1 (fr) * 2009-01-08 2010-07-15 第一三共株式会社 Oléfine
JP2014001208A (ja) * 2009-03-26 2014-01-09 Daiichi Sankyo Co Ltd 二環性化合物の製造方法
JP2015063547A (ja) * 2013-07-08 2015-04-09 第一三共株式会社 光学活性な二環性γ−アミノ酸誘導体の製造方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP0401141A3 (en) * 2001-08-03 2011-07-28 Ciba Sc Holding Ag Crystalline forms of fluvastatin sodium, process for their preparation and pharmaceutical compositions containing them
CN103951562B (zh) * 2014-05-09 2016-04-20 四川九章生物化工科技发展有限公司 一种绿原酸晶型及其制备方法
AU2015301054B2 (en) * 2014-08-08 2020-05-14 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009041453A1 (fr) * 2007-09-28 2009-04-02 Daiichi Sankyo Company, Limited Dérivé d'acide aminé γ bicyclique
WO2010079668A1 (fr) * 2009-01-08 2010-07-15 第一三共株式会社 Oléfine
JP2014001208A (ja) * 2009-03-26 2014-01-09 Daiichi Sankyo Co Ltd 二環性化合物の製造方法
JP2015063547A (ja) * 2013-07-08 2015-04-09 第一三共株式会社 光学活性な二環性γ−アミノ酸誘導体の製造方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3831373A4 (fr) * 2018-07-30 2022-06-01 Daiichi Sankyo Company, Limited Formulation de médicament solide contenant un stabilisant

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TW201806928A (zh) 2018-03-01

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