WO2015087853A1 - Forme cristalline de composé oxazinane et son procédé de préparation - Google Patents

Forme cristalline de composé oxazinane et son procédé de préparation Download PDF

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WO2015087853A1
WO2015087853A1 PCT/JP2014/082497 JP2014082497W WO2015087853A1 WO 2015087853 A1 WO2015087853 A1 WO 2015087853A1 JP 2014082497 W JP2014082497 W JP 2014082497W WO 2015087853 A1 WO2015087853 A1 WO 2015087853A1
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methyl
compound
degrees
triazol
methanone
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Japanese (ja)
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彩 二村
信隆 服部
洋樹 浦部
有也 尾形
尚人 大崎
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大正製薬株式会社
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Priority to JP2015512427A priority patent/JP5907310B2/ja
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Definitions

  • the present invention relates to ( ⁇ )-(2- ⁇ [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-
  • the present invention relates to a crystalline polymorph of methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone and a method for producing the same.
  • Orexin receptor antagonists expected to be useful as therapeutic and prophylactic agents for orexin (OX) receptor-related diseases such as epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension, and other diseases
  • OX orexin receptor-related diseases
  • epilepsy inflammation, immune-related diseases, endocrine-related diseases, hypertension, and other diseases
  • the present invention relates to a polymorph of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone and a method for producing the same.
  • Orexin is a neuropeptide spliced from preproorexin that is specifically expressed in the lateral hypothalamic area. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep / wake patterns and the regulation of food intake. .
  • OX-A and OX-B act on the OX receptor.
  • the OX receptor has been cloned so far in two subtypes of OX1 and OX2 receptors, both of which are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. .
  • the OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
  • the tissue distribution varies depending on the subtype of the OX receptor.
  • the OX1 receptor has a high density in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor in the nodule papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). Orexin neurons project to the brain stem and the monoamine nervous system in the hypothalamus and have an excitatory effect on those nerves.
  • OX2 receptors are also seen in the acetylcholine neurons of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).
  • Non-patent Documents 6 and 7 When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous movement is increased (see Non-patent Documents 6 and 7), the normal behavior is enhanced (see Non-Patent Document 7), and the awakening time is extended (non-patent documents). 6).
  • the effect of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8).
  • one aspect of the present invention is as follows: (1) having at least one of the following physical properties (a) to (c): ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-methyl-2- It is an anhydrous crystal of (2H-1,2,3-triazol-2-yl) phenyl] methanone.
  • Another aspect of the present invention is as follows: (2) ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) in ethanol -Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone is dissolved, crystallized and dried. It is a manufacturing method.
  • another aspect of the present invention is as follows: (3) having at least one of the following physical properties (a) to (c): ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone hydrate crystals.
  • another aspect of the present invention is as follows: (4) (-)-(2- ⁇ [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-in a mixed solvent of lower alcohol or acetone and water Oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone is dissolved, crystallized and dried (3 ) For producing a hydrate crystal.
  • crystallization of the anhydride of a compound (A) is shown.
  • crystallization of the anhydride of a compound (A) is shown.
  • crystallization of the anhydride of a compound (A) is shown.
  • 1 shows a powder X-ray diffraction pattern of a hydrate crystal of compound (A).
  • crystallization of the hydrate of a compound (A) is shown.
  • crystallization of the hydrate of a compound (A) is shown.
  • the anhydrous crystals of compound (A) have at least one of the following physical properties (a) to (c).
  • (A) In powder X-ray diffraction (Cu-K ⁇ ), there are peaks at 2 ⁇ 8.1 degrees, 13.4 degrees, 15.6 degrees and 21.6 degrees;
  • the powder X-ray diffraction pattern of the anhydride crystal of compound (A) is as shown in FIG. 1, the differential thermal analysis / thermal mass measurement curve is as shown in FIG. 2, and the infrared absorption spectrum is as shown in FIG.
