WO2022114135A1 - アミノ酸誘導体の結晶形及びその製造方法 - Google Patents

アミノ酸誘導体の結晶形及びその製造方法 Download PDF

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Publication number
WO2022114135A1
WO2022114135A1 PCT/JP2021/043413 JP2021043413W WO2022114135A1 WO 2022114135 A1 WO2022114135 A1 WO 2022114135A1 JP 2021043413 W JP2021043413 W JP 2021043413W WO 2022114135 A1 WO2022114135 A1 WO 2022114135A1
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carbonyl
compound
crystal
degrees
amino
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English (en)
French (fr)
Japanese (ja)
Inventor
裕子 山内
好博 木村
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Priority to JP2022565454A priority Critical patent/JPWO2022114135A1/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring

Definitions

  • the present invention relates to (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-( ⁇ (1S) -1-[(tricyclo [). 3.3.1.1 3,7 ] Decane-1-carbonyl) Oxy] ethoxy ⁇ carbonyl) Bicyclo [3.1.0] Hexane-6-carboxylic acid or its pharmaceutically acceptable salt crystal polyform and Regarding the manufacturing method. More specifically, for example, mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle rigidity, sleep disorders, Huntington chorea, feeding.
  • mood disorders including depression and bipolar disorders
  • anxiety disorders including depression and bipolar disorders
  • cognitive disorders including depression and bipolar disorders
  • cognitive disorders developmental disorders
  • Alzheimer's disease Parkinson's disease
  • motor disorders associated with muscle rigidity sleep disorders
  • sleep disorders Huntington chorea, feeding.
  • Metabolic active glutamate (mGlu) receptor effective for the treatment and prevention of disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorder, head trauma, inflammation, immune-related diseases, etc.
  • Bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (hereinafter, also referred to as parent compound or compound (B)) is a prodrug (1R, 2R, 3R, 5R, 6R) -2.
  • bicyclo [3.1.0] hexane-6-carboxylic acid (hereinafter, may be referred to as compound (A)) crystal polymorph and a method for producing the same.
  • the prodrug of the parent compound which is a compound acting on the metabotropic glutamate receptor, enhances mucosal absorbability such as oral absorption and increases the amount of the parent compound exposed in vivo.
  • the present invention relates to a crystal polymorph and a method for producing the same.
  • Metabotropic glutamate receptors are classified into three groups according to their amino acid sequence homology, signal transduction mechanism, and pharmacological properties. Among them, Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) are G protein-coupled receptors that bind to adenylcyclase and are cyclic adenosine monophosphate (cAMP) holscoline-stimulating. Suppresses accumulation (Non-Patent Document 1). In addition, Group II metabotropic glutamate receptors are mainly present in the presynapses of the glutamate nervous system and function as autoreceptors, thus suppressing excessive release of glutamate (Non-Patent Documents 2 and 3). ).
  • a prodrugization was carried out in which a small modifying group such as an alkyl group or an acyl group is bonded to the carboxy group or amino group of the compound.
  • a prodrug it exists stably as a prodrug before absorption, and absorption is improved by prodrugization, and chemically or enzymatically in the small intestine, liver, and / or plasma during and / or after absorption.
  • a compound that is rapidly converted to an active substance is desired.
  • An object of the present invention is to treat and prevent neuropsychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorders, epilepsy, developmental disorders, sleep disorders, as well as drug dependence and cognitive disorders. , Alzheimer's disease, Huntington butoh disease, Parkinson's disease, motor disorders associated with muscle rigidity, neurological diseases such as cerebral ischemia, cerebral insufficiency, spinal cord disorders, head disorders, etc.
  • neuropsychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorders, epilepsy, developmental disorders, sleep disorders, as well as drug dependence and cognitive disorders.
  • Alzheimer's disease Huntington butoh disease, Parkinson's disease, motor disorders associated with muscle rigidity, neurological diseases such as cerebral ischemia, cerebral insufficiency, spinal cord disorders, head disorders, etc.
  • the storage stability of prodrugs that enhance mucosal absorbability such as oral absorbability of parent compounds that act on Group 2 metabolic glutamate receptors and increase in vivo exposure.
  • It is an object of the present invention to provide