  • the anhydrous crystals of the present invention can be obtained by the following recrystallization operation. For example, after dissolving the compound (A) in ethanol with heating, the crystals are precipitated by slow cooling, and the precipitated crystals are collected by filtration, separated from a solvent by centrifugation, etc., and then dried to obtain anhydrous crystals. Obtainable. In addition, although recrystallization may be repeated not only once but twice or more, it is usually recrystallized only once.
  • the concentration for dissolving the compound (A) is 1 to 50% by mass, preferably 5 to 25% by mass.
  • the mass% is the mass percentage of the anhydride of the compound (A) in the solution or suspension. Crystallization of the anhydride of compound (A) is usually carried out at 0 to 80 ° C. Drying of the anhydride of compound (A) is usually performed at 100 ° C. or lower.
  • the hydrate crystals of compound (A) have at least one of the following physical properties (a) to (c).
  • the melting point is 124-129 ° C .; or
  • (c) in the infrared absorption spectrum the characteristic absorption bands are 1627 cm ⁇ 1 , 1504 cm ⁇ 1 , 1226 cm ⁇ 1 , 1076 cm ⁇ 1 , 822 cm ⁇ 1 and 783 cm ⁇ 1 .
  • the powder X-ray diffraction pattern of the hydrate crystal of compound (A) is as shown in FIG.
  • the differential thermal analysis / thermal mass measurement curve is as shown in FIG. 5
  • the infrared absorption spectrum is as shown in FIG.
  • the hydrate crystals of the compound (A) produced by the production method of the present invention are basically crystals of high purity.
  • the purity of the hydrate crystals is desirably high, and is preferably substantially free from other crystal forms.
  • the hydrate crystals of the compound (A) produced by the production method of the present invention can be obtained as a single crystal having a certain quality with good reproducibility. It can be stably supplied as a drug substance crystal used for the production of raw materials, and has physical properties excellent in storage stability.
  • crystallization of the hydrate of a compound (A) is demonstrated.
  • the hydrate crystals of the present invention can be obtained by the following recrystallization operation. For example, the compound (A) is heated and dissolved in a predetermined solvent, and then slowly cooled to precipitate crystals. The precipitated crystals are separated from the solvent by filtration, centrifugation, and the like, and then dried to obtain a hydrate. Crystals can be obtained.
  • recrystallization may be repeated not only once but twice or more, it is usually recrystallized only once.
  • the predetermined solvent for dissolving or suspending the raw material compound (A) before recrystallization includes, for example, a mixture of lower alcohol and water, or a mixture of water and an organic solvent having a property to be mixed with water.
  • Examples of the raw material compound (A) before recrystallization include anhydrous and hydrate crystals.
  • lower alcohols examples include methanol, ethanol, 1-propanol, 2-propanol and the like. Preferably, it is methanol or ethanol. More preferably, it is methanol.
  • Examples of the organic solvent having a miscibility with water include acetone, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and the like. Acetone is preferred.
  • the concentration for dissolving the compound (A) is 1 to 50% by mass, preferably 5 to 25% by mass.
  • the mass% is the mass percentage of the anhydride of the compound (A) in the solution or suspension. Crystallization of the hydrate of compound (A) is usually carried out at 0 to 100 ° C.
  • the hydrate of compound (A) is usually dried at 100 ° C. or lower.
  • the “sleep disorder” in the present specification is a disorder at the time of falling asleep, a sleep continuation phase, or awakening, and examples thereof include insomnia.
  • insomnia classification include sleep onset disorder, mid-wake awakening, early morning awakening, and deep sleep disorder.
  • 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 prescribed in the 15th revision Japanese Pharmacopoeia).
  • These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
  • These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
  • the compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
  • Elemental analysis was measured with a PerkinElmer 2400Z. Powder X-rays were measured with a Rigaku RINT 2200 Ultimate. Differential thermal analysis / thermal mass measurement (TG / DTA) was measured with a Rigaku Thermo plus EvoTG8120. The infrared absorption spectrum was measured with IRAffinity-1 (Shimadzu Corporation). Single crystal X-ray structural analysis was measured by R-AXIS RAPID II (Rigaku). The optical rotation was measured by RUDOLPH RESERCH ANALYTICAL (Systems Engineering).
  • chloroform (1290 mL) was added to a toluene solution (320.69 g) containing 47% of glyoxylate and stirred.
  • molecular sieve 4A manufactured by Sigma-Aldrich, 289 g was added, and then cooled to 10 ° C.
  • a mixture of 3-amino-1-propanol (110.89 g) and chloroform (160 mL) was added dropwise over 20 minutes while maintaining the temperature at 16 ° C. or lower. The mixture was heated to 25 ° C. and stirred for 23 hours.
  • the mixture was cooled to 0 ° C., and a mixture of triethylamine (429.80 g) and chloroform (700 mL) was added dropwise while maintaining the temperature at 0 ° C. or lower.
  • the amine solution was added dropwise to this mixture while keeping the temperature at 7 ° C. or lower, and then the temperature was raised to 5 ° C. and stirred for 30 minutes.
  • Water (1750 mL) was added to the mixture while maintaining the temperature at 21 ° C. or lower.
  • the organic layer and the aqueous layer were separated, and water (1750 mL) was added to the organic layer.
  • NH type silica gel (manufactured by Fuji Silysia Chemical Ltd., 690 g) was added to the separated organic layer and stirred.
  • the suspension was filtered using diatomaceous earth, and the silica gel on diatomaceous earth was washed with chloroform (700 mL).
  • Silica gel on diatomaceous earth was transferred to another container, and chloroform (1400 mL) was added and stirred there. This suspension was filtered through diatomaceous earth, and the silica gel on diatomaceous earth was washed with chloroform (400 mL). The obtained filtrates were mixed and concentrated under reduced pressure.
  • Silica gel (silica gel 60 N (spherical, neutral) 63-210 ⁇ m, 450 g) manufactured by Kanto Chemical Co., Inc.) was added to the residue, and the mixture was concentrated under reduced pressure.
  • the resulting eluate was concentrated under reduced pressure.
  • chloroform (1800 mL) was added to compound (( ⁇ )-D) (200.00 g), and the mixture was cooled to 3 ° C. with stirring. To this mixture was added a mixture of triethylamine (100.55 g) and chloroform (100 mL) at the same temperature. A mixture of mesyl chloride (91.63 g) and chloroform (100 mL) was added dropwise to this mixture while maintaining 19 ° C. or lower. The reaction mixture was warmed to 23 ° C. and stirred for 5 hours. Water (1 L) was added to this mixture, and the organic layer and the aqueous layer were separated.
  • Example 1 ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-methyl Preparation of anhydride of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (Compound (A))
  • Compound (A) obtained by the method of Reference Example 5 389.00 g
  • Ethanol (7500 mL) was added to and stirred for 1 hour while heating to 60 ° C. to dissolve the solid. The solution was cooled to 2 ° C. over 3 hours with stirring.
  • Example 2 ( ⁇ )-(2- ⁇ [3- (5-Fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl ⁇ -1,3-oxazinan-3-yl) [5-methyl Preparation of Hydrate of -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (Compound (A))
  • Compound (A) (250 g) obtained by the method of Example 1 was obtained.
  • ethanol (5 L) it was dissolved with heating and stirring to 61 ° C., and then filtered while hot.
  • the obtained filtrate was added dropwise to water (15 L) kept at 20-30 ° C. with stirring, and then cooled to 5 ° C.
  • the melting point was measured using a differential thermal balance (Thermo plus EVO TG8120) manufactured by Rigaku and an equivalent apparatus at a heating rate of 10 ° C./min from room temperature to about 250 ° C. in the atmosphere. As a result, an endothermic peak derived from melting was observed at 129 to 134 ° C.
  • the infrared spectrum was measured using a Fourier transform infrared spectrophotometer (IRAffinity-1) manufactured by Shimadzu Corporation under the total reflection method (ATR method) 20 times and with a resolution of 4 cm ⁇ 1 . 1626cm -1, 1497cm -1, 1227cm -1 , 1080cm -1, a peak was observed at around 818cm -1 and 785 cm -1.