  • the present inventors have (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6. -(1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro as a result of intensive research on prodrugs containing dicarboxylic acid (hereinafter sometimes referred to as compound (B)) as the parent compound.
  • compound (B) dicarboxylic acid
  • one aspect of the present invention is (1) (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy) having at least one of the following physical properties (a) to (c). ] -2-( ⁇ (1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy ⁇ carbonyl) bicyclo [3.1.0] hexane-6 -It is a D-type crystal of carboxylic acid.
  • another aspect of the present invention is (2) (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] in a lower alcohol, acetonitrile, ethyl acetate, an alkylamine or a mixed solvent thereof.
  • the present invention has an excellent group II metabolic glutamate receptor antagonism (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [ 3.1.0]
  • a prodrug of hexane-2,6-dicarboxylic acid (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-( ⁇ (1S) -1-[(tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy ⁇ carbonyl) bicyclo [3.1.0] hexane-6- It has become possible to provide crystals of carboxylic acid.
  • the crystal is stable at a temperature near room temperature and has excellent storage stability. Furthermore, it has been confirmed that it is easy to handle and can be a useful raw material for pharmaceuticals because it does not cause metastasis of crystalline form even by a pharmaceutical product operation such as crushing.
  • the powder X-ray diffraction pattern of the D-type crystal of compound (A) is shown.
  • the differential thermal analysis / thermal mass measurement curve of the D-type crystal of compound (A) is shown.
  • the infrared absorption spectrum (ATR method) of the D-type crystal of compound (A) is shown.
  • the powder X-ray diffraction pattern of the A-type crystal of compound (A) is shown.
  • the differential thermal analysis / thermal mass measurement curve of the A-type crystal of compound (A) is shown.
  • the powder X-ray diffraction pattern of the B-type crystal of compound (A) is shown.
  • the differential thermal analysis / thermal mass measurement curve of the B-type crystal of compound (A) is shown.
  • the powder X-ray diffraction pattern of the C-type crystal of compound (A) is shown.
  • the differential thermal analysis / thermal mass measurement curve of the C-type crystal of compound (A) is shown.
  • the powder X-ray diffraction pattern of the crystal of the compound (A) methanesulfonate is shown.
  • the powder X-ray diffraction pattern of the crystal of the compound (A) benzenesulfonate is shown.
  • the powder X-ray diffraction pattern of the crystal of the compound (A) phosphate is shown.
  • the compound of the present invention (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-( ⁇ (1S) -1-[((1S) -1-[( Tricyclo [3.3.1.1 3,7 ] decane-1-carbonyl) oxy] ethoxy ⁇ carbonyl) bicyclo [3.1.0] hexane-6-carboxylic acid (Compound (A)) is shown below. It has a chemical structure.
  • the D-type crystal of compound (A) has at least one of the following physical characteristics (a) to (c).
  • the characteristic endothermic bands are at 3310 cm -1 , 1762 cm -1 , 1731 cm -1 , 1583 cm -1 and 1236 cm -1 ; or
  • the D-type crystal of the compound (A) produced by the production method of the present invention is basically a crystal having high purity. It is desirable that the crystal has a high purity, and preferably it does not substantially contain other crystal forms. As shown in Examples described later, the D-type crystal of the compound (A) produced by the production method of the present invention can be obtained with good reproducibility as a single crystal having a certain quality, and can be used as a raw material for pharmaceuticals and pharmaceuticals. It can be stably supplied as crystals of the drug substance used in production, and has excellent physical properties with excellent storage stability.
  • the D-shaped crystal of the present invention can be obtained by the following recrystallization operation.
  • the compound (A) is heated and dissolved in a predetermined organic solvent and then slowly cooled, or a predetermined poor solvent is added and then slowly cooled to precipitate crystals, and the precipitated crystals are filtered and centrifuged.
  • a D-type crystal of compound (A) can be obtained by separating it from a solvent and then drying it.
  • the recrystallization may be repeated not only once but also twice or more, but usually, recrystallization is performed only once.
  • the predetermined organic solvent for dissolving the raw material compound (A) before recrystallization is, for example, general lower alcohol, ethyl acetate, diC 1-4 alkyl ether, acetone, acetonitrile, THF, DMF, DMSO and the like.
  • the organic solvent or alkylamine include organic bases such as triethylamine and diisopropylethylamine, or a mixed solution of these organic solvents.