  • IRAffinity-1 Fourier transform infrared spectrophotometer
  • a powder X-ray diffractometer Ultima III
  • the melting point was measured using a differential thermal balance (Thermo plus EVO TG8120)
  • Test example (measurement of orexin antagonistic activity)
  • the antagonistic activity of the test compound against human orexin type 1 receptor (hOX1R) and orexin type 2 receptor (hOX2R) is described in the literature (Toshikata Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). The method was modified. Chinese hamster ovary (CHO) cells forcibly expressing hOX1R and hOX2R were seeded in each well of a 96-well Black clear bottom plate (Nunc) at 24,000 cells, 0.1 mM MEM non-essential amino acids, 0.
  • CHO Chinese hamster ovary
  • the cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2 .
  • an assay buffer containing 25 ⁇ M Fluo-3AM ester (Dojin) (25 mM HEPES (Dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM probenecid, 100 ⁇ L of 200 ⁇ g / ml Amaranth (above Sigma-Aldrich), pH 7.4) was added and incubated for 60 minutes at 37 ° C., 5% CO 2 .
  • test compound was dissolved in dimethyl sulfoxide to 10 mM, diluted with assay buffer, 150 ⁇ L was added, and the mixture was incubated for 30 minutes.
  • Peptide substituted with 2 amino acids of human orexin-A ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is a final concentration of 500 pM for hOX1R and hOX2R The reaction was started by diluting with an assay buffer to 1 nM and adding 50 ⁇ L of this ligand solution.
  • the fluorescence value of each well was measured for 3 minutes every second using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics), and antagonistic activity was determined using the maximum fluorescence value as an index of intracellular Ca 2+ concentration.
  • the antagonistic activity of the test compound was calculated by setting the fluorescence value of the well to which only the dilution buffer was added to 100% and the fluorescence value of the well to which the buffer solution containing no ligand and compound was added to 0%.
  • the 50% inhibitory concentration (IC 50 value) was determined from the fluorescence value upon addition.
  • the compound of the present invention is a disease regulated by OX receptor antagonism such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, It can be used as a therapeutic or prophylactic agent for eating disorders, headaches, migraines, pain, gastrointestinal diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension and the like.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne une forme cristalline de (-)-(2-{[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]méthyl}-1,3-oxazinan-3-yl)[5-méthyl-2-(2H-1,2,3-triazol-2-yl)phényl]méthanone, ladite forme cristalline étant stable dans son environnement d'utilisation en tant que médicament. L'invention porte en outre sur son procédé de préparation. L'invention a trait à des cristaux de (-)-(2-{[3-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]méthyl}-1,3-oxazinan-3-yl)[5-méthyl-2-(2H-1,2,3-triazol-2-yl)phényl]méthanone qui possèdent au moins l'une des caractéristiques (a) à (c) suivantes : (a) dans une diffraction de rayons X sur poudres, (Cu-Kα), les pics apparaissent à 2θ = 11,1º, 12,5º, 20,3º et 24,2º ; (b) le point de fusion se situe entre 124 et 129 ºC ; et (c) dans le spectre d'absorption infrarouge, des bandes d'absorption caractéristiques apparaissent à 1 627 cm-1, 1 504 cm-1, 1 226 cm-1, 1 076 cm-1, 822 cm-1 et 783 cm-1. La présente invention porte en outre sur un procédé de préparation desdits cristaux qui se caractérise par les étapes suivantes : dissolution de (-)-(2-{[3- (5-fluoropyridin-2-yl)-1H-pyrazol-1-yl]méthyl}-1,3-oxazinan-3-yl)[5-méthyl-2-(2H-1,2,3-triazol-2-yl)phényl]méthanone dans un solvant mixte constitué d'eau et d'un alcool de faible poids moléculaire ou d'un acétone ; et soumission de la solution à cristallisation, puis séchage.
PCT/JP2014/082497 2013-12-13 2014-12-09 Forme cristalline de composé oxazinane et son procédé de préparation WO2015087853A1 (fr)

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JP2015512427A JP5907310B2 (ja) 2013-12-13 2014-12-09 オキサジナン化合物の結晶形及びその製造方法

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