  • Examples of the predetermined poor solvent to be added after that include water, C 5-8 saturated hydrocarbon, acetic acid and the like.
  • Examples of the lower alcohol include methanol, ethanol, 1-propanol, 2-propanol and the like.
  • Examples of the diC 1-4 alkyl ether include diethyl ether, diisopropyl ether, tbutyl-methyl ether and the like.
  • Examples of the C 5-8 saturated hydrocarbon include pentane, hexane, heptane and octane. Hexane or heptane is preferred.
  • the concentration at which the compound (A) is dissolved is 1 to 50% by mass.
  • the mass% is the mass percent of the D-type crystal of the compound (A) in the solution or the suspension. Crystallization of the D-type crystal of compound (A) is usually carried out at 0 to 100 ° C. Drying of the D-type crystal of compound (A) is usually carried out at 100 ° C. or lower.
  • the crystals of the compound of the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations. It can be manufactured by technology (for example, the method specified in the 17th revised Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, body weight, and purpose of treatment.
  • compositions containing the compounds of the invention are pharmacologically acceptable carriers for compositions containing the compounds of the invention, ie, excipients (eg, crystalline cellulose, starch, lactose, mannitol), binders (eg, hydroxypropyl cellulose). , Polyvinylpyrrolidone), lubricants (eg, magnesium stearate, talc), disintegrants (eg, carboxymethyl cellulose calcium), and various other pharmacologically acceptable additives can be blended and produced.
  • excipients eg, crystalline cellulose, starch, lactose, mannitol
  • binders eg, hydroxypropyl cellulose
  • Polyvinylpyrrolidone eg, polyvinylpyrrolidone
  • lubricants eg, magnesium stearate, talc
  • disintegrants eg, carboxymethyl cellulose calcium
  • various other pharmacologically acceptable additives can be blended and produced
  • Powder X-rays were measured by SmartLab (Rigaku). Differential thermal analysis / thermal mass measurement (TG / DTA) was measured with Thermo plus EvoTG8120 (Rigaku). The infrared absorption spectrum was measured by IRAfitity-1 (Shimadzu Corporation). The water vapor adsorption measurement was measured by DVS-1 Advantage (Surface Measurement Systems). In the reference example and the example, the room temperature is around 25 ° C.
  • the infrared spectrum was measured by a total reflection method (ATR method) using a Fourier transform infrared spectrophotometer (IRAffinity-1) manufactured by Shimadzu Corporation under the conditions of total integration 45 times and resolution: 2 cm -1 .
  • the product was dried at 60 ° C for 2 hours, the relative humidity was increased from 0% RH to 95% RH, and then the mass change in the process of decreasing the relative humidity to 5% RH was measured at 5% intervals.
  • the equilibrium condition was set when the mass change of 0.01% disappeared in 1 minute, and the humidity was set to the next.
  • the hygroscopicity (DVS) measurement the D-type crystal of compound (A) had no hygroscopicity and the crystal form did not change due to humidity.
  • the D-form crystal of compound (A) was 65 ° C. for 4 weeks, 40 ° C.
  • Disorders including depression and bipolar disorder
  • anxiety disorders including depression and bipolar disorder
  • cognitive disorders developmental disorders
  • Alzheimer's disease Parkinson's disease
  • motor disorders associated with muscle rigidity sleep disorders
  • Huntington chorea eating disorders
  • drug addiction epilepsy It can be used as a therapeutic and preventive drug for cerebral infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorder, head trauma, inflammation, immune-related diseases and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/JP2021/043413 2020-11-26 2021-11-26 アミノ酸誘導体の結晶形及びその製造方法 Ceased WO2022114135A1 (ja)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018117267A1 (ja) * 2016-12-22 2018-06-28 大鵬薬品工業株式会社 置換ピペリジン化合物の塩
JP2019513755A (ja) * 2016-04-18 2019-05-30 大正製薬株式会社 アミノ酸誘導体のプロドラッグ

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019513755A (ja) * 2016-04-18 2019-05-30 大正製薬株式会社 アミノ酸誘導体のプロドラッグ
WO2018117267A1 (ja) * 2016-12-22 2018-06-28 大鵬薬品工業株式会社 置換ピペリジン化合物の塩

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ASHIZAWA, KAZUHIDE: "Salt/Crystal Form Optimization and Crystallization Technology", PHARM TECH JAPAN, vol. 18, no. 10, 1 January 2002 (2002-01-01), pages 81 - 96 *
HIRAYAMA NORIAKI: "Handbook of organic compounds crystallization - principles and know-how", 1 January 2008, JP , ISBN: 978-4-621-07991-1, article HIRAYAMA, NORIAKI: "Passages; Organic Compound Crystal Production Handbook", pages: 17 - 51, 57-65, XP009536842 *

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